Prestel, Jürgen; Volkers, Peter; Mentzer, Dirk; Lehmann, Helmar C; Hartung, Hans-Peter; Keller-Stanislawski, Brigitte
Purpose A prospective, epidemiologic study was conducted to assess whether the 2009 pandemic influenza A(H1N1) vaccination in Germany almost exclusively using an AS03-adjuvanted vaccine (Pandemrix) impacts the risk of Guillain–Barré syndrome (GBS) and its variant Fisher syndrome (FS). Methods Potential cases of GBS/FS were reported by 351 participating hospitals throughout Germany. The self-controlled case series methodology was applied to all GBS/FS cases fulfilling the Brighton Collaboration (BC) case definition (levels 1–3 of diagnostic certainty) with symptom onset between 1 November 2009 and 30 September 2010 reported until end of December 2010. Results Out of 676 GBS/FS reports, in 30 cases, GBS/FS (BC levels 1–3) occurred within 150 days following influenza A(H1N1) vaccination. The relative incidence of GBS/FS within the primary risk period (days 5–42 post-vaccination) compared with the control period (days 43–150 post-vaccination) was 4.65 (95%CI [2.17, 9.98]). Similar results were found when stratifying for infections within 3 weeks prior to onset of GBS/FS and when excluding cases with additional seasonal influenza vaccination. The overall result of temporally adjusted analyses supported the primary finding of an increased relative incidence of GBS/FS following influenza A(H1N1) vaccination. Conclusions The results indicate an increased risk of GBS/FS in temporal association with pandemic influenza A(H1N1) vaccination in Germany. © 2014 The Authors. Pharmacoepidemiology and Drug Safety published by John Wiley & Sons, Ltd. PMID:24817531
Ropero-Álvarez, Alba María; El Omeiri, Nathalie; Kurtis, Hannah Jane; Danovaro-Holliday, M. Carolina; Ruiz-Matus, Cuauhtémoc
ABSTRACT Background: There has been considerable uptake of seasonal influenza vaccines in the Americas compared to other regions. We describe the current influenza vaccination target groups, recent progress in vaccine uptake and in generating evidence on influenza seasonality and vaccine effectiveness for immunization programs. We also discuss persistent challenges, 5 years after the A(H1N1) 2009 influenza pandemic. Methods: We compiled and summarized data annually reported by countries to the Pan American Health Organization/World Health Organization (PAHO/WHO) through the WHO/UNICEF joint report form on immunization, information obtained through PAHO's Revolving Fund for Vaccine Procurement and communications with managers of national Expanded Programs on Immunization (EPI). Results: Since 2008, 25 countries/territories in the Americas have introduced new target groups for vaccination or expanded the age ranges of existing target groups. As of 2014, 40 (89%) out of 45 countries/territories have policies established for seasonal influenza vaccination. Currently, 29 (64%) countries/territories target pregnant women for vaccination, the highest priority group according to WHO´s Stategic Advisory Group of Experts and PAHO/WHO's Technical Advisory Group on Vaccine-preventable Diseases, compared to only 7 (16%) in 2008. Among 23 countries reporting coverage data, on average, 75% of adults ≥60 years, 45% of children aged 6–23 months, 32% of children aged 5–2 years, 59% of pregnant women, 78% of healthcare workers, and 90% of individuals with chronic conditions were vaccinated during the 2013–14 Northern Hemisphere or 2014 Southern Hemisphere influenza vaccination activities. Difficulties however persist in the estimation of vaccination coverage, especially for pregnant women and persons with chronic conditions. Since 2007, 6 tropical countries have changed their vaccine formulation from the Northern to the Southern Hemisphere formulation and the timing of
d'Alessandro, Eugenie; Hubert, Dominique; Launay, Odile; Bassinet, Laurence; Lortholary, Olivier; Jaffre, Yannick; Sermet-Gaudelus, Isabelle
Background Our study analyses the main determinants of refusal or acceptance of the 2009 A/H1N1 vaccine in patients with cystic fibrosis, a high-risk population for severe flu infection, usually very compliant for seasonal flu vaccine. Methodology/Principal Findings We conducted a qualitative study based on semi-structured interviews in 3 cystic fibrosis referral centres in Paris, France. The study included 42 patients with cystic fibrosis: 24 who refused the vaccine and 18 who were vaccinated. The two groups differed quite substantially in their perceptions of vaccine- and disease-related risks. Those who refused the vaccine were motivated mainly by the fears it aroused and did not explicitly consider the 2009 A/H1N1 flu a potentially severe disease. People who were vaccinated explained their choice, first and foremost, as intended to prevent the flu's potential consequences on respiratory cystic fibrosis disease. Moreover, they considered vaccination to be an indirect collective prevention tool. Patients who refused the vaccine mentioned multiple, contradictory information sources and did not appear to consider the recommendation of their local health care provider as predominant. On the contrary, those who were vaccinated stated that they had based their decision solely on the clear and unequivocal advice of their health care provider. Conclusions/Significance These results of our survey led us to formulate three main recommendations for improving adhesion to new pandemic vaccines. (1) it appears necessary to reinforce patient education about the disease and its specific risks, but also general population information about community immunity. (2) it is essential to disseminate a clear and effective message about the safety of novel vaccines. (3) this message should be conveyed by local health care providers, who should be involved in implementing immunization. PMID:22506011
Garcia-Garcia, Lourdes; Valdespino-Gómez, Jose Luis; Lazcano-Ponce, Eduardo; Jimenez-Corona, Aida; Higuera-Iglesias, Anjarath; Cruz-Hervert, Pablo; Cano-Arellano, Bulmaro; Garcia-Anaya, Antonio; Ferreira-Guerrero, Elizabeth; Baez-Saldaña, Renata; Ferreyra-Reyes, Leticia; Ponce-de-León-Rosales, Samuel; Alpuche-Aranda, Celia; Rodriguez-López, Mario Henry; Perez-Padilla, Rogelio; Hernandez-Avila, Mauricio
Objective To evaluate the association of 2008-9 seasonal trivalent inactivated vaccine with cases of influenza A/H1N1 during the epidemic in Mexico. Design Frequency matched case-control study. Setting Specialty hospital in Mexico City, March to May 2009. Participants 60 patients with laboratory confirmed influenza A/H1N1 and 180 controls with other diseases (not influenza-like illness or pneumonia) living in Mexico City or the State of Mexico and matched for age and socioeconomic status. Main outcome measures Odds ratio and effectiveness of trivalent inactivated vaccine against influenza A/H1N1. Results Cases were more likely than controls to be admitted to hospital, undergo invasive mechanical ventilation, and die. Controls were more likely than cases to have chronic conditions that conferred a higher risk of influenza related complications. In the multivariate model, influenza A/H1N1 was independently associated with trivalent inactivated vaccine (odds ratio 0.27, 95% confidence interval 0.11 to 0.66) and underlying conditions (0.15, 0.08 to 0.30). Vaccine effectiveness was 73% (95% confidence interval 34% to 89%). None of the eight vaccinated cases died. Conclusions Preliminary evidence suggests some protection from the 2008-9 trivalent inactivated vaccine against pandemic influenza A/H1N1 2009, particularly severe forms of the disease, diagnosed in a specialty hospital during the influenza epidemic in Mexico City. PMID:19808768
Fabiani, Massimo; Bella, Antonino; Rota, Maria C; Clagnan, Elena; Gallo, Tolinda; D'Amato, Maurizio; Pezzotti, Patrizio; Ferrara, Lorenza; Demicheli, Vittorio; Martinelli, Domenico; Prato, Rosa; Rizzo, Caterina
Although concerns about safety of influenza vaccination during pregnancy have been raised in the past, vaccination of pregnant women was recommended in many countries during the 2009 A/H1N1 pandemic influenza. A retrospective cohort study was conducted to evaluate the risk of adverse maternal, fetal and neonatal outcomes among pregnant women vaccinated with a MF59-adjuvanted A/H1N1 pandemic influenza vaccine. The study was carried out in four Italian regions (Piemonte, Friuli-Venezia-Giulia, Lazio, and Puglia) among 102,077 pregnant women potentially exposed during the second or third trimester of gestation to the vaccination campaign implemented in 2009/2010. Based on data retrieved from the regional administrative databases, the statistical analysis was performed using the Cox proportional-hazards model, adjusting for the propensity score to account for the potential confounding effect due to the socio-demographic characteristics and the clinical and reproductive history of women. A total of 100,332 pregnant women were eligible for the analysis. Of these, 2003 (2.0%) received the A/H1N1 pandemic influenza vaccination during the second or third trimester of gestation. We did not observe any statistically significant association between the A/H1N1 pandemic influenza vaccination and different maternal outcomes (hospital admissions for influenza, pneumonia, hypertension, eclampsia, diabetes, thyroid disease, and anaemia), fetal outcomes (fetal death after the 22nd gestational week) and neonatal outcomes (pre-term birth, low birth weight, low 5-min Apgar score, and congenital malformations). Pre-existing health-risk conditions (hospital admissions and drug prescriptions for specific diseases before the onset of pregnancy) were observed more frequently among vaccinated women, thus suggesting that concomitant chronic conditions increased vaccination uptake. The results of this study add some evidence on the safety of A/H1N1 pandemic influenza vaccination during
Brandt, C; Rabenau, H F; Bornmann, S; Gottschalk, R; Wicker, S
The emergence of the influenza A(H1N1)2009 virus provided a major challenge to health services around the world. However, vaccination rates for the public and for healthcare workers (HCWs) have remained low. We performed a study to review the reasons put forward by HCWs to refuse immunisation with the pandemic vaccine in 2009/10 and characterise attitudes in the influenza season 2010/11 due to the emergence of influenza A(H1N1)2009. A survey among HCWs and medical students in the clinical phase of their studies was conducted, using an anonymous questionnaire, at a German university hospital during an influenza vaccination campaign. 1,366 of 3,900 HCWs (35.0%) were vaccinated in the 2010/11 influenza season. Of the vaccinated HCWs, 1,323 (96.9%) completed the questionnaire in addition to 322 vaccinated medical students. Of the 1,645 vaccinees who completed the questionnaire, 712 had not been vaccinated against the influenza A(H1N1)2009 virus in the 2009/10 season. The main reason put forward was the objection to the AS03 adjuvants (239/712, 33.6%). Of the HCWs and students surveyed, 270 of 1,645 (16.4%) stated that the pandemic had influenced their attitude towards vaccination in general. Many German HCWs remained unconvinced of the safety of the pandemic (adjuvanted) influenza vaccine. For this reason, effective risk communication should focus on educating the public and HCWs about influenza vaccine safety and the benefits of vaccination.
Gil Cuesta, Julita; Aavitsland, Preben; Englund, Hélène; Gudlaugsson, Ólafur; Hauge, Siri Helene; Lyytikäinen, Outi; Sigmundsdóttir, Guðrún; Tegnell, Anders; Virtanen, Mikko; Krause, Tyra Grove
During the 2009/10 influenza A(H1N1)pdm09 pandemic, the five Nordic countries adopted different approaches to pandemic vaccination. We compared pandemic vaccination strategies and severe influenza outcomes, in seasons 2009/10 and 2010/11 in these countries with similar influenza surveillance systems. We calculated the cumulative pandemic vaccination coverage in 2009/10 and cumulative incidence rates of laboratory confirmed A(H1N1)pdm09 infections, intensive care unit (ICU) admissions and deaths in 2009/10 and 2010/11. We estimated incidence risk ratios (IRR) in a Poisson regression model to compare those indicators between Denmark and the other countries. The vaccination coverage was lower in Denmark (6.1%) compared with Finland (48.2%), Iceland (44.1%), Norway (41.3%) and Sweden (60.0%). In 2009/10 Denmark had a similar cumulative incidence of A(H1N1)pdm09 ICU admissions and deaths compared with the other countries. In 2010/11 Denmark had a significantly higher cumulative incidence of A(H1N1)pdm09 ICU admissions (IRR: 2.4; 95% confidence interval (CI): 1.9-3.0) and deaths (IRR: 8.3; 95% CI: 5.1-13.5). Compared with Denmark, the other countries had higher pandemic vaccination coverage and experienced less A(H1N1)pdm09-related severe outcomes in 2010/11. Pandemic vaccination may have had an impact on severe influenza outcomes in the post-pandemic season. Surveillance of severe outcomes may be used to compare the impact of influenza between seasons and support different vaccination strategies.
Ahmed, S Sohail; Schur, Peter H; MacDonald, Noni E; Steinman, Lawrence
The vaccine safety surveillance system effectively detected a very rare adverse event, narcolepsy, in subjects receiving AS03-adjuvanted A(H1N1) pandemic vaccine made using the European inactivation/purification protocol. The reports of increased cases of narcolepsy in non-vaccinated subjects infected with wild A(H1N1) pandemic influenza virus suggest a role for the viral antigen(s) in disease development. However, additional investigations are needed to better understand what factor(s) in wild influenza infection trigger(s) narcolepsy in susceptible hosts. An estimated 31 million doses of European AS03-adjuvanted A(H1N1) pandemic vaccine were used in more than 47 countries. The Canadian AS03-adjuvanted A(H1N1) pandemic vaccine was used with high coverage in Canada where an estimated 12 million doses were administered. As no similar narcolepsy association has been reported to date with the AS03-adjuvanted A(H1N1) pandemic vaccine made using the Canadian inactivation/purification protocol, this suggests that the AS03 adjuvant alone may not be responsible for the narcolepsy association. To date, no narcolepsy association has been reported with the MF59®-adjuvanted A(H1N1) pandemic vaccine. This review article provides a brief background on narcolepsy, outlines the different types of vaccine preparations including the ones for influenza, reviews the accumulated evidence for the safety of adjuvants, and explores the association between autoimmune diseases and natural infections. It concludes by assimilating the historical observations and recent clinical studies to formulate a feasible hypothesis on why vaccine-associated narcolepsy may not be solely linked to the AS03 adjuvant but more likely be linked to how the specific influenza antigen component of the European AS03-adjuvanted pandemic vaccine was prepared. Careful and long-term epidemiological studies of subjects who developed narcolepsy in association with AS03-adjuvanted A(H1N1) pandemic vaccine prepared with
Xeuatvongsa, Anonh; Mirza, Sara; Winter, Christian; Feldon, Keith; Vongphrachanh, Phengta; Phonekeo, Darouny; Denny, Justin; Khanthamaly, Viengphone; Kounnavong, Bounheuang; Lylianou, Doualy; Phousavath, Sisouphane; Norasingh, Sisouveth; Boutta, Nao; Olsen, Sonja; Bresee, Joseph; Moen, Ann; Corwin, Andrew
The Lao PDR, as did most countries of the Mekong Region, embarked on a pandemic vaccine initiative to counter the threat posed by influenza A(H1N1)pdm09. Overall, estimated vaccine coverage of the Lao population was 14%, with uptake in targeted health care workers and pregnant women 99% and 41%, respectively. Adverse Events Following Immunization accounted for only 6% of survey driven, reported vaccination experiences, with no severe consequences or deaths. Public acceptability of the vaccine campaign was high (98%). Challenges to vaccine deployment included: 1) no previous experience in fielding a seasonal influenza vaccine, 2) safety and efficacy concerns, and 3) late arrival of vaccine 10 months into the pandemic. The Lao success in surmounting these hurdles was in large measure attributed to the oversight assigned the National Immunization Program, and national sensitivities in responding to the avian influenza A(H5N1) crisis in the years leading up to the pandemic. The Lao "lessons learned" from pandemic vaccine deployment are made even more relevant four years on, given the many avian influenza strains circulating in the region, all with pandemic potential.
Amour, Sélilah; Djhehiche, Khaled; Zamora, Adeline; Bergeret, Alain; Vanhems, Philippe
We assessed the perception and attitudes of university staff, including medical school and other science specialties, toward the 2009 A/H1N1 influenza pandemic and influenza vaccination program. A cross-sectional online survey was conducted among 4,529 university personnel on October 19-20, 2009. Seven hundred (15%) employees participated in the study. Only 18% were willing to be vaccinated, men more than women (29% versus 9%, P < 0.001), and professors/researchers more than administrative/technical staff (30% vs. 6%, P < 0.001). Intention to be vaccinated was insufficient. Additional efforts are needed to improve information dissemination among university staff. Medical university personnel should receive more information to increase vaccine coverage and protect them as well as patients.
Amour, Sélilah; Djhehiche, Khaled; Zamora, Adeline; Bergeret, Alain; Vanhems, Philippe
We assessed the perception and attitudes of university staff, including medical school and other science specialties, toward the 2009 A/H1N1 influenza pandemic and influenza vaccination program. A cross-sectional online survey was conducted among 4,529 university personnel on October 19–20, 2009. Seven hundred (15%) employees participated in the study. Only 18% were willing to be vaccinated, men more than women (29% versus 9%, P < 0.001), and professors/researchers more than administrative/technical staff (30% vs. 6%, P < 0.001). Intention to be vaccinated was insufficient. Additional efforts are needed to improve information dissemination among university staff. Medical university personnel should receive more information to increase vaccine coverage and protect them as well as patients. PMID:25715115
Bouadma, Lila; Barbier, François; Biard, Lucie; Esposito-Farèse, Marina; Le Corre, Bertrand; Macrez, Annick; Salomon, Laurence; Bonnal, Christine; Zanker, Caroline; Najem, Christophe; Mourvillier, Bruno; Lucet, Jean Christophe; Régnier, Bernard; Wolff, Michel; Tubach, Florence
Background Influenza-vaccination rates among healthcare workers (HCW) remain low worldwide, even during the 2009 A(H1N1) pandemic. In France, this vaccination is free but administered on a voluntary basis. We investigated the factors influencing HCW influenza vaccination. Methods In June–July 2010, HCW from wards of five French hospitals completed a cross-sectional survey. A multifaceted campaign aimed at improving vaccination coverage in this hospital group was conducted before and during the 2009 pandemic. Using an anonymous self-administered questionnaire, we assessed the relationships between seasonal (SIV) and pandemic (PIV) influenza vaccinations, and sociodemographic and professional characteristics, previous and current vaccination statuses, and 33 statements investigating 10 sociocognitive domains. The sociocognitive domains describing HCWs' SIV and PIV profiles were analyzed using the classification-and-regression–tree method. Results Of the HCWs responding to our survey, 1480 were paramedical and 401 were medical with 2009 vaccination rates of 30% and 58% for SIV and 21% and 71% for PIV, respectively (p<0.0001 for both SIV and PIV vaccinations). Older age, prior SIV, working in emergency departments or intensive care units, being a medical HCW and the hospital they worked in were associated with both vaccinations; while work shift was associated only with PIV. Sociocognitive domains associated with both vaccinations were self-perception of benefits and health motivation for all HCW. For medical HCW, being a role model was an additional domain associated with SIV and PIV. Conclusions Both vaccination rates remained low. Vaccination mainly depended on self-determined factors and for medical HCW, being a role model. PMID:22848342
Stowe, Julia; Andrews, Nicholas; Kosky, Christopher; Dennis, Gary; Eriksson, Sofia; Hall, Andrew; Leschziner, Guy; Reading, Paul; Shneerson, John M.; Donegan, Katherine; Miller, Elizabeth
Study Objectives: An increased risk of narcolepsy has been observed in children following ASO3-adjuvanted pandemic A/H1N1 2009 (Pandemrix) vaccine. We investigated whether this risk extends to adults in England. Methods: Six adult sleep centers in England were visited between November 2012 and February 2014 and vaccination/clinical histories obtained from general practitioners. Suspected narcolepsy cases aged older than 17 y were selected. The risk of narcolepsy following Pandemrix was calculated using cases diagnosed by the time of the center visits and those with a diagnosis by November 30, 2011 after which there was increased awareness of the risk in children. The odds of vaccination in cases and in matched population data were compared using a case-coverage design. Results: Of 1,446 possible cases identified, most had onset before 2009 or were clearly not narcolepsy. Of the 60 remaining cases, 20 were excluded after expert review, leaving 40 cases with narcolepsy; 5 had received Pandemrix between 3 and 18 mo before onset. All the vaccinated cases had cataplexy, two received a diagnosis by November 2011 and two were aged 40 y or older. The odds ratio for vaccination in cases compared to the population was 4.24 (95% confidence interval 1.45–12.38) using all cases and 9.06 (1.90–43.17) using cases with a diagnosis by November 2011, giving an attributable risk of 0.59 cases per 100,000 doses. Conclusions: We found a significantly increased risk of narcolepsy in adults following Pandemrix vaccination in England. The risk was lower than that seen in children using a similar study design. Citation: Stowe J, Andrews N, Kosky C, Dennis G, Eriksson S, Hall A, Leschziner G, Reading P, Shneerson JM, Donegan K, Miller E. Risk of narcolepsy after AS03 adjuvanted pandemic A/H1N1 2009 influenza vaccine in adults: a case-coverage study in England. SLEEP 2016;39(5):1051–1057. PMID:26856903
Gauger, Phillip C; Loving, Crystal L; Lager, Kelly M; Janke, Bruce H; Kehrli, Marcus E; Roth, James A; Vincent, Amy L
The implications of sequential prime and challenge with mismatched influenza A viruses is a concern in mammals, including humans. We evaluated the ability of pigs affected with vaccine-associated enhanced respiratory disease (VAERD) to generate a humoral immune response against the heterologous challenge virus inciting the VAERD. Vaccinated and challenged (V/C) pigs were administered an inactivated swine δ-cluster H1N2 (MN08) vaccine with an HA similar to pre-2009 seasonal human viruses and challenged with heterologous A(H1N1) pandemic 2009 (H1N1pdm09). Vaccination induced MN08-specific hemagglutination inhibition (HI) antibody but not cross-reacting H1N1pdm09 HI antibody. However, vaccinated pigs demonstrated significantly higher post-challenge anti-H1N1pdm09 serum neutralizing (SN) antibodies at 14 and 21 days post inoculation (dpi) compared to nonvaccinated, challenged pigs (NV/C), indicating a priming effect of the vaccine. Serum and lung whole virus anti-H1N1pdm09 IgG ELISA antibodies in the vaccinated group were significantly higher than the challenge only pigs at all-time points evaluated. Lung IgA ELISA antibodies to both antigens were detected at 2, 5, and 21 dpi in vaccine-primed pigs, contrasted against mucosal ELISA antibody responses detected only at 21 dpi in the naïve-challenged group. Collectively, vaccine-primed pigs demonstrated a robust humoral immune response and elevated local adaptive cytokine levels, indicating VAERD does not adversely affect the induction of an immune response to challenge with heterologous virus despite the severe clinical disease and underlying lung pathology. Thus, original antigenic sin does not appear to be a component of VAERD.
Kinetics of lung lesion development and pro-inflammatory cytokine response in pigs with vaccine-associated enhanced respiratory disease induced by challenge with pandemic (2009) A/H1N1 influenza virus
The objective of this report was to characterize the enhanced clinical disease and lung lesions observed in pigs vaccinated with inactivated H1N2 swine delta-cluster influenza A virus and challenged with pandemic 2009 A/H1N1 human influenza virus. Eighty-four, six-week-old, crossbred pigs were rand...
Labrosse, Béatrice; Tourdjman, Mathieu; Porcher, Raphaël; LeGoff, Jérôme; de Lamballerie, Xavier; Simon, François; Molina, Jean-Michel; Clavel, François
Background Cross-immunity between seasonal and pandemic A/H1N1 influenza viruses remains uncertain. In particular, the extent that previous infection or vaccination by seasonal A/H1N1 viruses can elicit protective immunity against pandemic A/H1N1 is unclear. Methodology/Principal Findings Neutralizing titers against seasonal A/H1N1 (A/Brisbane/59/2007) and against pandemic A/H1N1 (A/California/04/2009) were measured using an HIV-1-based pseudovirus neutralization assay. Using this highly sensitive assay, we found that a large fraction of subjects who had never been exposed to pandemic A/H1N1 express high levels of pandemic A/H1N1 neutralizing titers. A significant correlation was seen between neutralization of pandemic A/H1N1 and neutralization of a standard seasonal A/H1N1 strain. Significantly higher pandemic A/H1N1 neutralizing titers were measured in subjects who had received vaccination against seasonal influenza in 2008–2009. Higher pandemic neutralizing titers were also measured in subjects over 60 years of age. Conclusions/Significance Our findings reveal that the extent of protective cross-immunity between seasonal and pandemic A/H1N1 influenza viruses may be more important than previously estimated. This cross-immunity could provide a possible explanation of the relatively mild profile of the recent influenza pandemic. PMID:20543954
Gaygısız, Ümmügülsüm; Gaygısız, Esma; Özkan, Türker; Lajunen, Timo
This study investigated the acceptability of the A/H1N1 influenza vaccination and related factors among 1137 adults in the later stage of the A/H1N1 outbreak in Turkey. Having already been vaccinated or intending to get vaccinated were related to trust in the vaccine effectiveness, perceived risk of the side effects, and benefits of getting vaccinated. Perceived long term consequences of the A/H1N1 infection, perceptions of the A/H1N1 information in media, and barriers for getting vaccinated were related to intention whereas anticipated epidemic situation in Turkey, being chronically ill, and being not married were related to having already been vaccinated.
van der Most, Robbert; Van Mechelen, Marcelle; Destexhe, Eric; Wettendorff, Martine; Hanon, Emmanuel
Epidemiological data from several European countries suggested an increased risk of the chronic sleep disorder narcolepsy following vaccination with Pandemrix™, an AS03-adjuvanted, pandemic A(H1N1)pdm09 influenza vaccine. Further research to investigate potential associations between Pandemrix™ vaccination, A(H1N1)pdm09 influenza infection and narcolepsy is required. Narcolepsy is most commonly caused by a reduction or absence of hypocretin produced by hypocretin-secreting neurons in the hypothalamus, and is tightly associated with HLA-II DQB1*06:02. Consequently, research focusing on CD4+ T-cell responses, building on the hypothesis that for disease development, T cells specific for antigen(s) from hypocretin neurons must be activated or reactivated, is considered essential. Therefore, the following key areas of research can be identified, (1) characterization of hypothetical narcolepsy-specific auto-immune CD4+ T cells, (2) mapping epitopes of such T cells, and (3) evaluating potential mechanisms that would enable such cells to gain access to the hypothalamus. Addressing these questions could further our understanding of the potential links between narcolepsy and A(H1N1)pdm09 vaccination and/or infection. Of particular interest is that any evidence of a mimicry-based mechanism could also explain the association between narcolepsy and A(H1N1)pdm09 influenza infection. PMID:24342916
Bragstad, Karoline; Vinner, Lasse; Hansen, Mette Sif; Nielsen, Jens; Fomsgaard, Anders
The composition of current influenza protein vaccines has to be reconsidered every season to match the circulating influenza viruses, continuously changing antigenicity. Thus, influenza vaccines inducing a broad cross-reactive immune response would be a great advantage for protection against both seasonal and emerging influenza viruses. We have developed an alternative influenza vaccine based on DNA expressing selected influenza proteins of pandemic and seasonal origin. In the current study, we investigated the protection of a polyvalent influenza DNA vaccine approach in pigs. We immunised pigs intradermally with a combination of influenza DNA vaccine components based on the pandemic 1918 H1N1 (M and NP genes), pandemic 2009 H1N1pdm09 (HA and NA genes) and seasonal 2005 H3N2 genes (HA and NA genes) and investigated the protection against infection with virus both homologous and heterologous to the DNA vaccine components. We found that pigs challenged with a virus homologous to the HA and NA DNA vaccine components were well protected from infection. In addition, heterologous challenge virus was cleared rapidly compared to the unvaccinated control pigs. Immunisation by electroporation induced HI antibodies >40 HAU/ml seven days after second vaccination. Heterologous virus challenge as long as ten weeks after last immunisation was able to trigger a vaccine antibody HI response 26 times higher than in the control pigs. The H3N2 DNA vaccine HA and NA genes also triggered an effective vaccine response with protective antibody titres towards heterologous H3N2 virus. The described influenza DNA vaccine is able to induce broadly protective immune responses even in a larger animal, like the pig, against both heterologous and homologous virus challenges despite relatively low HI titres after vaccination. The ability of this DNA vaccine to limit virus shedding may have an impact on virus spread among pigs which could possibly extend to humans as well, thereby diminishing the
Liu, She-Lan; Wang, Jing; Yang, Xu-Hui; Chen, Jin; Huang, Ren-Jie; Ruan, Bing; He, Hong-Xuan; Wang, Cheng-Min; Zhang, Hong-Mei; Sun, Zhou; Xie, Li; Zhuang, Hui
Two hundred fourteen abstracts and 87 full texts regarding pregnant women infected with pandemic influenza A(H1N1) 2009 virus were systematically reviewed by using a PubMed search and assessing pandemic, clinical, laboratory test, vaccine, and control experiences. Both policy and health education were excluded. This review counted the total number of pregnant cases from different countries and analyzed their epidemic features, including trimester distribution, morbidity, hospitalization, intensive care unit admissions, maternal mortality, underlying diseases, complications, high-risk factors for death, pregnancy outcome, and clinical symptoms compared with the previous pandemic seasonal influenza A/H1N1 as compared with the general population. Early identification and treatment were the most important factors in different countries and areas examined. The vaccine and antiviral drugs that have been the most efficient means to control the novel virus appear to be safe but require more extensive study. In the future, the focus should be placed on understanding vertical transmission and the severe mechanisms.
Background Physicians of the Spanish Influenza Sentinel Surveillance System report and systematically swab patients attended to their practices for influenza-like illness (ILI). Within the surveillance system, some Spanish regions also participated in an observational study aiming at estimating influenza vaccine effectiveness (cycEVA study). During the season 2009-2010, we estimated pandemic influenza vaccine effectiveness using both the influenza surveillance data and the cycEVA study. Methods We conducted two case-control studies using the test-negative design, between weeks 48/2009 and 8/2010 of the pandemic season. The surveillance-based study included all swabbed patients in the sentinel surveillance system. The cycEVA study included swabbed patients from seven Spanish regions. Cases were laboratory-confirmed pandemic influenza A(H1N1)2009. Controls were ILI patients testing negative for any type of influenza. Variables collected in both studies included demographic data, vaccination status, laboratory results, chronic conditions, and pregnancy. Additionally, cycEVA questionnaire collected data on previous influenza vaccination, smoking, functional status, hospitalisations, visits to the general practitioners, and obesity. We used logistic regression to calculate adjusted odds ratios (OR), computing pandemic influenza vaccine effectiveness as (1-OR)*100. Results We included 331 cases and 995 controls in the surveillance-based study and 85 cases and 351 controls in the cycEVA study. We detected nine (2.7%) and two (2.4%) vaccine failures in the surveillance-based and cycEVA studies, respectively. Adjusting for variables collected in surveillance database and swabbing month, pandemic influenza vaccine effectiveness was 62% (95% confidence interval (CI): -5; 87). The cycEVA vaccine effectiveness was 64% (95%CI: -225; 96) when adjusting for common variables with the surveillance system and 75% (95%CI: -293; 98) adjusting for all variables collected. Conclusion
Ghaderi, Sara; Gunnes, Nina; Bakken, Inger Johanne; Magnus, Per; Trogstad, Lill; Håberg, Siri Eldevik
Vaccinations and infections are possible triggers of Guillain-Barré syndrome (GBS). However, studies on GBS after vaccinations during the influenza A(H1N1)pmd09 pandemic in 2009, show inconsistent results. Only few studies have addressed the role of influenza infection. We used information from national health data-bases with information on the total Norwegian population (N = 4,832,211). Cox regression analyses with time-varying covariates and self-controlled case series was applied. The risk of being hospitalized with GBS during the pandemic period, within 42 days after an influenza diagnosis or pandemic vaccination was estimated. There were 490 GBS cases during 2009-2012 of which 410 cases occurred after October 1, 2009 of which 46 new cases occurred during the peak period of the influenza pandemic. An influenza diagnosis was registered for 2.47% of the population and the vaccination coverage was 39.25%. The incidence rate ratio of GBS during the pandemic peak relative to other periods was 1.46 [95% confidence interval (CI) 1.08-1.98]. The adjusted hazard ratio (HR) of GBS within 42 days after a diagnosis of pandemic influenza was 4.89 (95% CI 1.17-20.36). After pandemic vaccination the adjusted HR was 1.11 (95% CI 0.51-2.43). Our results indicated that there was a significantly increased risk of GBS during the pandemic season and after pandemic influenza infection. However, vaccination did not increase the risk of GBS. The small number of GBS cases in this study warrants caution in the interpretation of the findings.
Introduction: In March 2009, a novel pandemic A/H1N1 emerged in the human population in North America (2). The gene constellation of the emerging virus was demonstrated to be a combination of genes from swine influenza A viruses (SIV) of North American and Eurasian lineages that had never before be...
Aguilar-Yáñez, José M.; Portillo-Lara, Roberto; Mendoza-Ochoa, Gonzalo I.; García-Echauri, Sergio A.; López-Pacheco, Felipe; Bulnes-Abundis, David; Salgado-Gallegos, Johari; Lara-Mayorga, Itzel M.; Webb-Vargas, Yenny; León-Angel, Felipe O.; Rivero-Aranda, Ramón E.; Oropeza-Almazán, Yuriana; Ruiz-Palacios, Guillermo M.; Zertuche-Guerra, Manuel I.; DuBois, Rebecca M.; White, Stephen W.; Schultz-Cherry, Stacey; Russell, Charles J.; Alvarez, Mario M.
Background The A/H1N1/2009 influenza pandemic made evident the need for faster and higher-yield methods for the production of influenza vaccines. Platforms based on virus culture in mammalian or insect cells are currently under investigation. Alternatively, expression of fragments of the hemagglutinin (HA) protein in prokaryotic systems can potentially be the most efficacious strategy for the manufacture of large quantities of influenza vaccine in a short period of time. Despite experimental evidence on the immunogenic potential of HA protein constructs expressed in bacteria, it is still generally accepted that glycosylation should be a requirement for vaccine efficacy. Methodology/Principal Findings We expressed the globular HA receptor binding domain, referred to here as HA63–286-RBD, of the influenza A/H1N1/2009 virus in Escherichia coli using a simple, robust and scalable process. The recombinant protein was refolded and purified from the insoluble fraction of the cellular lysate as a single species. Recombinant HA63–286-RBD appears to be properly folded, as shown by analytical ultracentrifugation and bio-recognition assays. It binds specifically to serum antibodies from influenza A/H1N1/2009 patients and was found to be immunogenic, to be capable of triggering the production of neutralizing antibodies, and to have protective activity in the ferret model. Conclusions/Significance Projections based on our production/purification data indicate that this strategy could yield up to half a billion doses of vaccine per month in a medium-scale pharmaceutical production facility equipped for bacterial culture. Also, our findings demonstrate that glycosylation is not a mandatory requirement for influenza vaccine efficacy. PMID:20661476
Safety and persistence of the humoral and cellular immune responses induced by 2 doses of an AS03-adjuvanted A(H1N1)pdm09 pandemic influenza vaccine administered to infants, children and adolescents: Two open, uncontrolled studies.
Garcia-Sicilia, José; Arístegui, Javier; Omeñaca, Félix; Carmona, Alfonso; Tejedor, Juan C; Merino, José M; García-Corbeira, Pilar; Walravens, Karl; Bambure, Vinod; Moris, Philippe; Caplanusi, Adrian; Gillard, Paul; Dieussaert, Ilse
In children, 2 AS03-adjuvanted A(H1N1)pdm09 vaccine doses given 21 days apart were previously shown to induce a high humoral immune response and to have an acceptable safety profile up to 42 days following the first vaccination. Here, we analyzed the persistence data from 2 open-label studies, which assessed the safety, and humoral and cell-mediated immune responses induced by 2 doses of this vaccine. The first study was a phase II, randomized trial conducted in 104 children aged 6-35 months vaccinated with the A(H1N1)pdm09 vaccine containing 1.9 µg haemagglutinin antigen (HA) and AS03B (5.93 mg tocopherol) and the second study, a phase III, non-randomized trial conducted in 210 children and adolescents aged 3-17 years vaccinated with the A(H1N1)pdm09 vaccine containing 3.75 µg HA and AS03A (11.86 mg tocopherol). Approximately one year after the first dose, all children with available data were seropositive for haemagglutinin inhibition and neutralising antibody titres, but a decline in geometric mean antibody titres was noted. The vaccine induced a cell-mediated immune response in terms of antigen-specific CD4(+) T-cells, which persisted up to one year post-vaccination. The vaccine did not raise any safety concern, though these trials were not designed to detect rare events. In conclusion, 2 doses of the AS03-adjuvanted A(H1N1)pdm09 vaccine at 2 different dosages had a clinically acceptable safety profile, and induced high and persistent humoral and cell-mediated immune responses in children aged 6-35 months and 3-17 years. These studies have been registered at www.clinicaltrials.gov NCT00971321 and NCT00964158.
Kinetics of lung lesion development and pro-inflammatory cytokine response in pigs with vaccine-associated enhanced respiratory disease induced by challenge with pandemic (2009) A/H1N1 influenza virus.
Gauger, P C; Vincent, A L; Loving, C L; Henningson, J N; Lager, K M; Janke, B H; Kehrli, M E; Roth, J A
The objective of this report was to characterize the enhanced clinical disease and lung lesions observed in pigs vaccinated with inactivated H1N2 swine δ-cluster influenza A virus and challenged with pandemic 2009 A/H1N1 human influenza virus. Eighty-four, 6-week-old, cross-bred pigs were randomly allocated into 3 groups of 28 pigs to represent vaccinated/challenged (V/C), non-vaccinated/challenged (NV/C), and non-vaccinated/non-challenged (NV/NC) control groups. Pigs were intratracheally inoculated with pH1N1 and euthanized at 1, 2, 5, and 21 days post inoculation (dpi). Macroscopically, V/C pigs demonstrated greater percentages of pneumonia compared to NV/C pigs. Histologically, V/C pigs demonstrated severe bronchointerstitial pneumonia with necrotizing bronchiolitis accompanied by interlobular and alveolar edema and hemorrhage at 1 and 2 dpi. The magnitude of peribronchiolar lymphocytic cuffing was greater in V/C pigs by 5 dpi. Microscopic lung lesion scores were significantly higher in the V/C pigs at 2 and 5 dpi compared to NV/C and NV/NC pigs. Elevated TNF-α, IL-1β, IL-6, and IL-8 were detected in bronchoalveolar lavage fluid at all time points in V/C pigs compared to NV/C pigs. These data suggest H1 inactivated vaccines followed by heterologous challenge resulted in potentiated clinical signs and enhanced pulmonary lesions and correlated with an elevated proinflammatory cytokine response in the lung. The lung alterations and host immune response are consistent with the vaccine-associated enhanced respiratory disease (VAERD) clinical outcome observed reproducibly in this swine model.
Reed, Carrie; Katz, Jacqueline M.; Hancock, Kathy; Balish, Amanda; Fry, Alicia M.
Background 2009 pandemic influenza A/H1N1 (A(H1N1)pdm09) was first detected in the United States in April 2009 and resulted in a global pandemic. We conducted a serologic survey to estimate the cumulative incidence of A(H1N1)pdm09 through the end of 2009 when pandemic activity had waned in the United States. Methods We conducted a pair of cross sectional serologic surveys before and after the spring/fall waves of the pandemic for evidence of seropositivity (titer ≥40) using the hemagglutination inhibition (HI) assay. We tested a baseline sample of 1,142 serum specimens from the 2007–2008 National Health and Nutrition Examination Survey (NHANES), and 2,759 serum specimens submitted for routine screening to clinical diagnostic laboratories from ten representative sites. Results The age-adjusted prevalence of seropositivity to A(H1N1)pdm09 by year-end 2009 was 36.9% (95%CI: 31.7–42.2%). After adjusting for baseline cross-reactive antibody, pandemic vaccination coverage and the sensitivity/specificity of the HI assay, we estimate that 20.2% (95%CI: 10.1–28.3%) of the population was infected with A(H1N1)pdm09 by December 2009, including 53.3% (95%CI: 39.0–67.1%) of children aged 5–17 years. Conclusions By December 2009, approximately one-fifth of the US population, or 61.9 million persons, may have been infected with A(H1N1)pdm09, including around half of school-aged children. PMID:23118949
Casado, Itziar; Martínez-Baz, Iván; Burgui, Rosana; Irisarri, Fátima; Arriazu, Maite; Elía, Fernando; Navascués, Ana; Ezpeleta, Carmen; Aldaz, Pablo; Castilla, Jesús
Background The transmission of influenza viruses occurs person to person and is facilitated by contacts within enclosed environments such as households. The aim of this study was to evaluate secondary attack rates and factors associated with household transmission of laboratory-confirmed influenza A(H1N1)pdm09 in the pandemic and post-pandemic seasons. Methods During the 2009–2010 and 2010–2011 influenza seasons, 76 sentinel physicians in Navarra, Spain, took nasopharyngeal and pharyngeal swabs from patients diagnosed with influenza-like illness. A trained nurse telephoned households of those patients who were laboratory-confirmed for influenza A(H1N1)pdm09 to ask about the symptoms, risk factors and vaccination status of each household member. Results In the 405 households with a patient laboratory-confirmed for influenza A(H1N1)pdm09, 977 susceptible contacts were identified; 16% of them (95% CI 14–19%) presented influenza-like illness and were considered as secondary cases. The secondary attack rate was 14% in 2009–2010 and 19% in the 2010–2011 season (p = 0.049), an increase that mainly affected persons with major chronic conditions. In the multivariate logistic regression analysis, the risk of being a secondary case was higher in the 2010–2011 season than in the 2009–2010 season (adjusted odds ratio: 1.72; 95% CI 1.17–2.54), and in children under 5 years, with a decreasing risk in older contacts. Influenza vaccination was associated with lesser incidence of influenza-like illness near to statistical significance (adjusted odds ratio: 0.29; 95% CI 0.08–1.03). Conclusion The secondary attack rate in households was higher in the second season than in the first pandemic season. Children had a greater risk of infection. Preventive measures should be maintained in the second pandemic season, especially in high-risk persons. PMID:25254376
van der Most, Robbert; Van Mechelen, Marcelle; Destexhe, Eric; Wettendorff, Martine; Hanon, Emmanuel
Epidemiological data from several European countries suggested an increased risk of the chronic sleep disorder narcolepsy following vaccination with Pandemrix(™), an AS03-adjuvanted, pandemic A(H1N1)pdm09 influenza vaccine. Further research to investigate potential associations between Pandemrix™ vaccination, A(H1N1)pdm09 influenza infection and narcolepsy is required. Narcolepsy is most commonly caused by a reduction or absence of hypocretin produced by hypocretin-secreting neurons in the hypothalamus, and is tightly associated with HLA-II DQB1*06:02. Consequently, research focusing on CD4(+) T-cell responses, building on the hypothesis that for disease development, T cells specific for antigen(s) from hypocretin neurons must be activated or reactivated, is considered essential. Therefore, the following key areas of research can be identified, (1) characterization of hypothetical narcolepsy-specific auto-immune CD4(+) T cells, (2) mapping epitopes of such T cells, and (3) evaluating potential mechanisms that would enable such cells to gain access to the hypothalamus. Addressing these questions could further our understanding of the potential links between narcolepsy and A(H1N1)pdm09 vaccination and/or infection. Of particular interest is that any evidence of a mimicry-based mechanism could also explain the association between narcolepsy and A(H1N1)pdm09 influenza infection.
Safety and persistence of the humoral and cellular immune responses induced by 2 doses of an AS03-adjuvanted A(H1N1)pdm09 pandemic influenza vaccine administered to infants, children and adolescents: Two open, uncontrolled studies
Garcia-Sicilia, José; Arístegui, Javier; Omeñaca, Félix; Carmona, Alfonso; Tejedor, Juan C; Merino, José M; García-Corbeira, Pilar; Walravens, Karl; Bambure, Vinod; Moris, Philippe; Caplanusi, Adrian; Gillard, Paul; Dieussaert, Ilse
In children, 2 AS03-adjuvanted A(H1N1)pdm09 vaccine doses given 21 days apart were previously shown to induce a high humoral immune response and to have an acceptable safety profile up to 42 days following the first vaccination. Here, we analyzed the persistence data from 2 open-label studies, which assessed the safety, and humoral and cell-mediated immune responses induced by 2 doses of this vaccine. The first study was a phase II, randomized trial conducted in 104 children aged 6–35 months vaccinated with the A(H1N1)pdm09 vaccine containing 1.9 µg haemagglutinin antigen (HA) and AS03B (5.93 mg tocopherol) and the second study, a phase III, non-randomized trial conducted in 210 children and adolescents aged 3–17 years vaccinated with the A(H1N1)pdm09 vaccine containing 3.75 µg HA and AS03A (11.86 mg tocopherol). Approximately one year after the first dose, all children with available data were seropositive for haemagglutinin inhibition and neutralising antibody titres, but a decline in geometric mean antibody titres was noted. The vaccine induced a cell-mediated immune response in terms of antigen-specific CD4+ T-cells, which persisted up to one year post-vaccination. The vaccine did not raise any safety concern, though these trials were not designed to detect rare events. In conclusion, 2 doses of the AS03-adjuvanted A(H1N1)pdm09 vaccine at 2 different dosages had a clinically acceptable safety profile, and induced high and persistent humoral and cell-mediated immune responses in children aged 6–35 months and 3–17 years. These studies have been registered at www.clinicaltrials.gov NCT00971321 and NCT00964158. PMID:26176592
Sawanpanyalert, Pathom; Hanchoworakul, Wanna; Sawanpanyalert, Narumol; Maloney, Susan A.; Brown, Richard Clive; Birmingham, Maureen Elizabeth; Chusuttiwat, Supamit
In 2009, Thailand experienced rapid spread of the pandemic influenza A(H1N1)pdm09 virus. The national response came under intense public scrutiny as the number of confirmed cases and associated deaths increased. Thus, during July–December 2009, the Ministry of Public Health and the World Health Organization jointly reviewed the response efforts. The review found that the actions taken were largely appropriate and proportionate to need. However, areas needing improvement were surveillance, laboratory capacity, hospital infection control and surge capacity, coordination and monitoring of guidelines for clinical management and nonpharmaceutical interventions, risk communications, and addressing vulnerabilities of non-Thai displaced and migrant populations. The experience in Thailand may be applicable to other countries and settings, and the lessons learned may help strengthen responses to other pandemics or comparable prolonged public health emergencies. PMID:22709628
Objective To verify whether vaccination against the A-H1N1 virus in the paediatric population was effective in preventing the occurrence of influenza-like illness (ILI) or was associated with adverse events of special interest. Design, setting and patients A case–control analysis was performed as part of surveillance of children hospitalised through the emergency departments of eight paediatric hospitals/wards for ILI, neurological disorders, non-infectious muco-cutaneous diseases and vasculitis, thrombocytopaenia and gastroduodenal lesions. Results Among 736 children enrolled from November 2009 to August 2010, only 25 had been vaccinated with the pandemic vaccine. Out of 268 children admitted for a diagnosis compatible with the adverse events of special interest, six had received the A-H1N1 vaccine, although none of the adverse events occurred within the predefined risk windows. Only 35 children out of 244 admitted with a diagnosis of ILI underwent laboratory testing: 11 were positive and 24 negative for the A-H1N1 virus. None of the A-H1N1 positive children had received the pandemic vaccine. The OR of ILI associated with any influenza vaccination was 0.9 (95% CI 0.1 to 5.5). Conclusions The study provides additional information on the benefit–risk profile of the pandemic vaccine. No sign of risk associated with the influenza A-H1N1 vaccine used in Italy was found, although several limitations were observed: in Italy, pandemic vaccination coverage was low, the epidemic was almost over by mid December 2009 and the A-H1N1 laboratory test was performed only during the epidemic phase (in <10% of children). This study supports the importance of the existing network of hospitals for the evaluation of signals relevant to new vaccines and drugs. PMID:22021877
Castilla, Jesús; Morán, Julio; Martínez-Artola, Víctor; Fernández-Alonso, Mirian; Guevara, Marcela; Cenoz, Manuel García; Reina, Gabriel; Alvarez, Nerea; Arriazu, Maite; Elía, Fernando; Salcedo, Esther; Barricarte, Aurelio
We defined a population-based cohort (596,755 subjects) in Navarre, Spain, using electronic records from physicians, to evaluate the effectiveness of the monovalent A(H1N1)2009 vaccine in preventing influenza in the 2009-2010 pandemic season. During the 9-week period of vaccine availability and circulation of the A(H1N1)2009 virus, 4608 cases of medically attended influenza-like illness (MA-ILI) were registered (46 per 1000 person-years). After adjustment for sociodemographic covariables, outpatient visits and major chronic conditions, vaccination was associated with a 32% (95% CI: 8-50%) reduction in the overall incidence of MA-ILI. In a test negative case-control analysis nested in the cohort, swabs from 633 patients were included, and 123 were confirmed for A(H1N1)2009 influenza. No confirmed case had received A(H1N1)2009 vaccine versus 9.6% of controls (p<0.001). The vaccine effectiveness in preventing laboratory-confirmed influenza was 89% (95% CI: 36-100%) after adjusting for age, health care setting, major chronic conditions and period. Pandemic vaccine was effective in preventing MA-ILI and confirmed cases of influenza A(H1N1)2009 in the 2009-2010 season.
Williams, Stephanie; Merianos, Angela; Mounts, Anthony
Abstract During the 2009 A(H1N1) influenza pandemic, the World Health Organization (WHO) asked all Member States to provide case-based data on at least the first 100 laboratory-confirmed influenza cases to generate an early understanding of the pandemic and provide appropriate guidance to affected countries. In reviewing the pandemic surveillance strategy, we evaluated the utility of case-based data collection and the challenges in interpreting these data at the global level. To do this, we assessed compliance with the surveillance recommendation and data completeness of submitted case records and described the epidemiological characteristics of up to the first 110 reported cases from each country, aggregated into regions. From April 2009 to August 2011, WHO received over 18 000 case records from 84 countries. Data reached WHO at different time intervals, in different formats and without information on collection methods. Just over half of the 18 000 records gave the date of symptom onset, which made it difficult to assess whether the cases were among the earliest to be confirmed. Descriptive epidemiological analyses were limited to summarizing age, sex and hospitalization ratios. Centralized analysis of case-based data had little value in describing key features of the pandemic. Results were difficult to interpret and would have been misleading if viewed in isolation. A better approach would be to identify critical questions, standardize data elements and methods of investigation, and create efficient channels for communication between countries and the international public health community. Regular exchange of routine surveillance data will help to consolidate these essential channels of communication. PMID:24391301
Williams, Stephanie; Fitzner, Julia; Merianos, Angela; Mounts, Anthony
During the 2009 A(H1N1) influenza pandemic, the World Health Organization (WHO) asked all Member States to provide case-based data on at least the first 100 laboratory-confirmed influenza cases to generate an early understanding of the pandemic and provide appropriate guidance to affected countries. In reviewing the pandemic surveillance strategy, we evaluated the utility of case-based data collection and the challenges in interpreting these data at the global level. To do this, we assessed compliance with the surveillance recommendation and data completeness of submitted case records and described the epidemiological characteristics of up to the first 110 reported cases from each country, aggregated into regions. From April 2009 to August 2011, WHO received over 18 000 case records from 84 countries. Data reached WHO at different time intervals, in different formats and without information on collection methods. Just over half of the 18 000 records gave the date of symptom onset, which made it difficult to assess whether the cases were among the earliest to be confirmed. Descriptive epidemiological analyses were limited to summarizing age, sex and hospitalization ratios. Centralized analysis of case-based data had little value in describing key features of the pandemic. Results were difficult to interpret and would have been misleading if viewed in isolation. A better approach would be to identify critical questions, standardize data elements and methods of investigation, and create efficient channels for communication between countries and the international public health community. Regular exchange of routine surveillance data will help to consolidate these essential channels of communication.
Wang, Wei; Vernet, Guy; Paranhos-Baccalà, Gláucia; Jin, Qi; Wang, Jianwei
To determine the role of the pandemic influenza A/H1N1 2009 (A/H1N1 2009pdm) in acute respiratory tract infections (ARTIs) and its impact on the epidemic of seasonal influenza viruses and other common respiratory viruses, nasal and throat swabs taken from 7,776 patients with suspected viral ARTIs from 2006 through 2010 in Beijing, China were screened by real-time PCR for influenza virus typing and subtyping and by multiplex or single PCR tests for other common respiratory viruses. We observed a distinctive dual peak pattern of influenza epidemic during the A/H1N1 2009pdm in Beijing, China, which was formed by the A/H1N1 2009pdm, and a subsequent influenza B epidemic in year 2009/2010. Our analysis also shows a small peak formed by a seasonal H3N2 epidemic prior to the A/H1N1 2009pdm peak. Parallel detection of multiple respiratory viruses shows that the epidemic of common respiratory viruses, except human rhinovirus, was delayed during the pandemic of the A/H1N1 2009pdm. The H1N1 2009pdm mainly caused upper respiratory tract infections in the sampled patients; patients infected with H1N1 2009pdm had a higher percentage of cough than those infected with seasonal influenza or other respiratory viruses. Our findings indicate that A/H1N1 2009pdm and other respiratory viruses except human rhinovirus could interfere with each other during their transmission between human beings. Understanding the mechanisms and effects of such interference is needed for effective control of future influenza epidemics. PMID:23029253
Veguilla, Vic; López-Gatell, Hugo; López-Martínez, Irma; Aparicio-Antonio, Rodrigo; Barrera-Badillo, Gisela; Rojo-Medina, Julieta; Gross, Felicia Liaini; Jefferson, Stacie N.; Katz, Jacqueline M.; Hernández-Ávila, Mauricio; Alpuche-Aranda, Celia M.
Background The 2009 H1N1 influenza pandemic initially affected Mexico from April 2009 to July 2010. By August 2010, a fourth of the population had received the monovalent vaccine against the pandemic virus (A(H1N1)pdm09). To assess the proportion of the Mexican population who remained potentially susceptible to infection throughout the summer of 2010, we estimated the population seroprevalence to A(H1N1)pdm09 in a serosurvey of blood donors. Methods We evaluated baseline cross-reactivity to the pandemic strain and set the threshold for seropositivity using pre-pandemic (2005–2008) stored serum samples and sera from confirmed A(H1N1)pdm09 infected individuals. Between June and September 2010, a convenience sample serosurvey of adult blood donors, children, and adolescents was conducted in six states of Mexico. Sera were tested by the microneutralization (MN) and hemagglutination inhibition (HI) assays, and regarded seropositive if antibody titers were equal or exceeded 1:40 for MN and 1:20 for HI. Age-standardized seroprevalence were calculated using the 2010 National Census population. Results Sera from 1,484 individuals were analyzed; 1,363 (92%) were blood donors, and 121 (8%) children or adolescents aged ≤19 years. Mean age (standard deviation) was 31.4 (11.5) years, and 276 (19%) were women. A total of 516 (35%) participants declared history of influenza vaccination after April 2009. The age-standardized seroprevalence to A(H1N1)pdm09 was 48% by the MN and 41% by the HI assays, respectively. The youngest quintile, aged 1 to 22 years, had the highest the seroprevalence; 61% (95% confidence interval [CI]: 56, 66%) for MN, and 56% (95% CI: 51, 62%) for HI. Conclusions Despite high transmission of A(H1N1)pdm09 observed immediately after its emergence and extensive vaccination, over a half of the Mexican population remained potentially susceptible to A(H1N1)pdm09 infection. Subsequent influenza seasons with high transmission of A(H1N1)pdm09, as 2011–2012 and
Thornley, Craig N; Mills, Clair; Roberts, Sally; Perera, Shanika; Peters, Julia; Kelso, Anne; Barr, Ian; Wilson, Nick
Objectives To assess the risk of transmission of pandemic A/H1N1 2009 influenza (pandemic A/H1N1) from an infected high school group to other passengers on an airline flight and the effectiveness of screening and follow-up of exposed passengers. Design Retrospective cohort investigation using a questionnaire administered to passengers and laboratory investigation of those with symptoms. Setting Auckland, New Zealand, with national and international follow-up of passengers. Participants Passengers seated in the rear section of a Boeing 747-400 long haul flight that arrived on 25 April 2009, including a group of 24 students and teachers and 97 (out of 102) other passengers in the same section of the plane who agreed to be interviewed. Main outcome measures Laboratory confirmed pandemic A/H1N1 infection in susceptible passengers within 3.2 days of arrival; sensitivity and specificity of influenza symptoms for confirmed infection; and completeness and timeliness of contact tracing. Results Nine members of the school group were laboratory confirmed cases of pandemic A/H1N1 infection and had symptoms during the flight. Two other passengers developed confirmed pandemic A/H1N1 infection, 12 and 48 hours after the flight. They reported no other potential sources of infection. Their seating was within two rows of infected passengers, implying a risk of infection of about 3.5% for the 57 passengers in those rows. All but one of the confirmed pandemic A/H1N1 infected travellers reported cough, but more complex definitions of influenza cases had relatively low sensitivity. Rigorous follow-up by public health workers located 93% of passengers, but only 52% were contacted within 72 hours of arrival. Conclusions A low but measurable risk of transmission of pandemic A/H1N1 exists during modern commercial air travel. This risk is concentrated close to infected passengers with symptoms. Follow-up and screening of exposed passengers is slow and difficult once they have left the
A dose-ranging study of MF59®-adjuvanted and non-adjuvanted A/H1N1 pandemic influenza vaccine in young to middle-aged and older adult populations to assess safety, immunogenicity, and antibody persistence one year after vaccination
Reisinger, Keith S; Holmes, Sandra J; Pedotti, Paola; Arora, Ashwani Kumar; Lattanzi, Maria
Background During development of an A/H1N1 pandemic influenza vaccine, this study was performed to identify the antigen and adjuvant content which would provide optimal antibody response and persistence in adults and the elderly. Dose-sparing strategies, such as inclusion of adjuvants, are critical in ensuring the widest possible population coverage in the event of an influenza pandemic, despite a limited global capacity for vaccine manufacture. Methods Healthy subjects aged 18−64 years (n = 1240) and ≥65 years (n = 1352) were vaccinated with 1 of 8 investigational vaccine formulations varying in antigen quantity (3.75 µg to 30 µg of hemagglutinin) and MF59® adjuvant (none, half dose, or full dose). All subjects received 2 vaccine doses administered 3 weeks apart. Antibody response was assessed by hemagglutination inhibition assay 1 and 3 weeks after administration of first and second doses. Antibody persistence was assessed after 6 and 12 mo. Vaccine safety was monitored over 12 mo. Results All 8 investigational A/H1N1 vaccine formulations were well tolerated, and rapidly induced high antibody titers which met all of the Center for Biologics Evaluation and Research (CBER) and Committee for Medicinal Products for Human Use (CHMP) licensure criteria 3 weeks after one dose. The highest antibody titers were observed in participants vaccinated with higher quantities of antigen and adjuvant. Conclusion A single vaccine dose containing 3.75 µg of A/California/7/2009 (H1N1) antigen with MF59 adjuvant was identified as optimal for young to middle-aged (18−64 years) and older (≥65 years) adult populations. PMID:25424947
Wu, Cynthia Sau Ting; Kwong, Enid Wai Yung; Wong, Ho Ting; Lo, Suet Hang; Wong, Anthony Siu Wo
Vaccination against AH1N1pdm09 infection (human swine infection, HSI) is an effective measure of preventing pandemic infection, especially for high-risk groups like children between the ages of 6 months and 6 years. This study used a cross-sectional correlation design and aimed to identify predicting factors of parental acceptance of the HSI vaccine (HSIV) and uptake of the vaccination by their preschool-aged children in Hong Kong. A total of 250 parents were recruited from four randomly selected kindergartens. A self-administered questionnaire based on the health belief framework was used for data collection. The results showed that a number of factors significantly affected the tendency toward new vaccination uptake; these factors included parental age, HSI vaccination history of the children in their family, preferable price of the vaccine, perceived severity, perceived benefits, perceived barriers, and motivating factors for taking new vaccines. Using these factors, a logistic regression model with a high Nagelkerke R2 of 0.63 was generated to explain vaccination acceptance. A strong correlation between parental acceptance of new vaccinations and the motivating factors of vaccination uptake was found, which indicates the importance of involving parents in policy implementation for any new vaccination schemes. Overall, in order to fight against pandemics and enhance vaccination acceptance, it is essential for the government to understand the above factors determining parental acceptance of new vaccinations for their preschool-aged children.
Matsuoka, Toshihiko; Sato, Tomoki; Akita, Tomoyuki; Yanagida, Jiturou; Ohge, Hiroki; Kuwabara, Masao; Tanaka, Junko
The objective of this study was to identify factors related to the expansion of infection and prevention of influenza A(H1N1)pdm09. A retrospective non-randomized cohort study (from June 2009 to May 2010) on influenza A(H1N1)pdm09 was conducted in a sample of residents from Hiroshima Prefecture, Japan. The cumulative incidence of the influenza A(H1N1)pdm09 and the pandemic vaccine effectiveness (VE) were estimated. The response rate was 53.5% (178,669/333,892). Overall, the odds ratio of non-vaccinated group to vaccinated group for cumulative incidence of influenza A(H1N1)pdm09 was 2.18 (95% confidence interval (CI): 2.13–2.23) and the VE was 43.9% (CI: 42.8–44.9). The expansion of infection, indicating the power of transmission from infected person to susceptible person, was high in the 7–15 years age groups in each area. In conclusion, results from this survey suggested that schoolchildren-based vaccination rate participates in determining the level of herd immunity to influenza and children might be the drivers of influenza transmission. For future pandemic preparedness, vaccination of schoolchildren may help to prevent disease transmission during influenza outbreak. PMID:27763532
Matsuoka, Toshihiko; Sato, Tomoki; Akita, Tomoyuki; Yanagida, Jiturou; Ohge, Hiroki; Kuwabara, Masao; Tanaka, Junko
The objective of this study was to identify factors related to the expansion of infection and prevention of influenza A(H1N1)pdm09. A retrospective non-randomized cohort study (from June 2009 to May 2010) on influenza A(H1N1)pdm09 was conducted in a sample of residents from Hiroshima Prefecture, Japan. The cumulative incidence of the influenza A(H1N1)pdm09 and the pandemic vaccine effectiveness (VE) were estimated. The response rate was 53.5% (178,669/333,892). Overall, the odds ratio of non-vaccinated group to vaccinated group for cumulative incidence of influenza A(H1N1)pdm09 was 2.18 (95% confidence interval (CI): 2.13-2.23) and the VE was 43.9% (CI: 42.8-44.9). The expansion of infection, indicating the power of transmission from infected person to susceptible person, was high in the 7-15 years age groups in each area. In conclusion, results from this survey suggested that schoolchildren-based vaccination rate participates in determining the level of herd immunity to influenza and children might be the drivers of influenza transmission. For future pandemic preparedness, vaccination of schoolchildren may help to prevent disease transmission during influenza outbreak.
During the swine flu pandemic of 2009-2010, all Swedish citizens were recommended to be vaccinated with the influenza vaccine Pandemrix. However, a very serious and unexpected side effect emerged during the summer of 2010: more than 200 children and young adults were diagnosed with narcolepsy after vaccination. Besides the tragic outcome for these children and their families, this adverse side effect suggests future difficulties in obtaining trust in vaccination in cases of emerging pandemics, and thus there is a growing need to find ways to understand the complexities of vaccination decision processes. This article explores written responses to a questionnaire from a Swedish folk life archive as an unconventional source for analysing vaccine decisions. The aim is to investigate how laypersons responded to and re-interpreted the message about the recommended vaccination in their answers. The answers show the confusion and complex circumstances and influences in everyday life that people reflect on when making such important decisions. The issue of confusion is traced back to the initial communications about the vaccination intervention in which both autonomy and solidarity were expected from the population. Common narratives and stories about the media or 'big pharma capitalism' are entangled with private memories, accidental coincidences and serendipitous associations. It is obvious that vaccination interventions that require compliance from large groups of people need to take into account the kind of personal experience narratives that are produced by the complex interplay of the factors described by the informants.
During the swine flu pandemic of 2009–2010, all Swedish citizens were recommended to be vaccinated with the influenza vaccine Pandemrix. However, a very serious and unexpected side effect emerged during the summer of 2010: more than 200 children and young adults were diagnosed with narcolepsy after vaccination. Besides the tragic outcome for these children and their families, this adverse side effect suggests future difficulties in obtaining trust in vaccination in cases of emerging pandemics, and thus there is a growing need to find ways to understand the complexities of vaccination decision processes. This article explores written responses to a questionnaire from a Swedish folk life archive as an unconventional source for analysing vaccine decisions. The aim is to investigate how laypersons responded to and re-interpreted the message about the recommended vaccination in their answers. The answers show the confusion and complex circumstances and influences in everyday life that people reflect on when making such important decisions. The issue of confusion is traced back to the initial communications about the vaccination intervention in which both autonomy and solidarity were expected from the population. Common narratives and stories about the media or ‘big pharma capitalism’ are entangled with private memories, accidental coincidences and serendipitous associations. It is obvious that vaccination interventions that require compliance from large groups of people need to take into account the kind of personal experience narratives that are produced by the complex interplay of the factors described by the informants. PMID:26077985
Kim, Jin Hyang; Reber, Adrian J.; Kumar, Amrita; Ramos, Patricia; Sica, Gabriel; Music, Nedzad; Guo, Zhu; Mishina, Margarita; Stevens, James; York, Ian A.; Jacob, Joshy; Sambhara, Suryaprakash
The association of seasonal trivalent influenza vaccine (TIV) with increased infection by 2009 pandemic H1N1 (A(H1N1)pdm09) virus, initially observed in Canada, has elicited numerous investigations on the possibility of vaccine-associated enhanced disease, but the potential mechanisms remain largely unresolved. Here, we investigated if prior immunization with TIV enhanced disease upon A(H1N1)pdm09 infection in mice. We found that A(H1N1)pdm09 infection in TIV-immunized mice did not enhance the disease, as measured by morbidity and mortality. Instead, TIV-immunized mice cleared A(H1N1)pdm09 virus and recovered at an accelerated rate compared to control mice. Prior TIV immunization was associated with potent inflammatory mediators and virus-specific CD8 T cell activation, but efficient immune regulation, partially mediated by IL-10R-signaling, prevented enhanced disease. Furthermore, in contrast to suggested pathological roles, pre-existing non-neutralizing antibodies (NNAbs) were not associated with enhanced virus replication, but rather with promoted antigen presentation through FcR-bearing cells that led to potent activation of virus-specific CD8 T cells. These findings provide new insights into interactions between pre-existing immunity and pandemic viruses. PMID:27849030
Background When novel influenza viruses cause human infections, it is critical to characterize the illnesses, viruses, and immune responses to infection in order to develop diagnostics, treatments, and vaccines. The objective of the study was to collect samples from patients with suspected or confirmed A(H1N1)pdm09 infections that could be made available to the scientific community. Respiratory secretions, sera and peripheral blood mononuclear cells (PBMCs) were collected sequentially (when possible) from patients presenting with suspected or previously confirmed A(H1N1)pdm09 infections. Clinical manifestations and illness outcomes were assessed. Respiratory secretions were tested for the presence of A(H1N1)pdm09 virus by means of isolation in tissue culture and real time RT-PCR. Sera were tested for the presence and level of HAI and neutralizing antibodies against the A(H1N1)pdm09 virus. Findings and conclusions Thirty patients with confirmed A(H1N1)pdm09 infection were enrolled at Baylor College of Medicine (BCM). Clinical manifestations of illness were consistent with typical influenza. Twenty-eight of 30 had virological confirmation of illness; all recovered fully. Most patients had serum antibody responses or high levels of antibody in convalescent samples. Virus-positive samples were sent to J. Craig Venter Institute for sequencing and sequences were deposited in GenBank. Large volumes of sera collected from 2 convalescent adults were used to standardize antibody assays; aliquots of these sera are available from the repository. Aliquots of serum, PBMCs and stool collected from BCM subjects and subjects enrolled at other study sites are available for use by the scientific community, upon request. PMID:23641940
Said, Abdelrahman; Lange, Elke; Beer, Martin; Damiani, Armando; Osterrieder, Nikolaus
Swine influenza virus (SIV) is not only an important respiratory pathogen in pigs but also a threat to human health. The pandemic influenza A(H1N1)pdm09 virus likely originated in swine through reassortment between a North American triple reassortant and Eurasian avian-like SIV. The North American triple reassortant virus harbors genes from avian, human and swine influenza viruses. An effective vaccine may protect the pork industry from economic losses and curb the development of new virus variants that may threaten public health. In the present study, we evaluated the efficacy of a recombinant equine herpesvirus type 1 (EHV-1) vaccine (rH_H1) expressing the hemagglutinin H1 of A(H1N1)pdm09 in the natural host. Our data shows that the engineered rH_H1 vaccine induces influenza virus-specific antibody responses in pigs and is able to protect at least partially against challenge infection: no clinical signs of disease were detected and virus replication was reduced as evidenced by decreased nasal virus shedding and faster virus clearance. Taken together, our results indicate that recombinant EHV-1 encoding H1 of A(H1N1)pdm09 may be a promising alternative for protection of pigs against infection with A(H1N1)pdm09 or other influenza viruses.
Wong, Li Ping; Sam, I-Ching
Providing health information during disease outbreaks is a fundamental component of outbreak control strategies. This study aimed to explore sources of influenza A(H1N1)-related information, specific information needs and preferences of the lay public during the peak of the outbreak. A cross-sectional, population-based, computer-assisted telephone interview of 1,050 respondents was conducted in Malaysia between July 11 and September 12, 2009. Newspaper, television and family were three main sources of information about A(H1N1). There were substantial ethnic differences; the Malays were significantly more likely to identify television as main source, while newspapers and family were identified as the main sources by the Chinese and Indians, respectively. Overall, the two main information needs identified were prevention and treatment. The Malays expressed lesser need for overall information than other ethnic groups. The three most preferred sources of information were television, newspapers and healthcare providers. There were significant positive correlations between amount of information received with knowledge (r = 0.149), perceived susceptibility to infection (r = 0.177), and other behavioral responses. Health information dissemination should be dedicated to meeting the information needs of diverse sociodemographic and ethnic groups. The findings highlight the importance of providing information that increases awareness and behavioral changes in disease prevention yet reduce fear.
Uraki, Ryuta; Kiso, Maki; Shinya, Kyoko; Goto, Hideo; Takano, Ryo; Iwatsuki-Horimoto, Kiyoko; Takahashi, Kazuo; Daniels, Rod S; Hungnes, Olav; Watanabe, Tokiko; Kawaoka, Yoshihiro
A novel swine-origin H1N1 influenza virus [A(H1N1)pdm09 virus] caused the 2009 influenza pandemic. Most patients exhibited mild symptoms similar to seasonal influenza, but some experienced severe clinical signs and, in the worst cases, died. Such differences in symptoms are generally associated with preexisting medical conditions, but recent reports indicate the possible involvement of viral factors in clinical severity. To better understand the mechanism of pathogenicity of the A(H1N1)pdm09 virus, here, we compared five viruses that are genetically similar but were isolated from patients with either severe or mild symptoms. In a mouse model, A/Norway/3487/2009 (Norway3487) virus exhibited greater pathogenicity than did A/Osaka/164/2009 (Osaka164) virus. By exploiting reassortant viruses between these two viruses, we found that viruses possessing the hemagglutinin (HA) gene of Norway3487 in the genetic background of Osaka164 were more pathogenic in mice than other reassortant viruses, indicating a role for HA in the high virulence of Norway3487 virus. Intriguingly, a virus possessing HA, NA, and NS derived from Norway3487 exhibited greater pathogenicity in mice in concert with PB2 and PB1 derived from Osaka164 than did the parental Norway3487 virus. These findings demonstrate that reassortment between A(H1N1)pdm09 viruses can lead to increased pathogenicity and highlight the need for continued surveillance of A(H1N1)pdm09 viruses.
Uchida, Mitsuo; Kaneko, Minoru; Yamamoto, Hiroshi; Honda, Takayuki; Kawa, Shigeyuki
Schools were closed worldwide during the 2009 influenza A/H1N1 pandemic to prevent the viral spread; however, to date, there has been insufficient evidence to conclude that the closures were beneficial. Therefore, in the present review, we evaluated the effects of school closure during the 2009 influenza A/H1N1 pandemic in Japan. A search of PubMed and Japanese journals identified 24 articles that evaluated the effects of school closure using the following methods: descriptive epidemiology, changes in absenteeism rate, a simulation model, and reproductive number. Almost all of the retrieved studies showed that school closure effectively reduced the number of new infections and thus subsequently suppressed the epidemic. On the other hand, two major sets of confounding variables were identified. First, the effect of school closure was confounded by the methods used to measure, viral infectivity, subject characteristics, increased immunization rates, nonpharmaceutical interventions, antiviral administration, student contact patterns during school closure, and individual household environments. Secondly, school closure implementation was affected by differences between proactive and reactive closures, differences between seasonal and pandemic influenza, decision factors regarding school closure, socioeconomic cost, and ethics of imposing restrictions on individuals. Therefore, a comprehensive, longitudinal study is necessary to clarify the effects of school closure during viral pandemics.
The gene constellation of the 2009 pandemic A/H1N1 virus is a unique combination from swine influenza A viruses (SIV) of North American and Eurasian lineages, but prior to April 2009 had never before been identified in swine or other species. Although its hemagglutinin gene is related to North Ameri...
Rossetto, Erika Valeska; Luna, Expedito José de Albuquerque
Influenza A viruses undergo frequent antigenic mutations and may thus cause seasonal epidemics and pandemics. The aim of this study was to recover the epidemiological history of the pandemic influenza A(H1N1)pdm09 in Brazil. A descriptive study was conducted in 2009-2010. The Brazilian Information System for reportable diseases (SINAN) was the data source. A total of 105,054 suspected cases of influenza A(H1N1)pdm09 were reported to SINAN. Of these, 53,797 (51.2%) were classified as the new influenza virus subtype. Among the confirmed cases, 56.7% were female, the mean age was 26.31 (SD ± 18.1) years. Fever was the most common sign among the confirmed cases (99.7%) and the presence of comorbidities was reported in 32.5% of cases. In 2009 there were confirmed cases in all 26 Brazilian States and the Federal District. The incidence (per 100,000 inhabitants) of severe influenza in the population was 28.0 in 2009 and 0.5 in 2010. The states of Paraná (301.3), Santa Catarina (36.0) and Rio Grande do Sul (27.4) presented the highest incidence; 46.4% of the confirmed cases were hospitalized and 47,643 were cured (93.8%). The case-fatality rate was 3.9% in 2009. The pandemic virus A(H1N1)pdm09 hit Brazil between April/2009 and December/2010 with an important difference in the geographic pattern distribution of the cases from the northeast to the south of the country. Children and young adults were the most affected. The limitations of the study were data quality and inconsistencies in the final classification of cases in SINAN. This study highlights the urgent need for improvements in the surveillance of emerging diseases in Brazil.
Kanehira, Katsushi; Takemae, Nobuhiro; Uchida, Yuko; Hikono, Hirokazu; Saito, Takehiko
In 2013, three reassortant swine influenza viruses (SIVs)-two H1N2 and one H3N2-were isolated from symptomatic pigs in Japan; each contained genes from the pandemic A(H1N1) 2009 virus and endemic SIVs. Phylogenetic analysis revealed that the two H1N2 viruses, A/swine/Gunma/1/2013 and A/swine/Ibaraki/1/2013, were reassortants that contain genes from the following three distinct lineages: (i) H1 and nucleoprotein (NP) genes derived from a classical swine H1 HA lineage uniquely circulating among Japanese SIVs; (ii) neuraminidase (NA) genes from human-like H1N2 swine viruses; and (iii) other genes from pandemic A(H1N1) 2009 viruses. The H3N2 virus, A/swine/Miyazaki/2/2013, comprised genes from two sources: (i) hemagglutinin (HA) and NA genes derived from human and human-like H3N2 swine viruses and (ii) other genes from pandemic A(H1N1) 2009 viruses. Phylogenetic analysis also indicated that each of the reassortants may have arisen independently in Japanese pigs. A/swine/Miyazaki/2/2013 were found to have strong antigenic reactivities with antisera generated for some seasonal human-lineage viruses isolated during or before 2003, whereas A/swine/Miyazaki/2/2013 reactivities with antisera against viruses isolated after 2004 were clearly weaker. In addition, antisera against some strains of seasonal human-lineage H1 viruses did not react with either A/swine/Gunma/1/2013 or A/swine/Ibaraki/1/2013. These findings indicate that emergence and spread of these reassortant SIVs is a potential public health risk.
ROSSETTO, Erika Valeska; LUNA, Expedito José de Albuquerque
SUMMARY Influenza A viruses undergo frequent antigenic mutations and may thus cause seasonal epidemics and pandemics. The aim of this study was to recover the epidemiological history of the pandemic influenza A(H1N1)pdm09 in Brazil. A descriptive study was conducted in 2009-2010. The Brazilian Information System for reportable diseases (SINAN) was the data source. A total of 105,054 suspected cases of influenza A(H1N1)pdm09 were reported to SINAN. Of these, 53,797 (51.2%) were classified as the new influenza virus subtype. Among the confirmed cases, 56.7% were female, the mean age was 26.31 (SD ± 18.1) years. Fever was the most common sign among the confirmed cases (99.7%) and the presence of comorbidities was reported in 32.5% of cases. In 2009 there were confirmed cases in all 26 Brazilian States and the Federal District. The incidence (per 100,000 inhabitants) of severe influenza in the population was 28.0 in 2009 and 0.5 in 2010. The states of Paraná (301.3), Santa Catarina (36.0) and Rio Grande do Sul (27.4) presented the highest incidence; 46.4% of the confirmed cases were hospitalized and 47,643 were cured (93.8%). The case-fatality rate was 3.9% in 2009. The pandemic virus A(H1N1)pdm09 hit Brazil between April/2009 and December/2010 with an important difference in the geographic pattern distribution of the cases from the northeast to the south of the country. Children and young adults were the most affected. The limitations of the study were data quality and inconsistencies in the final classification of cases in SINAN. This study highlights the urgent need for improvements in the surveillance of emerging diseases in Brazil. PMID:27828619
Guarnaccia, Teagan; Carolan, Louise A; Maurer-Stroh, Sebastian; Lee, Raphael T C; Job, Emma; Reading, Patrick C; Petrie, Stephen; McCaw, James M; McVernon, Jodie; Hurt, Aeron C; Kelso, Anne; Mosse, Jennifer; Barr, Ian G; Laurie, Karen L
Surveillance data indicate that most circulating A(H1N1)pdm09 influenza viruses have remained antigenically similar since they emerged in humans in 2009. However, antigenic drift is likely to occur in the future in response to increasing population immunity induced by infection or vaccination. In this study, sequential passaging of A(H1N1)pdm09 virus by contact transmission through two independent series of suboptimally vaccinated ferrets resulted in selection of variant viruses with an amino acid substitution (N156K, H1 numbering without signal peptide; N159K, H3 numbering without signal peptide; N173K, H1 numbering from first methionine) in a known antigenic site of the viral HA. The N156K HA variant replicated and transmitted efficiently between naïve ferrets and outgrew wildtype virus in vivo in ferrets in the presence and absence of immune pressure. In vitro, in a range of cell culture systems, the N156K variant rapidly adapted, acquiring additional mutations in the viral HA that also potentially affected antigenic properties. The N156K escape mutant was antigenically distinct from wildtype virus as shown by binding of HA-specific antibodies. Glycan binding assays demonstrated the N156K escape mutant had altered receptor binding preferences compared to wildtype virus, which was supported by computational modeling predictions. The N156K substitution, and culture adaptations, have been detected in human A(H1N1)pdm09 viruses with N156K preferentially reported in sequences from original clinical samples rather than cultured isolates. This study demonstrates the ability of the A(H1N1)pdm09 virus to undergo rapid antigenic change to evade a low level vaccine response, while remaining fit in a ferret transmission model of immunization and infection. Furthermore, the potential changes in receptor binding properties that accompany antigenic changes highlight the importance of routine characterization of clinical samples in human A(H1N1)pdm09 influenza surveillance.
Desdouits, Marion; Munier, Sandie; Prevost, Marie-Christine; Jeannin, Patricia; Butler-Browne, Gillian; Ozden, Simona; Gessain, Antoine; Van Der Werf, Sylvie; Naffakh, Nadia; Ceccaldi, Pierre-Emmanuel
Besides the classical respiratory and systemic symptoms, unusual complications of influenza A infection in humans involve the skeletal muscles. Numerous cases of acute myopathy and/or rhabdomyolysis have been reported, particularly following the outbreak of pandemic influenza A(H1N1) in 2009. The pathogenesis of these influenza-associated myopathies (IAM) remains unkown, although the direct infection of muscle cells is suspected. Here, we studied the susceptibility of cultured human primary muscle cells to a 2009 pandemic and a 2008 seasonal influenza A(H1N1) isolate. Using cells from different donors, we found that differentiated muscle cells (i. e. myotubes) were highly susceptible to infection by both influenza A(H1N1) isolates, whereas undifferentiated cells (i. e. myoblasts) were partially resistant. The receptors for influenza viruses, α2-6 and α2-3 linked sialic acids, were detected on the surface of myotubes and myoblasts. Time line of viral nucleoprotein (NP) expression and nuclear export showed that the first steps of the viral replication cycle could take place in muscle cells. Infected myotubes and myoblasts exhibited budding virions and nuclear inclusions as observed by transmission electron microscopy and correlative light and electron microscopy. Myotubes, but not myoblasts, yielded infectious virus progeny that could further infect naive muscle cells after proteolytic treatment. Infection led to a cytopathic effect with the lysis of muscle cells, as characterized by the release of lactate dehydrogenase. The secretion of proinflammatory cytokines by muscle cells was not affected following infection. Our results are compatible with the hypothesis of a direct muscle infection causing rhabdomyolysis in IAM patients.
Walter, D; Bohmer, Mm; Reiter, S; Krause, G; Wichmann, O
During the influenza A(H1N1)pdm09 pandemic in 2009/10, a total of 13 consecutive surveys were carried out of the general population in Germany to monitor knowledge, attitude and behaviour concerning the disease and vaccination against pandemic influenza in real time. In total, 13,010 persons aged 14 years or older were interviewed by computer-assisted telephone techniques between November 2009 and April 2010. During the peak of the pandemic, only 18% of participants stated that they perceived the risk of pandemic influenza as high; this proportion fell to 10% in January 2010. There was a significant difference in information-seeking behaviour among population subgroups concerning the disease and vaccine uptake. However, in all subgroups, conventional media sources such as television, radio and newspapers were more frequently used than the Internet. While the majority of participants (78%) felt sufficiently informed to make a decision for or against vaccination, overall vaccination coverage remained low. Among those who decided against vaccination, fear of adverse events and perception that the available vaccines were not sufficiently evaluated were the most frequently stated reasons. Such mistrust in the vaccines and the perceived low risk of the disease were the main barriers that contributed to the low vaccination coverage in Germany during the pandemic.
Petrović, Vladimir; Šeguljev, Zorica; Ćosić, Gorana; Ristić, Mioljub; Nedeljković, Jasminka; Dragnić, Nataša; Ukropina, Snežana
Aim To analyze the epidemiological data for pandemic influenza A(H1N1)v in the Autonomous Province of Vojvodina, Serbia, during the season of 2009/2010 and to assess whether including severe acute respiratory illness (SARI) hospitalization data to the surveillance system gives a more complete picture of the impact of influenza during the pandemic. Methods From September 2009 to September 2010, the Institute of Public Health of Vojvodina conducted sentinel surveillance of influenza-like illnesses and acute respiratory infections in all hospitalized patients with SARI and virological surveillance of population of Vojvodina according to the European Centers for Disease Control technical document. Results The pandemic influenza outbreak in the province started in October 2009 (week 44) in students who had returned from a school-organized trip to Prague, Bratislava, and Vienna. The highest incidence rate was 1090 per 100 000 inhabitants, found in the week 50. The most affected age group were children 5-14 years old. A total of 1591 patients with severe illness were admitted to regional hospitals, with a case fatality rate of 2%, representing a hospitalization rate of 78.3 per 100 000 inhabitants and a mortality rate of 1.6 per 100 000. Most frequently hospitalized were 15-19 years old patients, male patients, and patients with pneumonia (P < 0.001). The highest case fatality rate was found among patients with acute respiratory distress syndrome (P < 0.001). Nasal/throat swabs were obtained for polymerase chain reaction test from 315 hospitalized patients and 20 non-hospitalized patients, and 145 (46%) and 15 (75%) specimens, respectively, tested positive on A(H1N1)v. Conclusion Sentinel influenza-like illness and SARI surveillance, both followed with virological surveillance, seem to be the optimal method to monitor the full scope of the influenza pandemic (from mild to severe influenza) in Vojvodina. PMID:21495196
Objective: To test the applicability of the Theory of Planned Behavior (TPB) in college students who have not previously received the A/H1N1 vaccine. Participants: Undergraduate communication students at a metropolitan southern university. Methods: In January-March 2010, students from voluntarily participating communication classes completed a…
Prokop'eva, E A; Kurskaya, O G; Saifutdinova, S G; Glushchenko, A V; Shestopalova, L V; Shestopalov, A M; Shkurupii, V A
We studied biological characteristics of influenza A(H1N1)pdm09 virus circulating in Siberia during the 2009 pandemic and the post-pandemic period of 2011. BALB/c mice were chosen as the experimental model. Virus titers in the lungs were evaluated on days 1, 3, 6 and blood serum titers on day 15 after infection with different strains. Blood sera of convalescents after influenza of 2010-2011 epidemic season were analyzed. Influenza A(H1N1)pdm09 virus strains isolated during the post-pandemic period of 2011 were characterized by low epidemic activity and virulence in comparison with the strains isolated during 2009 pandemic period, which indicates completion of the pandemic cycle.
Kuether, G; Dietrich, B; Smith, T; Peter, C; Gruessner, S
In the recent pandemic influenza A-(H1N1) v-2009 vaccination campaign, adjuvanted vaccines have been used because of their antigen-sparing effect. According to available reports, the rate of severe vaccination reactions has not increased, as compared with previous seasonal influenza vaccinations. Here we describe an adult female patient who was vaccinated with an AS03 adjuvanted split-virus vaccine injected into the left arm. She experienced a prolonged and painful local reaction for 4 weeks. During this time, persistent incapacitating pain shifted into the left shoulder. Magnetic resonance imaging (MRI) at the injection site detected atraumatic humeral head osteonecrosis in conjunction with bursitis of the rotator cuff region. Clinical and laboratory examination revealed no other underlying disease. Using analgetic medication and physical therapy, resting pain completely remitted within the following 14 weeks. Pain on exertion declined within the following 6 months. Atraumatic osteonecrosis, a relatively rare disorder which initially presents non-specific clinical symptoms, has never been associated with parenteral influenza vaccination. Although the available data cannot establish a causal relationship, our patient's clinical course - with a continuous transition from increased local post-vaccination reactions to symptoms of a severe shoulder lesion with osteonecrosis - raises the question of a pathogenetic link. Considering the vascular pathogenesis of osteonecrosis, we hypothesize that our patient's enhanced local immunologic reaction may have led to regional vasculitis as the cause of bone destruction. As mild forms of osteonecrosis may have escaped previous clinical attention, it is the purpose of our report to increase awareness of this exceptional event as a possible side effect of parenteral adjuvanted vaccination.
Bürger, Raimund; Chowell, Gerardo; Mulet, Pep; Villada, Luis M
A spatial-temporal transmission model of 2009 A/H1N1 pandemic influenza across Chile, a country that spans a large latitudinal range, is developed to characterize the spatial variation in peak timing of that pandemic as a function of local transmission rates, spatial connectivity assumptions for Chilean regions, and the putative location of introduction of the novel virus into the country. Specifically, a metapopulation SEIR (susceptible-exposed-infected-removed) compartmental model that tracks the transmission dynamics of influenza in 15 Chilean regions is calibrated. The model incorporates population mobility among neighboring regions and indirect mobility to and from other regions via the metropolitan central region ('hub region'). The stability of the disease-free equilibrium of this model is analyzed and compared with the corresponding stability in each region, concluding that stability may occur even with some regions having basic reproduction numbers above 1. The transmission model is used along with epidemiological data to explore potential factors that could have driven the spatial-temporal progression of the pandemic. Simulations and sensitivity analyses indicate that this relatively simple model is sufficient to characterize the south-north gradient in peak timing observed during the pandemic, and suggest that south Chile observed the initial spread of the pandemic virus, which is in line with a retrospective epidemiological study. The 'hub region' in our model significantly enhanced population mixing in a short time scale.
Allwinn, R; Bickel, M; Lassmann, C; Wicker, S; Friedrichs, I
Influenza vaccination is advised annually to reduce the burden of influenza disease. For sufficient vaccine campaigns also a continuous adoption of influenza vaccines are necessary, due to particularly high genetic variability of influenza A virus. Therefore, we evaluate the effectiveness of the trivalent influenza vaccine 2010/2011, against influenza A (H1N1, H3N2) and influenza B. Immune response was investigated in paired sera from 92 healthcare workers with the hemagglutination inhibition assay (HI). Protective antibody levels (HI titer ≥40) were found after vaccination for influenza A/California/07/2009(H1N1): 84.71 % [GMT: 115.34]; for influenza A/Perth/16/2009(H3N2): 94.94 % [GMT: 268.47] and for influenza B/Brisbane/60/2008: 96.20 % [GMT: 176.83]; matching with the currently circulating virus strains. However, the highest seroprevalence rate was found against influenza B; pre- and post-vaccination titers as well, which may be due to comparatively high virus preservation. Remarkable, lowest seropositivity was seen against H1N1. Despite the significant titer rise, sufficient H1N1 herd immunity was still not achieved. It can be assumed that a high influenza A herd immunity may be a requirement for a successful booster vaccination.
Uchida, Mitsuo; Kaneko, Minoru; Tsukahara, Teruomi; Washizuka, Shinsuke; Kawa, Shigeyuki
The pandemic influenza A/H1N1 2009 virus is commonly known to affect younger individuals. Several epidemiological studies have clarified the epidemic features of university students in Japan. In this study, we reviewed these studies in Japan in comparison with reports from other countries. The average cumulative incidence rate among university students was 9.6 %, with the major symptoms being cough, sore throat, and rhinorrhea. These epidemiological features were similar between Japan and other countries. Attitudes and behaviors toward pandemic influenza control measures were different before and improved during and after the epidemic. These features were also similar to those in other countries. On the other hand, the epidemic spread through club activities or social events, and transmission was attenuated after temporary closure of such groups in Japan. This transmission pattern was inconsistent among countries, which may have been due to differences in lifestyle and cultural habits. Based on these results, infection control measures of pandemic influenza for university organizations in Japan should be considered.
Cuevas González-Nicolás, María Teresa; Ledesma Moreno, Juan; Pozo Sánchez, Francisco; Casas Flecha, Inmaculada; Pérez-Breña, Pilar
There are three types of influenza viruses: A, B, C. These viruses evolves constantly due to two main characteristics: the first one is the lack of the correction ability of the viral polymerase which causes the accumulation of single nucleotide mutations in the viral genes introduced by an error-prone viral RNA polymerase, (antigenic shift). The second one is the nature of their genome, formed by eight segments, which allows the interchange of genes between two different viral strains (antigenic drift). This viral plasticity, has allowed to the influenza A viruses to infect new host species and to cause infections with a pandemic characteristics. The Spanish influenza surveillance system, SVGE (its Spanish acronym), arises as a response to the possibility of facing a pandemic situation, especially after the transmission of avian influenza viruses to humans. This surveillance system is formed by sixteen physician and paediatrics network, nineteen epidemiological services coordinated by the National Epidemiological Centre (CNE) and eighteen laboratories , the Spanish Laboratories of Influenza network (ReLEG), coordinated by the National Centre of Microbiology. The aim of this article is to show the action of the ReLEG, in the pandemic caused by the influenza virus A(H1N1) during the season 2009-2010. The main objective of this network is the surveillance of the circulating viruses by means of their detection and their subsequent antigenic and genetic characterization, including the detection of resistance mutations against the main drugs, such as Oseltamivir.
Jürchott, Karsten; Schulz, Axel Ronald; Bozzetti, Cecilia; Pohlmann, Dominika; Stervbo, Ulrik; Warth, Sarah; Mälzer, Julia Nora; Waldner, Julian; Schweiger, Brunhilde; Olek, Sven; Grützkau, Andreas; Babel, Nina; Thiel, Andreas; Neumann, Avidan Uriel
Understanding the immune response after vaccination against new influenza strains is highly important in case of an imminent influenza pandemic and for optimization of seasonal vaccination strategies in high risk population groups, especially the elderly. Models predicting the best sero-conversion response among the three strains in the seasonal vaccine were recently suggested. However, these models use a large number of variables and/or information post- vaccination. Here in an exploratory pilot study, we analyzed the baseline immune status in young (<31 years, N = 17) versus elderly (≥50 years, N = 20) donors sero-negative to the newly emerged A(H1N1)pdm09 influenza virus strain and correlated it with the serological response to that specific strain after seasonal influenza vaccination. Extensive multi-chromatic FACS analysis (36 lymphocyte sub-populations measured) was used to quantitatively assess the cellular immune status before vaccination. We identified CD4+ T cells, and amongst them particularly naive CD4+ T cells, as the best correlates for a successful A(H1N1)pdm09 immune response. Moreover, the number of influenza strains a donor was sero-negative to at baseline (NSSN) in addition to age, as expected, were important predictive factors. Age, NSSN and CD4+ T cell count at baseline together predicted sero-protection (HAI≥40) to A(H1N1)pdm09 with a high accuracy of 89% (p-value = 0.00002). An additional validation study (N = 43 vaccinees sero-negative to A(H1N1)pdm09) has confirmed the predictive value of age, NSSN and baseline CD4+ counts (accuracy = 85%, p-value = 0.0000004). Furthermore, the inclusion of donors at ages 31-50 had shown that the age predictive function is not linear with age but rather a sigmoid with a midpoint at about 50 years. Using these results we suggest a clinically relevant prediction model that gives the probability for non-protection to A(H1N1)pdm09 influenza strain after seasonal multi-valent vaccination as a continuous
Eidem, Synnøve; Tete, Sarah M; Jul-Larsen, Åsne; Hoschler, Katja; Montomoli, Emanuele; Brokstad, Karl A; Cox, Rebecca J
Healthcare workers are at increased risk of influenza infection through direct patient care, particularly during the early stages of a pandemic. Although influenza vaccination is widely recommended in Healthcare workers, data on long-term immunogenicity of vaccination in healthcare workers are lacking. The present study was designed to assess the persistence of the humoral response after pandemic vaccination as well as the impact of repeated annual vaccination in healthcare workers (n=24). Pandemic influenza vaccination resulted in a significant increase in haemagglutination inhibition (HI) antibody titers with 93-100% of subjects achieving protective titers 21-days post each of the three annual vaccinations. Seroprotective antibodies measured by HI, microneutralization and single radial hemolysis assays were present in 77-94% of healthcare workers 6 months post-vaccination. Repeated vaccination resulted in an increased duration of seroprotective antibodies with seroprotective titers increasing from 35-62% 12 months after 2009 pandemic vaccination to 50-75% 12 months after 2010 vaccination. Furthermore, repeated annual vaccination augmented the avidity of influenza-specific IgG antibodies. In conclusion, we have shown that A(H1N1)pdm09 vaccination induces high seroprotective titers that persist for at least 6 months. We demonstrate that repeated vaccination is beneficial to healthcare workers and results in further avidity maturation of vaccine-induced antibodies.
Yaari, R.; Katriel, G.; Stone, L.; Mendelson, E.; Mandelboim, M.; Huppert, A.
Intensified surveillance during the 2009 A/H1N1 influenza pandemic in Israel resulted in large virological and serological datasets, presenting a unique opportunity for investigating the pandemic dynamics. We employ a conditional likelihood approach for fitting a disease transmission model to virological and serological data, conditional on clinical data. The model is used to reconstruct the temporal pattern of the pandemic in Israel in five age-groups and evaluate the factors that shaped it. We estimate the reproductive number at the beginning of the pandemic to be R = 1.4. We find that the combined effect of varying absolute humidity conditions and school vacations (SVs) is responsible for the infection pattern, characterized by three epidemic waves. Overall attack rate is estimated at 32% (28–35%) with a large variation among the age-groups: the highest attack rates within school children and the lowest within the elderly. This pattern of infection is explained by a combination of the age-group contact structure and increasing immunity with age. We assess that SVs increased the overall attack rates by prolonging the pandemic into the winter. Vaccinating school children would have been the optimal strategy for minimizing infection rates in all age-groups. PMID:27030041
Yaari, R; Katriel, G; Stone, L; Mendelson, E; Mandelboim, M; Huppert, A
Intensified surveillance during the 2009 A/H1N1 influenza pandemic in Israel resulted in large virological and serological datasets, presenting a unique opportunity for investigating the pandemic dynamics. We employ a conditional likelihood approach for fitting a disease transmission model to virological and serological data, conditional on clinical data. The model is used to reconstruct the temporal pattern of the pandemic in Israel in five age-groups and evaluate the factors that shaped it. We estimate the reproductive number at the beginning of the pandemic to beR= 1.4. We find that the combined effect of varying absolute humidity conditions and school vacations (SVs) is responsible for the infection pattern, characterized by three epidemic waves. Overall attack rate is estimated at 32% (28-35%) with a large variation among the age-groups: the highest attack rates within school children and the lowest within the elderly. This pattern of infection is explained by a combination of the age-group contact structure and increasing immunity with age. We assess that SVs increased the overall attack rates by prolonging the pandemic into the winter. Vaccinating school children would have been the optimal strategy for minimizing infection rates in all age-groups.
Lind, Alexander; Ramelius, Anita; Olsson, Tomas; Arnheim-Dahlström, Lisen; Lamb, Favelle; Khademi, Mohsen; Ambati, Aditya; Maeurer, Markus; Nilsson, Anna-Lena; Bomfim, Izaura Lima; Fink, Katharina; Lernmark, Åke
Narcolepsy is a lifelong sleep disorder related to hypocretin deficiency resulting from a specific loss of hypocretin-producing neurons in the lateral hypothalamic area. The disease is thought to be autoimmune due to a strong association with HLA-DQB1*06:02. In 2009 the World Health Organization (WHO) declared the H1N1 2009 flu pandemic (A/H1N1PDM09). In response to this, the Swedish vaccination campaign began in October of the same year, using the influenza vaccine Pandemrix(®). A few months later an excess of narcolepsy cases was observed. It is still unclear to what extent the vaccination campaign affected humoral autoimmunity associated with narcolepsy. We studied 47 patients with narcolepsy (6-69 years of age) and 80 healthy controls (3-61 years of age) selected after the Pandemrix vaccination campaign. The first aim was to determine antibodies against A/H1N1 and autoantibodies to Tribbles homolog 2 (TRIB2), a narcolepsy autoantigen candidate as well as to GAD65 and IA-2 as disease specificity controls. The second aim was to test if levels and frequencies of these antibodies and autoantibodies were associated with HLA-DQB1*06:02. In vitro transcribed and translated [(35)S]-methionine and -cysteine-labeled influenza A virus (A/California/04/2009/(H1N1)) segment 4 hemagglutinin was used to detect antibodies in a radiobinding assay. Autoantibodies to TRIB2, GAD65 and IA-2 were similarly detected in standard radiobinding assays. The narcolepsy patients had higher median levels of A/H1N1 antibodies than the controls (p = 0.006). A/H1N1 antibody levels were higher among the <13 years old (n = 12) compared to patients who were older than 30 years (n = 12, p = 0.014). Being HLA-DQB1*06:02 positive was associated with higher A/H1N1 antibody levels in both patients and controls (p = 0.026). Serum autoantibody levels to TRIB2 were low overall and high binders did not differ between patients and controls. We observed an association between levels of A/H1N1
Arriaga-Pizano, Lourdes; Ferat-Osorio, Eduardo; Mora-Velandia, Luz María; Pastelin-Palacios, Rodolfo; Villasís-Keever, Miguel Ángel; Alpuche-Aranda, Celia; Sánchez-Torres, Luvia Enid; Isibasi, Armando; Bonifaz, Laura; López-Macías, Constantino
PD-L1 expression plays a critical role in the impairment of T cell responses during chronic infections; however, the expression of PD-L1 on T cells during acute viral infections, particularly during the pandemic influenza virus (A(H1N1)pdm09), and its effects on the T cell response have not been widely explored. We found that A(H1N1)pdm09 virus induced PD-L1 expression on human dendritic cells (DCs) and T cells, as well as PD-1 expression on T cells. PD-L1 expression impaired the T cell response against A(H1N1)pdm09 by promoting CD8+ T cell death and reducing cytokine production. Furthermore, we found increased PD-L1 expression on DCs and T cells from influenza-infected patients from the first and second 2009 pandemic waves in Mexico City. PD-L1 expression on CD8+ T cells correlated inversely with T cell proportions in patients infected with A(H1N1)pdm09. Therefore, PD-L1 expression on DCs and T cells could be associated with an impaired T cell response during acute infection with A(H1N1)pdm09 virus. PMID:24187568
Valero-Pacheco, Nuriban; Arriaga-Pizano, Lourdes; Ferat-Osorio, Eduardo; Mora-Velandia, Luz María; Pastelin-Palacios, Rodolfo; Villasís-Keever, Miguel Ángel; Alpuche-Aranda, Celia; Sánchez-Torres, Luvia Enid; Isibasi, Armando; Bonifaz, Laura; López-Macías, Constantino
PD-L1 expression plays a critical role in the impairment of T cell responses during chronic infections; however, the expression of PD-L1 on T cells during acute viral infections, particularly during the pandemic influenza virus (A(H1N1)pdm09), and its effects on the T cell response have not been widely explored. We found that A(H1N1)pdm09 virus induced PD-L1 expression on human dendritic cells (DCs) and T cells, as well as PD-1 expression on T cells. PD-L1 expression impaired the T cell response against A(H1N1)pdm09 by promoting CD8⁺ T cell death and reducing cytokine production. Furthermore, we found increased PD-L1 expression on DCs and T cells from influenza-infected patients from the first and second 2009 pandemic waves in Mexico City. PD-L1 expression on CD8⁺ T cells correlated inversely with T cell proportions in patients infected with A(H1N1)pdm09. Therefore, PD-L1 expression on DCs and T cells could be associated with an impaired T cell response during acute infection with A(H1N1)pdm09 virus.
Boyanton, Bobby L; Almradi, Amro; Mehta, Tejal; Robinson-Dunn, Barbara
The Directigen EZ Flu A+B rapid influenza diagnostic test, as compared to real-time reverse transcriptase polymerase chain reaction, demonstrated suboptimal performance to detect pandemic influenza A/H1N1 2009. Age- and viral load-stratified test sensitivity ranged from 33.3 to 84.6% and 0 to 100%, respectively.
Pestre, Vincent; Morel, Bruno; Encrenaz, Nathalie; Brunon, Amandine; Lucht, Frédéric; Pozzetto, Bruno; Berthelot, Philippe
The investigation of clustered cases of pandemic A/H1N1 2009 influenza virus infection (21 children, 3 adults) during a summer camp, led to the identification of transportation as the circumstance of transmission. Results suggest that super-spreading of flu can occur in a confined space without sufficient air renewal.
Matsumoto, Yuji; Kawamura, Yoshiki; Nakai, Hidetaka; Sugata, Ken; Yoshikawa, Akiko; Ihira, Masaru; Ohashi, Masahiro; Kato, Tomochika; Yoshikawa, Tetsushi
Severe pneumonia and leukocytosis are characteristic, frequently observed, clinical findings in pediatric patients with pandemic A/H1N1/2009 influenza virus infection. The aim of this study was to elucidate the role of cytokines and chemokines in complicating pneumonia and leukocytosis in patients with pandemic A/H1N1/2009 influenza virus infection. Forty-seven patients with pandemic A/H1N1/2009 influenza virus infection were enrolled in this study. Expression of interleukin (IL)-10 (P = 0.027) and IL-5 (P = 0.014) was significantly greater in patients with pneumonia than in those without pneumonia. Additionally, serum concentrations of interferon-γ (P = 0.009), tumor necrosis factor-α (P = 0.01), IL-4 (P = 0.024), and IL-2 (P = 0.012) were significantly lower in pneumonia patients with neutrophilic leukocytosis than in those without neutrophilic leukocytosis. Of the five serum chemokine concentrations assessed, only IL-8 was significantly lower in pneumonia patients with neutrophilic leukocytosis than in those without leukocytosis (P = 0.001). These cytokines and chemokines may play important roles in the pathogenesis of childhood pneumonia associated with A/H1N1/2009 influenza virus infection.
Zúñiga, Joaquín; Torres, Martha; Romo, Javier; Torres, Diana; Jiménez, Luis; Ramírez, Gustavo; Cruz, Alfredo; Espinosa, Enrique; Herrera, Teresa; Buendía, Ivette; Ramírez-Venegas, Alejandra; González, Yolanda; Bobadilla, Karen; Hernández, Fernando; García, Jorge; Quiñones-Falconi, Francisco; Sada, Eduardo; Manjarrez, María E; Cabello, Carlos; Kawa, Simón; Zlotnik, Albert; Pardo, Annie; Selman, Moisés
The immune mechanisms underlying the pathogenesis of severe pneumonia associated with the A/H1N1 virus are not well known. The objective of this study was to determine whether severe A/H1N1-associated pneumonia can be explained by the emergence of particular T-cell subsets and the cytokines/chemokines they produced, as well as distinct responses to infection. T-cell subset distribution and cytokine/chemokine levels in peripheral blood and bronchoalveolar lavage (BAL) were determined in patients with severe A/H1N1 infection, asymptomatic household contacts, and healthy controls. Cytokine and chemokine production was also evaluated after in vitro infection with seasonal H1N1 and pandemic A/H1N1 strains. We found an increase in the frequency of peripheral Th2 and Tc2 cells in A/H1N1 patients. A trend toward increased Tc1 cells was observed in household contacts. Elevated serum levels of IL-6, CXCL8, and CCL2 were found in patients and a similar cytokine/chemokine profile was observed in BAL, in which CCL5 was also increased. Infection assays revealed that both strains induce the production of several cytokines/chemokines at 24 and 72 h, however, IL-6, CCL3, and CXCL8 were strongly up-regulated in 72-h cultures in presence of the A/H1N1 virus. Several inflammatory mediators are up-regulated in peripheral and lung samples from A/H1N1-infected patients who developed severe pneumonia. In addition, the A/H1N1 strain induces higher levels of pro-inflammatory cytokines and chemokines than the seasonal H1N1 strain. These findings suggest that it is possible to identify biomarkers of severe pneumonia and also suggest the therapeutic use of immunomodulatory drugs in patients with severe pneumonia associated with A/H1N1 infection.
Shubin, Mikhail; Lebedev, Artem; Lyytikäinen, Outi; Auranen, Kari
The threat of the new pandemic influenza A(H1N1)pdm09 imposed a heavy burden on the public health system in Finland in 2009-2010. An extensive vaccination campaign was set up in the middle of the first pandemic season. However, the true number of infected individuals remains uncertain as the surveillance missed a large portion of mild infections. We constructed a transmission model to simulate the spread of influenza in the Finnish population. We used the model to analyse the two first years (2009-2011) of A(H1N1)pdm09 in Finland. Using data from the national surveillance of influenza and data on close person-to-person (social) contacts in the population, we estimated that 6% (90% credible interval 5.1 - 6.7%) of the population was infected with A(H1N1)pdm09 in the first pandemic season (2009/2010) and an additional 3% (2.5 - 3.5%) in the second season (2010/2011). Vaccination had a substantial impact in mitigating the second season. The dynamic approach allowed us to discover how the proportion of detected cases changed over the course of the epidemic. The role of time-varying reproduction number, capturing the effects of weather and changes in behaviour, was important in shaping the epidemic.
Gachara, George; Symekher, Samuel; Otieno, Michael; Magana, Japheth; Opot, Benjamin; Bulimo, Wallace
An influenza pandemic caused by a novel influenza virus A(H1N1)pdm09 spread worldwide in 2009 and is estimated to have caused between 151,700 and 575,400 deaths globally. While whole genome data on new virus enables a deeper insight in the pathogenesis, epidemiology, and drug sensitivities of the circulating viruses, there are relatively limited complete genetic sequences available for this virus from African countries. We describe herein the full genome analysis of influenza A(H1N1)pdm09 viruses isolated in Kenya between June 2009 and August 2010. A total of 40 influenza A(H1N1)pdm09 viruses isolated during the pandemic were selected. The segments from each isolate were amplified and directly sequenced. The resulting sequences of individual gene segments were concatenated and used for subsequent analysis. These were used to infer phylogenetic relationships and also to reconstruct the time of most recent ancestor, time of introduction into the country, rates of substitution and to estimate a time-resolved phylogeny. The Kenyan complete genome sequences clustered with globally distributed clade 2 and clade 7 sequences but local clade 2 viruses did not circulate beyond the introductory foci while clade 7 viruses disseminated country wide. The time of the most recent common ancestor was estimated between April and June 2009, and distinct clusters circulated during the pandemic. The complete genome had an estimated rate of nucleotide substitution of 4.9×10(-3) substitutions/site/year and greater diversity in surface expressed proteins was observed. We show that two clades of influenza A(H1N1)pdm09 virus were introduced into Kenya from the UK and the pandemic was sustained as a result of importations. Several closely related but distinct clusters co-circulated locally during the peak pandemic phase but only one cluster dominated in the late phase of the pandemic suggesting that it possessed greater adaptability.
D'Ortenzio, E; Renault, P; Jaffar-Bandjee, M C; Gaüzère, B A; Lagrange-Xélot, M; Fouillet, A; Poubeau, P; Winer, A; Bourde, A; Staikowsky, F; Morbidelli, P; Rachou, E; Thouillot, F; Michault, A; Filleul, L
On Reunion Island, in response to the threat of emergence of the pandemic influenza A(H1N1)2009 virus, we implemented enhanced influenza surveillance from May 2009 onwards in order to detect the introduction of pandemic H1N1 influenza and to monitor its spread and impact on public health. The first 2009 pandemic influenza A(H1N1) virus was identified in Réunion on July 5, 2009, in a traveller returning from Australia; seasonal influenza B virus activity had already been detected. By the end of July, a sustained community pandemic virus transmission had been established. Pandemic H1N1 influenza activity peaked during week 35 (24-30 August 2009), 4 weeks after the beginning of the epidemic. The epidemic ended on week 38 and had lasted 9 weeks. During these 9 weeks, an estimated 66 915 persons who consulted a physician could have been infected by the influenza A(H1N1)2009 virus, giving a cumulative attack rate for consultants of 8.26%. Taking into account the people who did not consult, the total number of infected persons reached 104 067, giving a cumulative attack rate for symptomatics of 12.85%. The crude fatality rate (CFR) for influenza A(H1N1)2009 and the CFR for acute respiratory infection was 0.7/10 000 cases. Our data show that influenza pandemic did not have a health impact on overall mortality on Réunion Island. These findings demonstrate the value of an integrated epidemiological, virological and hospital surveillance programme to monitor the scope of an epidemic, identify circulating strains and provide some guidance to public health control measures.
Ninove, Laetitia; Sartor, Catherine; Badiaga, Sékéné; Botelho, Elizabeth; Brouqui, Philippe; Zandotti, Christine; De Lamballerie, Xavier; La Scola, Bernard; Drancourt, Michel; Gould, Ernest A.; Charrel, Rémi N.; Raoult, Didier
Background In France, there was a reluctance to accept vaccination against the A/H1N1 pandemic influenza virus despite government recommendation and investment in the vaccine programme. Methods and Findings We examined the willingness of different populations to accept A/H1N1vaccination (i) in a French hospital among 3315 employees immunized either by in-house medical personnel or mobile teams of MDs and (ii) in a shelter housing 250 homeless persons. Google was used to assess the volume of enquiries concerning incidence of influenza. We analyzed the information on vaccination provided by Google, the website of the major French newspapers, and PubMed. Two trust Surveys were used to assess public opinion on the trustworthiness of people in different professions. Paramedics were significantly more reluctant to accept immunisation than qualified medical staff. Acceptance was significantly increased when recommended directly by MDs. Anecdotal cases of directly observed severe infections were followed by enhanced acceptance of paramedical staff. Scientific literature was significantly more in favour of vaccination than Google and French newspaper websites. In the case of the newspaper websites, information correlated with their recognised political reputations, although they would presumably claim independence from political bias. The Trust Surveys showed that politicians were highly distrusted in contrast with doctors and pharmacists who were considered much more trustworthy. Conclusions The low uptake of the vaccine could reflect failure to convey high quality medical information and advice relating to the benefits of being vaccinated. We believe that the media and internet contributed to this problem by raising concerns within the general population and that failure to involve GPs in the control programme may have been a mistake. GPs are highly regarded by the public and can provide face-to-face professional advice and information. The top-down strategy of vaccine
Chambers, Catharine; Skowronski, Danuta M; Sabaiduc, Suzana; Winter, Anne Luise; Dickinson, James A; De Serres, Gaston; Gubbay, Jonathan B; Drews, Steven J; Martineau, Christine; Eshaghi, Alireza; Krajden, Mel; Bastien, Nathalie; Li, Yan
Using a test-negative design, the Canadian Sentinel Practitioner Surveillance Network (SPSN) assessed interim 2015/16 vaccine effectiveness (VE) against influenza A(H1N1)pdm09 viruses. Adjusted VE showed significant protection of 64% (95% confidence interval (CI): 44-77%) overall and 56% (95%CI: 26-73%) for adults between 20 and 64 years-old against medically attended, laboratory-confirmed A(H1N1)pdm09 illness. Among the 67 A(H1N1)pdm09-positive specimens that were successfully sequenced, 62 (> 90%) belonged to the emerging genetic 6B.1 subclade, defined by S162N (potential gain of glycosylation) and I216T mutations in the haemagglutinin protein. Findings from the Canadian SPSN indicate that the 2015/16 northern hemisphere vaccine provided significant protection against A(H1N1)pdm09 illness despite genetic evolution in circulating viruses.
Takayama, Yoko; Yano, Hisakazu; Nojima, Yasuhiro; Nakano, Ryuichi; Okamoto, Ryoichi; Hirakata, Yoichi; Sunakawa, Keisuke; Akahoshi, Tohru; Kaku, Mitsuo
Secondary bacterial pneumonia due to community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA) has become a highly publicized cause of death associated with influenza. In this study, we performed the gentamicin-killing assay using Madin-Darby canine kidney (MDCK) cells and MRSA strains to investigate whether prior infection from pandemic A(H1N1)2009 virus (A[H1N1]pdm09) lead to increased invasion of MDCK cells by MRSA. We found that the invasion rate of two MRSA strains (ATCC BAA-1680 [USA 300] and ATCC BAA-1699 [USA 100]) into intact MDCK cell monolayers was 0.29 ± 0.15% and 0.007 ± 0.002%, respectively (p < 0.01, n ≥ 3). In addition, the relative invasion rate of both ATCC BAA-1680 and ATCC BAA-1699 was significantly increased by prior A(H1N1)pdm09 infection of MDCK monolayers from 1 ± 0.28 to 1.38 ± 0.02 and from 1 ± 0.24 to 1.73 ± 0.29, respectively (p < 0.01). These results indicate that ATCC BAA-1680 displays much stronger invasiveness of MDCK cells than ATCC BAA-1699, although invasion of both strains was increased by prior A(H1N1)pdm09 infection. In conclusion, this study provided the first evidence that prior A(H1N1)pdm09 infection facilitates the invasion of MDCK cells by MRSA, presumably due to cellular injury caused by the virus.
van Dijk, Christel E.; Hooiveld, Mariette; Jentink, Anne; Isken, Leslie D.; Timen, Aura; Yzermans, C. Joris
Objectives Since few pandemics have occurred since the Spanish influenza pandemic, we should learn from every (mild) pandemic that occurs. The objective of this study was to report on general practitioners’ and practice assistants’ acceptance of the chosen national policy, and experiences in the Netherlands during the influenza A(H1N1)pdm09 pandemic. Methods Data on experience and acceptance of the chosen national policy were obtained by structured questionnaires for general practitioners (n = 372) and practice assistants (n = 503) in April 2010. Results The primary policy chosen for general practice was not always accepted and complied with by general practitioners, although the communication (of changes) and collaboration with involved organisations were rated as positive. In particular, the advised personal protective measures were difficult to implement in daily work and thus not executed by 44% of general practitioners. Half of the general practitioners were not satisfied with the patient information provided by the government. The influenza A(H1N1) pandemic highly impacted on general practitioners’ and practice assistants’ workloads, which was not always deemed to be adequately compensated. Discussion Involvement of general practitioners in future infectious disease outbreaks is essential. This study addresses issues in the pandemic policy which might be critical in a more severe pandemic. PMID:26313147
Cagigi, Alberto; Pensieroso, Simone; Ruffin, Nicolas; Sammicheli, Stefano; Thorstensson, Rigmor; Pan-Hammarström, Qiang; Hejdeman, Bo; Nilsson, Anna; Chiodi, Francesca
The relevance of CD4+T-cells, viral load and age in the immunological response to influenza infection and vaccination in HIV-1 infected individuals has previously been pointed out. Our study aimed at assessing, in the setting of 2009 A(H1N1)pdm09 influenza vaccination, whether quantification of activation-induced deaminase (AID) expression in blood B-cells may provide additional indications for predicting antibody response to vaccination in HIV-1 infected patients with similar CD4+T-cell counts and age. Forty-seven healthy controls, 37 ART-treated and 17 treatment-naïve HIV-1 infected patients were enrolled in the study. Blood was collected prior to A(H1N1)pdm09 vaccination and at 1, 3 and 6 months after vaccination. Antibody titers to A(H1N1)pdm09 vaccine were measured by hemagglutination inhibition (HI) assay while the mRNA expression levels of AID were measured by quantitative real time PCR. Upon B-cell activation in vitro, AID increase correlated to antibody response to the A(H1N1)pdm09 vaccine at 1 month after vaccination in all individuals. In addition, the maximum expression levels of AID were significantly higher in those individuals who still carried protective levels of A(H1N1)pdm09 antibodies after 6 months from vaccination. No correlation was found between CD4+T-cell counts or age at vaccination or HIV-1 viral load and levels of A(H1N1)pdm09 antibodies. Assessing AID expression before vaccination may be an additional useful tool for defining a vaccination strategy in immune-compromised individuals at risk of immunization failure.
Masalova, O V; Chichev, E V; Fediakina, I T; Mukasheva, E A; Klimova, R R; Shchelkanov, M Iu; Burtseva, E I; Ivanova, V T; Kushch, A A; L'vov, D K
The goal of this work was to analyze the antigenic structure of the hemagglutinin (HA) of the pandemic influenza virus A(H1N1)pdm09 using monoclonal antibodies (MAbs) and to develop a sandwich ELISA for identification of pandemic strains. Competitive ELISA demonstrated that 6 MAbs against HA of the pandemic influenza A/ IIV-Moscow/01/2009 (H1N1)pdm09 virus identified six epitopes. Binding of MAbs with 22 strains circulating in Russian Federation during 2009-2012 was analyzed in the hemagglutination-inhibition test (HI). The MAbs differed considerably in their ability to decrease the HI activity of these strains. MAb 5F7 identified all examined strains; MAbs 3A3 and 10G2 reacted with the majority of them. A highly sensitive sandwich ELISA was constructed based on these three MAbs that can differentiate the pandemic influenza strains from the seasonal influenza virus. The constancy of the HA epitope that reacts with MAb 5F7 provides its use for identification of the pandemic influenza strains in HI test. MAbs 3D9, 6A3 and 1E7 are directed against the variable HA epitopes, being sensitive to several amino acid changes in Sa, Sb, and Ca2 antigenic sites and in receptor binding site. These MAbs can be used to detect differences in HA structure and to study the antigenic drift of the pandemic influenza virus A(H1N1)pdm09.
Souza, Thiago Moreno L.; Resende, Paola C.; Fintelman-Rodrigues, Natalia; Gregianini, Tatiana Schaffer; Ikuta, Nilo; Fernandes, Sandra Bianchini; Cury, Ana Luisa Furtado; Rosa, Maria do Carmo Debur; Siqueira, Marilda M.
Although surveillance efforts that monitor the emergence of drug-resistant strains of influenza are critical, systematic analysis is overlooked in most developing countries. We report on the occurrence of strains of pandemic influenza A(H1N1)pdm09 with resistance and decreased susceptibility to oseltamivir (OST) in Brazil in 2009, 2011 and 2012. We found 7 mutant viruses, 2 with the mutation S247N and other 5 with the mutation H275Y. Most of these viruses were from samples concentrated in the southern region of Brazil. Some of these resistant viruses were detected prior to the initiation of OST treatment, suggesting that community transmission of mutant viruses may exist. Moreover, we show that one of these OST-resistant (H275Y) strains of A(H1N1)pdm09 was discovered in the tri-border region between Brazil, Argentina and Paraguay, highlighting that this strain could also be found in other Latin American countries. Our findings reinforce the importance of enhanced antiviral resistance surveillance in Brazil and in other Latin American countries to confirm or rule out the community transmission of OST-resistant strains of A(H1N1)pdm09. PMID:24244615
Background The role of demographic factors, climatic conditions, school cycles, and connectivity patterns in shaping the spatio-temporal dynamics of pandemic influenza is not clearly understood. Here we analyzed the spatial, age and temporal evolution of the 2009 A/H1N1 influenza pandemic in Chile, a southern hemisphere country covering a long and narrow strip comprising latitudes 17°S to 56°S. Methods We analyzed the dissemination patterns of the 2009 A/H1N1 pandemic across 15 regions of Chile based on daily hospitalizations for severe acute respiratory disease and laboratory confirmed A/H1N1 influenza infection from 01-May to 31-December, 2009. We explored the association between timing of pandemic onset and peak pandemic activity and several geographical and demographic indicators, school vacations, climatic factors, and international passengers. We also estimated the reproduction number (R) based on the growth rate of the exponential pandemic phase by date of symptoms onset, estimated using maximum likelihood methods. Results While earlier pandemic onset was associated with larger population size, there was no association with connectivity, demographic, school or climatic factors. In contrast, there was a latitudinal gradient in peak pandemic timing, representing a 16-39-day lag in disease activity from the southern regions relative to the northernmost region (P < 0.001). Geographical differences in latitude of Chilean regions, maximum temperature and specific humidity explained 68.5% of the variability in peak timing (P = 0.01). In addition, there was a decreasing gradient in reproduction number from south to north Chile (P < 0.0001). The regional mean R estimates were 1.6-2.0, 1.3-1.5, and 1.2-1.3 for southern, central and northern regions, respectively, which were not affected by the winter vacation period. Conclusions There was a lag in the period of most intense 2009 pandemic influenza activity following a South to North traveling pattern across regions
Tanaka, Seiji; Saikusa, Tomoko; Katafuchi, Yuno; Ushijima, Kosuke; Ohtsu, Yasushi; Tsumura, Naoki; Ito, Yuhei
A limited number of reports are available regarding the effect of the influenza vaccine in pediatric patients receiving steroid and immunosuppressant therapy. The influenza A(H1N1)pdm09 vaccine was administered to 15 children with renal disease who were receiving steroid and immunosuppressant therapy (treatment group) and 23 children with who were not receiving these drugs (non-treatment group). Titer transition of the hemagglutination inhibition antibody was compared between the 2 groups immediately before vaccination and 4 weeks and 6 months after vaccination. Multivariate analysis showed a significant correlation between geometric mean titer, SCR, and SPR with age, while no correlation was observed between treatment with immunosuppressant therapy and efficacy. No serious adverse reactions occurred after vaccination. This strain is not present in existing influenza vaccines, and A(H1N1)pdm09HA vaccination was administered alone in 2009. The children in this study had not previously been exposed to this strain. Therefore, we evaluated the effect of the A(H1N1)pdm09HA vaccine without the effects of vaccination or past infection with A(H1N1)pdm09HA or A(H3N2) vaccination in the previous year.
Nelson, N P; Brownstein, J S; Hartley, D M
The emergence of the 2009 pandemic influenza A(H1N1) virus in North America and its subsequent global spread highlights the public health need for early warning of infectious disease outbreaks. Event-based biosurveillance, based on local- and regional-level Internet media reports, is one approach to early warning as well as to situational awareness. This study analyses media reports in Mexico collected by the Argus biosurveillance system between 1 October 2007 and 31 May 2009. Results from Mexico are compared with the United States and Canadian media reports obtained from the HealthMap system. A significant increase in reporting frequency of respiratory disease in Mexico during the 2008-9 influenza season relative to that of 2007-8 was observed (p<0.0001). The timing of events, based on media reports, suggests that respiratory disease was prevalent in parts of Mexico, and was reported as unusual, much earlier than the microbiological identification of the pandemic virus. Such observations suggest that abnormal respiratory disease frequency and severity was occurring in Mexico throughout the winter of 2008-2009, though its connection to the emergence of the 2009 pandemic influenza A(H1N1) virus remains unclear.
Kara, E O; Elliot, A J; Bagnall, H; Foord, D G F; Pnaiser, R; Osman, H; Smith, G E; Olowokure, B
Certain influenza outbreaks, including the 2009 influenza A(H1N1) pandemic, can predominantly affect school-age children. Therefore the use of school absenteeism data has been considered as a potential tool for providing early warning of increasing influenza activity in the community. This study retrospectively evaluates the usefulness of these data by comparing them with existing syndromic surveillance systems and laboratory data. Weekly mean percentages of absenteeism in 373 state schools (children aged 4-18 years) in Birmingham, UK, from September 2006 to September 2009, were compared with established syndromic surveillance systems including a telephone health helpline, a general practitioner sentinel network and laboratory data for influenza. Correlation coefficients were used to examine the relationship between each syndromic system. In June 2009, school absenteeism generally peaked concomitantly with the existing influenza surveillance systems in England. Weekly school absenteeism surveillance would not have detected pandemic influenza A(H1N1) earlier but daily absenteeism data and the development of baselines could improve the timeliness of the system.
Sypsa, Vana; Bonovas, Stefanos; Tsiodras, Sotirios; Baka, Agoritsa; Efstathiou, Panos; Malliori, Meni; Panagiotopoulos, Takis; Nikolakopoulos, Ilias; Hatzakis, Angelos
Background The aim of this study was to assess the disease burden of the 2009 pandemic influenza A(H1N1) in Greece. Methodology/Principal Findings Data on influenza-like illness (ILI), collected through cross-sectional nationwide telephone surveys of 1,000 households in Greece repeated for 25 consecutive weeks, were combined with data from H1N1 virologic surveillance to estimate the incidence and the clinical attack rate (CAR) of influenza A(H1N1). Alternative definitions of ILI (cough or sore throat and fever>38°C [ILI-38] or fever 37.1–38°C [ILI-37]) were used to estimate the number of symptomatic infections. The infection attack rate (IAR) was approximated using estimates from published studies on the frequency of fever in infected individuals. Data on H1N1 morbidity and mortality were used to estimate ICU admission and case fatality (CFR) rates. The epidemic peaked on week 48/2009 with approximately 750–1,500 new cases/100,000 population per week, depending on ILI-38 or ILI-37 case definition, respectively. By week 6/2010, 7.1%–15.6% of the population in Greece was estimated to be symptomatically infected with H1N1. Children 5–19 years represented the most affected population group (CAR:27%–54%), whereas individuals older than 64 years were the least affected (CAR:0.6%–2.2%). The IAR (95% CI) of influenza A(H1N1) was estimated to be 19.7% (13.3%, 26.1%). Per 1,000 symptomatic cases, based on ILI-38 case definition, 416 attended health services, 108 visited hospital emergency departments and 15 were admitted to hospitals. ICU admission rate and CFR were 37 and 17.5 per 100,000 symptomatic cases or 13.4 and 6.3 per 100,000 infections, respectively. Conclusions/Significance Influenza A(H1N1) infected one fifth and caused symptomatic infection in up to 15% of the Greek population. Although individuals older than 65 years were the least affected age group in terms of attack rate, they had 55 and 185 times higher risk of ICU admission and CFR
Arbefeville, Sophie S; Fickle, Ann R; Ferrieri, Patricia
To confirm a diagnosis of influenza at the point of care, healthcare professionals may rely on rapid influenza diagnostic tests (RIDTs). RIDTs have low to moderate sensitivity compared with viral culture or real-time reverse-transcription polymerase chain reaction (rRT-PCR). With the resurgence of the influenza A (Flu A; subtype H1N1) pandemic 2009 (pdm09) strain in the years 2013 and 2014, we evaluated the accuracy of the United State Food and Drug Administration (FDA)-approved Sofia Influenza A+B Fluorescent Immunoassay to detect epidemic Flu A(H1N1)pdm09 in specimens from the upper-respiratory tract. During a 3-month period, we collected 40 specimens that tested positive via PCR and/or culture for Flu A of the H1N1 pdm09 subtype. Of the 40 specimens, 27 tested positive (67.5%) via Sofia assay for Flu A. Of the 13 specimens with a negative result via Sofia testing, 4 had coinfection, as detected by the GenMark Diagnostics eSensor Respiratory Viral Panel. This sensitivity of the RIDT Sofia assay to detect Flu A(H1N1) pdm09 was comparable to previously reported sensitivities ranging from 10% to 75% for older RIDTs.
Lefevre, Eric A.; Carr, B. Veronica; Inman, Charlotte F.; Prentice, Helen; Brown, Ian H.; Brookes, Sharon M.; Garcon, Fanny; Hill, Michelle L.; Iqbal, Munir; Elderfield, Ruth A.; Barclay, Wendy S.; Gubbins, Simon; Bailey, Mick; Charleston, Bryan
Following the emergence and global spread of a novel H1N1 influenza virus in 2009, two A(H1N1)pdm/09 influenza vaccines produced from the A/California/07/09 H1N1 strain were selected and used for the national immunisation programme in the United Kingdom: an adjuvanted split virion vaccine and a non-adjuvanted whole virion vaccine. In this study, we assessed the immune responses generated in inbred large white pigs (Babraham line) following vaccination with these vaccines and after challenge with A(H1N1)pdm/09 virus three months post-vaccination. Both vaccines elicited strong antibody responses, which included high levels of influenza-specific IgG1 and haemagglutination inhibition titres to H1 virus. Immunisation with the adjuvanted split vaccine induced significantly higher interferon gamma production, increased frequency of interferon gamma-producing cells and proliferation of CD4−CD8+ (cytotoxic) and CD4+CD8+ (helper) T cells, after in vitro re-stimulation. Despite significant differences in the magnitude and breadth of immune responses in the two vaccinated and mock treated groups, similar quantities of viral RNA were detected from the nasal cavity in all pigs after live virus challenge. The present study provides support for the use of the pig as a valid experimental model for influenza infections in humans, including the assessment of protective efficacy of therapeutic interventions. PMID:22427834
Skowronski, Danuta M.; Hamelin, Marie-Eve; De Serres, Gaston; Janjua, Naveed Z.; Li, Guiyun; Sabaiduc, Suzana; Bouhy, Xavier; Couture, Christian; Leung, Anders; Kobasa, Darwyn; Embury-Hyatt, Carissa; de Bruin, Erwin; Balshaw, Robert; Lavigne, Sophie; Petric, Martin; Koopmans, Marion; Boivin, Guy
During spring-summer 2009, several observational studies from Canada showed increased risk of medically-attended, laboratory-confirmed A(H1N1)pdm09 illness among prior recipients of 2008–09 trivalent inactivated influenza vaccine (TIV). Explanatory hypotheses included direct and indirect vaccine effects. In a randomized placebo-controlled ferret study, we tested whether prior receipt of 2008–09 TIV may have directly influenced A(H1N1)pdm09 illness. Thirty-two ferrets (16/group) received 0.5 mL intra-muscular injections of the Canadian-manufactured, commercially-available, non-adjuvanted, split 2008–09 Fluviral or PBS placebo on days 0 and 28. On day 49 all animals were challenged (Ch0) with A(H1N1)pdm09. Four ferrets per group were randomly selected for sacrifice at day 5 post-challenge (Ch+5) and the rest followed until Ch+14. Sera were tested for antibody to vaccine antigens and A(H1N1)pdm09 by hemagglutination inhibition (HI), microneutralization (MN), nucleoprotein-based ELISA and HA1-based microarray assays. Clinical characteristics and nasal virus titers were recorded pre-challenge then post-challenge until sacrifice when lung virus titers, cytokines and inflammatory scores were determined. Baseline characteristics were similar between the two groups of influenza-naïve animals. Antibody rise to vaccine antigens was evident by ELISA and HA1-based microarray but not by HI or MN assays; virus challenge raised antibody to A(H1N1)pdm09 by all assays in both groups. Beginning at Ch+2, vaccinated animals experienced greater loss of appetite and weight than placebo animals, reaching the greatest between-group difference in weight loss relative to baseline at Ch+5 (7.4% vs. 5.2%; p = 0.01). At Ch+5 vaccinated animals had higher lung virus titers (log-mean 4.96 vs. 4.23pfu/mL, respectively; p = 0.01), lung inflammatory scores (5.8 vs. 2.1, respectively; p = 0.051) and cytokine levels (p>0.05). At Ch+14, both groups had recovered. Findings in
Bosch, Berend Jan; Bodewes, Rogier; de Vries, Robert P; Kreijtz, Joost H C M; Bartelink, Willem; van Amerongen, Geert; Rimmelzwaan, Guus F; de Haan, Cornelis A M; Osterhaus, Albert D M E; Rottier, Peter J M
The emergence and subsequent swift and global spread of the swine-origin influenza virus A(H1N1) in 2009 once again emphasizes the strong need for effective vaccines that can be developed rapidly and applied safely. With this aim, we produced soluble, multimeric forms of the 2009 A(H1N1) HA (sHA(3)) and NA (sNA(4)) surface glycoproteins using a virus-free mammalian expression system and evaluated their efficacy as vaccines in ferrets. Immunization twice with 3.75-microg doses of these antigens elicited strong antibody responses, which were adjuvant dependent. Interestingly, coadministration of both antigens strongly enhanced the HA-specific but not the NA-specific responses. Distinct patterns of protection were observed upon challenge inoculation with the homologous H1N1 virus. Whereas vaccination with sHA(3) dramatically reduced virus replication (e.g., by lowering pulmonary titers by about 5 log(10) units), immunization with sNA(4) markedly decreased the clinical effects of infection, such as body weight loss and lung pathology. Clearly, optimal protection was achieved by the combination of the two antigens. Our observations demonstrate the great vaccine potential of multimeric HA and NA ectodomains, as these can be easily, rapidly, flexibly, and safely produced in high quantities. In particular, our study underscores the underrated importance of NA in influenza vaccination, which we found to profoundly and specifically contribute to protection by HA. Its inclusion in a vaccine is likely to reduce the HA dose required and to broaden the protective immunity.
Tsao, Kuo-Chien; Kuo, Yung-Bin; Huang, Chung-Guei; Chau, Shao-Wen; Chan, Err-Cheng
The early detection of pandemic influenza strains is a key factor for clinicians in treatment decisions and infection control practices. The aims of this study were to determine the analytical sensitivity and clinical performance of the commercially available influenza rapid tests in Taiwan. Four rapid tests for influenza virus (BinaxNow test, QuickVue test, TRU test, and Formosa Rapid test) were evaluated for their detection limit against four influenza viruses (the 2009 pandemic influenza A virus H1N1, seasonal influenza virus H1N1, H3N2, and influenza B virus) circulating in Taiwan. The viral load of these isolates were quantified by rtRT-PCR and then diluted 2-fold serially for the comparison. The lowest detectable viral load of the pandemic influenza A virus H1N1 by the Formosa Rapid test, QuickVue test, TRU test, and Binax Now test was 5.3×10(4), 1.0×10(5), 1.0×10(5), and 4.2×10(5)copies/μL, respectively. Of these four tests, the two most sensitive tests (the QuickVue test and the Formosa Rapid test) were chosen to evaluate 62 nasopharyngeal specimens from patients who were suspected of infection with pandemic influenza A virus H1N1. The positive rate for the Formosa Rapid test and the QuickVue test were 53.2% (33/62) and 45.2% (28/62) (McNemar's test, P=0.125), respectively. In conclusion, the Formosa Rapid test was the most sensitive test in the present study for the detection of influenza antigens and its clinical performance was similar to that of the QuickVue test (Kappa=0.776). This suggests that the Formosa Rapid test could be used to aid clinical decision making in primary health care settings during outbreaks of influenza.
Knuf, Markus; Leroux-Roels, Geert; Rümke, Hans; Rivera, Luis; Pedotti, Paola; Arora, Ashwani Kumar; Lattanzi, Maria; Kieninger, Dorothee; Cioppa, Giovanni Della
Mass immunization of children has the potential to decrease infection rates and prevent the transmission of influenza. We evaluated the immunogenicity, safety, and tolerability of different formulations of cell-derived MF59-adjuvanted and nonadjuvanted A/H1N1 influenza vaccine in children and adolescents. This was a randomized, single-blind, multicenter study with a total of 666 healthy subjects aged 6 months–17 y in one of 3 vaccination groups, each receiving formulations containing different amounts of influenza A/H1N1 antigen with or without MF59. A booster trivalent seasonal MF59 vaccine was administered one year after primary vaccinations. Antibody titers were assessed by hemagglutination inhibition (HI) and microneutralization assays obtained on days 1, 22, 43, 366, and 387 (3 weeks post booster). Safety was monitored throughout the study. One vaccination with 3.75 μg of A/H1N1 antigen formulated with 50% MF59 (3.75_halfMF59) or 7.5 μg of A/H1N1 antigen formulated with 100% MF59 (7.5_fullMF59) induced an HI titer ≥1:40 in >70% of children in the 1–<3, 3–8, and 9–17 y cohorts; however, 2 vaccinations with nonadjuvanted 15 μg A/H1N1 antigen were needed to achieve this response in the 1–<3 and 3–8 y cohorts. Among children aged 6–11 months, 1 dose of 7.5_fullMF59 resulted in an HI titer ≥1:40 in >70% while 2 doses of 3.75_halfMF59 were required to achieve this result. All vaccines were well tolerated. Our findings support the immunogenicity and safety of the 3.75_halfMF59 (2 doses for children <12 months) and 7.5_fullMF59 vaccine formulations for use in children and adolescents aged 6 months to 17 y The use of the 3.75_halfMF59 could have the benefit of antigen and adjuvant sparing, increasing the available vaccine doses allowing vaccination of more people. PMID:25621884
Remiche, Gauthier; Abramowicz, Marc; Mavroudakis, Nicolas
Neurological complications of AH1N1 vaccination such as Guillain-Barré syndrome were described in the previous years. Several reports suggest that hereditary neuropathies may be a predisposing factor for immune-mediated neuropathies. We report the case of a 54-year-old female who developed chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) 5 weeks after AH1N1 vaccination. She had no previous neurological history, but neurophysiological features led us to suspect an underlying hereditary neuropathy. PMP22 gene analysis showed a typical deletion, confirming the diagnosis of hereditary neuropathy with liability to pressure palsies (HNPP). We observed a significant clinical and neurophysiological improvement of the neuropathy after intravenous immunoglobulin treatment. This is, to our knowledge, the first reported case of CIDP potentially triggered by AH1N1 vaccination. This and previous observations suggest that genetic-determined neuropathies could predispose to the occurrence of immune-mediated neuropathies. One must recall the possibility of a superimposed hereditary neuropathy like HNPP in patients with a clinical presentation of CIDP, especially when positive family history or unexpected neurophysiological features are present.
Background To guide policy and control measures, decent scientific data are needed for a comprehensive assessment of epidemiological, clinical and virological characteristics of the First Few hundred (FF100) cases. We discuss the feasibility of the FF100 approach during the 2009 pandemic and the added value compared with alternative data sources available. Methods The pandemic preparedness plan enabled us to perform a case–control study, assessing patient characteristics and risk factors for experiencing symptomatic influenza A(H1N1)2009 infection and providing insight into transmission. We assessed to what extent timely and novel data were generated compared to other available data sources. Results In May-December 2009, a total of 68 cases and 48 controls were included in the study. Underlying non-respiratory diseases were significantly more common among cases compared to controls, while a protective effect was found for frequent hand washing. Seroconversion was found for 7/30 controls (23%), and persisting high titers for 4/30 controls (13%). The labour-intensive study design resulted in slow and restricted recruitment. Conclusions The findings of our case–control study gave new insights in transmission risks and possible interventions for improved control. Nevertheless, the FF100 approach lacked timeliness and power due to limited recruitment. For future pandemics we suggest pooling data from several countries, to enable collecting sufficient data in a relatively short period. PMID:22995284
Finelli, Lyn; Heffernan, Richard T.; Leung, Gabriel M.; Redd, Stephen C.
This article synthesizes and extends discussions held during an international meeting on “Surveillance for Decision Making: The Example of 2009 Pandemic Influenza A/H1N1,” held at the Center for Communicable Disease Dynamics (CCDD), Harvard School of Public Health, on June 14 and 15, 2010. The meeting involved local, national, and global health authorities and academics representing 7 countries on 4 continents. We define the needs for surveillance in terms of the key decisions that must be made in response to a pandemic: how large a response to mount and which control measures to implement, for whom, and when. In doing so, we specify the quantitative evidence required to make informed decisions. We then describe the sources of surveillance and other population-based data that can presently—or in the future—form the basis for such evidence, and the interpretive tools needed to process raw surveillance data. We describe other inputs to decision making besides epidemiologic and surveillance data, and we conclude with key lessons of the 2009 pandemic for designing and planning surveillance in the future. PMID:21612363
Burkom, H; Kniss, K; Meltzer, M; Brammer, L; Elbert, Y; Finelli, L; Swerdlow, D
A pandemic H1N1 infection wave in the USA occurred during spring 2009. Some hypothesized that for regions affected by the spring wave, an autumn outbreak would be less likely or delayed compared to unaffected regions because of herd immunity. We investigated this hypothesis using the Outpatient Influenza-like Illness (ILI) Network, a collaboration among the Centers for Disease Control and Prevention, health departments, and care providers. We evaluated the likelihood of high early autumn incidence given high spring incidence in core-based statistical areas (CBSAs). Using a surrogate incidence measure based on influenza-related illness ratios, we calculated the odds of high early autumn incidence given high spring incidence. CBSAs with high spring ILI ratios proved more likely than unaffected CBSAs to have high early autumn ratios, suggesting that elevated spring illness did not protect against early autumn increases. These novel methods are applicable to planning and studies involving other infectious diseases.
Téllez-Sosa, Juan; Rodríguez, Mario Henry; Gómez-Barreto, Rosa E.; Valdovinos-Torres, Humberto; Hidalgo, Ana Cecilia; Cruz-Hervert, Pablo; Luna, René Santos; Carrillo-Valenzo, Erik; Ramos, Celso; García-García, Lourdes; Martínez-Barnetche, Jesús
Background Influenza viruses display a high mutation rate and complex evolutionary patterns. Next-generation sequencing (NGS) has been widely used for qualitative and semi-quantitative assessment of genetic diversity in complex biological samples. The “deep sequencing” approach, enabled by the enormous throughput of current NGS platforms, allows the identification of rare genetic viral variants in targeted genetic regions, but is usually limited to a small number of samples. Methodology and Principal Findings We designed a proof-of-principle study to test whether redistributing sequencing throughput from a high depth-small sample number towards a low depth-large sample number approach is feasible and contributes to influenza epidemiological surveillance. Using 454-Roche sequencing, we sequenced at a rather low depth, a 307 bp amplicon of the neuraminidase gene of the Influenza A(H1N1) pandemic (A(H1N1)pdm) virus from cDNA amplicons pooled in 48 barcoded libraries obtained from nasal swab samples of infected patients (n = 299) taken from May to November, 2009 pandemic period in Mexico. This approach revealed that during the transition from the first (May-July) to second wave (September-November) of the pandemic, the initial genetic variants were replaced by the N248D mutation in the NA gene, and enabled the establishment of temporal and geographic associations with genetic diversity and the identification of mutations associated with oseltamivir resistance. Conclusions NGS sequencing of a short amplicon from the NA gene at low sequencing depth allowed genetic screening of a large number of samples, providing insights to viral genetic diversity dynamics and the identification of genetic variants associated with oseltamivir resistance. Further research is needed to explain the observed replacement of the genetic variants seen during the second wave. As sequencing throughput rises and library multiplexing and automation improves, we foresee that the approach
Karpova, L S; Sominina, A A; Burtseva, E I; Pelikh, M Yu; Feodoritova, E L; Popovtseva, N M; Stolyarov, T P; Kiselev, O I
Comparative analysis of the three past epidemics with the participation of the pandemic influenza A(H1N1)pdm09 was conducted according to the results of the epidemiological trials of two WHO National influenza centers for the morbidity, hospitalization, and mortality of the influenza in 59 cities of Russia for the period from 2009 to 2013. The first wave of the pandemic of 2009 was the most severe. Compared with this wave, during the next epidemics of 2011 and 2013, the involvement of urban population in the epidemic was reduced, as well as the morbidity in the people 15-64 years old and schoolchildren 7-14 years old. The duration of the epidemic among the adult population, the mortality rate of the total population, and the mortality rates in all age groups were also decreased. Vice versa, the incidence in the children of preschool age and the elderly people and the duration of the epidemic among children (especially preschool children) were increased. The share of patients 65 years and older, children 0-2 years old, and patients with pathology of the cardiovascular systems among the deceased patients increased to 33.6%.
Haralambieva, Iana H.; Painter, Scott D.; Kennedy, Richard B.; Ovsyannikova, Inna G.; Lambert, Nathaniel D.; Goergen, Krista M.; Oberg, Ann L.; Poland, Gregory A.
Background Although influenza causes significant morbidity and mortality in the elderly, the factors underlying the reduced vaccine immunogenicity and efficacy in this age group are not completely understood. Age and immunosenescence factors, and their impact on humoral immunity after influenza vaccination, are of growing interest for the development of better vaccines for the elderly. Methods We assessed associations between age and immunosenescence markers (T cell receptor rearrangement excision circles – TREC content, peripheral white blood cell telomerase – TERT expression and CD28 expression on T cells) and influenza A/H1N1 vaccine-induced measures of humoral immunity in 106 older subjects at baseline and three timepoints post-vaccination. Results TERT activity (TERT mRNA expression) was significantly positively correlated with the observed increase in the influenza-specific memory B cell ELISPOT response at Day 28 compared to baseline (p-value=0.025). TREC levels were positively correlated with the baseline and early (Day 3) influenza A/H1N1-specific memory B cell ELISPOT response (p-value=0.042 and p-value=0.035, respectively). The expression and/or expression change of CD28 on CD4+ and/or CD8+ T cells at baseline and Day 3 was positively correlated with the influenza A/H1N1-specific memory B cell ELISPOT response at baseline, Day 28 and Day 75 post-vaccination. In a multivariable analysis, the peak antibody response (HAI and/or VNA at Day 28) was negatively associated with age, the percentage of CD8+CD28low T cells, IgD+CD27- naïve B cells, and percentage overall CD20- B cells and plasmablasts, measured at Day 3 post-vaccination. The early change in influenza-specific memory B cell ELISPOT response was positively correlated with the observed increase in influenza A/H1N1-specific HAI antibodies at Day 28 and Day 75 relative to baseline (p-value=0.007 and p-value=0.005, respectively). Conclusion Our data suggest that influenza-specific humoral immunity
Rossetto, Érika Valeska; Luna, Expedito José de Albuquerque
ABSTRACT Objective: To describe the clinical aspects of cases of influenza A(H1N1)pdm09 in Brazil. Methods: A descriptive study of cases reported in Sistema de Informação de Agravos de Notificação (SINAN), 2009-2010. Results: As the final classification, we obtained 53,797 (56.79%) reported cases confirmed as a new influenza virus subtype, and 40,926 (43.21%) cases discarded. Fever was the most common sign, recorded in 99.74% of the confirmed and 98.92% of the discarded cases. Among the confirmed cases, the presence of comorbidities was reported in 32.53%, and in 38.29% of the discarded cases. The case fatality rate was 4.04%; 3,267 pregnant women were confirmed positive for influenza A new viral subtype and 2,730 of them were cured. The case fatality rate of pregnant women was 6.88%. Conclusion: The findings suggested concern of the health system with pregnant women, and patients with comorbidities and quality of care may have favored a lower mortality. We recommend that, when caring for patients with severe respiratory symptoms, with comorbidities, or pregnant women, health professionals should consider the need for hospital care, as these factors make up a worse prognosis of infection by the pandemic influenza virus. PMID:26154537
Staikowsky, F; Vanhecke, C; D'Andréa, C; Souab, A; Rakotoson, R; Michault, A
A new H1N1 virus originating from swine recently emerged as the first influenza pandemic of the 21st century. On July 3, 2009, this new influenza A(H1N1) virus (S-OIV) of swine origins was identified in Réunion Island, a French overseas department located in the southern hemisphere. The present study describes the characteristics of the epidemic from July 3 to September 30, 2009. Among the 479 patients included in our study (236 males, 37.3 ± 19.0 years), 255 (53.2%) were reported to have comorbidities or risk factors (RF) for complications. Complications occurred in 160 patients (33.4%). The most common complications were bronchial hyperreactivity (52.7%), pneumonia (32.1%), and decompensation caused by comorbidity (17.9%). 111 patients (23.2%) required hospitalization. Patients aged 65 and over, accounted for 11.9% of all patients, 32.4% of hospitalized patients and 22.5% of complicated S-OIV infections. Regardless of age, comorbidity and/or RF were reported in 80.0% of complicated S-OIV infections and 91.0% of hospitalized patients. Recommendations for surveillance, prevention and policy for persons with RF, particularly respiratory disease, are justified. However, the absence of risk factors did not prevent the occurrence of complications, present in 14.3% of the cases.
Nicholson, Karl G.; Lim, Wei Shen; Read, Robert C.; Taylor, Bruce L.; Brett, Stephen J.; Openshaw, Peter J. M.; Enstone, Joanne E.; McMenamin, James; Bannister, Barbara; Nguyen-Van-Tam, Jonathan S.
During severe influenza pandemics healthcare demand can exceed clinical capacity to provide normal standards of care. Community Assessment Tools (CATs) could provide a framework for triage decisions for hospital referral and admission. CATs have been developed based on evidence that supports the recognition of severe influenza and pneumonia in the community (including resource limited settings) for adults, children and infants, and serious feverish illness in children. CATs use six objective criteria and one subjective criterion, any one or more of which should prompt urgent referral and admission to hospital. A retrospective evaluation of the ability of CATs to predict use of hospital-based interventions and patient outcomes in a pandemic was made using the first recorded routine clinical assessment on or shortly after admission from 1520 unselected patients (800 female, 480 children <16 years) admitted with PCR confirmed A(H1N1)pdm09 infection (the FLU-CIN cohort). Outcome measures included: any use of supplemental oxygen; mechanical ventilation; intravenous antibiotics; length of stay; intensive or high dependency care; death; and “severe outcome” (combined: use of intensive or high dependency care or death during admission). Unadjusted and multivariable analyses were conducted for children (age <16 years) and adults. Each CATs criterion independently identified both use of clinical interventions that would in normal circumstances only be provided in hospital and patient outcome measures. “Peripheral oxygen saturation ≤92% breathing air, or being on oxygen” performed well in predicting use of resources and outcomes for both adults and children; supporting routine measurement of peripheral oxygen saturation when assessing severity of disease. In multivariable analyses the single subjective criterion in CATs “other cause for clinical concern” independently predicted death in children and in adults predicted length of stay, mechanical ventilation and
Myles, Puja R; Semple, Malcolm G; Lim, Wei Shen; Openshaw, Peter J M; Gadd, Elaine M; Read, Robert C; Taylor, Bruce L; Brett, Stephen J; McMenamin, James; Enstone, Joanne E; Armstrong, Colin; Bannister, Barbara; Nicholson, Karl G
Background Although generally mild, the 2009–2010 influenza A/H1N1 pandemic caused two major surges in hospital admissions in the UK. The characteristics of patients admitted during successive waves are described. Methods Data were systematically obtained on 1520 patients admitted to 75 UK hospitals between May 2009 and January 2010. Multivariable analyses identified factors predictive of severe outcome. Results Patients aged 5–54 years were over-represented compared with winter seasonal admissions for acute respiratory infection, as were non-white ethnic groups (first wave only). In the second wave patients were less likely to be school age than in the first wave, but their condition was more likely to be severe on presentation to hospital and they were more likely to have delayed admission. Overall, 45% had comorbid conditions, 16.5% required high dependency (level 2) or critical (level 3) care and 5.3% died. As in 1918–1919, the likelihood of severe outcome by age followed a W-shaped distribution. Pre-admission antiviral drug use decreased from 13.3% to 10% between the first and second waves (p=0.048), while antibiotic prescribing increased from 13.6% to 21.6% (p<0.001). Independent predictors of severe outcome were age 55–64 years, chronic lung disease (non-asthma, non-chronic obstructive pulmonary disease), neurological disease, recorded obesity, delayed admission (≥5 days after illness onset), pneumonia, C-reactive protein ≥100 mg/litre, and the need for supplemental oxygen or intravenous fluid replacement on admission. Conclusions There were demographic, ethnic and clinical differences between patients admitted with pandemic H1N1 infection and those hospitalised during seasonal influenza activity. Despite national policies favouring use of antiviral drugs, few patients received these before admission and many were given antibiotics. PMID:22407890
Bomfim, I L; Lamb, F; Fink, K; Szakács, A; Silveira, A; Franzén, L; Azhary, V; Maeurer, M; Feltelius, N; Darin, N; Hallböök, T; Arnheim-Dahlström, L; Kockum, I; Olsson, T
The influenza A(H1N1)pdm09 vaccination campaign from 2009 to 2010 was associated with a sudden increase in the incidence of narcolepsy in several countries. Narcolepsy with cataplexy is strongly associated with the human leukocyte antigen (HLA) class II DQB1*06:02 allele, and protective associations with the DQB1*06:03 allele have been reported. Several non-HLA gene loci are also associated, such as common variants of the T-cell receptor-α (TRA), the purinergic receptor P2RY11, cathepsin H (CTSH) and TNFSF4/OX40L/CD252. In this retrospective multicenter study, we investigated if these predisposing gene loci were also involved in vaccination-associated narcolepsy. We compared HLA- along with single-nucleotide polymorphism genotypes for non-HLA regions between 42 Pandemrix-vaccinated narcolepsy cases and 1990 population-based controls. The class II gene loci associations supported previous findings. Nominal association (P-value<0.05) with TRA as well as suggestive (P-value<0.1) associations with P2RY11 and CTSH were found. These associations suggest a very strong gene-environment interaction, in which the influenza A(H1N1)pdm09 strain or Pandemrix vaccine can act as potent environmental triggers.Genes and Immunity advance online publication, 23 March 2017; doi:10.1038/gene.2017.1.
Kurečić Filipović, S; Gjenero-Margan, I; Kissling, E; Kaić, B; Cvitković, A
This is a retrospective study using the test-negative case-control method to estimate seasonal 2010-2011 influenza vaccine effectiveness (VE) in Croatia. Of patients consulting a physician for influenza-like illness (ILI) and for whom a swab was taken, we compared RT-PCR influenza-positive and RT-PCR influenza-negative patients. We used a structured questionnaire and physicians' records to obtain information on vaccination status and potential confounders. We conducted a complete case analysis using logistic regression to measure adjusted VE overall, against A(H1N1)pdm09 and in age groups. Out of 785 interviewed patients, 495 eligible patients were included in the study, after applying exclusion criteria [217 cases, of which 92·6% were A(H1N1)pdm09 positive, 278 controls]. Crude VE was 31·9% [95% confidence interval (CI) -40·9 to 67·1] and adjusted VE was 20·7% (95% CI -71·4 to 63·3), with higher VE in youngest and oldest age groups. Results from this first VE study in Croatia suggest a low to moderate VE for the 2010-2011 season. Studies year on year are needed with a greater sample size to provide more precise estimates, and also by age group and risk groups for vaccination.
Xu, Wanghui; Han, Lu; Lin, Zhanglin
The antigenic structure of the membrane protein hemagglutinin (HA) from the 2009 A(H1N1) influenza virus was dissected with a high-throughput screening method using complex antisera. The approach involves generating yeast cell libraries displaying a pool of random peptides of controllable lengths on the cell surface, followed by one round of fluorescence-activated cell sorting (FACS) against antisera from mouse, goat and human, respectively. The amino acid residue frequency appearing in the antigenic peptides at both the primary sequence and structural level was determined and used to identify “hot spots” or antigenically important regions. Unexpectedly, different antigenic structures were seen for different antisera. Moreover, five antigenic regions were identified, of which all but one are located in the conserved HA stem region that is responsible for membrane fusion. Our findings are corroborated by several recent studies on cross-neutralizing H1 subtype antibodies that recognize the HA stem region. The antigenic peptides identified may provide clues for creating peptide vaccines with better accessibility to memory B cells and better induction of cross-neutralizing antibodies than the whole HA protein. The scheme used in this study enables a direct mapping of the antigenic regions of viral proteins recognized by antisera, and may be useful for dissecting the antigenic structures of other viral proteins. PMID:21437206
Ramirez, Lorenzo A; Daniel, Alexander; Frank, Ian; Tebas, Pablo; Boyer, Jean D
Human immunodeficiency virus type 1 (HIV-1)-infected individuals, despite receipt of antiretroviral therapy (ART), often have impaired vaccine responses. We examined the role that immune activation and cellular phenotypes play in influenza A(H1N1) vaccine responsiveness in HIV-infected subjects receiving ART. Subjects received the H1N1 vaccine (15-µg dose; Novartis), and antibody titers at baseline and after immunization were evaluated. Subjects were classified as responders if, by week 3, seroprotection guidelines were met. Responders had higher percentages of baseline naive T cells and lower percentages of terminally differentiated T cells, compared with nonresponders. Additionally, the naive CD4(+) T-cell percentage and age were negatively correlated. Preservation of naive T-cell populations by starting therapy early could impact vaccine responses against influenza virus and other pathogens, especially as this population ages.
Ramirez, Lorenzo A.; Daniel, Alexander; Frank, Ian; Tebas, Pablo; Boyer, Jean D.
Human immunodeficiency virus type 1 (HIV-1)–infected individuals, despite receipt of antiretroviral therapy (ART), often have impaired vaccine responses. We examined the role that immune activation and cellular phenotypes play in influenza A(H1N1) vaccine responsiveness in HIV-infected subjects receiving ART. Subjects received the H1N1 vaccine (15-µg dose; Novartis), and antibody titers at baseline and after immunization were evaluated. Subjects were classified as responders if, by week 3, seroprotection guidelines were met. Responders had higher percentages of baseline naive T cells and lower percentages of terminally differentiated T cells, compared with nonresponders. Additionally, the naive CD4+ T-cell percentage and age were negatively correlated. Preservation of naive T-cell populations by starting therapy early could impact vaccine responses against influenza virus and other pathogens, especially as this population ages. PMID:24610877
Rattan, Ajitanuj; Pawar, Shailesh D.; Nawadkar, Renuka; Kulkarni, Neeraja
The pandemic influenza A(H1N1) 2009 virus caused significant morbidity and mortality worldwide thus necessitating the need to understand the host factors that influence its control. Previously, the complement system has been shown to provide protection during the seasonal influenza virus infection, however, the role of individual complement pathways is not yet clear. Here, we have dissected the role of intact complement as well as of its individual activation pathways during the pandemic influenza virus infection using mouse strains deficient in various complement components. We show that the virus infection in C3-/- mice results in increased viral load and 100% mortality, which can be reversed by adoptive transfer of naïve wild-type (WT) splenocytes, purified splenic B cells, or passive transfer of immune sera from WT, but not C3-/- mice. Blocking of C3a and/or C5a receptor signaling in WT mice using receptor antagonists and use of C3aR-/- and C5aR-/- mice showed significant mortality after blocking/ablation of C3aR, with little or no effect after blocking/ablation of C5aR. Intriguingly, deficiency of C4 and FB in mice resulted in only partial mortality (24%-32%) suggesting a necessary cross-talk between the classical/lectin and alternative pathways for providing effective protection. In vitro virus neutralization experiments performed to probe the cross-talk between the various pathways indicated that activation of the classical and alternative pathways in concert, owing to coating of viral surface by antibodies, is needed for its efficient neutralization. Examination of the virus-specific complement-binding antibodies in virus positive subjects showed that their levels vary among individuals. Together these results indicate that cooperation between the classical and alternative pathways not only result in efficient direct neutralization of the pandemic influenza virus, but also lead to the optimum generation of C3a, which when sensed by the immune cells along
Lamb, Favelle; Ploner, Alexander; Fink, Katharina; Maeurer, Markus; Bergman, Peter; Piehl, Fredrik; Weibel, Daniel; Sparén, Pär; Dahlström, Lisen Arnheim
Objectives To investigate disease history before A(H1N1)pdm09 vaccination as a risk factor for narcolepsy. Methods Case-control study in Sweden. Cases included persons referred for a Multiple Sleep Latency Test between 2009 and 2010, identified through diagnostic sleep centres and confirmed through independent review of medical charts. Controls, selected from the total population register, were matched to cases on age, gender, MSLT-referral date and county of residence. Disease history (prescriptions and diagnoses) and vaccination history was collected through telephone interviews and population-based healthcare registers. Conditional logistic regression was used to investigate disease history before A(H1N1)pdm09 vaccination as a risk-factor for narcolepsy. Results In total, 72 narcolepsy cases and 251 controls were included (range 3–69 years mean19-years). Risk of narcolepsy was increased in individuals with a disease history of nervous system disorders (OR range = 3.6–8.8) and mental and behavioural disorders (OR = 3.8, 95% CI 1.6–8.8) before referral. In a second analysis of vaccinated individuals only, nearly all initial associations were no longer statistically significant and effect sizes were smaller (OR range = 1.3–2.6). A significant effect for antibiotics (OR = 0.4, 95% CI 0.2–0.8) and a marginally significant effect for nervous system disorders was observed. In a third case-only analysis, comparing cases referred before vaccination to those referred after; prescriptions for nervous system disorders (OR = 26.0 95% CI 4.0–170.2) and ADHD (OR = 35.3 95% CI 3.4–369.9) were statistically significant during the vaccination period, suggesting initial associations were due to confounding by indication. Conclusion The findings of this study do not support disease history before A(H1N1)pdm09 vaccination as a risk factor for narcolepsy. PMID:27120092
Roman, François; Clément, Frédéric; Dewé, Walthère; Walravens, Karl; Maes, Cathy; Willekens, Julie; De Boever, Fien; Hanon, Emmanuel; Leroux-Roels, Geert
The influence of AS03A, a tocopherol oil-in-water emulsion-based adjuvant system, on humoral and cell-mediated responses to A/California/7/2009 H1N1 pandemic vaccine was investigated. In two observer-blind studies, a total of 261 healthy adults aged 18 to 60 years were randomized to receive either AS03A-adjuvanted H1N1 vaccine containing 3.75 μg hemagglutinin (HA) or nonadjuvanted H1N1 vaccine containing 15 or 3.75 μg HA on days 0 and 21. Hemagglutination inhibition (HI) antibody and T-cell responses were analyzed up to day 42. A first dose of AS03A-adjuvanted vaccine (3.75 μg HA) or nonadjuvanted vaccine (15 μg HA) induced HI responses of similar magnitudes that exceeded licensure criteria (e.g., 94 to 100% with titers of ≥40). A lower response following 3.75 μg HA without adjuvant was observed (73% with titers of ≥40). Following a second dose, geometric mean HI titers at day 42 were higher for AS03A-adjuvanted vaccine (636 and 637) relative to nonadjuvanted vaccine (341 for 15 μg HA and 150 for 3.75 μg HA). Over the 42-day period, the increase in frequency of A/H1N1/2009-specific CD4+ T cells was significantly higher in the adjuvanted group than in the nonadjuvanted group. There was no evidence of correlation between baseline CD4+ T-cell frequencies and day 21 HI antibody titers, while there was some correlation (R = 0.35) between day 21 CD4+ T-cell frequencies and day 42 HI titers. AS03A adjuvant enhanced the humoral and CD4+ T-cell-mediated responses to A/H1N1/2009 vaccine. Baseline A/H1N1/2009-specific CD4+ T-cell frequencies did not predict post-dose 1 antibody responses, but there was some correlation between post-dose 1 CD4+ T-cell frequencies and post-dose 2 antibody responses. PMID:21450978
Adeola, Oluwagbenga A.; Olugasa, Babasola O.; Emikpe, Benjamin O.
Background Human and animal influenza are inextricably linked. In particular, the pig is uniquely important as a mixing vessel for genetic reassortment of influenza viruses, leading to emergence of novel strains which may cause human pandemics. Significant reduction in transmission of influenza viruses from humans, and other animals, to swine may therefore be crucial for preventing future influenza pandemics. This study investigated the presence of the 2009 pandemic influenza A/H1N1 virus, A(H1N1)pdm09, in Nigerian and Ghanaian pigs, and also determined levels of acceptance of preventive measures which could significantly reduce the transmission of this virus from humans to pigs. Methods Nasal swab specimens from 125 pigs in Ibadan, Nigeria, and Kumasi, Ghana, were tested for the presence of influenza A/California/04/2009 (H1N1) by quantitative antigen-detection ELISA. A semi-structured questionnaire was also administered to pig handlers in the two study areas and responses were analyzed to evaluate their compliance with seven measures for preventing human-to-swine transmission of influenza viruses. Results The virus was detected among pigs in the two cities, with prevalence of 8% in Ibadan and 10% in Kumasi. Levels of compliance of pig handlers with relevant preventive measures were also found to be mostly below 25 and 40% in Ibadan and Kumasi, respectively. Conclusion Detection of influenza A(H1N1)pdm09 among pigs tested suggests the possibility of human-to-swine transmission, which may proceed even more rapidly, considering the very poor acceptance of basic preventive measures observed in this study. This is also the first report on detection of influenza A(H1N1)pdm09 in Ghanaian pigs. We recommend improvement on personal hygiene among pig handlers, enforcement of sick leave particularly during the first few days of influenza-like illnesses, and training of pig handlers on recognition of influenza-like signs in humans and pigs. These could be crucial for
Zhao, H; Harris, R J; Ellis, J; Pebody, R G
The relationship between risk of death following influenza A(H1N1)pdm09 infection and ethnicity and deprivation during the 2009/2010 pandemic period and the first post-pandemic season of 2010/2011 in England was examined. Poisson regression models were used to estimate the mortality risk, adjusted for age, gender, and place of residence. Those of non-White ethnicity experienced an increased mortality risk compared to White populations during the 2009/2010 pandemic [10·5/1000 vs. 6·0/1000 general population; adjusted risk ratio (RR) 1·84, 95% confidence interval (CI) 1·39-2·54] with the highest risk in those of Pakistani ethnicity. However, no significant difference between ethnicities was observed during the following 2010/2011 season. Persons living in areas with the highest level of deprivation had a significantly higher risk of death (RR 2·08, 95% CI 1·49-2·91) compared to the lowest level for both periods. These results highlight the importance of rapid identification of groups at higher risk of severe disease in the early stages of future pandemics to enable the implementation of optimal prevention and control measures for vulnerable populations.
Skowronski, Danuta M; Chambers, Catharine; Sabaiduc, Suzana; Janjua, Naveed Z; Li, Guiyun; Petric, Martin; Krajden, Mel; Purych, Dale; Li, Yan; De Serres, Gaston
To understand the epidemic resurgence of influenza due to the 2009 pandemic influenza A(H1N1) strain (A[H1N1]pdm09) during the 2013-2014 influenza season, we compared age-related cross-sectional estimates of seroprotection before the pandemic (during 2009) and after the pandemic (during 2010 and 2013) to subsequent surveillance-based, laboratory-confirmed incidence of influenza due to A(H1N1)pdm09 in British Columbia, Canada. Prepandemic seroprotection was negligible except for very old adults (defined as adults aged ≥ 80 years), among whom 80% had seroprotection. Conversely, postpandemic seroprotection followed a U-shaped distribution, with detection in approximately 35%-45% of working-aged adults but in ≥ 70% of very old adults and young children, excluding children aged <5 years in 2013, among whom seroprotection again decreased to <20%. The incidence was 5-fold higher during 2013-2014, compared with 2010-2011, and was highest among children aged <5 years and working-aged adults, reflecting a mirror image of the age-based seroprotection data.
Ovsyannikova, Inna G.; Salk, Hannah M.; Kennedy, Richard B.; Haralambieva, Iana H.; Zimmermann, Michael T.; Grill, Diane E.; Oberg, Ann L.; Poland, Gregory A.
This study aimed to identify gene expression markers shared between both influenza hemagglutination-inhibition (HAI) and virus-neutralization antibody (VNA) responses. We enrolled 158 older subjects who received the 2010–2011 trivalent inactivated influenza vaccine (TIV). Influenza-specific HAI and VNA titers, and mRNA-sequencing were performed using blood samples obtained at Days 0, 3 and 28 post-vaccination. For antibody response at Day 28 vs Day 0, several genesets were identified as significant in predictive models for HAI (n=7) and VNA (n=35) responses. Five genesets (comprising the genes MAZ, TTF, GSTM, RABGGTA, SMS, CA, IFNG, and DOPEY) were in common for both HAI and VNA. For response at Day 28 vs Day 3, many genesets were identified in predictive models for HAI (n=13) and VNA (n=41). Ten genesets (comprising biologically related genes, such as MAN1B1, POLL, CEBPG, FOXP3, IL12A, TLR3, TLR7, and others) were shared between HAI and VNA. These identified genesets demonstrated a high degree of network interactions and likelihood for functional relationships. Influenza-specific HAI and VNA responses demonstrated a remarkable degree of similarity. Although unique geneset signatures were identified for each humoral outcome, several genesets were determined to be in common with both HAI and VNA response to influenza vaccine. PMID:27534615
Phillips, J. C.
Influenza virus contains two highly variable envelope glycoproteins, hemagglutinin (HA) and neuraminidase (NA). The structure and properties of HA, which is responsible for binding the virus to the cell that is being infected, change significantly when the virus is transmitted from avian or swine species to humans. Here we focus first on the simpler problem of the much smaller human individual evolutionary amino acid mutational changes in NA, which cleaves sialic acid groups and is required for influenza virus replication. Our thermodynamic panorama shows that very small amino acid changes can be monitored very accurately across many historic (1945–2011) Uniprot and NCBI strains using hydropathicity scales to quantify the roughness of water film packages. Quantitative sequential analysis is most effective with the fractal differential hydropathicity scale based on protein self-organized criticality (SOC). Our analysis shows that large-scale vaccination programs have been responsible for a very large convergent reduction in common influenza severity in the last century. Hydropathic analysis is capable of interpreting and even predicting trends of functional changes in mutation prolific viruses directly from amino acid sequences alone. An engineered strain of NA1 is described which could well be significantly less virulent than current circulating strains. PMID:25143953
Belanov, Sergei S; Bychkov, Dmitrii; Benner, Christian; Ripatti, Samuli; Ojala, Teija; Kankainen, Matti; Kai Lee, Hong; Wei-Tze Tang, Julian; Kainov, Denis E
Here we analyzed whole-genome sequences of 3,969 influenza A(H1N1)pdm09 and 4,774 A(H3N2) strains that circulated during 2009-2015 in the world. The analysis revealed changes at 481 and 533 amino acid sites in proteins of influenza A(H1N1)pdm09 and A(H3N2) strains, respectively. Many of these changes were introduced as a result of random drift. However, there were 61 and 68 changes that were present in relatively large number of A(H1N1)pdm09 and A(H3N2) strains, respectively, that circulated during relatively long time. We named these amino acid substitutions evolutionary markers, as they seemed to contain valuable information regarding the viral evolution. Interestingly, influenza A(H1N1)pdm09 and A(H3N2) viruses acquired non-overlapping sets of evolutionary markers. We next analyzed these characteristic markers in vaccine strains recommended by the World Health Organization for the past five years. Our analysis revealed that vaccine strains carried only few evolutionary markers at antigenic sites of viral hemagglutinin (HA) and neuraminidase (NA). The absence of these markers at antigenic sites could affect the recognition of HA and NA by human antibodies generated in response to vaccinations. This could, in part, explain moderate efficacy of influenza vaccines during 2009-2014. Finally, we identified influenza A(H1N1)pdm09 and A(H3N2) strains, which contain all the evolutionary markers of influenza A strains circulated in 2015, and which could be used as vaccine candidates for the 2015/2016 season. Thus, genome-wide analysis of evolutionary markers of influenza A(H1N1)pdm09 and A(H3N2) viruses may guide selection of vaccine strain candidates.
Belanov, Sergei S.; Bychkov, Dmitrii; Benner, Christian; Ripatti, Samuli; Ojala, Teija; Kankainen, Matti; Kai Lee, Hong; Wei-Tze Tang, Julian; Kainov, Denis E.
Here we analyzed whole-genome sequences of 3,969 influenza A(H1N1)pdm09 and 4,774 A(H3N2) strains that circulated during 2009–2015 in the world. The analysis revealed changes at 481 and 533 amino acid sites in proteins of influenza A(H1N1)pdm09 and A(H3N2) strains, respectively. Many of these changes were introduced as a result of random drift. However, there were 61 and 68 changes that were present in relatively large number of A(H1N1)pdm09 and A(H3N2) strains, respectively, that circulated during relatively long time. We named these amino acid substitutions evolutionary markers, as they seemed to contain valuable information regarding the viral evolution. Interestingly, influenza A(H1N1)pdm09 and A(H3N2) viruses acquired non-overlapping sets of evolutionary markers. We next analyzed these characteristic markers in vaccine strains recommended by the World Health Organization for the past five years. Our analysis revealed that vaccine strains carried only few evolutionary markers at antigenic sites of viral hemagglutinin (HA) and neuraminidase (NA). The absence of these markers at antigenic sites could affect the recognition of HA and NA by human antibodies generated in response to vaccinations. This could, in part, explain moderate efficacy of influenza vaccines during 2009–2014. Finally, we identified influenza A(H1N1)pdm09 and A(H3N2) strains, which contain all the evolutionary markers of influenza A strains circulated in 2015, and which could be used as vaccine candidates for the 2015/2016 season. Thus, genome-wide analysis of evolutionary markers of influenza A(H1N1)pdm09 and A(H3N2) viruses may guide selection of vaccine strain candidates. PMID:26615216
Lahlou Amine, I; Bajjou, T; El Rhaffouli, H; Laraqui, A; Hilali, F; Menouar, K; Ennibi, K; Boudlal, M; Bouaiti, E A; Sbai, K; Rbai, M; Hachim, M; Zouhair, S
On 12 June 2009, Morocco was the first country in North Africa to report a laboratory-confirmed case of influenza A(H1N1)2009 virus infection. This study describes the epidemiological and clinical characteristics of 240 laboratory-confirmed cases among 594 outpatients with influenza-like illness at the Mohammed V Military Teaching Hospital, Rabat, from 12 June to 24 December 2009. Real-time reverse transcription-PCR was used to confirm the infection. The epidemic peaked in weeks 47 to 49 (16 November to 6 December 2009). The mean age of cases was 23 years (standard deviation: 14 years). Cough was the most common symptom in 200 cases (83%), followed by fever (≥38 °C) in 195 (81%). Diarrhoea or vomiting was reported in 12 (5%) patients. None of the cases developed any complications and no deaths occurred during the study period.
Hoa, Le Nguyen Minh; Mai, Le Quynh; Bryant, Juliet E.; Thai, Pham Quang; Hang, Nguyen Le Khanh; Yen, Nguyen Thi Thu; Duong, Tran Nhu; Thoang, Dang Dinh; Horby, Peter; Werheim, Heiman F. L.
ABSTRACT The discovery of influenza virus broadly neutralizing (BrN) antibodies prompted efforts to develop universal vaccines. Influenza virus stem-reactive (SR) broadly neutralizing antibodies have been detected by screening antibody phage display libraries. However, studies of SR BrN antibodies in human serum, and their association with natural infection, are limited. To address this, pre- and postpandemic sera from a prospective community cohort study in Vietnam were assessed for antibodies that inhibit SR BrN monoclonal antibody (MAb) (C179) binding to H1N1 pandemic 2009 virus (H1N1pdm09). Of 270 households, 33 with at least one confirmed H1N1pdm09 illness or at least two seroconverters were included. The included households comprised 71 infected and 41 noninfected participants. Sera were tested as 2-fold dilutions between 1:5 and 1:40. Fifty percent C179 inhibition (IC50) titers did not exceed 10, although both IC50 titers and percent C179 inhibition by sera diluted 1:5 or 1:10 correlated with hemagglutination inhibition (HI) and microneutralization (MN) titers (all P < 0.001). Thirteen (12%) participants had detectable prepandemic IC50 titers, but only one reached a titer of 10. This proportion increased to 44% after the pandemic, when 39 participants had a titer of 10, and 67% of infected compared to 44% of noninfected had detectable IC50 titers (P < 0.001). The low levels of SR antibodies in prepandemic sera were not associated with subsequent H1N1pdm09 infection (P = 0.241), and the higher levels induced by H1N1pdm09 infection returned to prepandemic levels within 2 years. The findings indicate that natural infection induces only low titers of SR antibodies that are not sustained. IMPORTANCE Universal influenza vaccines could have substantial health and economic benefits. The focus of universal vaccine research has been to induce antibodies that prevent infection by diverse influenza virus strains. These so-called broadly neutralizing antibodies are
Flasche, Stefan; Hens, Niel; Boëlle, Pierre-Yves; Mossong, Joël; van Ballegooijen, W Marijn; Nunes, Baltazar; Rizzo, Caterina; Popovici, Florin; Santa-Olalla, Patricia; Hrubá, Frantiska; Parmakova, Kremena; Baguelin, Marc; van Hoek, Albert Jan; Desenclos, Jean-Claude; Bernillon, Pascale; Cámara, Amparro Larrauri; Wallinga, Jacco; Asikainen, Tommi; White, Peter J; Edmunds, W John
Following the emergence of a novel strain of influenza A(H1N1) in Mexico and the United States in April 2009, its epidemiology in Europe during the summer was limited to sporadic and localised outbreaks. Only the United Kingdom experienced widespread transmission declining with school holidays in late July. Using statistical modelling where applicable we explored the following causes that could explain this surprising difference in transmission dynamics: extinction by chance, differences in the susceptibility profile, age distribution of the imported cases, differences in contact patterns, mitigation strategies, school holidays and weather patterns. No single factor was able to explain the differences sufficiently. Hence an additive mixed model was used to model the country-specific weekly estimates of the effective reproductive number using the extinction probability, school holidays and weather patterns as explanatory variables. The average extinction probability, its trend and the trend in absolute humidity were found to be significantly negatively correlated with the effective reproduction number - although they could only explain about 3% of the variability in the model. By comparing the initial epidemiology of influenza A (H1N1) across different European countries, our analysis was able to uncover a possible role for the timing of importations (extinction probability), mixing patterns and the absolute humidity as underlying factors. However, much uncertainty remains. With better information on the role of these epidemiological factors, the control of influenza could be improved.
Gomez-Barroso, D; Martinez-Beneito, M A; Flores, V; Amorós, R; Delgado, C; Botella, P; Zurriaga, O; Larrauri, A
The aim of this study was to monitor the spatio-temporal spread of influenza incidence in Spain during the 2009 pandemic and the following two influenza seasons 2010-2011 and 2011-2012 using a Bayesian Poisson mixed regression model; and implement this model of geographical analysis in the Spanish Influenza Surveillance System to obtain maps of influenza incidence for every week. In the pandemic wave the maps showed influenza activity spreading from west to east. The 2010-2011 influenza epidemic wave plotted a north-west/south-east pattern of spread. During the 2011-2012 season the spread of influenza was geographically heterogeneous. The most important source of variability in the model is the temporal term. The model of spatio-temporal spread of influenza incidence is a supplementary tool of influenza surveillance in Spain.
Babin, Steven M.; Hsieh, Yu-Hsiang; Rothman, Richard E.; Gaydos, Charlotte A.
This paper reviews fourteen published studies describing performance characteristics, including sensitivity and specificity, of commercially-available rapid, point-of-care (POC) influenza tests in patients affected by an outbreak of a novel swine-related influenza A (H1N1) that was declared a pandemic in 2009. Although these POC tests weren’t intended to be specific for this pandemic influenza strain, the non-specialized skills required and the timeliness of results make these POC tests potentially valuable for clinical and public health use. Pooled sensitivity and specificity for the POC tests studied were 68% and 81%, respectively, but published values were not homogeneous with sensitivities and specificities ranging from 10–88% and 51–100%, respectively. Pooled positive and negative likelihood ratios were 5.94 and 0.42, respectively. These results support current recommendations for use of rapid POC tests when H1N1 is suspected, recognizing that positive results are more reliable than negative results in determining infection, especially when disease prevalence is high. PMID:21396538
Escalera-Zamudio, Marina; Cobián-Güemes, Georgina; de los Dolores Soto-del Río, María; Isa, Pavel; Sánchez-Betancourt, Iván; Parissi-Crivelli, Aurora; Martínez-Cázares, María Teresa; Romero, Pedro; Velázquez-Salinas, Lauro; Huerta-Lozano, Belem; Nelson, Martha; Montero, Hilda; Vinuesa, Pablo; López, Susana; Arias, Carlos F
In the spring of 2009, swine-origin influenza H1N1pdm09 viruses caused the first influenza pandemic of this century. We characterized the influenza viruses that circulated early during the outbreak in Mexico, including one newly sequenced swine H1N1pdm09 virus and three newly sequenced human H1N1pdm09 viruses that circulated in the outbreak of respiratory disease in La Gloria, Veracruz. Phylogenetic analysis revealed that the swine isolate (A/swine/Mexico/4/2009) collected in April 2009 is positioned in a branch that is basal to the rest of the H1N1pdm09 clade in two (NP and PA) of the eight single-gene trees. In addition, the concatenated HA-NA and the complete whole-genome trees also showed a basal position for A/swine/Mexico/4/2009. Furthermore, this swine virus was found to share molecular traits with non-H1N1pdm09 H1N1 viral lineages. These results suggest that this isolate could potentially be the first one detected from a sister lineage closely related to the H1N1pdm09 viruses.
Fu, Chuanxi; Xu, Jianxiong; Lin, Jinyan; Wang, Ming; Li, Kuibiao; Ge, Jing; Thompson, Mark G
In 2012-2013, we examined 1729 laboratory-confirmed A(H1N1)pdm09 influenza cases matched 1:1 with healthy controls and estimated influenza vaccine effectiveness (VE) for trivalent inactivated influenza vaccine (IIV3) to be 67% (95% confidence interval=58-74%) for ages 8 months to 6 years old. Among children aged 8-35 months old, VE for fully vaccinated children (73%, 60-81%) was significantly higher than VE for partially vaccinated children (55%, 33-70%). Significant cross-season protection from prior IIV3 was noted, including VE of 31% (8-48%) from IIV3 received in 2010-2011 against influenza illness in 2012--2013 without subsequent boosting doses.
Dhand, Navneet K; Hernandez-Jover, Marta; Taylor, Melanie; Holyoake, Patricia
A cross-sectional study was conducted at the height of the pandemic influenza H1N1/09 outbreak in Australia in 2009. The objectives of the study were to evaluate public perceptions about transmission and prevention of the disease, to understand their concerns and preparedness to cope with the disease, and to investigate drivers influencing their behaviour. A questionnaire was designed and administered to 510 customers visiting 15 butcher shops in the Greater Sydney region between 26th June and 2nd August 2009. Data were analysed to estimate the proportion of people with certain perceptions and to evaluate the influence of these perceptions on two binary outcome variables: (1) whether or not people believed that avoiding pork would protect them from contracting H1N1/09, and (2) whether or not they actually made some changes to pork consumption after the outbreak. A majority of the respondents had perceptions based on fact about transmission and prevention of H1N1/09. As many as 96.8% of the respondents believed that washing their hands frequently was likely to protect them from contracting H1N1/09. Similarly, most believed that they could contract H1N1/09 by travelling on public transport with a sick person present (94.1%), by shaking hands with a sick person (89.2%), or by attending a community gathering (73.7%). Women were more likely than men to have factual perceptions about protective behaviours. Misconceptions regarding transmission of the disease were evident, with 21.7% believing that avoiding eating pork could protect them against H1N1/09, 11.1% believing that they could contract H1N1/09 by drinking tap water, 22.8% by handling uncooked pork meat and 15.6% by eating cooked pork. Approximately one third of respondents believed that working in a pig farm or an abattoir increased their likelihood of contracting H1N1/09 (36.9% and 32.3%, respectively). Younger people (<35 years old) were more likely to have these misconceptions than older people. Reduction in
Hennessy, T W; Bruden, D; Castrodale, L; Komatsu, K; Erhart, L M; Thompson, D; Bradley, K; O'Leary, D R; McLaughlin, J; Landen, M
Historically, American Indian/Alaska Native (AI/AN) populations have suffered excess morbidity and mortality from influenza. We investigated the risk factors for death from 2009 pandemic influenza A(H1N1) in persons residing in five states with substantial AI/AN populations. We conducted a case-control investigation using pandemic influenza fatalities from 2009 in Alaska, Arizona, New Mexico, Oklahoma and Wyoming. Controls were outpatients with influenza. We reviewed medical records and interviewed case proxies and controls. We used multiple imputation to predict missing data and multivariable conditional logistic regression to determine risk factors. We included 145 fatal cases and 236 controls; 22% of cases were AI/AN. Risk factors (P 45 years vs. <18 years], pre-existing medical conditions (mOR 7·1), smoking (mOR 3·0), delayed receipt of antivirals (mOR 6·5), and barriers to healthcare access (mOR 5·3). AI/AN race was not significantly associated with death. The increased influenza mortality in AI/AN individuals was due to factors other than racial status. Prevention of influenza deaths should focus on modifiable factors (smoking, early antiviral use, access to care) and identifying high-risk persons for immunization and prompt medical attention.
Influenza A virus (IAV) vaccines that provide broad cross-protection against antigenic variants are necessary to prevent infection and shedding of the wide array of IAV cocirculating in swine. Whole inactivated virus (WIV) vaccines provide only partial protection against IAV with substantial antigen...
Rondy, M.; Castilla, J.; Launay, O.; Costanzo, S.; Ezpeleta, C.; Galtier, F.; de Gaetano Donati, K.; Moren, A.
ABSTRACT We conducted a multicentre test negative case control study to estimate the 2013–14 influenza vaccine effectiveness (IVE) against hospitalised laboratory confirmed influenza in 12 hospitals in France, Italy and Spain. We included all ≥18 years hospitalised patients targeted by local influenza vaccination campaign reporting an influenza-like illness within 7 days before admission. We defined as cases patients RT-PCR positive for influenza and as controls those negative for all influenza virus. We used a logistic regression to calculate IVE adjusted for country, month of onset, chronic diseases and age. We included 104 A(H1N1)pdm09, 157 A(H3N2) cases and 585 controls. The adjusted IVE was 42.8% (95%CI: 6.3;65;0) against A(H1N1)pdm09. It was respectively 61.4% (95%CI: −1.9;85.4), 39.4% (95%CI: −32.2;72.2) and 19.7% (95%CI:-148.1;74.0) among patients aged 18–64, 65–79 and ≥80 years. The adjusted IVE against A(H3N2) was 38.1% (95%CI: 8.3;58.2) overall. It was respectively 7.8% (95%CI: −145.3;65.4), 25.6% (95%CI: −36.0;59.2) and 55.2% (95%CI: 15.4;76.3) among patients aged 18–64, 65–79 and ≥80 years. These results suggest a moderate and age varying effectiveness of the 2013–14 influenza vaccine to prevent hospitalised laboratory-confirmed influenza. While vaccination remains the most effective prevention measure, developing more immunogenic influenza vaccines is needed to prevent severe outcomes among target groups. PMID:27065000
Schnitzler, Sebastian U; Schnitzler, Paul
Influenza viruses cause annual epidemics and occasional pandemics that have claimed the lives of millions. The emergence of new strains will continue to pose challenges to public health and the scientific communities. The recent flu pandemic caused by a swine-origin influenza virus A/H1N1 (S-OIV) presents an opportunity to examine virulence factors, the spread of the infection and to prepare for major influenza outbreaks in the future. The virus contains a novel constellation of gene segments, the nearest known precursors being viruses found in swine and it probably arose through reassortment of two viruses of swine origin. Specific markers for virulence can be evaluated in the viral genome, PB1-F2 is a molecular marker of pathogenicity but is not present in the new S-OIV. While attention was focused on a threat of an avian influenza H5N1 pandemic emerging from Asia, a novel influenza virus of swine origin emerged in North America, and is now spreading worldwide. However, S-OIV demonstrates that even serotypes already encountered in past human pandemics may constitute new pandemic threats. There are concerns that this virus may mutate or reassort with existing influenza viruses giving rise to more transmissible or more pathogenic viruses. The 1918 Spanish flu pandemic virus was relatively mild in its first wave and acquired more virulence when it returned in the winter. Thus preparedness on a global scale against a potential more virulent strain is highly recommended. Most isolates of the new S-OIVs are susceptible to neuraminidase inhibitors, and currently a vaccine against the pandemic strain is being manufactured and will be available this fall. This review summarizes the current information on the new pandemic swine-origin influenza virus A/H1N1.
Scherließ, Regina; Ajmera, Ankur; Dennis, Mike; Carroll, Miles W; Altrichter, Jens; Silman, Nigel J; Scholz, Martin; Kemter, Kristina; Marriott, Anthony C
Currently, the need for cooled storage and the impossibility of terminal sterilisation are major drawbacks in vaccine manufacturing and distribution. To overcome current restrictions a preclinical safety and efficacy study was conducted to evaluate new influenza A vaccine formulations regarding thermal resistance, resistance against irradiation-mediated damage and storage stability. We evaluated the efficacy of novel antigen stabilizing and protecting solutions (SPS) to protect influenza A(H1N1)pdm09 split virus antigen under experimental conditions in vitro and in vivo. Original or SPS re-buffered vaccine (Pandemrix) was spray-dried and terminally sterilised by irradiation with 25 kGy (e-beam). Antigen integrity was monitored by SDS-PAGE, dynamic light scattering, size exclusion chromatography and functional haemagglutination assays. In vitro screening experiments revealed a number of highly stable compositions containing glycyrrhizinic acid (GA) and/or chitosan. The most stable composition was selected for storage tests and in vivo assessment of seroconversion in non-human primates (Macaca fascicularis) using a prime-boost strategy. Redispersed formulations with original adjuvant were administered intramuscularly. Storage data revealed high stability of protected vaccines at 4°C and 25°C, 60% relative humidity, for at least three months. Animals receiving original Pandemrix exhibited expected levels of seroconversion after 21 days (prime) and 48 days (boost) as assessed by haemagglutination inhibition and microneutralisation assays. Animals vaccinated with spray-dried and irradiated Pandemrix failed to exhibit seroconversion after 21 days whereas spray-dried and irradiated, SPS-protected vaccines elicited similar seroconversion levels to those vaccinated with original Pandemrix. Boost immunisation with SPS-protected vaccine resulted in a strong increase in seroconversion but had only minor effects in animals treated with non SPS-protected vaccine. In conclusion
Cardinale, Eric; Pascalis, Hervé; Temmam, Sarah; Hervé, Séverine; Saulnier, Aure; Turpin, Magali; Barbier, Nicolas; Hoarau, Johny; Quéguiner, Stéphane; Gorin, Stéphane; Foray, Coralie; Roger, Matthieu; Porphyre, Vincent; André, Paul; Thomas, Thierry; de Lamballerie, Xavier; Dellagi, Koussay; Simon, Gaëlle
During 2009, pandemic influenza A(H1N1)pdm09 virus affected humans on Réunion Island. Since then, the virus has sustained circulation among local swine herds, raising concerns about the potential for genetic evolution of the virus and possible retransmission back to humans of variants with increased virulence. Continuous surveillance of A(H1N1)pdm09 infection in pigs is recommended.
Background Vaccination coverage rates against pandemic flu were far below those required by Italian Public Health Authorities. The aim of this retrospective study was to assess how the management of vaccination against pandemic flu in the Health District of Piacenza (Northern Italy) had conditioned the adherence of patients at risk to the H1N1flu immunization program. Methods From a population of 27.018 children aged between 6 months and 16 years, 2361 pediatric patients considered at risk according to the guidelines of the Ministry of Health were enrolled to receive pandemic flu vaccination. Children enrolled in the immunization program were vaccinated with one of the following three options: A) by their pediatrician in his office after contacting him directly or by phone B) by their pediatrician in his office or in a public Health District office with the assistance of a nurse after an appointment had been booked by patient’s parents using a dedicated free of charge phone number C) by a doctor of the public Health District after an appointment had been booked as for option B Results The best outcomes of population vaccination coverage for pandemic flu were achieved when patients were vaccinated with option B (44.2%). For options A and C rates coverage results were 22.8% (OR 2,69) and 24.9% (OR 2, 39) respectively. Conclusion The results of this study may be taken into account by the public health Authorities when planning the management of future immunization campaigns out of the usual vaccination schedule or in an emergency event. PMID:22594575
Krog, Jesper Schak; Hjulsager, Charlotte Kristiane; Larsen, Michael Albin; Larsen, Lars Erik
This report describes a triple-reassortant influenza A virus with a HA that resembles H3 of human seasonal influenza from 2004 to 2005, N2 from influenza A virus already established in swine, and the internal gene cassette from A(H1N1)pdm09 has spread in Danish pig herds. The virus has been detected in several Danish pig herds during the last 2-3 years and may possess a challenge for human as well as animal health.
Araz, Ozgur M; Galvani, Alison; Meyers, Lauren A
Pandemic influenza is an international public health concern. In light of the persistent threat of H5N1 avian influenza and the recent pandemic of A/H1N1swine influenza outbreak, public health agencies around the globe are continuously revising their preparedness plans. The A/H1N1 pandemic of 2009 demonstrated that influenza activity and severity might vary considerably among age groups and locations, and the distribution of an effective influenza vaccine may be significantly delayed and staggered. Thus, pandemic influenza vaccine distribution policies should be tailored to the demographic and spatial structures of communities. Here, we introduce a bi-criteria decision-making framework for vaccine distribution policies that is based on a geospatial and demographically-structured model of pandemic influenza transmission within and between counties of Arizona in the Unites States. Based on data from the 2009-2010 H1N1 pandemic, the policy predicted to reduce overall attack rate most effectively is prioritizing counties expected to experience the latest epidemic waves (a policy that may be politically untenable). However, when we consider reductions in both the attack rate and the waiting period for those seeking vaccines, the widely adopted pro rata policy (distributing according to population size) is also predicted to be an effective strategy.
Ambrozaitis, Arvydas; Radzišauskienė, Daiva; Kuprevičienė, Nerija; Gravenstein, Stefan; Jančorienė, Ligita
Abstract The objective of this study is to describe the clinical and epidemiological characteristics of patients hospitalized in Lithuania who are infected with influenza A(H1N1)pdm09 and to compare pandemic A(H1N1) pdm09 infection with postpandemic. In total, 146 subjects hospitalized with influenza A(H1N1) pdm09 were identified from 2009–2011. There were 53 during the initial pandemic wave in the summer of 2009, 69 during the peak pandemic period, and 24 during the “postpandemic” period that we included in this study. There were 22 subjects who died after laboratory confirmation of influenza A(H1N1)pdm09. No deaths were documented during the first wave. Subjects presenting during the peak of pandemic influenza had a greater incidence of fever (100% vs 77.4%; p<0.001), dry cough (95.7% vs 82.7%; p=0.01), and vomiting (26.1% vs 1.9%, p<0.001) as compared with patients infected during the first wave. The rate of bacterial pneumonia was 18.8% (13/69) during the peak pandemic period and 12.5% (3/24, p=0.754) during the postpandemic period. None of the postpandemic influenza subjects’ intensive care unit stays were due to pneumonia. The hospitalized early 2009 H1N1 pandemic cases and postpandemic cases were milder compared with those at the peak of pandemic activity. PMID:28352819
Moya, Mireya; Bautista, Edgar G.; Velázquez-González, Antonio; Vázquez-Gutiérrez, Felipe; Tzintzun, Guadalupe; García-Arreola, María Elena; Castillejos, Manuel; Hernández, Andrés
During spring of 2009, a new influenza virus AH1N1 spread in the world causing acute respiratory illness and death, resulting in the first influenza pandemic since 1968. Blood levels of potentially-toxic and essential elements of 40 pneumonia and confirmed AH1N1 were evaluated against two different groups of controls, both not infected with the pandemic strain. Significant concentrations of potentially-toxic elements (lead, mercury, cadmium, chromium, arsenic) along with deficiency of selenium or increased Zn/Cu ratios characterized AH1N1 cases under study when evaluated versus controlled cases. Deficiency of selenium is progressively observed from controls I (influenza like illness) through controls II (pneumonia) and finally pneumonia -AH1N1 infected patients. Cases with blood Se levels greater than the recommended for an optimal cut-off to activate glutathione peroxidase (12.5 μg/dL) recovered from illness and survived. Evaluation of this essential element in critical pneumonia patients at the National Institutes is under evaluation as a clinical trial. PMID:23422930
He, Xiao-Song; Sasaki, Sanae; Baer, Jane; Khurana, Surender; Golding, Hana; Treanor, John J.; Topham, David J.; Sangster, Mark Y.; Jin, Hong; Dekker, Cornelia L.; Subbarao, Kanta; Greenberg, Harry B.
Background. The generation of heterovariant immunity is a highly desirable feature of influenza vaccines. The goal of this study was to compare the heterovariant B-cell response induced by the monovalent inactivated 2009 pandemic influenza A virus subtype H1N1 (A[H1N1]pdm09) vaccine with that induced by the 2009 seasonal trivalent influenza vaccine (sTIV) containing a seasonal influenza A virus subtype H1N1 (A[H1N1]) component in young and elderly adults. Methods. Plasmablast-derived polyclonal antibodies (PPAb) from young and elderly recipients of A(H1N1)pdm09 vaccine or sTIV were tested for binding activity to various influenza antigens. Results. In A(H1N1)pdm09 recipients, the PPAb titers against homotypic A(H1N1)pdm09 vaccine were similar to those against the heterovariant seasonal A(H1N1) vaccine and were similar between young and elderly subjects. The PPAb avidity was higher among elderly individuals, compared with young individuals. In contrast, the young sTIV recipients had 10-fold lower heterovariant PPAb titers against the A(H1N1)pdm09 vaccine than against the homotypic seasonal A(H1N1) vaccine. In binding assays with recombinant head and stalk domains of hemagglutinin, PPAb from the A(H1N1)pdm09 recipients but not PPAb from the sTIV recipients bound to the conserved stalk domain. Conclusion. The A(H1N1)pdm09 vaccine induced production of PPAb with heterovariant reactivity, including antibodies targeting the conserved hemagglutinin stalk domain. PMID:23107783
Aras, Siddhesh; Aiyar, Ashok; Amedee, Angela M; Gallaher, William R
The world is experiencing a pandemic of influenza that emerged in March 2009, due to a novel strain designated influenza A/H1N1 2009. This strain is closest in molecular sequence to swine influenza viruses, but differs from all previously known influenza by a minimum of 6.1%, and from prior "seasonal" H1N1 by 27.2%, giving it great potential for widespread human infection. While spread into India was delayed for two months by an aggressive interdiction program, since 1 August 2009 most cases in India have been indigenous. H1N1 2009 has differentially struck younger patients who are naïve susceptibles to its antigenic subtype, while sparing those >60 who have crossreactive antibody from prior experience with influenza decades ago and the 1977 "swine flu" vaccine distributed in the United States. It also appears to more severely affect pregnant women. It emanated from a single source in central Mexico, but its precise geographical and circumstantial origins, from either Eurasia or the Americas, remain uncertain. While currently a mild pandemic by the standard of past pandemics, the seriousness of H1N1 2009 especially among children should not be underestimated. There is potential for the virus, which continues to adapt to humans, to change over time into a more severe etiologic agent by any of several foreseeable mutations. Mass acceptance of the novel H1N1 2009 vaccine worldwide will be essential to its control. Having spread globally in a few months, affecting millions of people, it is likely to remain circulating in the human population for a decade or more.
Desaint, Corinne; Durier, Christine; Loulergue, Pierre; Duval, Xavier; Jacomet, Christine; Pialoux, Gilles; Ghosn, Jade; Raffi, François; Rey, David; Ajana, Faiza; Colin de Verdière, Nathalie; Reynes, Jacques; Foubert, Valérie; Roman, François; Devaster, Jeanne-Marie; Delfraissy, Jean-François; Aboulker, Jean-Pierre
Background. Human immunodeficiency virus (HIV)–infected patients have decreased immune response to vaccines. Few data are available about pandemic flu vaccination in this population. Methods. We conducted a multicenter, patient-blinded, randomized trial in a cohort of HIV-infected adults. Patients received 2 injections 21 days apart of a AS03A-adjuvanted H1N1v vaccine containing 3.75 μg hemagglutinin (HA) or a nonadjuvanted H1N1v vaccine containing 15 μg HA to assess hemagglutination inhibition (HI) response and safety. Results. A total of 309 patients were randomized, and 306 were vaccinated. After the first vaccine dose, HI titers ≥1:40 were observed in 93.4% of the patients in the adjuvanted group (A group) (n = 155) and in 75.5% in the nonadjuvanted group (B group) (n = 151) (P < .001); seroconversion rates were 88.8% and 71.2%, and factor increases in geometric mean titers (GMT) of 21.9 and 15.1, respectively. After 2 injections, 98.6% of patients of the A group and 92.1% of the B group demonstrated HI titers ≥1:40 (P = .018); seroconversion rates were 96.5% and 87.1%, respectively, and factor increases in GMT were 45.5 and 21.2, respectively. The majority of adverse events were mild to moderate in severity; no impact on CD4+ cell count or viral load has been detected. Conclusions. In HIV-1–infected adults, the AS03A-adjuvanted H1N1v vaccine yielded a higher immune response than did the nonadjuvanted one, with no impact on HIV infection. PMID:21628666
Luo, Lizhong; Nishi, Krista; Macleod, Erin; Sabara, Marta I; Coleman, Brenda L; Gubbay, Jonathan B; Li, Yan
The hemagglutinin genes (HA1 subunit) from human and animal 2009 pandemic H1N1 virus isolates were expressed with a baculovirus vector. Recombinant HA1 (rHA1) protein-based ELISA was evaluated for detection of specific influenza A(H1N1)pdm09 antibodies in serum samples from vaccinated humans. It was found that rHA1 ELISA consistently differentiated between antibodies recognizing the seasonal influenza H1N1 and pdm09 viruses, with a concordance of 94% as compared to the hemagglutination inhibition test. This study suggests the utility of rHA1 ELISA in serosurveillance.
Mukherjee, Anupam; Nayak, Mukti Kant; Dutta, Shanta; Panda, Samiran; Satpathi, Biswa Ranjan; Chawla-Sarkar, Mamta
In 2015, the swine derived A(H1N1)pdm09 pandemic strain outbreak became widespread throughout the different states of India. The reported cases and deaths in 2015 surpassed the previous years with more than 39000 laboratory confirmed cases and a death toll of more than 2500 people. There are relatively limited complete genetic sequences available for this virus from Asian countries. In this study, we describe the full genome analysis of influenza 2015 A(H1N1)pdm09 viruses isolated from West Bengal between January through December 2015. The phylogenetic analysis of the haemagglutinin sequence revealed clustering with globally circulating strains of genogroup 6B. This was further confirmed by the constructed concatenated tree using all eight complete gene segments of Kolkata A(H1N1)pdm09 isolates with the other strains from different timeline and lineages. A study from Massachusetts Institute of Technology (MIT) in 2015 reported novel mutations T200A and D225N in haemagglutinin gene of a 2014 Indian strain (A/India/6427/2014). However, in all the pandemic strains of 2014–2015 reported from India, so far including A(H1N1)pdm09 strains from Kolkata, D225N mutation was not observed, though the T200A mutation was found to be conserved. Neuraminidase gene of the analyzed strains did not show any oseltamivir resistant mutation H275Y suggesting continuation of Tamiflu® as drug of choice. The amino acid sequences of the all gene segments from 2015 A(H1N1)pdm09 isolates identified several new mutations compared to the 2009 A(H1N1)pdm09 strains, which may have contributed towards enhanced virulence, compared to 2009 A(H1N1)pdm09 strains. PMID:27997573
Vaccine effectiveness in preventing laboratory-confirmed influenza in primary care patients in a season of co-circulation of influenza A(H1N1)pdm09, B and drifted A(H3N2), I-MOVE Multicentre Case-Control Study, Europe 2014/15.
Valenciano, Marta; Kissling, Esther; Reuss, Annicka; Rizzo, Caterina; Gherasim, Alin; Horváth, Judit Krisztina; Domegan, Lisa; Pitigoi, Daniela; Machado, Ausenda; Paradowska-Stankiewicz, Iwona Anna; Bella, Antonino; Larrauri, Amparo; Ferenczi, Annamária; Lazar, Mihaela; Pechirra, Pedro; Korczyńska, Monika Roberta; Pozo, Francisco; Moren, Alain
Influenza A(H3N2), A(H1N1)pdm09 and B viruses co-circulated in Europe in 2014/15. We undertook a multicentre case-control study in eight European countries to measure 2014/15 influenza vaccine effectiveness (VE) against medically-attended influenza-like illness (ILI) laboratory-confirmed as influenza. General practitioners swabbed all or a systematic sample of ILI patients. We compared the odds of vaccination of ILI influenza positive patients to negative patients. We calculated adjusted VE by influenza type/subtype, and age group. Among 6,579 ILI patients included, 1,828 were A(H3N2), 539 A(H1N1)pdm09 and 1,038 B. VE against A(H3N2) was 14.4% (95% confidence interval (CI): -6.3 to 31.0) overall, 20.7% (95%CI: -22.3 to 48.5), 10.9% (95%CI -30.8 to 39.3) and 15.8% (95% CI: -20.2 to 41.0) among those aged 0-14, 15-59 and ≥60 years, respectively. VE against A(H1N1)pdm09 was 54.2% (95%CI: 31.2 to 69.6) overall, 73.1% (95%CI: 39.6 to 88.1), 59.7% (95%CI: 10.9 to 81.8), and 22.4% (95%CI: -44.4 to 58.4) among those aged 0-14, 15-59 and ≥60 years respectively. VE against B was 48.0% (95%CI: 28.9 to 61.9) overall, 62.1% (95%CI: 14.9 to 83.1), 41.4% (95%CI: 6.2 to 63.4) and 50.4% (95%CI: 14.6 to 71.2) among those aged 0-14, 15-59 and ≥60 years respectively. VE against A(H1N1)pdm09 and B was moderate. The low VE against A(H3N2) is consistent with the reported mismatch between circulating and vaccine strains.
Renault, P; Thouillot, F; Do, C; Baroux, N; Cadivel, A; Balleydier, E; Brottet, E; Kermarec, F; D'Ortenzio, E; Filleul, L
In Reunion Island, a French subtropical island located in the southern hemisphere, the monitoring of the epidemiological dynamics of the epidemic linked to the emergence of pandemic virus A(H1N1) 2009 was achieved through the regular influenza surveillance system which has been reinforced on that occasion. It was mainly based on a network of sentinel physicians, combined with virologic monitoring, and on surveillance of severe cases and deaths. The data were analyzed and retroinformation was distributed according to a weekly frequency. The first imported case was confirmed on July 5, 2009 in a traveler arriving from Australia, whereas the first autochthonous cases were reported on July 23. The epidemic peak was reached in five weeks and the duration of the whole epidemic episode was 9 weeks. Pandemic virus has quickly supplanted seasonal viruses that had begun to circulate. The estimated attack rate for symptomatic cases of infection with virus influenza A(H1N1) 2009 was 12.85%. The hospitalization rate was 32 per 10,000 estimated cases, and 24 people had a serious form requiring care in ICU. Among death certificates received at the regional office for health and social affairs, 14 mentioned the influenza, including 7 in whom the pandemic virus has been laboratory confirmed. These deaths occurred in patients significantly younger than usually observed in Reunion Island during the seasonal influenza epidemics. Overall, the epidemic intensity and severity have been similar to those of seasonal influenza in Reunion Island.
with federal funds from the National Institute of Allergy and Infectious Diseases, National Institutes of Health, Department of Health and Human...disease outbreaks [1,2,3,4]. Military members are particularly susceptible to epidemics from seasonal or novel influenza viruses, such as in 1918 when...Centers for Disease Control and Prevention [CDC] FluView. 2010–2011 influenza season week 10; http://www.cdc.gov/flu/weekly/weeklyarchives2010-2011
Butler, Jeff; Hooper, Kathryn A; Petrie, Stephen; Lee, Raphael; Maurer-Stroh, Sebastian; Reh, Lucia; Guarnaccia, Teagan; Baas, Chantal; Xue, Lumin; Vitesnik, Sophie; Leang, Sook-Kwan; McVernon, Jodie; Kelso, Anne; Barr, Ian G; McCaw, James M; Bloom, Jesse D; Hurt, Aeron C
Oseltamivir is relied upon worldwide as the drug of choice for the treatment of human influenza infection. Surveillance for oseltamivir resistance is routinely performed to ensure the ongoing efficacy of oseltamivir against circulating viruses. Since the emergence of the pandemic 2009 A(H1N1) influenza virus (A(H1N1)pdm09), the proportion of A(H1N1)pdm09 viruses that are oseltamivir resistant (OR) has generally been low. However, a cluster of OR A(H1N1)pdm09 viruses, encoding the neuraminidase (NA) H275Y oseltamivir resistance mutation, was detected in Australia in 2011 amongst community patients that had not been treated with oseltamivir. Here we combine a competitive mixtures ferret model of influenza infection with a mathematical model to assess the fitness, both within and between hosts, of recent OR A(H1N1)pdm09 viruses. In conjunction with data from in vitro analyses of NA expression and activity we demonstrate that contemporary A(H1N1)pdm09 viruses are now more capable of acquiring H275Y without compromising their fitness, than earlier A(H1N1)pdm09 viruses circulating in 2009. Furthermore, using reverse engineered viruses we demonstrate that a pair of permissive secondary NA mutations, V241I and N369K, confers robust fitness on recent H275Y A(H1N1)pdm09 viruses, which correlated with enhanced surface expression and enzymatic activity of the A(H1N1)pdm09 NA protein. These permissive mutations first emerged in 2010 and are now present in almost all circulating A(H1N1)pdm09 viruses. Our findings suggest that recent A(H1N1)pdm09 viruses are now more permissive to the acquisition of H275Y than earlier A(H1N1)pdm09 viruses, increasing the risk that OR A(H1N1)pdm09 will emerge and spread worldwide.
Ahn, Insung; Son, Hyeon Seok
In this study, we performed computer simulations to evaluate the changes of selection potentials of codons in influenza A/H1N1 from 1999 to 2009. We artificially generated the sequences by using the transition matrices of positively selected codons over time, and their similarities against the database of influenzavirus A genus were determined by BLAST search. This is the first approach to predict the evolutionary direction of influenza A virus (H1N1) by simulating the codon substitutions over time. We observed that the BLAST results showed the high similarities with pandemic influenza A/H1N1 in 2009, suggesting that the classical human-origin influenza A/H1N1 isolated before 2009 might contain some selection potentials of swine-origin viruses. Computer simulations using the time series codon substitution patterns resulted dramatic changes of BLAST results in influenza A/H1N1, providing a possibility of developing a method for predicting the viral evolution in silico.
Kotsimbos, Tom; Waterer, Grant; Jenkins, Christine; Kelly, Paul M; Cheng, Allen; Hancox, Robert J; Holmes, Mark; Wood-Baker, Richard; Bowler, Simon; Irving, Louis; Thompson, Philip
Influenza A/H1N1_09 emerged in Mexico at the end of the Northern Hemisphere winter. Within weeks, the focus shifted to the Southern Hemisphere as the introduction of the novel virus coincided with the beginning of the influenza season. Intensive public health and health services planning had occurred in Australia and New Zealand as preparation for an influenza pandemic before 2009. However, this first pandemic wave was quite different to what had been expected. Key elements of the pandemic and response are outlined from the perspective of clinicians working at the frontline of patient care. In particular, they examine why past influenza pandemics and recent history are poor predictors of the current pandemic, the discordance between potential for transmission and disease severity, the broad clinical spectrum of H1N1_09 infection, clinical and health service management issues, and the relationship between health care and government policy. Finally, they address the need for the respiratory community to show leadership in times of crisis. Lessons learned in Australia and New Zealand during 2009 have important messages for similarly resourced countries in the Northern Hemisphere in the coming months as they face their own influenza season.
Russo, Mara L; Pontoriero, Andrea V; Benedetti, Estefania; Czech, Andrea; Avaro, Martin; Periolo, Natalia; Campos, Ana M; Savy, Vilma L; Baumeister, Elsa G
This study was conducted as part of the Argentinean Influenza and other Respiratory Viruses Surveillance Network, in the context of the Global Influenza Surveillance carried out by the World Health Organization (WHO). The objective was to study the activity and the antigenic and genomic characteristics of circulating viruses for three consecutive seasons (2010, 2011 and 2012) in order to investigate the emergence of influenza viral variants. During the study period, influenza virus circulation was detected from January to December. Influenza A and B, and all current subtypes of human influenza viruses, were present each year. Throughout the 2010 post-pandemic season, influenza A(H1N1)pdm09, unexpectedly, almost disappeared. The haemagglutinin (HA) of the A(H1N1)pdm09 viruses studied were segregated in a different genetic group to those identified during the 2009 pandemic, although they were still antigenically closely related to the vaccine strain A/California/07/2009. Influenza A(H3N2) viruses were the predominant strains circulating during the 2011 season, accounting for nearly 76 % of influenza viruses identified. That year, all HA sequences of the A(H3N2) viruses tested fell into the A/Victoria/208/2009 genetic clade, but remained antigenically related to A/Perth/16/2009 (reference vaccine recommended for this three-year period). A(H3N2) viruses isolated in 2012 were antigenically closely related to A/Victoria/361/2011, recommended by the WHO as the H3 component for the 2013 Southern Hemisphere formulation. B viruses belonging to the B/Victoria lineage circulated in 2010. A mixed circulation of viral variants of both B/Victoria and B/Yamagata lineages was detected in 2012, with the former being predominant. A(H1N1)pdm09 viruses remained antigenically closely related to the vaccine virus A/California/7/2009; A(H3N2) viruses continually evolved into new antigenic clusters and both B lineages, B/Victoria/2/87-like and B/Yamagata/16/88-like viruses, were observed
Córdova-Villalobos, José A; Sarti, Elsa; Arzoz-Padrés, Jacqueline; Manuell-Lee, Gabriel; Méndez, Josefina Romero; Kuri-Morales, Pablo
Several influenza pandemics have taken place throughout history and it was assumed that the pandemic would emerge from a new human virus resulting from the adaptation of an avian virus strain. Mexico, since 2003 had developed a National Preparedness and Response Plan for an Influenza Pandemic focused in risk communication, health promotion, healthcare, epidemiological surveillance, strategic stockpile, research and development. This plan was challenged on April 2009, when a new influenza A(H1N1) strain of swine origen was detected in Mexico. The situation faced, the decisions and actions taken, allowed to control the first epidemic wave in the country. This document describes the critical moments faced and explicitly point out the lessons learned focused on the decided support by the government, the National Pandemic Influenza Plan, the coordination among all the government levels, the presence and solidarity of international organizations with timely and daily information, diagnosis and the positive effect on the population following the preventive hygienic measures recommended by the health authorities. The international community will be able to use the Mexican experience in the interest of global health.
Watcharananan, S P; Suwatanapongched, T; Wacharawanichkul, P; Chantratitaya, W; Mavichak, V; Mossad, S B
We report 2 cases of severe pneumonia due to the novel pandemic influenza A/H1N1 2009 in kidney transplant recipients. Our patients initially experienced influenza-like illness that rapidly progressed to severe pneumonia within 48 h. The patients became hypoxic and required non-invasive ventilation. The novel influenza A/H1N1 2009 was identified from their nasal swabs. These cases were treated successfully with a relatively high dose of oseltamivir, adjusted for their renal function. Clinical improvement was documented only after a week of antiviral therapy. Despite early antiviral treatment, we showed that morbidity following novel pandemic influenza A/H1N1 2009 infection is high among kidney transplant recipients.
Perdigão, Anne Carolinne Bezerra; Ramalho, Izabel Letícia Cavalcante; Guedes, Maria Izabel Florindo; Braga, Deborah Nunes Melo; Cavalcanti, Luciano Pamplona Góes; de Melo, Maria Elisabeth Lisboa; Araújo, Rafael Montenegro de Carvalho; Lima, Elza Gadelha; da Silva, Luciene Alexandre Bié; Araújo, Lia de Carvalho; Araújo, Fernanda Montenegro de Carvalho
Abstract We report on four patients with fatal influenza A(H1N1)pdm09 and dengue virus coinfections. Clinical, necropsy and histopathologic findings presented in all cases were characteristic of influenza-dengue coinfections, and all were laboratory-confirmed for both infections. The possibility of influenza and dengue coinfection should be considered in locations where these two viruses’ epidemic periods coincide to avoid fatal outcomes. Dengue is a mosquito-borne viral infection caused by one of the four dengue viruses (DENV-1 to 4). Each of these viruses is capable of causing nonspecific febrile illnesses, classic dengue fever and dengue haemorrhagic fever (Gubler 1998). As a result, dengue is often difficult to diagnose clinically, especially because peak dengue season often coincides with that of other common febrile illnesses in tropical regions (Chacon et al. 2015). In April 2009, a new virus, inﬂuenza A/H1N1/pandemic (FluA/H1N1/09pdm), caused a severe outbreak in Mexico. The virus quickly spread throughout the world, and in June 2009, the World Health Organization declared a pandemic (WHO 2010). In Brazil, the first laboratory confirmed case of FluA/H1N1/09pdm was in July 2009 (Pires Neto et al. 2013). The state of Ceará, in Northeast Brazil, is a dengue endemic area. In this state, the virus influenza A(H1N1)pdm09 has circulated since 2009, and through the first half of 2012, 11 deaths caused by the virus were confirmed (Pires Neto et al. 2013). The influenza and dengue seasons in Ceará overlap, which led to diagnostic difficulties. We report four cases of laboratory-confirmed coinfection of deadly influenza A(H1N1)pdm09 with DENV, which occurred during the dengue and influenza season in 2012 and 2013 in Ceará. PMID:27598244
Perdigão, Anne Carolinne Bezerra; Ramalho, Izabel Letícia Cavalcante; Guedes, Maria Izabel Florindo; Braga, Deborah Nunes Melo; Cavalcanti, Luciano Pamplona Góes; Melo, Maria Elisabeth Lisboa de; Araújo, Rafael Montenegro de Carvalho; Lima, Elza Gadelha; Silva, Luciene Alexandre Bié da; Araújo, Lia de Carvalho; Araújo, Fernanda Montenegro de Carvalho
We report on four patients with fatal influenza A(H1N1)pdm09 and dengue virus coinfections. Clinical, necropsy and histopathologic findings presented in all cases were characteristic of influenza-dengue coinfections, and all were laboratory-confirmed for both infections. The possibility of influenza and dengue coinfection should be considered in locations where these two viruses' epidemic periods coincide to avoid fatal outcomes. Dengue is a mosquito-borne viral infection caused by one of the four dengue viruses (DENV-1 to 4). Each of these viruses is capable of causing nonspecific febrile illnesses, classic dengue fever and dengue haemorrhagic fever (Gubler 1998). As a result, dengue is often difficult to diagnose clinically, especially because peak dengue season often coincides with that of other common febrile illnesses in tropical regions (Chacon et al. 2015). In April 2009, a new virus, inﬂuenza A/H1N1/pandemic (FluA/H1N1/09pdm), caused a severe outbreak in Mexico. The virus quickly spread throughout the world, and in June 2009, the World Health Organization declared a pandemic (WHO 2010). In Brazil, the first laboratory confirmed case of FluA/H1N1/09pdm was in July 2009 (Pires Neto et al. 2013). The state of Ceará, in Northeast Brazil, is a dengue endemic area. In this state, the virus influenza A(H1N1)pdm09 has circulated since 2009, and through the first half of 2012, 11 deaths caused by the virus were confirmed (Pires Neto et al. 2013). The influenza and dengue seasons in Ceará overlap, which led to diagnostic difficulties. We report four cases of laboratory-confirmed coinfection of deadly influenza A(H1N1)pdm09 with DENV, which occurred during the dengue and influenza season in 2012 and 2013 in Ceará.
Majda-Stanisławska, Ewa; Sobieraj, Iwona
High influenza morbidity due to new antigenic strain AH1N1 was announced in Mexico in spring 2009. Influenza pandemic caused by the virus AH1N1/2009 spread around the world. Two pandemic waves were noted in most European countries: the first one was due to summer months migration, the second wave started in the beginning of common influenza season. We present features of both waves in children from the district of Lodz. We describe mild clinical course in 14 children who came from holiday in Spain with influenza and who were hospitalized and treated with osltamimivir due to unpredictable course of new influenza. We also present 22 influenza cases of the autumn pandemic wave, when children with severe complications of influenza and children from high risk groups were hospitalized and treated with antivirals. Experience that we have gained during 2009 influenza pandemic indicates that International Influenza Control System is very efficient, however more flexibility is required in application of treatment and prophylaxis procedures with new influenza strains. Applied methods of control should mostly depend on the virulence of pandemic strain.
The influenza pandemic of 2009 demonstrated the inability of the established global capacity for egg-based vaccine production technology to provide sufficient vaccine for the population in a timely fashion. Several alternative technologies for developing influenza vaccines have been proposed, among which non-replicating virus-like particles (VLPs) represent an attractive option because of their safety and immunogenic characteristics. VLP vaccines against pandemic influenza have been developed in tobacco plant cells and in Sf9 insect cells infected with baculovirus that expresses protein genes from pandemic influenza strains. These technologies allow rapid and large-scale production of vaccines (3-12 weeks). The 2009 influenza outbreak provided an opportunity for clinical testing of a pandemic influenza VLP vaccine in the midst of the outbreak at its epicenter in Mexico. An influenza A(H1N1)2009 VLP pandemic vaccine (produced in insect cells) was tested in a phase II clinical trial involving 4,563 healthy adults. Results showed that the vaccine is safe and immunogenic despite high preexisting anti-A(H1N1)2009 antibody titers present in the population. The safety and immunogenicity profile presented by this pandemic VLP vaccine during the outbreak in Mexico suggests that VLP technology is a suitable alternative to current influenza vaccine technologies for producing pandemic and seasonal vaccines.
Neatherlin, John; Cramer, Elaine H; Dubray, Christine; Marienau, Karen J; Russell, Michelle; Sun, Hong; Whaley, Melissa; Hancock, Kathy; Duong, Krista K; Kirking, Hannah L; Schembri, Christopher; Katz, Jacqueline M; Cohen, Nicole J; Fishbein, Daniel B
The global spread of the influenza A(H1N1)pdm09 virus (pH1N1) associated with travelers from North America during the onset of the 2009 pandemic demonstrates the central role of international air travel in virus migration. To characterize risk factors for pH1N1 transmission during air travel, we investigated travelers and airline employees from four North American flights carrying ill travelers with confirmed pH1N1 infection. Of 392 passengers and crew identified, information was available for 290 (74%) passengers were interviewed. Overall attack rates for acute respiratory infection and influenza-like illness 1-7 days after travel were 5.2% and 2.4% respectively. Of 43 individuals that provided sera, 4 (9.3%) tested positive for pH1N1 antibodies, including 3 with serologic evidence of asymptomatic infection. Investigation of novel influenza aboard aircraft may be instructive. However, beyond the initial outbreak phase, it may compete with community-based mitigation activities, and interpretation of findings will be difficult in the context of established community transmission.
Pujol, J; Godoy, P; Soldevila, N; Castilla, J; González-Candelas, F; Mayoral, J M; Astray, J; Garcia, S; Martin, V; Tamames, S; Delgado, M; Domínguez, A
This study aimed to analyse the existence of an association between social class (categorized by type of occupation) and the occurrence of A(H1N1)pmd09 infection and hospitalization for two seasons (2009-2010 and 2010-2011). This multicentre study compared ambulatory A(H1N1)pmd09 confirmed cases with ambulatory controls to measure risk of infection, and with hospitalized A(H1N1)pmd09 confirmed cases to asses hospitalization risk. Study variables were: age, marital status, tobacco and alcohol use, pregnancy, chronic obstructive pulmonary disease, chronic respiratory failure, cardiovascular disease, diabetes, chronic liver disease, body mass index >40, systemic corticosteroid treatment and influenza vaccination status. Occupation was registered literally and coded into manual and non-manual worker occupational social class groups. A conditional logistic regression analysis was performed. There were 720 hospitalized cases, 996 ambulatory cases and 1062 ambulatory controls included in the study. No relationship between occupational social class and A(H1N1)pmd09 infection was found [adjusted odds ratio (aOR) 0·97, 95% confidence interval (CI) 0·74-1·27], but an association (aOR 1·53, 95% CI 1·01-2·31) between occupational class and hospitalization for A(H1N1)pmd09 was observed. Influenza vaccination was a protective factor for A(H1N1)pmd09 infection (aOR 0·41, 95% CI 0·23-0·73) but not for hospitalization. We conclude that manual workers have the highest risk of hospitalization when infected by influenza than other occupations but they do not have a different probability of being infected by influenza.
Zhang, Xu-Sheng; Pebody, Richard; De Angelis, Daniela; White, Peter J.; Charlett, Andre; McCauley, John W.
Background One pathway through which pandemic influenza strains might emerge is reassortment from coinfection of different influenza A viruses. Seasonal influenza vaccines are designed to target the circulating strains, which intuitively decreases the prevalence of coinfection and the chance of pandemic emergence due to reassortment. However, individual-based analyses on 2009 pandemic influenza show that the previous seasonal vaccination may increase the risk of pandemic A(H1N1) pdm09 infection. In view of pandemic influenza preparedness, it is essential to understand the overall effect of seasonal vaccination on pandemic emergence via reassortment. Methods and Findings In a previous study we applied a population dynamics approach to investigate the effect of infection-induced cross-immunity on reducing such a pandemic risk. Here the model was extended by incorporating vaccination for seasonal influenza to assess its potential role on the pandemic emergence via reassortment and its effect in protecting humans if a pandemic does emerge. The vaccination is assumed to protect against the target strains but only partially against other strains. We find that a universal seasonal vaccine that provides full-spectrum cross-immunity substantially reduces the opportunity of pandemic emergence. However, our results show that such effectiveness depends on the strength of infection-induced cross-immunity against any novel reassortant strain. If it is weak, the vaccine that induces cross-immunity strongly against non-target resident strains but weakly against novel reassortant strains, can further depress the pandemic emergence; if it is very strong, the same kind of vaccine increases the probability of pandemic emergence. Conclusions Two types of vaccines are available: inactivated and live attenuated, only live attenuated vaccines can induce heterosubtypic immunity. Current vaccines are effective in controlling circulating strains; they cannot always help restrain pandemic
The influenza pandemic of 2009 demonstrated the inability of the established global capacity for egg-based vaccine production technology to provide sufficient vaccine for the population in a timely fashion. Several alternative technologies for developing influenza vaccines have been proposed, among which non-replicating virus-like particles (VLPs) represent an attractive option because of their safety and immunogenic characteristics. VLP vaccines against pandemic influenza have been developed in tobacco plant cells and in Sf9 insect cells infected with baculovirus that expresses protein genes from pandemic influenza strains. These technologies allow rapid and large-scale production of vaccines (3–12 weeks). The 2009 influenza outbreak provided an opportunity for clinical testing of a pandemic influenza VLP vaccine in the midst of the outbreak at its epicenter in Mexico. An influenza A(H1N1)2009 VLP pandemic vaccine (produced in insect cells) was tested in a phase II clinical trial involving 4,563 healthy adults. Results showed that the vaccine is safe and immunogenic despite high preexisting anti-A(H1N1)2009 antibody titers present in the population. The safety and immunogenicity profile presented by this pandemic VLP vaccine during the outbreak in Mexico suggests that VLP technology is a suitable alternative to current influenza vaccine technologies for producing pandemic and seasonal vaccines. PMID:22330956
Background The A/H1N1 pandemic originated in Mexico in April 2009, amid high uncertainty, social and economic disruption, and media reports of panic. The aim of this research project was to evaluate the psychological response of family primary caregivers of patients hospitalised in the Intensive Care Unit (ICU) with suspected influenza A/H1N1 to establish whether there was empirical evidence of high adverse psychological response, and to identify risk factors for such a response. If such evidence was found, a secondary aim was to develop a specific early intervention of psychological support for these individuals, to reduce distress and possibly lessen the likelihood of post-traumatic stress disorder (PTSD) in the longer term. Methods Psychological assessment questionnaires were administered to the family primary caregivers of patients hospitalised in the ICU in the General Hospital of Zone 1 of the Mexican Institute for Social Security (IMSS), Oaxaca, Mexico with suspected influenza A/H1N1, during the month of November 2009. The main outcome measures were ratings of reported perceived stress (PSS-10), depression (CES-D), and death anxiety (DAQ). Data were subjected to simple and multiple linear regression analysis to identify risk factors for adverse psychological response. Results Elevated levels of perceived stress and depression, compared to population normative data, and moderate levels of death anxiety were noted. Levels of depression were similar to those found in comparable studies of family members of ICU patients admitted for other conditions. Multiple regression analysis indicated that increasing age and non-spousal family relationship were significantly associated with depression and perceived stress. Female gender, increasing age, and higher levels of education were significantly associated with high death anxiety. Comparisons with data collected in previous studies in the same hospital ICU with groups affected by a range of other medical conditions
Fielding, James E; Kelly, Heath A; Mercer, Geoffry N; Glass, Kathryn
Duration of viral shedding following infection is an important determinant of disease transmission, informing both control policies and disease modelling. We undertook a systematic literature review of the duration of influenza A(H1N1)pdm09 virus shedding to examine the effects of age, severity of illness and receipt of antiviral treatment. Studies were identified by searching the PubMed database using the keywords 'H1N1', 'pandemic', 'pandemics', 'shed' and 'shedding'. Any study of humans with an outcome measure of viral shedding was eligible for inclusion in the review. Comparisons by age, degree of severity and antiviral treatment were made with forest plots. The search returned 214 articles of which 22 were eligible for the review. Significant statistical heterogeneity between studies precluded meta-analysis. The mean duration of viral shedding generally increased with severity of clinical presentation, but we found no evidence of longer shedding duration of influenza A(H1N1)pdm09 among children compared with adults. Shorter viral shedding duration was observed when oseltamivir treatment was administered within 48 hours of illness onset. Considerable differences in the design and analysis of viral shedding studies limit their comparison and highlight the need for a standardised approach. These insights have implications not only for pandemic planning, but also for informing responses and study of seasonal influenza now that the A(H1N1)pdm09 virus has become established as the seasonal H1N1 influenza virus.
Faverio, Paola; Messinesi, Grazia; Brenna, Ambrogio; Pesci, Alberto
We present the results of bronchoalveolar lavage (BAL) performed in three patients with severe influenza A/H1N1 pneumonia complicated by acute respiratory distress syndrome (ARDS). Light microscopy analysis of BAL cytocentrifugates showed the presence of characteristic large, mononuclear, plasmoblastic/plasmocytoid-like cells never described before. Via transmission electron microscopy, these cells were classified as atypical type II pneumocytes and some of them showed cytoplasmic vesicles and inclusions. We concluded that plasmoblastic/plasmocytoid-like type II pneumocytes might represent a morphologic marker of A/H1N1 influenza virus infection as well as reparative cellular activation after diffuse alveolar damage. PMID:25383078
Faverio, Paola; Aliberti, Stefano; Ezekiel, Clinton; Messinesi, Grazia; Brenna, Ambrogio; Pesci, Alberto
We present the results of bronchoalveolar lavage (BAL) performed in three patients with severe influenza A/H1N1 pneumonia complicated by acute respiratory distress syndrome (ARDS). Light microscopy analysis of BAL cytocentrifugates showed the presence of characteristic large, mononuclear, plasmoblastic/plasmocytoid-like cells never described before. Via transmission electron microscopy, these cells were classified as atypical type II pneumocytes and some of them showed cytoplasmic vesicles and inclusions. We concluded that plasmoblastic/plasmocytoid-like type II pneumocytes might represent a morphologic marker of A/H1N1 influenza virus infection as well as reparative cellular activation after diffuse alveolar damage.
Manabe, Toshie; Higuera Iglesias, Anjarath Lorena; Vazquez Manriquez, Maria Eugenia; Martinez Valadez, Eduarda Leticia; Ramos, Leticia Alfaro; Izumi, Shinyu; Takasaki, Jin; Kudo, Koichiro
Background In addition to clinical aspects and pathogen characteristics, people's health-related behavior and socioeconomic conditions can affect the occurrence and severity of diseases including influenza A(H1N1)pdm09. Methodology and Principal Findings A face-to-face interview survey was conducted in a hospital in Mexico City at the time of follow-up consultation for hospitalized patients with pneumonia due to influenza virus infection. In all, 302 subjects were enrolled and divided into two groups based on the period of hospitalization. Among them, 211 tested positive for influenza A(H1N1)pdm09 virus by real-time reverse-transcriptase-polymerase-chain-reaction during the pandemic period (Group-pdm) and 91 tested positive for influenza A virus in the post-pandemic period (Group-post). All subjects were treated with oseltamivir. Data on the demographic characteristics, socioeconomic status, living environment, and information relating to A(H1N1)pdm09, and related clinical data were compared between subjects in Group-pdm and those in Group-post. The ability of household income to pay for utilities, food, and health care services as well as housing quality in terms of construction materials and number of rooms revealed a significant difference: Group-post had lower socioeconomic status than Group-pdm. Group-post had lower availability of information regarding H1N1 influenza than Group-pdm. These results indicate that subjects in Group-post had difficulty receiving necessary information relating to influenza and were more likely to be impoverished than those in Group-pdm. Possible factors influencing time to seeking health care were number of household rooms, having received information on the necessity of quick access to health care, and house construction materials. Conclusions Health-care-seeking behavior, poverty level, and the distribution of information affect the occurrence and severity of pneumonia due to H1N1 virus from a socioeconomic point of view. These
Murakami, T; Haruki, K; Seto, Y; Kimura, T; Minoshiro, S; Shibe, K
The hemagglutinin titers of 10 influenza A (H1N1) viruses were examined using the erythrocytes of several species. Human O erythrocytes showed the highest agglutination titer to the viruses, whereas chicken erythrocytes showed a low titer. These findings were noted for at least 10 passages by serial dilutions of the viruses in Madin-Darby canine kidney (MDCK) cells. All influenza A(H1N1) viruses, plaque-cloned directly from throat-washing specimens of patients, also agglutinated human O but not chicken erythrocytes. The results of a hemadsorption test indicated that chicken erythrocytes possess less affinity to MDCK cells infected with the A/Osaka City/2/88(H1N1) stain than to those infected with the A/Yamagata/120/86(H1N1) strain which is used as an inactivated influenza vaccine in Japan. However, there were no significant differences between the A/Osaka City/2/88 and the A/Yamagata/120/86 strains in the hemagglutination inhibition test. Since human O erythrocytes have high agglutination activity to influenza A(H1N1) and also to A(H3N2) and B viruses in MDCK cells, these erythrocytes may be useful for the serological diagnosis of influenza.
Li, Desheng; Zhu, Ling; Cui, Hengmin; Ling, Shanshan; Fan, Shengtao; Yu, Zhijun; Zhou, Yuancheng; Wang, Tiecheng; Qian, Jun; Xia, Xianzhu; Xu, Zhiwen; Wang, Chengdong
We confirmed infection with influenza A(H1N1)pdm09 in giant pandas in China during 2009 by using virus isolation and serologic analysis methods. This finding extends the host range of influenza viruses and indicates a need for increased surveillance for and control of influenza viruses among giant pandas. PMID:24565026
Li, Desheng; Zhu, Ling; Cui, Hengmin; Ling, Shanshan; Fan, Shengtao; Yu, Zhijun; Zhou, Yuancheng; Wang, Tiecheng; Qian, Jun; Xia, Xianzhu; Xu, Zhiwen; Gao, Yuwei; Wang, Chengdong
We confirmed infection with influenza A(H1N1)pdm09 in giant pandas in China during 2009 by using virus isolation and serologic analysis methods. This finding extends the host range of influenza viruses and indicates a need for increased surveillance for and control of influenza viruses among giant pandas.
Castelán-Vega, Juan A; Magaña-Hernández, Anastasia; Jiménez-Alberto, Alicia; Ribas-Aparicio, Rosa María
The last influenza A pandemic provided an excellent opportunity to study the adaptation of the influenza A(H1N1)pdm09 virus to the human host. Particularly, due to the availability of sequences taken from isolates since the beginning of the pandemic until date, we could monitor amino acid changes that occurred in the hemagglutinin (HA) as the virus spread worldwide and became the dominant H1N1 strain. HA is crucial to viral infection because it binds to sialidated cell-receptors and mediates fusion of cell and viral membranes; because antibodies that bind to HA may block virus entry to the cell, this protein is subjected to high selective pressure. Multiple alignment analysis of sequences of the HA from isolates taken since 2009 to date allowed us to find amino acid changes that were positively selected as the pandemic progressed. We found nine changes that became prevalent: HA1 subunits D104N, K166Q, S188T, S206T, A259T, and K285E; and HA2 subunits E47K, S124N, and E172K. Most of these changes were located in areas involved in inter- and intrachain interactions, while only two (K166Q and S188T) were located in known antigenic sites. We conclude that selective pressure on HA was aimed to improve its functionality and hence virus fitness, rather than at avoidance of immune recognition. PMID:25328411
Tewawong, Nipaporn; Prachayangprecha, Slinporn; Vichiwattana, Preeyaporn; Korkong, Sumeth; Klinfueng, Sirapa; Vongpunsawad, Sompong; Thongmee, Thanunrat; Theamboonlers, Apiradee; Poovorawan, Yong
Under selective pressure from the host immune system, antigenic epitopes of influenza virus hemagglutinin (HA) have continually evolved to escape antibody recognition, termed antigenic drift. We analyzed the genomes of influenza A(H3N2) and A(H1N1)pdm09 virus strains circulating in Thailand between 2010 and 2014 and assessed how well the yearly vaccine strains recommended for the southern hemisphere matched them. We amplified and sequenced the HA gene of 120 A(H3N2) and 81 A(H1N1)pdm09 influenza virus samples obtained from respiratory specimens and calculated the perfect-match vaccine efficacy using the pepitope model, which quantitated the antigenic drift in the dominant epitope of HA. Phylogenetic analysis of the A(H3N2) HA1 genes classified most strains into genetic clades 1, 3A, 3B, and 3C. The A(H3N2) strains from the 2013 and 2014 seasons showed very low to moderate vaccine efficacy and demonstrated antigenic drift from epitopes C and A to epitope B. Meanwhile, most A(H1N1)pdm09 strains from the 2012–2014 seasons belonged to genetic clades 6A, 6B, and 6C and displayed the dominant epitope mutations at epitopes B and E. Finally, the vaccine efficacy for A(H1N1)pdm09 (79.6–93.4%) was generally higher than that of A(H3N2). These findings further confirmed the accelerating antigenic drift of the circulating influenza A(H3N2) in recent years. PMID:26440103
He, Xiao-Song; Holmes, Tyson H.; Sanyal, Mrinmoy; Albrecht, Randy A.; García-Sastre, Adolfo; Dekker, Cornelia L.; Davis, Mark M.; Greenberg, Harry B.
Background. The human B-cell response to natural influenza virus infection has not been extensively investigated at the polyclonal level. Methods. The overall B-cell response of patients acutely infected with the 2009 pandemic influenza A(H1N1)pdm09 virus (A[H1N1]pdm09) was analyzed by determining the reactivity of plasmablast-derived polyclonal antibodies (PPAbs) to influenza proteins. Recipients of inactivated influenza vaccine containing the same A(H1N1)pdm09 strain were studied for comparison. Results. During acute infection, robust plasmablast responses to the infecting virus were detected, characterized by a greater PPAb reactivity to the conserved influenza virus nuclear protein and to heterovariant and heterosubtypic hemagglutinins, in comparison to responses to the inactivated A(H1N1)pdm09 vaccine. In A(H1N1)pdm09 vaccinees, the presence of baseline serum neutralizing antibodies against A(H1N1)pdm09, suggesting previous exposure to natural A(H1N1)pdm09 infection, did not affect the plasmablast response to vaccination, whereas repeated immunization with inactivated A(H1N1)pdm09 vaccine resulted in significantly reduced vaccine-specific and cross-reactive PPAb responses. Conclusions. Natural A(H1N1)pdm09 infection and inactivated A(H1N1)pdm09 vaccination result in very distinct patterns of B-cell activation and priming. These differences are likely to be associated with differences in protective immunity, especially cross-protection against heterovariant and heterosubtypic influenza virus strains. PMID:25336731
Yoneda, Masaki; Okayama, Akiko; Kitahori, Yoshiteru
We examined the incidence of oseltamivir-resistant seasonal A(H1N1) and A(H1N1)pdm09 influenza viruses from the 2007/2008 to 2012/2013 season in Nara Prefecture, Japan. To detect the oseltamivir resistance marker in neuraminidase (NA), 365 influenza viruses (60 seasonal A(H1N1) and 305 A(H1N1)pdm09) were sequenced. The H275Y mutation in the NA gene, which confers resistance to oseltamivir, was identified in 93.8% (30/32) of seasonal A(H1N1) viruses that were circulating during the 2008/2009 season. Moreover, the detection rate of oseltamivir-resistant A(H1N1)pdm09 viruses was 4.1% (3/74) and 2.8% (5/180) in the 2009/2010 and 2010/2011 season, respectively. Four cases of oseltamivir-resistant A(H1N1)pdm09 virus infection occurred in the same hematology ward during the 2010/2011 season. Our data show a low frequency of oseltamivir-resistant A(H1N1)pdm09 virus in Nara Prefecture but suggested the possibility of human-to-human transmission of this virus.
McLeish, Nigel J.; Simmonds, Peter; Robertson, Chris; Handel, Ian; McGilchrist, Mark; Singh, Brajendra K.; Kerr, Shona; Chase-Topping, Margo E.; Sinka, Katy; Bronsvoort, Mark; Porteous, David J.; Carman, William; McMenamin, James; Leigh-Brown, Andrew; Woolhouse, Mark E. J.
Background Sero-prevalence is a valuable indicator of prevalence and incidence of A/H1N1 2009 infection. However, raw sero-prevalence data must be corrected for background levels of cross-reactivity (i.e. imperfect test specificity) and the effects of immunisation programmes. Methods and Findings We obtained serum samples from a representative sample of 1563 adults resident in Scotland between late October 2009 and April 2010. Based on a microneutralisation assay, we estimate that 44% (95% confidence intervals (CIs): 40–47%) of the adult population of Scotland were sero-positive for A/H1N1 2009 influenza by 1 March 2010. Correcting for background cross-reactivity and for recorded vaccination rates by time and age group, we estimated that 34% (27–42%) were naturally infected with A/H1N1 2009 by 1 March 2010. The central estimate increases to >40% if we allow for imperfect test sensitivity. Over half of these infections are estimated to have occurred during the study period and the incidence of infection in late October 2009 was estimated at 4.3 new infections per 1000 people per day (1.2 to 7.2), falling close to zero by April 2010. The central estimate increases to over 5.0 per 1000 if we allow for imperfect test specificity. The rate of infection was higher for younger adults than older adults. Raw sero-prevalences were significantly higher in more deprived areas (likelihood ratio trend statistic = 4.92,1 df, P = 0.03) but there was no evidence of any difference in vaccination rates. Conclusions We estimate that almost half the adult population of Scotland were sero-positive for A/H1N1 2009 influenza by early 2010 and that the majority of these individuals (except in the oldest age classes) sero-converted as a result of natural infection with A/H1N1 2009. Public health planning should consider the possibility of higher rates of infection with A/H1N1 2009 influenza in more deprived areas. PMID:21687661
Prokopyeva, E A; Sobolev, I A; Prokopyev, M V; Shestopalov, A M
In the present study, three mouse-adapted variants of influenza A(H1N1)pdm09 virus were obtained by lung-to-lung passages of BALB/c, C57BL/6z and CD1 mice. The significantly increased virulence and pathogenicity of all of the mouse-adapted variants induced 100% mortality in the adapted mice. Genetic analysis indicated that the increased virulence of all of the mouse-adapted variants reflected the incremental acquisition of several mutations in PB2, PB1, HA, NP, NA, and NS2 proteins. Identical amino acid substitutions were also detected in all of the mouse-adapted variants of A(H1N1)pdm09 virus, including PB2 (K251R), PB1 (V652A), NP (I353V), NA (I106V, N248D) and NS1 (G159E). Apparently, influenza A(H1N1)pdm09 virus easily adapted to the host after serial passages in the lungs, inducing 100% lethality in the last experimental group. However, cross-challenge revealed that not all adapted variants are pathogenic for different laboratory mice. Such important results should be considered when using the influenza mice model.
Lynfield, Ruth; Davey, Richard; Dwyer, Dominic E.; Losso, Marcelo H.; Wentworth, Deborah; Cozzi-Lepri, Alessandro; Herman-Lamin, Kathy; Cholewinska, Grazyna; David, Daniel; Kuetter, Stefan; Ternesgen, Zelalem; Uyeki, Timothy M.; Lane, H. Clifford; Lundgren, Jens; Neaton, James D.
Background Data from prospectively planned cohort studies on risk of major clinical outcomes and prognostic factors for patients with influenza A(H1N1)pdm09 virus are limited. In 2009, in order to assess outcomes and evaluate risk factors for progression of illness, two cohort studies were initiated: FLU 002 in outpatients and FLU 003 in hospitalized patients. Methods and Findings Between October 2009 and December 2012, adults with influenza-like illness (ILI) were enrolled; outpatients were followed for 14 days and inpatients for 60 days. Disease progression was defined as hospitalization and/or death for outpatients, and hospitalization for >28 days, transfer to intensive care unit (ICU) if enrolled from general ward, and/or death for inpatients. Infection was confirmed by RT-PCR. 590 FLU 002 and 392 FLU 003 patients with influenza A (H1N1)pdm09 were enrolled from 81 sites in 17 countries at 2 days (IQR 1–3) and 6 days (IQR 4–10) following ILI onset, respectively. Disease progression was experienced by 29 (1 death) outpatients (5.1%; 95% CI: 3.4–7.2%) and 80 inpatients [death (32), hospitalization >28 days (43) or ICU transfer (20)] (21.6%; 95% CI: 17.5–26.2%). Disease progression (death) for hospitalized patients was 53.1% (26.6%) and 12.8% (3.8%), respectively, for those enrolled in the ICU and general ward. In pooled analyses for both studies, predictors of disease progression were age, longer duration of symptoms at enrollment and immunosuppression. Patients hospitalized during the pandemic period had a poorer prognosis than in subsequent seasons. Conclusions Patients with influenza A(H1N1)pdm09, particularly when requiring hospital admission, are at high risk for disease progression, especially if they are older, immunodeficient, or admitted late in infection. These data reinforce the need for international trials of novel treatment strategies for influenza infection and serve as a reminder of the need to monitor the severity of seasonal and pandemic
Lee, Jonggul; Jung, Eunok
We developed a spatial-temporal model of the 2009 A/H1N1 influenza pandemic in the Seoul metropolitan area (SMA), which is located in the north-west of South Korea and is the second-most complex metropolitan area worldwide. This multi-patch influenza model consists of a SEIAR influenza transmission model and flow model between two districts. This model is based on the daily confirmed cases of A/H1N1 influenza collected by the Korea Center for Disease Control and Prevention from April 27 to September 15, 2009 and the daily commuting data from 33 districts of SMA reported in the 2010 Population and Housing Census (PHC). We analyzed the spread patterns of 2009 influenza in the SMA by the reproductive numbers and geographic information systems. During the early period of novel influenza pandemics, when pharmaceutical interventions are lacking, non-pharmaceutical public health interventions will be the most critical strategies for impeding the spread of influenza and delaying an epidemic. Using the spatial-temporal model developed herein, we also investigated the impact of non-pharmaceutical public health interventions, isolation and/or commuting restrictions, on the incidence reduction in various scenarios. Our model provides scientific evidence for predicting the spread of disease and preparedness for a future pandemic.
Endemic strains of swine influenza A virus (IAV) in North America consist of the subtypes H1N1, H1N2, and H3N2. These circulating strains contain the triple reassortant internal gene (TRIG) cassette resulting from incorporation of genes from swine, avian, and human IAV’s. Genetic drift and reassortm...
Farrell, Margaret; Sebeny, Peter; Klena, John D.; DeMattos, Cecilia; Pimentel, Guillermo; Turner, Mark; Joseph, Antony; Espiritu, Jennifer; Zumwalt, John; Dueger, Erica
Background At the onset of an influenza pandemic, when the severity of a novel strain is still undetermined and there is a threat of introduction into a new environment, e.g., via the deployment of military troops, sensitive screening criteria and conservative isolation practices are generally recommended. Objectives In response to elevated rates of influenza-like illness among U.S. military base camps in Kuwait, U.S. Naval Medical Research Unit No. 3 partnered with local U.S. Army medical units to conduct an A(H1N1) pdm09 outbreak investigation. Patients/Methods Initial clinical data and nasal specimens were collected via the existent passive surveillance system and active surveillance was conducted using a modified version of the World Health Organization/U.S. Centers for Disease Control and Prevention influenza-like illness case definition [fever (T > 100.5˚F/38˚C) in addition to cough and/or sore throat in the previous 72 hours] as the screening criteria. Samples were tested via real-time reverse-transcription PCR and sequenced for comparison to global A(H1N1) pdm09 viruses from the same time period. Results The screening criteria used in Kuwait proved insensitive, capturing only 16% of A(H1N1) pdm09-positive individuals. While still not ideal, using cough as the sole screening criteria would have increased sensitivity to 73%. Conclusions The results of and lessons learned from this outbreak investigation suggest that pandemic influenza risk management should be a dynamic process (as information becomes available regarding true attack rates and associated mortality, screening and isolation criteria should be re-evaluated and revised as appropriate), and that military operational environments present unique challenges to influenza surveillance. PMID:23874699
Introduction. Swine influenza A viruses (SIV) in the major swine producing regions of North America consist of multiple subtypes of endemic H1N1, H1N2, and H3N2 derived from swine, avian and human influenza viruses with a triple reassortant internal gene (TRIG) constellation (1). Genetic drift and r...
Garcia-Etxebarria, Koldo; Bracho, María Alma; Galán, Juan Carlos; Pumarola, Tomàs; Castilla, Jesús; Ortiz de Lejarazu, Raúl; Rodríguez-Dominguez, Mario; Quintela, Inés; Bonet, Núria; Garcia-Garcerà, Marc; Domínguez, Angela; González-Candelas, Fernando; Calafell, Francesc
While most patients affected by the influenza A(H1N1) pandemic experienced mild symptoms, a small fraction required hospitalization, often without concomitant factors that could explain such a severe course. We hypothesize that host genetic factors could contribute to aggravate the disease. To test this hypothesis, we compared the allele frequencies of 547,296 genome-wide single nucleotide polymorphisms (SNPs) between 49 severe and 107 mild confirmed influenza A cases, as well as against a general population sample of 549 individuals. When comparing severe vs. mild influenza A cases, only one SNP was close to the conventional p = 5×10−8. This SNP, rs28454025, sits in an intron of the GSK233 gene, which is involved in a neural development, but seems not to have any connections with immunological or inflammatory functions. Indirectly, a previous association reported with CD55 was replicated. Although sample sizes are low, we show that the statistical power in our design was sufficient to detect highly-penetrant, quasi-Mendelian genetic factors. Hence, and assuming that rs28454025 is likely to be a false positive, no major genetic factor was detected that could explain poor influenza A course. PMID:26379185
Okomo-Adhiambo, Margaret; Fry, Alicia M.; Su, Su; Nguyen, Ha T.; Elal, Anwar Abd; Negron, Elizabeth; Hand, Julie; Garten, Rebecca J.; Barnes, John; Xiyan, Xu; Villanueva, Julie M.
We report characteristics of oseltamivir-resistant influenza A(H1N1)pdm09 viruses and patients infected with these viruses in the United States. During 2013–14, fifty-nine (1.2%) of 4,968 analyzed US influenza A(H1N1)pdm09 viruses had the H275Y oseltamivir resistance–conferring neuraminidase substitution. Our results emphasize the need for local surveillance for neuraminidase inhibitor susceptibility among circulating influenza viruses. PMID:25532050
Dhere, Rajeev; Yeolekar, Leena; Kulkarni, Prasad; Menon, Ravi; Vaidya, Vivek; Ganguly, Milan; Tyagi, Parikshit; Barde, Prajakt; Jadhav, Suresh
In the event of a highly pathogenic influenza pandemic, the Indian subcontinent would need 1.2 billion doses of vaccine to immunize its entire population, double if two doses were required to assure immunity. Serum Institute of India Limited (SII) thus became one of six initial grantees of the World Health Organization (WHO) technology transfer initiative to create capacity in developing countries to manufacture H5N1 pandemic influenza vaccine. At the outbreak of the A(H1N1) 2009 influenza pandemic, experience gained from the H5N1 project was used to develop a live attenuated influenza vaccine (LAIV), since this was the only option for the level of surge capacity required for a large-scale immunization campaign in India. SII took <12 months to develop and market its LAIV intranasal vaccine from receipt of the seed strain from WHO. As of November 2010, over 2.5 million persons have been vaccinated with Nasovac(®) with no serious adverse reactions or vaccine failure after 3 months' post-marketing surveillance. The product has been submitted for prequalification by WHO for purchase by United Nations agencies. In parallel, SII also developed an inactivated influenza vaccine, and is currently looking to ensure the sustainability of its influenza vaccine manufacturing capacity.
Correia, Vanessa; Santos, Luis A; Gíria, Marta; Almeida-Santos, Maria M; Rebelo-de-Andrade, Helena
Neuraminidase inhibitors (NAIs) oseltamivir and zanamivir are currently the only effective antiviral drugs available worldwide for the management of influenza. The potential development of resistance is continually threatening their use, rationalizing and highlighting the need for a close and sustained evaluation of virus susceptibility. This study aimed to analyze and characterize the phenotypic and genotypic NAIs susceptibility profiles of A(H1N1)pdm09 viruses circulating in Portugal from 2009 to 2010/2011. A total of 144 cases of A(H1N1)pdm09 virus infection from community and hospitalized patients were studied, including three suspected cases of clinical resistance to oseltamivir. Oseltamivir resistance was confirmed for two of the suspected cases. Neuraminidase (NA) H275Y resistant marker was found in viruses from both cases but for one it was only present in 26.2% of virus population, raising questions about the minimal percentage of resistant virus that should be considered relevant. Cross-decreased susceptibility to oseltamivir and zanamivir (2-4 IC50 fold-change) was detected on viruses from two potentially linked community patients from 2009. Both viruses harbored the NA I223V mutation. NA Y155H mutation was found in 18 statistical non-outlier viruses from 2009, having no impact on virus susceptibility. The mutations at NA N369K and V241I may have contributed to the significantly higher baseline IC50 value obtained to oseltamivir for 2010/2011 viruses, compared to viruses from the pandemic period. These results may contribute to a better understanding of the relationship between phenotype and genotype, which is currently challenging, and to the global assessment of A(H1N1)pdm09 virus susceptibility profile and baseline level to NAIs.
Piralla, Antonio; Pariani, Elena; Rovida, Francesca; Campanini, Giulia; Muzzi, Alba; Emmi, Vincenzo; Iotti, Giorgio A.; Pesenti, Antonio; Conaldi, Pier Giulio; Zanetti, Alessandro; Baldanti, Fausto
Background Since its appearance in 2009, the pandemic influenza A(H1N1) virus circulated worldwide causing several severe infections. Methods Respiratory samples from patients with 2009 influenza A(H1N1) and acute respiratory distress attending 24 intensive care units (ICUs) as well as from patients with lower respiratory tract infections not requiring ICU admission and community upper respiratory tract infections in the Lombardy region (10 million inhabitants) of Italy during the 2010–2011 winter-spring season, were analyzed. Results In patients with severe ILI, the viral load was higher in bronchoalveolar lavage (BAL) with respect to nasal swab (NS), (p<0.001) suggesting a higher virus replication in the lower respiratory tract. Four distinct virus clusters (referred to as cluster A to D) circulated simultaneously. Most (72.7%, n = 48) of the 66 patients infected with viruses belonging to cluster A had a severe (n = 26) or moderate ILI (n = 22). Amino acid mutations (V26I, I116M, A186T, D187Y, D222G/N, M257I, S263F, I286L/M, and N473D) were observed only in patients with severe ILI. D222G/N variants were detected exclusively in BAL samples. Conclusions Multiple virus clusters co-circulated during the 2010–2011 winter-spring season. Severe or moderate ILI were associated with specific 2009 influenza A(H1N1) variants, which replicated preferentially in the lower respiratory tract. PMID:22194826
Gaüzère, B-A; Bussienne, F; Bouchet, B; Jabot, J; Roussiaux, A; Drouet, D; Djourhi, S; Leauté, B; Belcour, D; Bossard, G; Champion, S; Jaffar-Bandjee, M-C; Belmonte, O; Vilain, P; Brottet, E; Hoang, L; Vandroux, D
In the Southern hemisphere, Réunion Island acts as a sentinel for infections preferentially occurring during the austral winter that are likely to reach the Northern hemisphere a few months later. We relate the main features concerning patients that were admitted during years 2009 and 2010 in our intensive care unit with an A(H1N1)v2009 infection, mainly for acute respiratory distress. Demographic, clinical, and biological data as well as given medications and outcome were prospectively collected among all PCR-confirmed influenza-infected patients. In 2009 and 2010, 25 patients met the criteria. Patients' median age was 40.4 (±17.4) years. Most of them (22/25) had comorbidities such as: chronic diseases, overweight, obesity, pregnancy, and Down syndrome. Maximum bed-occupation rate was 10 days per million inhabitants. Main diagnosis for ICU admission was virus-related pneumonia. Twenty-two out of 25 patients needed mechanical ventilation, some required rescue therapies such as extracorporeal membranous oxygenation (ECMO) or hi-frequency oscillation ventilation (HFOV), both only available in few French hospitals. Within the study period, 12 patients died (48%) mainly of multi-organ failure. Through 2009 and 2010 autumn and winter periods, for several weeks, the A(H1N1)v2009 virus infection resulted in a significant increase of workload in Réunion Island ICUs. In 2010, the failure of the mass immunization campaign, particularly among the at-risk groups, led to severe cases of A(H1N1)v2009 infections, particularly among patients with comorbidities. Our data may contribute toward better management of influenza virus pandemics in the future.
O'Flanagan, D; Barret, A S; Foley, M; Cotter, S; Bonner, C; Crowe, C; Lynch, B; Sweeney, B; Johnson, H; McCoy, B; Purcell, E
In 2011, the Irish Medicines Board received reports of onset of narcolepsy following vaccination against influenza A(H1N1)pdm09 with Pandemrix. A national steering committee was convened to examine the association between narcolepsy and pandemic vaccination. We conducted a retrospective population-based cohort study. Narcolepsy cases with onset from 1 April 2009 to 31 December 2010 were identified through active case finding. Narcolepsy history was gathered from medical records. Pandemic vaccination status was obtained from vaccination databases. Two independent experts classified cases using the Brighton case definition. Date of onset was defined as date of first healthcare contact for narcolepsy symptoms. Incidence of narcolepsy in vaccinated and non-vaccinated individuals was compared. Of 32 narcolepsy cases identified, 28 occurred in children/adolescents and for 24 first healthcare contact was between April 2009 and December 2010. Narcolepsy incidence was 5.7 (95% confidence interval (CI): 3.4–8.9) per 100,000 children/adolescents vaccinated with Pandemrix and 0.4 (95% CI: 0.1–1.0) per 100,000 unvaccinated children/adolescents (relative risk: 13.9; absolute attributable risk: 5.3 cases per 100,000 vaccinated children/adolescents). This study confirms the crude association between Pandemrix vaccination and narcolepsy as observed in Finland and Sweden. The vaccine is no longer in use in Ireland. Further studies are needed to explore the immunogenetic mechanism of narcolepsy.
González-Parra, Gilberto; Villanueva, Rafael-J; Ruiz-Baragaño, Javier; Moraño, Jose-A
In this paper we propose the use of a random network model for simulating and understanding the epidemics of influenza A(H1N1). The proposed model is used to simulate the transmission process of influenza A(H1N1) in a community region of Venezuela using distributed computing in order to accomplish many realizations of the underlying random process. These large scale epidemic simulations have recently become an important application of high-performance computing. The network model proposed performs better than the traditional epidemic model based on ordinary differential equations since it adjusts better to the irregularity of the real world data. In addition, the network model allows the consideration of many possibilities regarding the spread of influenza at the population level. The results presented here show how well the SEIR model fits the data for the AH1N1 time series despite the irregularity of the data and returns parameter values that are in good agreement with the medical data regarding AH1N1 influenza virus. This versatile network model approach may be applied to the simulation of the transmission dynamics of several epidemics in human networks. In addition, the simulation can provide useful information for the understanding, prediction and control of the transmission of influenza A(H1N1) epidemics.
WHO recommendations for the viruses used in the 2013-2014 Northern Hemisphere influenza vaccine: Epidemiology, antigenic and genetic characteristics of influenza A(H1N1)pdm09, A(H3N2) and B influenza viruses collected from October 2012 to January 2013.
Barr, Ian G; Russell, Colin; Besselaar, Terry G; Cox, Nancy J; Daniels, Rod S; Donis, Ruben; Engelhardt, Othmar G; Grohmann, Gary; Itamura, Shigeyuki; Kelso, Anne; McCauley, John; Odagiri, Takato; Schultz-Cherry, Stacey; Shu, Yuelong; Smith, Derek; Tashiro, Masato; Wang, Dayan; Webby, Richard; Xu, Xiyan; Ye, Zhiping; Zhang, Wenqing
In February the World Health Organisation (WHO) recommends influenza viruses to be included in influenza vaccines for the forthcoming winter in the Northern Hemisphere. These recommendations are based on data collected by National Influenza Centres (NICs) through the WHO Global Influenza Surveillance and Response System (GISRS) and a more detailed analysis of representative and potential antigenically variant influenza viruses from the WHO Collaborating Centres for Influenza (WHO CCs) and Essential Regulatory Laboratories (ERLs). This article provides a detailed summary of the antigenic and genetic properties of viruses and additional background data used by WHO experts during development of the recommendations of the 2013-2014 Northern Hemisphere influenza vaccine composition.
Background During the initial containment phase of influenza A/H1N1 2009, close contacts of cases were traced to provide antiviral prophylaxis within 48 h after exposure and to alert them on signs of disease for early diagnosis and treatment. Passengers seated on the same row, two rows in front or behind a patient infectious for influenza, during a flight of ≥ 4 h were considered close contacts. This study evaluates the timeliness of flight-contact tracing (CT) as performed following national and international CT requests addressed to the Center of Infectious Disease Control (CIb/RIVM), and implemented by the Municipal Health Services of Schiphol Airport. Methods Elapsed days between date of flight arrival and the date passenger lists became available (contact details identified - CI) was used as proxy for timeliness of CT. In a retrospective study, dates of flight arrival, onset of illness, laboratory diagnosis, CT request and identification of contacts details through passenger lists, following CT requests to the RIVM for flights landed at Schiphol Airport were collected and analyzed. Results 24 requests for CT were identified. Three of these were declined as over 4 days had elapsed since flight arrival. In 17 out of 21 requests, contact details were obtained within 7 days after arrival (81%). The average delay between arrival and CI was 3,9 days (range 2-7), mainly caused by delay in diagnosis of the index patient after arrival (2,6 days). In four flights (19%), contacts were not identified or only after > 7 days. CI involving Dutch airlines was faster than non-Dutch airlines (P < 0,05). Passenger locator cards did not improve timeliness of CI. In only three flights contact details were identified within 2 days after arrival. Conclusion CT for influenza A/H1N1 2009 among flight passengers was not successful for timely provision of prophylaxis. CT had little additional value for alerting passengers for disease symptoms, as this information already was provided during and after the flight. Public health authorities should take into account patient delays in seeking medical advise and laboratory confirmation in relation to maximum time to provide postexposure prophylaxis when deciding to install contact tracing measures. International standardization of CT guidelines is recommended. PMID:22204494
Han, Yan; Sun, Nan; Lv, Qiu-Yue; Liu, Dan-Hong; Liu, Da-Peng
The objective of the present study was to evaluate the epidemiology of influenza A(H1N1)pdm09 and its hemagglutinin (HA) molecular and phylogenetic analysis during 2010-2014 in Dalian, North China. A total of 3717 influenza-like illness (ILI) cases were tested by real-time PCR and 493 were found to be positive. Out of these 493 cases, 121 were subtype influenza A(H1N1)pdm09, of which 14 cases were reported in 2010-2011, 29 in 2012-2013, and 78 in 2013-2014. HA coding regions of 45 isolates were compared to that of the vaccine strain A/California/7/09(H1N1), and a number of variations were detected. P83S, S185T, S203T, R223Q, and I321V mutations were observed in all of the Dalian isolates. Furthermore, a high proportion >71 % of the strains possessed the variation D97N and K283E. Phylogenetic analysis confirmed the close match of the majority of circulating strains with the vaccine strains. However, it also reveals a trend of strains to accumulate amino acid variations and form new phylogenetic groups.
2009 novel A/H1N1 virus . Moreover, while these tests can distinguish between influenza A and B viruses , they are rarely able to subtype specific...and viruses isolated from these activities were used as seed strains for the 2009 pandemic influenza vaccine. Partners also provided diagnostic...several other countries, and viruses isolated from these activities were used as seed strains for the 2009 pandemic influenza vaccine. Partners also
Sleeman, Katrina; Mishin, Vasiliy P; Deyde, Varough M; Furuta, Yousuke; Klimov, Alexander I; Gubareva, Larisa V
Favipiravir (T-705) has previously been shown to have a potent antiviral effect against influenza virus and some other RNA viruses in both cell culture and in animal models. Currently, favipiravir is undergoing clinical evaluation for the treatment of influenza A and B virus infections. In this study, favipiravir was evaluated in vitro for its ability to inhibit the replication of a representative panel of seasonal influenza viruses, the 2009 A(H1N1) strains, and animal viruses with pandemic (pdm) potential (swine triple reassortants, H2N2, H4N2, avian H7N2, and avian H5N1), including viruses which are resistant to the currently licensed anti-influenza drugs. All viruses were tested in a plaque reduction assay with MDCK cells, and a subset was also tested in both yield reduction and focus inhibition (FI) assays. For the majority of viruses tested, favipiravir significantly inhibited plaque formation at 3.2 muM (0.5 microg/ml) (50% effective concentrations [EC(50)s] of 0.19 to 22.48 muM and 0.03 to 3.53 microg/ml), and for all viruses, with the exception of a single dually resistant 2009 A(H1N1) virus, complete inhibition of plaque formation was seen at 3.2 muM (0.5 microg/ml). Due to the 2009 pandemic and increased drug resistance in circulating seasonal influenza viruses, there is an urgent need for new drugs which target influenza. This study demonstrates that favipiravir inhibits in vitro replication of a wide range of influenza viruses, including those resistant to currently available drugs.
Booth, J. Leland; Metcalf, Jordan P.
Influenza infection is a major cause of morbidity and mortality. Retinoic acid-inducible gene I (RIG-I) is believed to play an important role in the recognition of, and response to, influenza virus and other RNA viruses. Our study focuses on the hypothesis that pandemic H1N1/09 influenza virus alters the influenza-induced proinflammatory response and suppresses host antiviral activity. We first compared the innate response to a clinical isolate of influenza A(H1N1)pdm09 virus, OK/09, a clinical isolate of seasonal H3N2 virus, OK/06, and to a laboratory adapted seasonal H1N1 virus, PR8, using a unique human lung organ culture model. Exposure of human lung tissue to either pandemic or seasonal influenza virus resulted in infection and replication in alveolar epithelial cells. Pandemic virus induces a diminished RIG-I mRNA and antiviral cytokine response than seasonal virus in human lung. The suppression of antiviral response and RIG-I mRNA expression was confirmed at the protein level by ELISA and western blot. We performed a time course of RIG-I and interferon-β (IFN-β) mRNA induction by the two viruses. RIG-I and IFN-β induction by OK/09 was of lower amplitude and shorter duration than that caused by PR8. In contrast, the pandemic virus OK/09 caused similar induction of proinflammatory cytokines, IL-8 and IL-6, at both the transcriptional and translational level as PR8 in human lung. Differential antiviral responses did not appear to be due to a difference in cellular infectivity as immunohistochemistry showed that both viruses infected alveolar macrophages and epithelial cells. These findings show that influenza A(H1N1)pdm09 virus suppresses anti-viral immune responses in infected human lung through inhibition of viral-mediated induction of the pattern recognition receptor, RIG-I, though proinflammatory cytokine induction was unaltered. This immunosuppression of the host antiviral response by pandemic virus may have contributed to the more serious lung
Shankar, Ananda G.; Janmohamed, Kulsum; Smith, Gillian E.; Hogan, Angela H.; De Souza, Valerie; Wallensten, Anders; Oliver, Isabel; Blatchford, Oliver; Cleary, Paul; Ibbotson, Sue
In April 2009, influenza A(H1N1)pdm09 virus infection was confirmed in a person who had been symptomatic while traveling on a commercial flight from Mexico to the United Kingdom. Retrospective public health investigation and contact tracing led to the identification of 8 additional confirmed cases among passengers and community contacts of passengers. PMID:24377724
Whiley, David M; Bialasiewicz, Seweryn; Bletchly, Cheryl; Faux, Cassandra E; Harrower, Bruce; Gould, Allan R; Lambert, Stephen B; Nimmo, Graeme R; Nissen, Michael D; Sloots, Theo P
Accurate and rapid diagnosis of novel influenza A(H1N1) infection is critical for minimising further spread through timely implementation of antiviral treatment and other public health based measures. In this study we developed two TaqMan-based reverse transcription PCR (RT-PCR) methods for the detection of novel influenza A(H1N1) virus targeting the haemagglutinin and neuraminidase genes. The assays were validated using 152 clinical respiratory samples, including 61 Influenza A positive samples, collected in Queenland, Australia during the years 2008 to 2009 and a further 12 seasonal H1N1 and H3N2 influenza A isolates collected from years 2000 to 2002. A wildtype swine H1N1 isolate was also tested. RNA from an influenza A(H1N1) virus isolate (Auckland, 2009) was used as a positive control. Overall, the results showed that the RT-PCR methods were suitable for sensitive and specific detection of novel influenza A(H1N1) RNA in human samples.
Omeñaca, Manuel; Panadero, Carolina; Royo, Laura; Vengoechea, Jose J.; Fandos, Sergio; de Pablo, Francisco; Bello, Salvador
Background Recent pandemics of influenza A H1N1pdm09 virus have caused severe illness, especially in young people. Very few studies on influenza A H1N1pdm09 in post-pandemic periods exist, and there is no information on the severity of both seasonal influenza A(H1N1) and A(H3N2) from the same season, adjusting for potential confounders, including vaccine. Methods and Results We performed a retrospective observational study of adults hospitalized during the 2014 season with influenza A(H1N1) or A(H3N2). All patients underwent the same diagnostic and therapeutic protocol in a single hospital, including early Oseltamivir therapy. We included 234 patients: 146 (62.4%) influenza A(H1N1) and 88 (37.6%) A(H3N2). A(H1N1) patients were younger (p<0.01), developed more pneumonia (p<0.01), respiratory complications (p = 0.015), ARDS (p = 0.047), and septic shock (p = 0.049), were more frequently admitted to the ICU (p = 0.022), required IMV (p = 0.049), and were less frequently vaccinated (p = 0.008). After adjusting for age, comorbidities, time from onset of illness, and vaccine status, influenza A(H1N1) (OR, 2.525), coinfection (OR, 2.821), and no vaccination (OR, 3.086) were independent risk factors for severe disease. Conclusions Hospitalized patients with influenza A(H1N1) were more than twice as likely to have severe influenza. They were younger and most had not received the vaccine. Our findings suggest that seasonal influenza A(H1N1) maintains some features of pandemic viruses, and recommend wider use of vaccination in younger adult high-risk patients. PMID:27832114
Canini, Laetitia; Carrat, Fabrice
Influenza virus kinetics (VK) is used as a surrogate of infectiousness, while the natural history of influenza is described by symptom dynamics (SD). We used an original virus kinetics/symptom dynamics (VKSD) model to characterize human influenza virus infection and illness, based on a population approach. We combined structural equations and a statistical model to describe intra- and interindividual variability. The structural equations described influenza based on the target epithelial cells, the virus, the innate host response, and systemic symptoms. The model was fitted to individual VK and SD data obtained from 44 volunteers experimentally challenged with influenza A/H1N1 virus. Infection and illness parameters were calculated from best-fitted model estimates. We predicted that the cytokine level and NK cell activity would peak at days 2.2 and 4.2 after inoculation, respectively. Infectiousness, measured as the area under the VK curve above a viral titer threshold, lasted between 7.0 and 1.3 days and was 15 times lower in participants without systemic symptoms than in those with systemic symptoms (P < 0.001). The latent period, defined as the time between inoculation and infectiousness, varied from 0.7 to 1.9 days. The incubation period, defined as the time from inoculation to first symptoms, varied from 1.0 to 2.4 days. Our approach extends previous work by including the innate response and providing realistic estimates of infection and illness parameters, taking into account the strong interindividual variability. This approach could help to optimize studies of influenza VK and SD and to predict the effect of antivirals on infectiousness and symptoms.
Zaraket, Hassan; Saito, Reiko; Suzuki, Yasushi; Baranovich, Tatiana; Dapat, Clyde; Caperig-Dapat, Isolde; Suzuki, Hiroshi
The emergence and widespread occurrence of antiviral drug-resistant seasonal human influenza A viruses, especially oseltamivir-resistant A/H1N1 virus, are major concerns. To understand the genetic background of antiviral drug-resistant A/H1N1 viruses, we performed full genome sequencing of prepandemic A/H1N1 strains. Seasonal influenza A/H1N1 viruses, including antiviral-susceptible viruses, amantadine-resistant viruses, and oseltamivir-resistant viruses, obtained from several areas in Japan during the 2007-2008 and 2008-2009 influenza seasons were analyzed. Sequencing of the full genomes of these viruses was performed, and the phylogenetic relationships among the sequences of each individual genome segment were inferred. Reference genome sequences from the Influenza Virus Resource database were included to determine the closest ancestor for each segment. Phylogenetic analysis revealed that the oseltamivir-resistant strain evolved from a reassortant oseltamivir-susceptible strain (clade 2B) which circulated in the 2007-2008 season by acquiring the H275Y resistance-conferring mutation in the NA gene. The oseltamivir-resistant lineage (corresponding to the Northern European resistant lineage) represented 100% of the H1N1 isolates from the 2008-2009 season and further acquired at least one mutation in each of the polymerase basic protein 2 (PB2), polymerase basic protein 1 (PB1), hemagglutinin (HA), and neuraminidase (NA) genes. Therefore, a reassortment event involving two distinct oseltamivir-susceptible lineages, followed by the H275Y substitution in the NA gene and other mutations elsewhere in the genome, contributed to the emergence of the oseltamivir-resistant lineage. In contrast, amantadine-resistant viruses from the 2007-2008 season distinctly clustered in clade 2C and were characterized by extensive amino acid substitutions across their genomes, suggesting that a fitness gap among its genetic components might have driven these mutations to maintain it in the population.
Wan, Hongquan; Yang, Hua; Shore, David A.; Garten, Rebecca J.; Couzens, Laura; Gao, Jin; Jiang, Lianlian; Carney, Paul J.; Villanueva, Julie; Stevens, James; Eichelberger, Maryna C.
A(H1N1)pdm09 influenza A viruses predominated in the 2013–2014 USA influenza season, and although most of these viruses remain sensitive to Food and Drug Administration-approved neuraminidase (NA) inhibitors, alternative therapies are needed. Here we show that monoclonal antibody CD6, selected for binding to the NA of the prototypic A(H1N1)pdm09 virus, A/California/07/2009, protects mice against lethal virus challenge. The crystal structure of NA in complex with CD6 Fab reveals a unique epitope, where the heavy-chain complementarity determining regions (HCDRs) 1 and 2 bind one NA monomer, the light-chain CDR2 binds the neighbouring monomer, whereas HCDR3 interacts with both monomers. This 30-amino-acid epitope spans the lateral face of an NA dimer and is conserved among circulating A(H1N1)pdm09 viruses. These results suggest that the large, lateral CD6 epitope may be an effective target of antibodies selected for development as therapeutic agents against circulating H1N1 influenza viruses. PMID:25668439
Introduction. The gene constellation of the 2009 pandemic H1N1 virus is a unique combination from swine influenza A viruses (SIV) of North American and Eurasian lineages, but prior to April 2009 had never before been identified in swine or other species (1). Although the hemagglutinin gene is relate...
Table 1. WHO Influenza Pandemic Phases (Current alert level is highlighted) Phase Description Phase 1 No animal influenza virus circulating among... animals has been reported to cause infection in humans. Phase 2 An animal influenza virus circulating in domesticated or wild animals is known to have...community-level outbreaks. Phase 4 Human-to-human transmission of an animal or human- animal influenza reassortant a virus able to sustain community
Elderfield, Ruth A.; Watson, Simon J.; Godlee, Alexandra; Adamson, Walt E.; Thompson, Catherine I.; Dunning, Jake; Fernandez-Alonso, Mirian; Blumenkrantz, Deena; Hussell, Tracy; Zambon, Maria; Openshaw, Peter; Kellam, Paul
ABSTRACT The influenza pandemic that emerged in 2009 provided an unprecedented opportunity to study adaptation of a virus recently acquired from an animal source during human transmission. In the United Kingdom, the novel virus spread in three temporally distinct waves between 2009 and 2011. Phylogenetic analysis of complete viral genomes showed that mutations accumulated over time. Second- and third-wave viruses replicated more rapidly in human airway epithelial (HAE) cells than did the first-wave virus. In infected mice, weight loss varied between viral isolates from the same wave but showed no distinct pattern with wave and did not correlate with viral load in the mouse lungs or severity of disease in the human donor. However, second- and third-wave viruses induced less alpha interferon in the infected mouse lungs. NS1 protein, an interferon antagonist, had accumulated several mutations in second- and third-wave viruses. Recombinant viruses with the third-wave NS gene induced less interferon in human cells, but this alone did not account for increased virus fitness in HAE cells. Mutations in HA and NA genes in third-wave viruses caused increased binding to α-2,6-sialic acid and enhanced infectivity in human mucus. A recombinant virus with these two segments replicated more efficiently in HAE cells. A mutation in PA (N321K) enhanced polymerase activity of third-wave viruses and also provided a replicative advantage in HAE cells. Therefore, multiple mutations allowed incremental changes in viral fitness, which together may have contributed to the apparent increase in severity of A(H1N1)pdm09 influenza virus during successive waves. IMPORTANCE Although most people infected with the 2009 pandemic influenza virus had mild or unapparent symptoms, some suffered severe and devastating disease. The reasons for this variability were unknown, but the numbers of severe cases increased during successive waves of human infection in the United Kingdom. To determine the causes
Ropero-Álvarez, A M; Whittembury, A; Bravo-Alcántara, P; Kurtis, H J; Danovaro-Holliday, M C; Velandia-González, M
As part of the vaccination activities against influenza A[H1N1]pdm vaccine in 2009-2010, countries in Latin American and the Caribbean (LAC) implemented surveillance of events supposedly attributable to vaccines and immunization (ESAVI). We describe the serious ESAVI reported in LAC in order to further document the safety profile of this vaccine and highlight lessons learned. We reviewed data from serious H1N1 ESAVI cases from LAC countries reported to the Pan American Health Organization/World Health Organization. We estimated serious ESAVI rates by age and target group, as well as by clinical diagnosis, and completed descriptive analyses of final outcomes and classifications given in country. A total of 1000 serious ESAVI were reported by 18 of the 29 LAC countries that vaccinated against A[H1N1]pdm. The overall reporting rate in LAC was 6.91 serious ESAVI per million doses, with country reporting rates ranging from 0.77 to 64.68 per million doses. Rates were higher among pregnant women (16.25 per million doses) when compared to health care workers (13.54 per million doses) and individuals with chronic disease (4.03 per million doses). The top three most frequent diagnoses were febrile seizures (12.0%), Guillain-Barré Syndrome (10.5%) and acute pneumonia (8.0%). Almost half (49.1%) of the serious ESAVI were reported among children aged <18 years of age; within this group, the highest proportion of cases was reported among those aged <2 years (53.1%). Of all serious ESAVI reported, 37.8% were classified as coincidental, 35.3% as related to vaccine components, 26.4% as non-conclusive and 0.5% as a programmatic error. This regional overview of A[H1N1]pdm vaccine safety data in LAC estimated the rate of serious ESAVI at lower levels than other studies. However, the ESAVI diagnosis distribution is comparable to the published literature. Lessons learned can be applied in the response to future pandemics.
Bodas, Moran; Davidovich, Nadav; Balicer, Ran D
Swine influenza is a disease known since 1918. Four decades Later, scientists were already isolating the disease-causing agent and learning more about its ability to infect humans. Generally, swine influenza viruses, similarly to avian influenza viruses, do not easily infect humans; however, the viruses' ability to undergo substantial genetic re-assortment enhances the emergence of novel influenza viruses, better capable of infecting and transmitting between humans. Pigs also form good "mixing vessels" for human and avian origin influenza viruses, enabling the emergence of highly virulent influenza strains. Human infection with swine influenza has been recorded in the past, both as sporadic infections and as outbreaks. The best known human swine influenza outbreak took place in Fort Dix (USA) in 1976, concluding in the immunization of almost 45 million U.S. citizens, in a highly controversial immunization program. The current H1N1 (S-OIV) Influenza outbreak was declared by the WHO as an influenza pandemic, setting to rest the lately popular question "when will the next pandemic occur?" and laying the foundations for the evaluation of preparedness plans. There is great importance in data collection and subsequent updating of current procedures and doctrines.
Lycett, Samantha; McLeish, Nigel J.; Robertson, Christopher; Carman, William; Baillie, Gregory; McMenamin, James; Rambaut, Andrew; Simmonds, Peter; Woolhouse, Mark
The spread of influenza has usually been described by a ‘density’ model, where the largest centres of population drive the epidemic within a country. An alternative model emphasizing the role of air travel has recently been developed. We have examined the relative importance of the two in the context of the 2009 H1N1 influenza epidemic in Scotland. We obtained genome sequences of 70 strains representative of the geographical and temporal distribution of H1N1 influenza during the summer and winter phases of the pandemic in 2009. We analysed these strains, together with another 128 from the rest of the UK and 292 globally distributed strains, using maximum-likelihood phylogenetic and Bayesian phylogeographical methods. This revealed strikingly different epidemic patterns within Scotland in the early and late parts of 2009. The summer epidemic in Scotland was characterized by multiple independent introductions from both international and other UK sources, followed by major local expansion of a single clade that probably originated in Birmingham. The winter phase, in contrast, was more diverse genetically, with several clades of similar size in different locations, some of which had no particularly close phylogenetic affinity to strains sampled from either Scotland or England. Overall there was evidence to support both models, with significant links demonstrated between North American sequences and those from England, and between England and East Asia, indicating that major air-travel routes played an important role in the pattern of spread of the pandemic, both within the UK and globally. PMID:22337637
Lepek, Krzysztof; Pajak, Beata; Rabalski, Lukasz; Urbaniak, Kinga; Kucharczyk, Krzysztof; Markowska-Daniel, Iwona; Szewczyk, Boguslaw
Monitoring and control of infections are key parts of surveillance systems and epidemiological risk prevention. In the case of influenza A viruses (IAVs), which show high variability, a wide range of hosts, and a potential of reassortment between different strains, it is essential to study not only people, but also animals living in the immediate surroundings. If understated, the animals might become a source of newly formed infectious strains with a pandemic potential. Special attention should be focused on pigs, because of the receptors specific for virus strains originating from different species, localized in their respiratory tract. Pigs are prone to mixed infections and may constitute a reservoir of potentially dangerous IAV strains resulting from genetic reassortment. It has been reported that a quadruple reassortant, A(H1N1)pdm09, can be easily transmitted from humans to pigs and serve as a donor of genetic segments for new strains capable of infecting humans. Therefore, it is highly desirable to develop a simple, cost-effective, and rapid method for evaluation of IAV genetic variability. We describe a method based on multitemperature single-strand conformational polymorphism (MSSCP), using a fragment of the hemagglutinin (HA) gene, for detection of coinfections and differentiation of genetic variants of the virus, difficult to identify by conventional diagnostic. PMID:25961024
Broberg, Eeva; Melidou, Angeliki; Prosenc, Katarina; Bragstad, Karoline; Hungnes, Olav
Influenza A(H1N1)pdm09 viruses predominated in the European influenza 2015/16 season. Most analysed viruses clustered in a new genetic subclade 6B.1, antigenically similar to the northern hemisphere vaccine component A/California/7/2009. The predominant influenza B lineage was Victoria compared with Yamagata in the previous season. It remains to be evaluated at the end of the season if these changes affected the effectiveness of the vaccine for the 2015/16 season.
Harvey, William T.; Benton, Donald J.; Gregory, Victoria; Hall, James P. J.; Daniels, Rodney S.; Bedford, Trevor; Haydon, Daniel T.; Hay, Alan J.; McCauley, John W.; Reeve, Richard
Determining phenotype from genetic data is a fundamental challenge. Identification of emerging antigenic variants among circulating influenza viruses is critical to the vaccine virus selection process, with vaccine effectiveness maximized when constituents are antigenically similar to circulating viruses. Hemagglutination inhibition (HI) assay data are commonly used to assess influenza antigenicity. Here, sequence and 3-D structural information of hemagglutinin (HA) glycoproteins were analyzed together with corresponding HI assay data for former seasonal influenza A(H1N1) virus isolates (1997–2009) and reference viruses. The models developed identify and quantify the impact of eighteen amino acid substitutions on the antigenicity of HA, two of which were responsible for major transitions in antigenic phenotype. We used reverse genetics to demonstrate the causal effect on antigenicity for a subset of these substitutions. Information on the impact of substitutions allowed us to predict antigenic phenotypes of emerging viruses directly from HA gene sequence data and accuracy was doubled by including all substitutions causing antigenic changes over a model incorporating only the substitutions with the largest impact. The ability to quantify the phenotypic impact of specific amino acid substitutions should help refine emerging techniques that predict the evolution of virus populations from one year to the next, leading to stronger theoretical foundations for selection of candidate vaccine viruses. These techniques have great potential to be extended to other antigenically variable pathogens. PMID:27057693
Kobayashi, Takaaki; Miwa, Takashi; Odawara, Masato
The major causes of central diabetes insipidus (CDI) are neoplastic or infiltrative lesions of the hypothalamus or pituitary gland, severe head injuries, or pituitary or hypothalamic surgery. Lymphocytic infundibuloneurophysitis (LINH) is associated with autoimmune inflammatory disease of the pituitary gland, but the exact etiology is unknown. CDI caused by viral infections has been rarely reported. Here, we describe the case of a 22-year-old man who was in good health until 2 months prior to admission, presented with acute development of polyuria and polydipsia, and showed increased urinary volume up to 9000 mL/day. The patient showed elevated serum osmolality and low urine osmolality, with a low level of antidiuretic hormone. Endocrinological findings revealed CDI, but his arterial pituitary function appeared normal. Magnetic resonance imaging revealed significant enlargement of the pituitary stalk. We suspected CDI due to LINH based on non-transsphenoidal biopsy findings. He was diagnosed as type A influenza,and given oral therapeutic agents. However, acute onset of polyuria and polydipsia occurred 10 days after the influenza diagnosis. The available epidemiological information regarding the outbreak of influenza around that time strongly suggested that the patient was infected with the A/H1N1 influenza virus, although this virus had not been detected on polymerase chain reaction testing. In the present case, the autoimmune mechanism of LINH may have been associated with novel influenza A/H1N1 virus infection.
Limited production capacity and delays in vaccine development are major obstacles to vaccination programs that are designed to mitigate a pandemic influenza. In order to evaluate and compare the impact of various vaccination strategies during a pandemic influenza, we developed an age/risk-structured model of influenza transmission, and parameterized it with epidemiological data from the 2009 H1N1 influenza A pandemic. Our model predicts that the impact of vaccination would be considerably diminished by delays in vaccination and staggered vaccine supply. Nonetheless, prioritizing limited H1N1 vaccine to individuals with a high risk of complications, followed by school-age children, and then preschool-age children, would minimize an over-all attack rate as well as hospitalizations and deaths. This vaccination scheme would maximize the benefits of vaccination by protecting the high-risk people directly, and generating indirect protection by vaccinating children who are most likely to transmit the disease. PMID:21361402
Lee, N-K; Lee, J-H; Lim, S-M; Lee, K A; Kim, Y B; Chang, P-S; Paik, H-D
Subcritical water extract (SWE) of Brassica juncea was studied for antiviral effects against influenza virus A/H1N1 and for the possibility of application as a nonfat milk supplement for use as an "antiviral food." At maximum nontoxic concentrations, SWE had higher antiviral activity against influenza virus A/H1N1 than n-hexane, ethanol, or hot water (80°C) extracts. Addition of 0.5mg/mL of B. juncea SWE to culture medium led to 50.35% cell viability (% antiviral activity) for Madin-Darby canine kidney cells infected with influenza virus A/H1N1. Nonfat milk supplemented with 0.28mg/mL of B. juncea SWE showed 39.62% antiviral activity against influenza virus A/H1N1. Thus, the use of B. juncea SWE as a food supplement might aid in protection from influenza viral infection.
Khodadad, Nastaran; Moattari, Afagh; Shamsi Shahr Abadi, Mahmoud; Kadivar, Mohammad Rahim; Sarvari, Jamal; Tavakoli, Forough; Pirbonyeh, Neda; Emami, Amir
Background: Oseltamivir has been used as a drug of choice for the prophylaxis and treatment of human influenza A(H1N1)pdm09 infection across the world. However, the most frequently identified oseltamivir resistant virus, influenza A(H1N1)pdm09, exhibit the H275Y substitution in NA gene. Objectives: This study aimed to determine the prevalence and phylogenetic relationships of oseltamivir resistance in influenza A(H1N1)pdm09 viruses isolated in Shiraz, Iran. Patients and Methods: Throat swab samples were collected from 200 patients with influenza-like disease from December 2012 until February 2013. A total of 77 influenza A(H1N1)pdm09 positive strains were identified by real-time polymerase chain reaction (PCR). Oseltamivir resistance was detected using quantal assay and nested-PCR method. The NA gene sequencing was conducted to detect oseltamivir-resistant mutants and establish the phylogeny of the prevalent influenza variants. Results: Our results revealed that A(H1N1)pdm09 viruses present in these samples were susceptible to oseltamivir, and contained 5 site specific mutations (V13G, V106I, V241I, N248D, and N369K) in NA gene. These mutations correlated with increasing expression and enzymatic activity of NA protein in the influenza A(H1N1)pdm09 viruses, which were closely related to a main influenza A(H1N1)pdm09 cluster isolated around the world. Conclusions: A(H1N1)pdm09 viruses, identified in this study in Shiraz, Iran, contained 5 site specific mutations and were susceptible to oseltamivir. PMID:26464773
Dickmann, P.; Rubin, G. J.; Gaber, W.; Wessely, S.; Wicker, S.; Serve, H.; Gottschalk, R.
Please cite this paper as: Dickmann et al. (2010) New Influenza A/H1N1 (“Swine Flu”): information needs of airport passengers and staff. . Influenza and Other Respiratory Viruses 5(1), 39–46. Background Airports are the entrances of infectious diseases. Particularly at the beginning of an outbreak, information and communication play an important role to enable the early detection of signs or symptoms and to encourage passengers to adopt appropriate preventive behaviour to limit the spread of the disease. Objectives To determine the adequacy of the information provided to airport passengers and staff in meeting their information needs in relation to their concerns. Methods At the start of the influenza A/H1N1 epidemic (29–30 April 2009), qualitative semi‐structured interviews (N = 101) were conducted at Frankfurt International Airport with passengers who were either returning from or going to Mexico and with airport staff who had close contact with these passengers. Interviews focused on knowledge about swine flu, information needs and fear or concern about the outbreak. Results The results showed that a desire for more information was associated with higher concern – the least concerned participants did not want any additional information, while the most concerned participants reported a range of information needs. Airport staff in contact with passengers travelling from the epicentre of the outbreak showed the highest levels of fear or concern, coupled with a desire to be adequately briefed by their employer. Conclusions Our results suggest that information strategies should address not only the exposed or potentially exposed but also groups that feel at risk. Identifying what information these different passenger and staff groups wish to receive will be an important task in any future infectious disease outbreak. PMID:21138539
Mesquita, Milene; Fintelman-Rodrigues, Natalia; Sacramento, Carolina Q.; Abrantes, Juliana L.; Costa, Eduardo; Temerozo, Jairo R.; Siqueira, Marilda M.; Bou-Habib, Dumith Chequer; Souza, Thiago Moreno L.
HIV-1-infected patients co-infected with A(H1N1)pdm09 surprisingly presented benign clinical outcome. The knowledge that HIV-1 changes the host homeostatic equilibrium, which may favor the patient resistance to some co-pathogens, prompted us to investigate whether HIV-1 infection could influence A(H1N1)pdm09 life cycle in vitro. We show here that exposure of A(H1N1)pdm09-infected epithelial cells to HIV-1 viral particles or its gp120 enhanced by 25% the IFITM3 content, resulting in a decrease in influenza replication. This event was dependent on toll-like receptor 2 and 4. Moreover, knockdown of IFITM3 prevented HIV-1 ability to inhibit A(H1N1)pdm09 replication. HIV-1 infection also increased IFITM3 levels in human primary macrophages by almost 100%. Consequently, the arrival of influenza ribonucleoproteins (RNPs) to nucleus of macrophages was inhibited, as evaluated by different approaches. Reduction of influenza RNPs entry into the nucleus tolled A(H1N1)pdm09 life cycle in macrophages earlier than usual, limiting influenza's ability to induce TNF-α. As judged by analysis of the influenza hemagglutin (HA) gene from in vitro experiments and from samples of HIV-1/A(H1N1)pdm09 co-infected individuals, the HIV-1-induced reduction of influenza replication resulted in delayed viral evolution. Our results may provide insights on the mechanisms that may have attenuated the clinical course of Influenza in HIV-1/A(H1N1)pdm09 co-infected patients during the recent influenza form 2009/2010. PMID:24978204
Dia, Ndongo; Ndiaye, Mbayame Niang; Monteiro, Maria de Lourdes; Koivogui, Lamine; Bara, Mohamed Ould; Diop, Ousmane M
During the pandemic 2009 episode, we conducted laboratory-based surveillance in four countries from West Africa: Senegal, Mauritania, Cape Verde, and Guinea. Specimens were obtained from 3,155 patients: 2,264 patients from Senegal, 498 patients from Cape Verde, 227 patients from Mauritania, and 166 patients from Guinea; 911 (28.9%) patients were positive for influenza, 826 (90.7%) patients were positive for influenza A, and 85 (9.3%) patients were positive for influenza B. Among the influenza A positives, 503 (60.9%) positives were H1N1pdm09, 314 (38.0%) positives were H3N2, and 9 (1.1%) positives were seasonal H1N1. The highest detection rate for seasonal influenza viruses (17.1%) occurred in the 5-14 years age group. However, for A(H1N1)pdm09, the detection rate was highest in the 15-24 years age group (35.8%). Based on the present study data, the timeline of detection of A(H1N1)pdm09 viruses in these four countries should be Cape Verde, Guinea, Mauritania, and finally, Senegal. Genetic and antigenic analyses were performed in some isolates.
Tsuneki, Akeno; Itagaki, Asao; Tsuchie, Hideaki; Tokuhara, Misato; Okada, Takayoshi; Narai, Sakae; Kasagi, Masaaki; Tanaka, Kiyoshi; Kageyama, Seiji
A novel swine-origin influenza A(H1N1)pdm09 virus has been circulating in humans since March-April, 2009. The 2009-2010 epidemic involved predominantly a single subtype of A(H1N1)pdm09 (at 96%, 46/48) in the sentinel sites of this study. However, A(H1N1)pdm09 started to circulate together with other type/subtype (49%, 33/68) at the first peak in the next epidemic season in 2010-2011: A(H1N1)pdm09/A(H3N2) (9%, 6/68), A(H1N1)pdm09/B (35%, 24/68), and A(H1N1)pdm09/A(H3N2)/B (4%, 3/68). Single infection of A(H1N1)pdm09 became a rare event (8%, 5/65) at the second peak of the same season in 2010-2011 compared with that at the first peak (50%, 34/68). Concurrently with this decline, single infections of others, A(H3N2) or B, became evident (6%, 4/65; 14%, 9/65, respectively). Triple infections were more common (29%, 19/65) at the second peak than at the first peak (4%). The A(H1N1)pdm09 detected in 2010-2011 produced less virus upon 72 hr of incubation in vitro after the inoculations at 10(4) and 3,300 copies/ml (2.3 × 10(9) and 2.3 × 10(9) copies/ml on average) than that in 2009-2010 (3.7 × 10(9) and 1.3 × 10(10) copies/ml on average; P<0.05 by ANOVA test), respectively. As described above, the replication capacity of A(H1N1)pdm09 seems to have deteriorated in the 2010-2011 season presumably due to substantial herd immunity and allowed the existence of other type/subtype. These results suggest that assessment of replication capacity is indispensable for analysis of influenza epidemics.
Background Mathematical and computational models for infectious diseases are increasingly used to support public-health decisions; however, their reliability is currently under debate. Real-time forecasts of epidemic spread using data-driven models have been hindered by the technical challenges posed by parameter estimation and validation. Data gathered for the 2009 H1N1 influenza crisis represent an unprecedented opportunity to validate real-time model predictions and define the main success criteria for different approaches. Methods We used the Global Epidemic and Mobility Model to generate stochastic simulations of epidemic spread worldwide, yielding (among other measures) the incidence and seeding events at a daily resolution for 3,362 subpopulations in 220 countries. Using a Monte Carlo Maximum Likelihood analysis, the model provided an estimate of the seasonal transmission potential during the early phase of the H1N1 pandemic and generated ensemble forecasts for the activity peaks in the northern hemisphere in the fall/winter wave. These results were validated against the real-life surveillance data collected in 48 countries, and their robustness assessed by focusing on 1) the peak timing of the pandemic; 2) the level of spatial resolution allowed by the model; and 3) the clinical attack rate and the effectiveness of the vaccine. In addition, we studied the effect of data incompleteness on the prediction reliability. Results Real-time predictions of the peak timing are found to be in good agreement with the empirical data, showing strong robustness to data that may not be accessible in real time (such as pre-exposure immunity and adherence to vaccination campaigns), but that affect the predictions for the attack rates. The timing and spatial unfolding of the pandemic are critically sensitive to the level of mobility data integrated into the model. Conclusions Our results show that large-scale models can be used to provide valuable real-time forecasts of
Talarek, Ewa; Dembiński, Łukasz; Radzikowski, Andrzej; Smalisz-Skrzypczyk, Katarzyna; Jackowska, Teresa; Marczyńska, Magdalena
In the autumn 2009 in Poland there was an outbreak of influenza A(H1N1)v, approximately 1/3 of confirmed cases in children younger than 14 years. The aim of the study was an epidemiologic and clinical characteristics of pediatric patients with influenza A(H1N1)v and evaluation of antiviral treatment safety. The medical records of 100 children with confirmed influenza A(H1N1)v were reviewed. 48% of children had risk factors for severe clinical course, including 23 younger than 2 years. The most common symptoms were fever (89%) and cough (68%). In 20% children pneumonia was diagnosed, other complications were uncommon. 4 patients required mechanical ventilation and 3 died, all with severe underlying conditions. In 62% of patients oseltamivir was used and it was well tolerated.
... HUMAN SERVICES Office of the Secretary Pandemic Influenza Vaccines--Amendment ACTION: Notice of... influenza vaccines, which has been amended a number of times. The original pandemic influenza vaccine... (2010). The major actions taken by this pandemic influenza vaccine declaration are the following:...
Trauer, James M; Bandaranayake, Don; Booy, Robert; Chen, Mark I; Cretikos, Michelle; Dowse, Gary K; Dwyer, Dominic E; Greenberg, Michael E; Huang, Q Sue; Khandaker, Gulam; Kok, Jen; Laurie, Karen L; Lee, Vernon J; McVernon, Jodie; Walter, Scott; Markey, Peter G
To estimate population attack rates of influenza A(H1N1)pdm2009 in the Southern Hemisphere during June-August 2009, we conducted several serologic studies. We pooled individual-level data from studies using hemagglutination inhibition assays performed in Australia, New Zealand, and Singapore. We determined seropositive proportions (titer ≥40) for each study region by age-group and sex in pre- and postpandemic phases, as defined by jurisdictional notification data. After exclusions, the pooled database consisted of, 4,414 prepandemic assays and 7,715 postpandemic assays. In the prepandemic phase, older age groups showed greater seropositive proportions, with age-standardized, community-based proportions ranging from 3.5% in Singapore to 11.9% in New Zealand. In the postpandemic phase, seropositive proportions ranged from 17.5% in Singapore to 30.8% in New Zealand, with highest proportions seen in school-aged children. Pregnancy and residential care were associated with lower postpandemic seropositivity, whereas Aboriginal and Torres Strait Islander Australians and Pacific Peoples of New Zealand had greater postpandemic seropositivity.
Ramírez-Salinas, Gema L; García-Machorro, J; Quiliano, Miguel; Zimic, Mirko; Briz, Verónica; Rojas-Hernández, Saul; Correa-Basurto, J
The goal of this study was to identify neuraminidase (NA) residue mutants from human influenza AH1N1 using sequences from 1918 to 2012. Multiple alignment studies of complete NA sequences (5732) were performed. Subsequently, the crystallographic structure of the 1918 influenza (PDB ID: 3BEQ-A) was used as a wild-type structure and three-dimensional (3-D) template for homology modeling of the mutated selected NA sequences. The 3-D mutated NAs were refined using molecular dynamics (MD) simulations (50 ns). The refined 3-D models were used to perform docking studies using oseltamivir. Multiple sequence alignment studies showed seven representative mutations (A232V, K262R, V263I, T264V, S367L, S369N, and S369K). MD simulations applied to 3-D NAs showed that each NA had different active-site shapes according to structural surface visualization and docking results. Moreover, Cartesian principal component analyses (cPCA) show structural differences among these NA structures caused by mutations. These theoretical results suggest that the selected mutations that are located outside of the active site of NA could affect oseltamivir recognition and could be associated with resistance to oseltamivir.
Song, Min-Suk; Baek, Yun Hee; Pascua, Philippe Noriel Q; Kwon, Hyeok-Il; Park, Su-Jin; Kim, Eun-Ha; Lim, Gyo-Jin; Choi, Young-Ki
The constant threat of newly emerging influenza viruses with pandemic potential requires the need for prompt vaccine production. Here, we utilized the Vero cell polymerase I (PolI) promoter, rather than the commonly used human PolI promoter, in an established reverse-genetics system to rescue viable influenza viruses in Vero cells, an approved cell line for human vaccine production. The Vero PolI promoter was more efficient in Vero cells and demonstrated enhanced transcription levels and virus rescue rates commensurate with that of the human RNA PolI promoter in 293T cells. These results appeared to be associated with more efficient generation of A(H1N1)pdm09- and H5N1-derived vaccine seed viruses in Vero cells, whilst the rescue rates in 293T cells were comparable. Our study provides an alternative means for improving vaccine preparation by using a novel reverse-genetics system for generating influenza A viruses.
Iskander, John; Haber, Penina; Herrera, Guillermo
In the event that a vaccine is available during an influenza pandemic, vaccine safety monitoring will occur as part of comprehensive public health surveillance of the vaccination campaign. Though inactivated influenza vaccines have been widely used in the United States and much is known about their safety profile, attention will need to be paid to both common self-limited adverse reactions and rarer, more serious events that may or may not be causally related to vaccination. The primary surveillance systems used to generate and test hypotheses about vaccine safety concerns are the Vaccine Adverse Event Reporting System (VAERS) and the Vaccine Safety Datalink (VSD), respectively. Examples of recent use of these systems to investigate influenza vaccine safety and enhancements planned for use during a pandemic are presented. Ethical issues that will need to be addressed as part of an overall vaccine safety response include risk communication and injury compensation. Advance planning and the use of available technologic solutions are needed to respond to the scientific and logistic challenges involved in safely implementing mass vaccination during a pandemic. PMID:17132333
Panagiotopoulos, T; Bonovas, S; Danis, K; Iliopoulos, D; Dedoukou, X; Pavli, A; Smeti, P; Mentis, A; Kossivakis, A; Melidou, A; Diza, E; Chatzidimitriou, D; Koratzanis, E; Michailides, S; Passalidou, E; Kollaras, P; Nikolaides, P; Tsiodras, S
On 26 and 27 May, the Hellenic Centre for Disease Control and Prevention in Greece reported two confirmed cases of new influenza A(H1N1) virus infection in travellers returning from Scotland. The two cases had no apparent traceable links to an infectious source. Herein we report details of the two cases and potential public health implications.
Zhu, Wenfei; Zhang, Hong; Xiang, Xingyu; Zhong, Lili; Yang, Lei; Guo, Junfeng; Xie, Yiran; Li, Fangcai; Deng, Zhihong; Feng, Hong; Huang, Yiwei; Hu, Shixiong; Xu, Xin; Zou, Xiaohui; Li, Xiaodan; Bai, Tian; Chen, Yongkun; Li, Zi
In 2015, a novel influenza A(H1N1) virus was isolated from a boy in China who had severe pneumonia. The virus was a genetic reassortant of Eurasian avian-like influenza A(H1N1) (EA-H1N1) virus. The hemagglutinin, neuraminidase, and matrix genes of the reassortant virus were highly similar to genes in EA-H1N1 swine influenza viruses, the polybasic 1 and 2, polymerase acidic, and nucleoprotein genes originated from influenza A(H1N1)pdm09 virus, and the nonstructural protein gene derived from classical swine influenza A(H1N1) (CS H1N1) virus. In a mouse model, the reassortant virus, termed influenza A/Hunan/42443/2015(H1N1) virus, showed higher infectivity and virulence than another human EA-H1N1 isolate, influenza A/Jiangsu/1/2011(H1N1) virus. In the respiratory tract of mice, virus replication by influenza A/Hunan/42443/2015(H1N1) virus was substantially higher than that by influenza A/Jiangsu/1/2011(H1N1) virus. Human-to-human transmission of influenza A/Hunan/42443/2015(H1N1) virus has not been detected; however, given the circulation of novel EA-H1N1 viruses in pigs, enhanced surveillance should be instituted among swine and humans. PMID:27767007
Trebbien, Ramona; Pedersen, Svend Stenvang; Vorborg, Kristine; Franck, Kristina Træholt; Fischer, Thea Kølsen
Antiviral treatment of immunocompromised patients with prolonged influenza virus infection can lead to multidrug resistance. This study reveals the selection of antiviral resistance mutations in influenza A(H1N1)pdm09 virus in an immunocompromised patient during a 6-month period. The patient was treated with two courses of oseltamivir (5 days and 2 months, respectively), with the first course starting at symptom onset, and subsequently zanamivir (2 months and 10 days, respectively). Respiratory samples were investigated by Sanger and next generation sequencing (NGS) and, for NGS data, low-frequency-variant-detection analysis was performed. Neuraminidase-inhibition tests were conducted for samples isolated in Madin-Darby canine kidney cells. In a sample collected 15 days after the end of the first treatment with oseltamivir (Day 20 post-symptom onset), oseltamivir resistance was detected (mutation H275Y with 60.3% frequency by NGS). Day 149 when the patient had almost completed the second zanamivir treatment, mixes of the following resistance mutations were detected; H275Y(65.1%), I223R(9.2%), and E119G(89.6%), accompanied by additional mutations, showing a more complex viral population in the long-term treated patient. Two samples obtained on Day 151 from bronchoalveolar lavage (BAL) and nasopharyngeal swab, respectively, showed different mutation profiles, with a higher frequency of antiviral resistance mutations in BAL. The results emphasise the importance of timely antiviral resistance testing both for treatment of individual patients as well as for preventive measures to control the development and transmission of antiviral resistant viruses. PMID:28128091
Mitamura, Keiko; Kawakami, Chiharu; Shimizu, Hideaki; Abe, Takashi; Konomi, Yasushi; Yasumi, Yuki; Yamazaki, Masahiko; Ichikawa, Masataka; Sugaya, Norio
We evaluated Clearline Influenza A/B/(H1N1)2009, a new multi-line immunochromatographic assay for rapid detection of antigens of influenza A (Flu A), B (Flu B), and A(H1N1)2009 viruses. Clearline detected Flu A, Flu B, and A(H1N1)2009 viruses with a detection limit of 4.6 × 10(3) to 7.5 × 10(4) pfu/assay. The sensitivity and specificity of detection of influenza virus by Clearline, using RT-PCR as reference standard, were determined for A(H1N1)2009, Flu A, and Flu B, in nasopharyngeal aspirate, nasopharyngeal swab, and self-blown nasal discharge specimens. Sensitivity for nasopharyngeal aspirate specimens was: A(H1N1)2009 = 97.3 %, Flu A = 94.5 %, and Flu B = 96.8 %, and specificity was Flu A = 99.1 % and Flu B = 100 %. Sensitivity for nasopharyngeal swab specimens was: A(H1N1)2009 = 91.9 %, Flu A = 92.8 %, and Flu B = 100 %, and specificity was Flu A = 98.2 % and Flu B = 100 %. Sensitivity for self-blown nasal discharge specimens was: A(H1N1)2009 = 75.7 %, Flu A = 86.5 %, and Flu B = 76.2 %, and specificity was Flu A = 98.4 % and Flu B = 100 %. Sensitivity and specificity of Clearline were sufficient for nasopharyngeal aspirate and swab specimens. For self-blown nasal discharge specimens, sensitivity was lower than for nasopharyngeal aspirates and nasopharyngeal swabs. The sensitivity of Clearline for A(H1N1)2009 was good even 6 h after the onset of symptoms. These findings suggest that Clearline may be useful for early clinical diagnosis of influenza.
Moncorgé, Olivier; Panthu, Baptiste; Prchal, Jan; Décimo, Didier; Ohlmann, Théophile; Lina, Bruno; Favard, Cyril; Decroly, Etienne; Ottmann, Michèle; Roingeard, Philippe; Muriaux, Delphine
The influenza A(H1N1)pdm09 virus caused the first influenza pandemic of the 21st century. In this study, we wanted to decipher the role of conserved basic residues of the viral M1 matrix protein in virus assembly and release. M1 plays many roles in the influenza virus replication cycle. Specifically, it participates in viral particle assembly, can associate with the viral ribonucleoprotein complexes and can bind to the cell plasma membrane and/or the cytoplasmic tail of viral transmembrane proteins. M1 contains an N-terminal domain of 164 amino acids with two basic domains: the nuclear localization signal on helix 6 and an arginine triplet (R76/77/78) on helix 5. To investigate the role of these two M1 basic domains in influenza A(H1N1)pdm09 virus molecular assembly, we analyzed M1 attachment to membranes, virus-like particle (VLP) production and virus infectivity. In vitro, M1 binding to large unilamellar vesicles (LUVs), which contain negatively charged lipids, decreased significantly when the M1 R76/77/78 motif was mutated. In cells, M1 alone was mainly observed in the nucleus (47%) and in the cytosol (42%). Conversely, when co-expressed with the viral proteins NS1/NEP and M2, M1 was relocated to the cell membranes (55%), as shown by subcellular fractionation experiments. This minimal system allowed the production of M1 containing-VLPs. However, M1 with mutations in the arginine triplet accumulated in intracellular clusters and its incorporation in VLPs was strongly diminished. M2 over-expression was essential for M1 membrane localization and VLP production, whereas the viral trans-membrane proteins HA and NA seemed dispensable. These results suggest that the M1 arginine triplet participates in M1 interaction with membranes. This R76/77/78 motif is essential for M1 incorporation in virus particles and the importance of this motif was confirmed by reverse genetic demonstrating that its mutation is lethal for the virus. These results highlight the molecular
In late March of 2009, an outbreak of influenza in Mexico, was eventually identified as H1N1 influenza A. In June 2009, the World Health Organization raised a pandemic alert to the highest level. More than 214 countries have reported confirmed cases of pandemic H1N1 influenza A. In Korea, the first case of pandemic influenza A/H1N1 infection was reported on May 2, 2009. Between May 2009 and August 2010, 750,000 cases of pandemic influenza A/H1N1 were confirmed by laboratory test. The H1N1-related death toll was estimated to reach 252 individuals. Almost one billion cases of influenza occurs globally every year, resulting in 300,000 to 500,000 deaths. Influenza vaccination induces virus-neutralizing antibodies, mainly against hemagglutinin, which provide protection from invading virus. New quadrivalent inactivated influenza vaccine generates similar immune responses against the three influenza strains contained in two types of trivalent vaccines and superior responses against the additional B strain. PMID:27066083
Samson, Mélanie; Abed, Yacine; Desrochers, François-Marc; Hamilton, Stephanie; Luttick, Angela; Tucker, Simon P.; Pryor, Melinda J.
Neuraminidase inhibitors (NAIs) play a major role for managing influenza virus infections. The widespread oseltamivir resistance among 2007-2008 seasonal A(H1N1) viruses and community outbreaks of oseltamivir-resistant A(H1N1)pdm09 strains highlights the need for additional anti-influenza virus agents. Laninamivir is a novel long-lasting NAI that has demonstrated in vitro activity against influenza A and B viruses, and its prodrug (laninamivir octanoate) is in phase II clinical trials in the United States and other countries. Currently, little information is available on the mechanisms of resistance to laninamivir. In this study, we first performed neuraminidase (NA) inhibition assays to determine the activity of laninamivir against a set of influenza A viruses containing NA mutations conferring resistance to one or many other NAIs. We also generated drug-resistant A(H1N1) and A(H3N2) viruses under in vitro laninamivir pressure. Laninamivir demonstrated a profile of susceptibility that was similar to that of zanamivir. More specifically, it retained activity against oseltamivir-resistant H275Y and N295S A(H1N1) variants and the E119V A(H3N2) variant. In vitro, laninamivir pressure selected the E119A NA substitution in the A/Solomon Islands/3/2006 A(H1N1) background, whereas E119K and G147E NA changes along with a K133E hemagglutinin (HA) substitution were selected in the A/Quebec/144147/2009 A(H1N1)pdm09 strain. In the A/Brisbane/10/2007 A(H3N2) background, a large NA deletion accompanied by S138A/P194L HA substitutions was selected. This H3N2 variant had altered receptor-binding properties and was highly resistant to laninamivir in plaque reduction assays. Overall, we confirmed the similarity between zanamivir and laninamivir susceptibility profiles and demonstrated that both NA and HA changes can contribute to laninamivir resistance in vitro. PMID:24957832
Marques, Joana Isabel; Ribeiro Vaz, Inês; Santos, Cristina; Polónia, Jorge
Introdução: Os profissionais de saúde foram um grupo prioritário para vacinação contra a pandemia da Gripe A (H1N1), Pandemrix®. Assim, monitorizar os eventos adversos relacionados com esta vacina neste grupo específico poderá originar informação valiosa relacionada com o perfil de segurança da vacina. O nosso objetivo foi identificar os eventos adversos após imunização com a vacina Pandemrix® em profissionais de saúde. Material e Métodos: Foi desenhado um questionário de monitorização dos eventos adversos ocorridos com a vacina Pandemrix®. O questionário foi distribuído aos profissionais de saúde a trabalhar em três centros hospitalares da região norte do País, vacinados no período de 26 de Outubro de 2009 a 31 de janeiro de 2009. Resultados: Dos 2358 profissionais de saúde que aceitaram participar no estudo, 864 (37%) devolveram o questionário preenchido. Destes, 73% experienciaram pelo menos um evento adverso após imunização, mas só 8% experienciaram um evento inesperado. Os eventos adversos mais frequentemente reportados foram os esperados e muito comuns: reações locais no local de administração (57%), mialgia (31%), fadiga (incluindo astenia) (24%) e dor de cabeça (19%). Não foram reportados casos de eventos de maior gravidade para a saúde, tais como morte ou risco de vida. O género feminino e a existência de doença de base foram fatores de risco independentes para o desenvolvimento de pelo menos um evento adverso após imunização com a Pandemrix®. Conclusões: O nosso trabalho sugere um perfil de segurança aceitável da vacina pandémica Pandermix® em profissionais de saúde. Tanto a frequência como a severidade dos eventos adversos não se verificaram superiores ao esperado.
Phillips, J. C.
Influenza virus contains two highly variable envelope glycoproteins, hemagglutinin (HA) and neuraminidase (NA). Here we show that, while HA evolution is much more complex than NA evolution, it still shows abrupt punctuation changes linked to punctuation changes of NA. HA exhibits proteinquakes, which resemble earthquakes and are related to hydropathic shifting of sialic acid binding regions. HA proteinquakes based on shifting sialic acid interactions are required for optimal balance between the receptor-binding and receptor-destroying activities of HA and NA for efficient virus replication. Our comprehensive results present a historical (1945–2011) panorama of HA evolution over thousands of strains and are consistent with many studies of HA and NA interactions based on a few mutations of a few strains. PMID:25654090
Hincapié, Doracelly; Ospina, Juan
Algebraic analysis of social networks exhibited by SARS-Beijing-2003 and AH1N1 flu-México-2009 was realized. The main tools were the Tutte polynomials and Maple package Graph-Theory. The topological structures like graphs and networks were represented by invariant polynomials. The evolution of a given social network was represented like an evolution of the algebraic complexity of the corresponding Tutte polynomial. The reduction of a given social network was described like an involution of the algebraic complexity of the associated Tutte polynomial. The outbreaks of SARS and AH1N1 Flu were considered like represented by a reduction of previously existing contact networks via the control measures executed by health authorities. From Tutte polynomials were derived numerical indicators about efficiency of control measures.
Li, Hui; Cao, Bin
The intermittent outbreak of pandemic influenza and emergence of novel avian influenza A virus is worldwide threat. Although most patients present with mild symptoms, some deteriorate to severe pneumonia and even death. Great progress in the understanding of the mechanism of disease pathogenesis and a series of vaccines has been promoted worldwide; however, incidence, morbidity, and mortality remains high. To step up vigilance and improve pandemic preparedness, this article elucidates the virology, epidemiology, pathogenesis, clinical characteristics, and treatment of human infections by influenza A viruses, with an emphasis on the influenza A(H1N1)pdm09, H5N1, and H7N9 subtypes.
Friede, M; Serdobova, I; Palkonyay, L; Kieny, M P
Increase of influenza vaccine production capacity in developing countries has been identified as an important element of global pandemic preparedness. Nevertheless, technology transfer for influenza vaccine production to developing country vaccine manufacturers has proven difficult because of lack of interested technology providers. As an alternative to an individual provider-recipient relationship, a technology and training platform (a "hub") for a generic non-proprietary process was established at a public sector European manufacturer's site. The conditions for setting up such a platform and the potential applicability of this model to other biologicals are discussed.
Ahmed, S Sohail; Montomoli, Emanuele; Pasini, Franco Laghi; Steinman, Lawrence
Despite the very high benefit-to-risk ratio of vaccines, the fear of negative side effects has discouraged many people from getting vaccinated, resulting in the reemergence of previously controlled diseases such as measles, pertussis and diphtheria. This fear has been amplified more recently by multiple epidemiologic studies that confirmed the link of an AS03-adjuvanted pandemic influenza vaccine (Pandemrix, GlaxoSmithKline Biologicals, Germany) used in Europe during the 2009 H1N1 influenza pandemic [A(H1N1) pdm09] with the development of narcolepsy, a chronic sleep disorder, in children and adolescents. However, public misperceptions of what adjuvants are and why they are used in vaccines has created in some individuals a closed "black box" attitude towards all vaccines. The focus of this review article is to revisit this "black box" using the example of narcolepsy associated with the European AS03-adjuvanted pandemic influenza vaccine.
Seringe, E; Agut, H
The outbreak of influenza A(H1N1)pdm09 was a challenge for the laboratories of Paris Île-de-France region in charge of virological diagnosis. In order to evaluate the quality of their response to this challenge, a retrospective survey based on a self-administered standardized questionnaire was undertaken among the 18 hospital laboratories involved in A(H1N1)pdm09 virus detection over a period of 10 months from April 2009 to January 2010. All concerned laboratories responded to the survey. Due to imposed initial biosafety constraints and indications, virological diagnosis was performed in only two laboratories at the start of the studied period. Step by step, it was further settled in the other laboratories starting from June to November 2009. From the beginning, A(H1N1)pdm09-specific RT-PCR was considered the reference method while the use of rapid influenza detection tests remained temporary and concerned a minority of these laboratories. Among the overall 21,656 specimens received, a positive diagnosis of influenza A(H1N1)pdm09 was obtained in 5,390 cases (25%), the positivity range being significantly higher among women as compared to men (P<0.0001) and subjects below 45 years of age as compared to those over 65 years (P<0.0001). Two peaks in positivity frequency were observed at weeks 24 (30%, 8-12 June 2009) and 44 (50%, 26-30 October 2009) respectively, the latter one occurring 2 weeks earlier than the peak of epidemic at the national level. In contrast, a low positivity rate was detected at weeks 38-40 in relationship with other respiratory virus infections which were clinically misinterpreted as a peak of influenza epidemic. These data demonstrate the ability of medical virology laboratories of Paris Île-de-France region to provide in real time a valuable diagnosis of A(H1N1)pdm09 virus infection and a relevant view of outbreak evolution, suggesting they will be a crucial component in the management of future influenza epidemics.
Henrich, Natalie J
Communicating effectively with the public about the importance of vaccination during a pandemic poses a challenge to health communicators. The public's concerns about the safety, effectiveness and necessity of vaccines lead many people to refuse vaccination and the current communication strategies are often unsuccessful at overcoming the public's resistance to vaccinate. Convincing the public to receive a vaccination, especially during a pandemic when there can be so much uncertainty about the vaccine and the disease, requires a revised communication approach. This revised approach should integrate into messages information that the public identifies as important, as well as presenting messages in a way that is consistent with our evolved social learning biases. These biases will impact both the content of the message and who delivers the message to different target populations. Additionally, an improved understanding between media and health communicators about the role each plays during a crisis may increase the effectiveness of messages disseminated to the public. Lastly, given that the public is increasingly seeking health information from on-line and other electronic sources, health communication needs to continue to find ways to integrate new technologies into communication strategies.
Prosper, Olivia; Saucedo, Omar; Thompson, Doria; Torres-Garcia, Griselle; Wang, Xiaohong; Castillo-Chavez, Carlos
The lessons learned from the 2009-2010 H1N1 influenza pandemic, as it moves out of the limelight, should not be under-estimated, particularly since the probability of novel influenza epidemics in the near future is not negligible and the potential consequences might be huge. Hence, as the world, particularly the industrialized world, responded to the potentially devastating effects of this novel A-H1N1 strain with substantial resources, reminders of the recurrent loss of life from a well established foe, seasonal influenza, could not be ignored. The uncertainties associated with the reported and expected levels of morbidity and mortality with this novel A-H1N1 live in a backdrop of deaths, over 200,000 hospitalizations, and millions of infections (20% of the population) attributed to seasonal influenza in the USA alone, each year. So, as the Northern Hemisphere braced for the possibility of a potentially "lethal" second wave of the novel A-H1N1 without a vaccine ready to mitigate its impact, questions of who should be vaccinated first if a vaccine became available, came to the forefront of the discussion. Uncertainty grew as we learned that the vaccine, once available, would be unevenly distributed around the world. Nations capable of acquiring large vaccine supplies soon became aware that those who could pay would have to compete for a limited vaccine stockpile. The challenges faced by nations dealing jointly with seasonal and novel A-H1N1 co-circulating strains under limited resources, that is, those with no access to novel A-H1N1 vaccine supplies, limited access to the seasonal influenza vaccine, and limited access to antivirals (like Tamiflu) are explored in this study. One- and two-strain models are introduced to mimic the influenza dynamics of a single and co-circulating strains, in the context of a single epidemic outbreak. Optimal control theory is used to identify and evaluate the "best" control policies. The controls account for the cost associated with
Lipsitch, Marc; Lajous, Martin; O'Hagan, Justin J.; Cohen, Ted; Miller, Joel C.; Goldstein, Edward; Danon, Leon; Wallinga, Jacco; Riley, Steven; Dowell, Scott F.; Reed, Carrie; McCarron, Meg
Background An accurate estimate of the total number of cases and severity of illness of an emerging infectious disease is required both to define the burden of the epidemic and to determine the severity of disease. When a novel pathogen first appears, affected individuals with severe symptoms are more likely to be diagnosed. Accordingly, the total number of cases will be underestimated and disease severity overestimated. This problem is manifest in the current epidemic of novel influenza A/H1N1. Methods and Results We used a simple approach to leverage measures of incident influenza A/H1N1 among a relatively small and well observed group of US, UK, Spanish and Canadian travelers who had visited Mexico to estimate the incidence among a much larger and less well surveyed population of Mexican residents. We estimate that a minimum of 113,000 to 375,000 cases of novel influenza A/H1N1 have occurred in Mexicans during the month of April, 2009. Such an estimate serves as a lower bound because it does not account for underreporting of cases in travelers or for nonrandom mixing between Mexican residents and visitors, which together could increase the estimates by more than an order of magnitude. Conclusions We find that the number of cases in Mexican residents may exceed the number of confirmed cases by two to three orders of magnitude. While the extent of disease spread is greater than previously appreciated, our estimate suggests that severe disease is uncommon since the total number of cases is likely to be much larger than those of confirmed cases. PMID:19742302
Mossad, Sherif B
Influenza vaccination remains our best measure to prevent epidemic and pandemic influenza. We must continue to improve vaccination rates for targeted populations. Antiviral options are currently limited to the neuraminidase inhibitors.
Zhang, Lijie; Peng, Zhibin; Ou, Jianming; Zeng, Guang; Fontaine, Robert E; Liu, Mingbin; Cui, Fuqiang; Hong, Rongtao; Zhou, Hang; Huai, Yang; Chuang, Shuk-Kwan; Leung, Yiu-Hong; Feng, Yunxia; Luo, Yuan; Shen, Tao; Zhu, Bao-Ping; Widdowson, Marc-Alain; Yu, Hongjie
In response to several influenza A(H1N1)pdm09 infections that developed in passengers after they traveled on the same 2 flights from New York, New York, USA, to Hong Kong, China, to Fuzhou, China, we assessed transmission of influenza A(H1N1)pdm09 virus on these flights. We defined a case of infection as onset of fever and respiratory symptoms and detection of virus by PCR in a passenger or crew member of either flight. Illness developed only in passengers who traveled on the New York to Hong Kong flight. We compared exposures of 9 case-passengers with those of 32 asymptomatic control-passengers. None of the 9 case-passengers, compared with 47% (15/32) of control-passengers, wore a face mask for the entire flight (odds ratio 0, 95% CI 0-0.71). The source case-passenger was not identified. Wearing a face mask was a protective factor against influenza infection. We recommend a more comprehensive intervention study to accurately estimate this effect.
Abed, Yacine; Pizzorno, Andrés; Bouhy, Xavier; Boivin, Guy
Permissive neuraminidase (NA) substitutions such as R222Q, V234M and D344N have facilitated the emergence and worldwide spread of oseltamivir-resistant influenza A/Brisbane/59/2007 (H1N1)-H275Y viruses. However, the potential contribution of genetic changes in other viral segments on viral fitness remains poorly investigated. A series of recombinant A(H1N1)pdm09 and A/WSN/33 7:1 reassortants containing the wild-type (WT) A/Brisbane/59/2007 NA gene or its single (H275Y) and double (H275Y/Q222R, H275Y/M234V and H275Y/N344D) variants were generated and their replicative properties were assessed in vitro. The Q222R reversion substitution significantly reduced viral titers when evaluated in both A(H1N1)pdm09 and A/WSN/33 backgrounds. The permissive role of the R222Q was further confirmed using A/WSN/33 7:1 reassortants containing the NA gene of the oseltamivir-susceptible or oseltamivir-resistant influenza A/Mississippi/03/2001 strains. Therefore, NA permissive substitutions play a dominant role for improving viral replication of oseltamivir-resistant A (H1N1)-H275Y viruses in vitro.
Zhang, Lijie; Peng, Zhibin; Ou, Jianming; Zeng, Guang; Fontaine, Robert E.; Liu, Mingbin; Cui, Fuqiang; Hong, Rongtao; Zhou, Hang; Huai, Yang; Chuang, Shuk-Kwan; Leung, Yiu-Hong; Feng, Yunxia; Luo, Yuan; Shen, Tao; Zhu, Bao-Ping; Widdowson, Marc-Alain
In response to several influenza A(H1N1)pdm09 infections that developed in passengers after they traveled on the same 2 flights from New York, New York, USA, to Hong Kong, China, to Fuzhou, China, we assessed transmission of influenza A(H1N1)pdm09 virus on these flights. We defined a case of infection as onset of fever and respiratory symptoms and detection of virus by PCR in a passenger or crew member of either flight. Illness developed only in passengers who traveled on the New York to Hong Kong flight. We compared exposures of 9 case-passengers with those of 32 asymptomatic control-passengers. None of the 9 case-passengers, compared with 47% (15/32) of control-passengers, wore a face mask for the entire flight (odds ratio 0, 95% CI 0–0.71). The source case-passenger was not identified. Wearing a face mask was a protective factor against influenza infection. We recommend a more comprehensive intervention study to accurately estimate this effect. PMID:23968983
Lee, Vernon J.; Tok, Mei Yin; Chow, Vincent T.; Phua, Kai Hong; Ooi, Eng Eong; Tambyah, Paul A.; Chen, Mark I.
Background All influenza pandemic plans advocate pandemic vaccination. However, few studies have evaluated the cost-effectiveness of different vaccination strategies. This paper compares the economic outcomes of vaccination compared with treatment with antiviral agents alone, in Singapore. Methodology We analyzed the economic outcomes of pandemic vaccination (immediate vaccination and vaccine stockpiling) compared with treatment-only in Singapore using a decision-based model to perform cost-benefit and cost-effectiveness analyses. We also explored the annual insurance premium (willingness to pay) depending on the perceived risk of the next pandemic occurring. Principal Findings The treatment-only strategy resulted in 690 deaths, 13,950 hospitalization days, and economic cost of USD$497 million. For immediate vaccination, at vaccine effectiveness of >55%, vaccination was cost-beneficial over treatment-only. Vaccine stockpiling is not cost-effective in most scenarios even with 100% vaccine effectiveness. The annual insurance premium was highest with immediate vaccination, and was lower with increased duration to the next pandemic. The premium was also higher with higher vaccine effectiveness, attack rates, and case-fatality rates. Stockpiling with case-fatality rates of 0.4–0.6% would be cost-beneficial if vaccine effectiveness was >80%; while at case-fatality of >5% stockpiling would be cost-beneficial even if vaccine effectiveness was 20%. High-risk sub-groups warrant higher premiums than low-risk sub-groups. Conclusions The actual pandemic vaccine effectiveness and lead time is unknown. Vaccine strategy should be based on perception of severity. Immediate vaccination is most cost-effective, but requires vaccines to be available when required. Vaccine stockpiling as insurance against worst-case scenarios is also cost-effective. Research and development is therefore critical to develop and stockpile cheap, readily available effective vaccines. PMID:19771173
Hsieh, Ying-Hen; Huang, Hsiang-Min; Lan, Yu-Ching
) pdm09 was substantially higher at r = 0.89 (95% CI: 0.49, 1.28), in fact highest among all the waves detected in this study. Moreover, when AH3 or A(H1N1)pdm09 exhibit high incidence, reported cases of subtype B decreases and vice versa. Further modeling analysis indicated that during the study period, Taiwan nearly experienced at least one wave of influenza epidemic of some strain every summer except in 2012. Discussion Estimates of R for seasonal influenza are consistent with that of temperate and tropical-subtropical regions, while estimate of R for A(H1N1)pdm09 is comparatively less than countries in Europe and North America, but similar to that of tropical-subtropical regions. This offers indication of regional differences in transmissibility of influenza virus that exists only for pandemic influenza. Despite obvious limitations in the data used, this study, designed to qualitatively compare the temporal patterns and transmissibility of the waves of different strains, illustrates how influenza subtyping data can be utilized to explore the mechanism for various influenza strains to compete or to circulate, to possibly provide predictors of future trends in the evolution of influenza viruses of various subtypes, and perhaps more importantly, to be of use to future annual seasonal influenza vaccine design. PMID:27139905
Virk, Ramandeep Kaur; Gunalan, Vithiagaran; Lee, Hong Kai; Inoue, Masafumi; Chua, Catherine; Tan, Boon-Huan; Tambyah, Paul Anantharajah
Background In the recent years, the data on the molecular epidemiology of influenza viruses have expanded enormously because of the availability of cutting-edge sequencing technologies. However, much of the information is from the temperate regions with few studies from tropical regions such as South-east Asia. Despite the fact that influenza has been known to transmit rapidly within semi-closed communities, such as military camps and educational institutions, data are limited from these communities. Objectives To determine the phylogeography of influenza viruses on a university campus, we examined the spatial distribution of influenza virus on the National University of Singapore (NUS) campus. Methods Consenting students from the NUS who sought medical attention at the UHC provided two nasopharyngeal swabs and demographic data. PCR was used for detection of influenza viruses. 34 full-genomes of pH1N1/09 viruses were successfully sequenced by Sanger method and concatenated using Geneious R7. Phylogenetic analysis was conducted using these 34 sequences and 1518 global sequences. Phylogeographic analysis was done using BaTS software and Association index and Fitch parsimony scores were determined. Results Integrating whole genome sequencing data with epidemiological data, we found strong evidence of influenza transmission on campus as isolates from students residing on-campus were highly similar to each other (AI, P value = 0.009; PS, P value = 0.04). There was also evidence of multiple introductions from the community. Conclusions Such data are useful in formulating pandemic preparedness plans which can use these communities as sentinel sites for detection and monitoring of emerging respiratory viral infections. PMID:28060851
Ahmed, S. Sohail; Steinman, Lawrence
ABSTRACT We previously reported an increased frequency of antibodies to hypocretin (HCRT) receptor 2 in sera obtained from narcoleptic patients who received the European AS03-adjuvanted vaccine Pandemrix (GlaxoSmithKline Biologicals, s.a.) for the global influenza A H1N1 pandemic in 2009 [A(H1N1)pdm09]. These antibodies cross-reacted with a particular fragment of influenza nucleoprotein (NP) – one of the proteins naturally contained in the virus used to make seasonal influenza vaccine and pandemic influenza vaccines. The purpose of this commentary is to provide additional insights and interpretations of the findings and share additional data not presented in the original paper to help the reader appreciate the key messages of that publication. First, a brief background to narcolepsy and vaccine-induced narcolepsy will be provided. Then, additional insights and clarification will be provided on the following topics: 1) the critical difference identified in the adjuvanted A(H1N1)pdm09 vaccines, 2) the contributing factor likely for the discordant association of narcolepsy between the AS03-adjuvanted pandemic vaccines Pandemrix and Arepanrix (GlaxoSmithKline Biologicals, s.a.), 3) the significance of detecting HCRT receptor 2 (HCRTr2) antibodies in some Finnish control subjects, 4) the approach used for the detection of HCRTr2 antibodies in vaccine-associated narcolepsy, and 5) the plausibility of the proposed mechanism involving HCRTr2 modulation in vaccine-associated narcolepsy. PMID:27031682
Brett, Stephen J.; Enstone, Joanne E.; Read, Robert C.; Openshaw, Peter J. M.; Semple, Malcolm G.; Lim, Wei Shen; Taylor, Bruce L.; McMenamin, James; Nicholson, Karl G.; Bannister, Barbara; Nguyen-Van-Tam, Jonathan S.
Introduction The Influenza Clinical Information Network (FLU-CIN) was established to gather detailed clinical and epidemiological information about patients with laboratory confirmed A(H1N1)pdm09 infection in UK hospitals. This report focuses on the clinical course and outcomes of infection in pregnancy. Methods A standardised data extraction form was used to obtain detailed clinical information from hospital case notes and electronic records, for patients with PCR-confirmed A(H1N1)pdm09 infection admitted to 13 sentinel hospitals in five clinical 'hubs' and a further 62 non-sentinel hospitals, between 11th May 2009 and 31st January 2010.Outcomes were compared for pregnant and non-pregnant women aged 15–44 years, using univariate and multivariable techniques. Results Of the 395 women aged 15–44 years, 82 (21%) were pregnant; 73 (89%) in the second or third trimester. Pregnant women were significantly less likely to exhibit severe respiratory distress at initial assessment (OR = 0.49 (95% CI: 0.30–0.82)), require supplemental oxygen on admission (OR = 0.40 (95% CI: 0.20–0.80)), or have underlying co-morbidities (p-trend <0.001). However, they were equally likely to be admitted to high dependency (Level 2) or intensive care (Level 3) and/or to die, after adjustment for potential confounders (adj. OR = 0.93 (95% CI: 0.46–1.92). Of 11 pregnant women needing Level 2/3 care, 10 required mechanical ventilation and three died. Conclusions Since the expected prevalence of pregnancy in the source population was 6%, our data suggest that pregnancy greatly increased the likelihood of hospital admission with A(H1N1)pdm09. Pregnant women were less likely than non-pregnant women to have respiratory distress on admission, but severe outcomes were equally likely in both groups. PMID:22870239
Neuzil, Kathleen M; Tsvetnitsky, Vadim; Nyari, Linda J; Bright, Rick A; Boslego, John W
The 2009 influenza A/H1N1 pandemic demonstrated that a pandemic influenza virus has the potential to spread more rapidly in today's highly interconnected world than in the past. While pandemic morbidity and mortality are likely to be greatest in low-resource countries, manufacturing capacity and access to influenza vaccines predominantly exist in countries with greater resources and infrastructure. Even with recently expanded manufacturing capacity, the number of doses available within a 6-month timeframe would be inadequate to fully immunize the global population if the decision to implement a global vaccination program were made today. Improved, affordable vaccines are needed to limit the consequences of a global influenza outbreak and protect low-resource populations. PATH's Influenza Vaccine Project is supporting a range of activities in collaboration with private- and public-sector partners to advance the development of promising influenza vaccines that can be accessible and affordable for people in low-resource countries.
Barrios, Lisa; Cordell, Ralph; Delozier, David; Gorman, Susan; Koenig, Linda J.; Odom, Erica; Polder, Jacquelyn; Randolph, Jean; Shimabukuro, Tom; Singleton, Christa
Children represent one quarter of the US population. Because of its enormous size and special needs, it is critically important to address this population group in pandemic influenza planning. Here we describe the ways in which children are vulnerable in a pandemic, provide an overview of existing plans, summarize the resources available, and, given our experience with influenza A(H1N1), outline the evolving lessons we have learned with respect to planning for a severe influenza pandemic. We focus on a number of issues affecting children—vaccinations, medication availability, hospital capacity, and mental health concerns—and emphasize strategies that will protect children from exposure to the influenza virus, including infection control practices and activities in schools and child care programs. PMID:19797738
Harvey, Ruth; Engelhardt, Othmar G.; Robertson, James S.
Previous studies on influenza A(H1N1)pdm09 candidate vaccine viruses (CVVs) that had adapted to growth in embryonated chicken eggs by the acquisition of amino acid substitutions at HA positions 222 or 223 showed that improved protein yield could be conferred by additional amino acid substitutions in the haemagglutinin (HA) that arose naturally during passaging of the virus in eggs. In this study we investigated, by means of reverse genetics, the ability of a non-egg adapted (cell-like) A(H1N1)pdm09 virus to egg-adapt at HA loci other than 222/223, introducing amino acid substitutions previously identified as egg adaptations in pre-H1N1pdm09 H1N1 viruses and assessing their effect on protein yield and antigenicity. We also investigated the effect on the protein yield of these substitutions in viruses that had A(H1N1)pdm09 internal genes rather than the traditional PR8 internal genes of a CVV. The data show that a cell-like A/Christchurch/16/2010 can be egg-adapted via amino acid substitutions in at least three alternative HA loci (187, 190 and 216), in viruses with either PR8 or A/California/7/2009 internal genes, but that the effects on protein yield vary depending on the amino acid substitution and the internal genes of the virus. Since CVVs need to produce high protein yields to be suitable for vaccine manufacture, the findings of this study will assist in the future characterisation of both wild type viruses and lab-derived CVVs for vaccine use. PMID:27861557
Koul, Parvaiz; Khan, Umar; Bhat, Khursheed; Saha, Siddhartha; Broor, Shobha; Lal, Renu; Chadha, Mandeep
Some parts of world, including India observed a recrudescent wave of influenza A/H1N1pdm09 in 2012. We undertook a study to examine the circulating influenza strains, their clinical association and antigenic characteristics to understand the recrudescent wave of A/H1N1pdm09 from November 26, 2012 to Feb 28, 2013 in Kashmir, India. Of the 751 patients (545 outpatient and 206 hospitalized) presenting with acute respiratory infection at a tertiary care hospital in Srinagar; 184 (24.5%) tested positive for influenza. Further type and subtype analysis revealed that 106 (58%) were influenza A (H1N1pdm09 =105, H3N2=1) and 78 (42%) were influenza B. The influenza positive cases had a higher frequency of chills, nasal discharge, sore throat, body aches and headache, compared to influenza negative cases. Of the 206 patients hospitalized for pneumonia/acute respiratory distress syndrome or an exacerbation of an underlying lung disease, 34 (16.5%) tested positive for influenza (22 for H1N1pdm09, 11 for influenza B). All influenza-positive patients received oseltamivir and while most patients responded well to antiviral therapy and supportive care, 6 patients (4 with H1N1pdm09 and 2 with influenza B) patients died of progressive respiratory failure and multi-organ dysfunction. Following a period of minimal circulation, H1N1pdm09 re-emerged in Kashmir in 2012-2013, causing serious illness and fatalities. As such the healthcare administrators and policy planners need to be wary and monitor the situation closely. PMID:24818063
An influenza pandemic will place an enormous strain on the world's vaccine production, distribution and administration systems. Following a pandemic declaration, industry's priority will be to deliver as much vaccine in as short a timeframe as possible. In respect to this challenge, manufacturers have successfully developed antigen-sparing strategies and significantly increased production capacity, with further growth planned assuming ongoing rising demand for seasonal vaccines. The combination of these factors has the potential to closer meet global needs for vaccine supply than ever before through increased availability of pandemic and pre-pandemic vaccines. The demonstration of cross-clade reactivity with H5N1 viruses makes the concept of pre-pandemic stockpiling and vaccination a reality for this subtype. Ensuring these vaccines are made available in a timely fashion to those who need them will present significant challenges. For local authorities, national governments and international organisations this means defining vaccine allocation and procurement processes as well as strengthening, and where necessary establishing, the critical health systems and infrastructure required for vaccine deployment. For vaccine producers this means addressing the technical and logistical issues associated with supply. This includes working with regulators to streamline key procedures, including generic labelling and batch release, while establishing flexibility in supply formats, including bulk and finished products, to maximise the speed of delivery. Similarly, the deployment of large quantities of vaccines in an emergency situation requires appropriate transport infrastructure and the distribution of associated medical supplies. As well as addressing these issues, specific consideration must be given to the logistics and storage aspects associated with stockpiling pre-pandemic vaccines. Finally, mutually agreed contractual arrangements between manufacturers and governments
Determann, Domino; Korfage, Ida J.; Lambooij, Mattijs S.; Bliemer, Michiel; Richardus, Jan Hendrik; Steyerberg, Ewout W.; de Bekker-Grob, Esther W.
Background Preventive measures are essential to limit the spread of new viruses; their uptake is key to their success. However, the vaccination uptake in pandemic outbreaks is often low. We aim to elicit how disease and vaccination characteristics determine preferences of the general public for new pandemic vaccinations. Methods In an internet-based discrete choice experiment (DCE) a representative sample of 536 participants (49% participation rate) from the Dutch population was asked for their preference for vaccination programs in hypothetical communicable disease outbreaks. We used scenarios based on two disease characteristics (susceptibility to and severity of the disease) and five vaccination program characteristics (effectiveness, safety, advice regarding vaccination, media attention, and out-of-pocket costs). The DCE design was based on a literature review, expert interviews and focus group discussions. A panel latent class logit model was used to estimate which trade-offs individuals were willing to make. Results All above mentioned characteristics proved to influence respondents’ preferences for vaccination. Preference heterogeneity was substantial. Females who stated that they were never in favor of vaccination made different trade-offs than males who stated that they were (possibly) willing to get vaccinated. As expected, respondents preferred and were willing to pay more for more effective vaccines, especially if the outbreak was more serious (€6–€39 for a 10% more effective vaccine). Changes in effectiveness, out-of-pocket costs and in the body that advises the vaccine all substantially influenced the predicted uptake. Conclusions We conclude that various disease and vaccination program characteristics influence respondents’ preferences for pandemic vaccination programs. Agencies responsible for preventive measures during pandemics can use the knowledge that out-of-pocket costs and the way advice is given affect vaccination uptake to improve
[Recommendations of the Infectious Diseases Work Group (GTEI) of the Spanish Society of Intensive and Critical Care Medicine and Coronary Units (SEMICYUC) and the Infections in Critically Ill Patients Study Group (GEIPC) of the Spanish Society of Infectious Diseases and Clinical Microbiology (SEIMC) for the diagnosis and treatment of influenza A/H1N1 in seriously ill adults admitted to the Intensive Care Unit].
Rodríguez, A; Alvarez-Rocha, L; Sirvent, J M; Zaragoza, R; Nieto, M; Arenzana, A; Luque, P; Socías, L; Martín, M; Navarro, D; Camarena, J; Lorente, L; Trefler, S; Vidaur, L; Solé-Violán, J; Barcenilla, F; Pobo, A; Vallés, J; Ferri, C; Martín-Loeches, I; Díaz, E; López, D; López-Pueyo, M J; Gordo, F; del Nogal, F; Marqués, A; Tormo, S; Fuset, M P; Pérez, F; Bonastre, J; Suberviola, B; Navas, E; León, C
be provided due to the possibility of bacterial coinfection. A beta-lactam plus a macrolide should be administered as soon as possible. The microbiological findings and clinical or laboratory test variables may decide withdrawal or not of antibiotic treatment. Pneumococcal vaccination is recommended as a preventive measure in the population at risk of suffering severe complications. Although the use of moderate- or low-dose corticosteroids has been proposed for the treatment of influenza A/H1N1 pneumonia, the existing scientific evidence is not sufficient to recommend the use of corticosteroids in these patients. The treatment of acute respiratory distress syndrome in patients with influenza A/H1N1 must be based on the use of a protective ventilatory strategy (tidal volume <10 ml / kg and plateau pressure <35 mmHg) and positive end-expiratory pressure set to high patient lung mechanics, combined with the use of prone ventilation, muscle relaxation and recruitment maneuvers. Noninvasive mechanical ventilation cannot be considered a technique of choice in patients with acute respiratory distress syndrome, though it may be useful in experienced centers and in cases of respiratory failure associated with chronic obstructive pulmonary disease exacerbation or heart failure. Extracorporeal membrane oxygenation is a rescue technique in refractory acute respiratory distress syndrome due to influenza A/H1N1 infection. The scientific evidence is weak, however, and extracorporeal membrane oxygenation is not the technique of choice. Extracorporeal membrane oxygenation will be advisable if all other options have failed to improve oxygenation. The centralization of extracorporeal membrane oxygenation in referral hospitals is recommended. Clinical findings show 50-60% survival rates in patients treated with this technique. Cardiovascular complications of influenza A/H1N1 are common. Such problems may appear due to the deterioration of pre-existing cardiomyopathy, myocarditis
Resende, Paola Cristina; Motta, Fernando Couto; Born, Priscila Silva; Machado, Daniela; Caetano, Braulia Costa; Brown, David; Siqueira, Marilda Mendonça
Pandemic influenza A H1N1 [A(H1N1)pdm09] was first detected in Brazil in May 2009, and spread extensively throughout the country causing a peak of infection during June to August 2009. Since then, it has continued to circulate with a seasonal pattern, causing high rates of morbidity and mortality. Over this period, the virus has continually evolved with the accumulation of new mutations. In this study we analyze the phylogenetic relationship in a collection of 220 A(H1N1)pdm09 hemagglutinin (HA) gene sequences collected during and after the pandemic period (2009 to 2014) in Brazil. In addition, we have looked for evidence of viral polymorphisms associated with severe disease and compared the range of viral variants with the vaccine strain (A/California/7/2009) used throughout this period. The phylogenetic analyses in this study revealed the circulation of at least eight genetic groups in Brazil. Two (G6-pdm and G7-pdm) co-circulated during the pandemic period, showing an early pattern of viral diversification with a low genetic distance from vaccine strain. Other phylogenetic groups, G5, G6 (including 6B, 6C and 6D subgroups), and G7 were found in the subsequent epidemic seasons from 2011 to 2014. These viruses exhibited more amino acid differences from the vaccine strain with several substitutions at the antigenic sites. This is associated with a theoretical decrease in the vaccine efficacy. Furthermore, we observed that the presence of any polymorphism at residue 222 of the HA gene was significantly associated with severe/fatal cases, reinforcing previous reports that described this residue as a potential virulence marker. This study provides new information about the circulation of some viral variants in Brazil, follows up potential genetic markers associated with virulence and allows infer if the efficacy of the current vaccine against more recent A(H1N1)pdm09 strains may be reduced.
Tham, Nguyen thi; Hang, Vu thi Ty; Khanh, Trong Huu; Viet, Do Chau; Hien, Tran Tinh; Farrar, Jeremy; van Vinh Chau, Nguyen; van Doorn, H. Rogier
Background Real-time PCR can be considered the gold standard for detection of influenza viruses due to its high sensitivity and specificity. Roche has developed the RealTime ready Influenza A/H1N1 Detection Set, consisting of a generic influenza virus A PCR targeting the M2 gene (M2 PCR) and a specific PCR targeting the HA of A/H1N1-pdm09 (HA PCR, 2009 H1N1), with the intention to make a reliable, rapid, and simple test to detect and quantify 2009 H1N1 in clinical samples. Methods We evaluated this kit against the USCDC/WHO real-time PCR for influenza virus using 419 nose and throat swabs from 210 patients collected in 3 large hospitals in Ho Chi Minh city, Vietnam. Results In the per patient analysis, when compared to CDC PCR, the sensitivity and specificity of the M2 PCR were 85.8 and 97.6%, respectively; the sensitivity and specificity of HA PCR were 88.2 and 100%, respectively. In the per sample analysis, the sensitivity and specificity in nose swabs were higher than in throat swabs for both M2 and HA PCRs. The viral loads as determined with the M2 and HA PCRs correlated well with the Ct values of the CDC PCR. Conclusion Compared with the CDC PCR, the kit has a reasonable sensitivity and very good specificity for the detection and quantification of Influenza A virus and A/H1N1-pdm09. However, given the current status of 2009 H1N1, a kit that can detect all circulating seasonal influenza viruses would be preferable. PMID:22785431
Luke, Catherine J; Subbarao, Kanta
A variety of platforms are being explored for the development of vaccines for pandemic influenza. Observations that traditional inactivated subvirion vaccines and live-attenuated vaccines against H5 and some H7 influenza viruses were poorly immunogenic spurred efforts to evaluate new approaches, including whole virus vaccines, higher doses of antigen, addition of adjuvants and combinations of different vaccine modalities in heterologous prime-boost regimens to potentiate immune responses. Results from clinical trials of prime-boost regimens have been very promising. Further studies are needed to determine optimal combinations of platforms, intervals between doses of vaccines and the logistics of deployment in pre-pandemic and early pandemic settings.
Milne, George; Kelso, Joel; Kelly, Heath
The recent worldwide spread of the swine-origin H1N1 2009 influenza outbreak has resulted in its designation as a pandemic by the World Health Organization. While it appears to result in mild symptoms, concern still exists that a more severe influenza pandemic with a high case fatality ratio might arise by reassortment or mutation of the currently circulating avian influenza (H5N1) virus. Given that recently developed candidate pre-pandemic H5N1 vaccines have shown potential for cross-strain protection, we investigated alternative vaccination strategies that exploit such vaccines using an agent-based simulation model of an actual community of approximately 30 000 people in a developed country. Assuming that a two-dose vaccination regimen would be required, we examined three vaccination strategies: pre-emptive, with vaccination applied prior to emergence of human-transmissible H5N1 influenza; reactive, where vaccination was initiated immediately after the first cases in the community were diagnosed; and a 'split' strategy where the first dose was administered pre-emptively during the pre-pandemic phase, with the second dose administered reactively. We showed that by effectively moving the delay between first and second doses into the pre-pandemic period, the split vaccination strategy achieved a substantially better attack rate reduction than the reactive strategy. Our results for an influenza strain with a reproduction number of 1.5 suggest reactive vaccination strategies that may be applicable to the current H1N1 2009 pandemic.
Pizzorno, Andrés; Abed, Yacine; Rhéaume, Chantal; Boivin, Guy
The efficacy of oseltamivir-zanamivir combination therapy compared to that of monotherapy was evaluated in mice infected with influenza A(H3N2) or A(H1N1)pdm09 viruses. For A(H3N2) virus, zanamivir monotherapy and oseltamivir-zanamivir combination showed significant reduction of mean weight loss compared to oseltamivir. Zanamivir monotherapy also conferred decreased mortality, weight loss and lung viral titers (LVT) compared to oseltamivir for A(H1N1)pdm09 wild-type virus. Intermediate benefits were observed for the oseltamivir-zanamivir combination. For the oseltamivir-resistant A(H1N1)pdm09 H275Y virus, the efficacy of oseltamivir-zanamivir was comparable to that of zanamivir and significantly higher than that of oseltamivir in terms of survival, weight loss and LVT.
Grødeland, Gunnveig; Bogen, Bjarne
There are two major limitations to vaccine preparedness in the event of devastating influenza pandemics: the time needed to generate a vaccine and rapid generation of sufficient amounts. DNA vaccination could represent a solution to these problems, but efficacy needs to be enhanced. In a separate line of research, it has been established that targeting of vaccine molecules to antigen-presenting cells enhances immune responses. We have combined the two principles by constructing DNA vaccines that encode bivalent fusion proteins; these target hemagglutinin to MHC class II molecules on antigen-presenting cells. Such DNA vaccines rapidly induce hemagglutinin-specific antibodies and T cell responses in immunized mice. Responses are long-lasting and protect mice against challenge with influenza virus. In a pandemic situation, targeted DNA vaccines could be produced and tested within a month. The novel DNA vaccines could represent a solution to pandemic preparedness in the advent of novel influenza pandemics.
Bavagnoli, L; Maga, G
The influenza A virus is the main circulating influenza virus in the human population. It can cause disease also in birds and other mammals and is responsible for annual epidemics and occasional pandemics. The most known and deadly pandemic was the "Spanish flu" (influenza type A/H1N1), which struck the human population between 1918 and 1919, with probably the heaviest toll ever recorded in terms of human lives. The most recent flu pandemic, caused in 2009 by the swine-origin reassortant virus (pH1N1), has raised several critical issues in terms of our preparedness in responding fast to new pandemic influenza strains. Probably, the most instructive lesson that has been learned from the 2009 pandemic, was that the speed of manufacturing and distributing an effective vaccine will not be able to keep up with the pace of a rapidly spreading pandemic virus, failing to grant accessibility to the vaccine for a significant percentage of the susceptible population, before the onset of the pandemic peak. Thus, our first and most effective line of defense against a pandemic influenza virus, particularly in the early phases, are the antiviral drugs. Here we analyze our current understanding of the influenza pandemic viruses, in general, and of the pH1N1 in particular, along with the most recent approaches being pursued to design new anti-influenza drugs.
Coelingh, Kathleen L; Luke, Catherine J; Jin, Hong; Talaat, Kawsar R
Avian and animal influenza viruses can sporadically transmit to humans, causing outbreaks of varying severity. In some cases, further human-to-human virus transmission does not occur, and the outbreak in humans is limited. In other cases, sustained human-to-human transmission occurs, resulting in worldwide influenza pandemics. Preparation for future pandemics is an important global public health goal. A key objective of preparedness is to gain an understanding of how to design, test, and manufacture effective vaccines that could be stockpiled for use in a pandemic. This review summarizes results of an ongoing collaboration to produce, characterize, and clinically test a library of live attenuated influenza vaccine strains (based on Ann Arbor attenuated Type A strain) containing protective antigens from influenza viruses considered to be of high pandemic potential.
Cox, Manon M. J.
Pandemic influenza has become a high priority item for all public health authorities. An influenza pandemic is believed to be imminent, and scientists agree that it will be a matter of when, where, and what will be the causative agent. Recently, most attention has been directed to human cases of avian influenza caused by a H5N1 avian influenza virus. An effective vaccine will be needed to substantially reduce the impact of an influenza pandemic. Current influenza vaccine manufacturing technology is not adequate to support vaccine production in the event of an avian influenza outbreak, and it has now become clear that new innovative production technology is required. Antiviral drugs, on the other hand, can play a very important role in slowing the disease spread but are in short supply and resistance has been a major issue. Here, we provide an update on the status of pandemic vaccine development and antiviral drugs. Finally, we conclude with some proposed areas of focus in pandemic vaccine preparedness. PMID:17132338
Killingley, Benjamin; Greatorex, Jane; Digard, Paul; Wise, Helen; Garcia, Fayna; Varsani, Harsha; Cauchemez, Simon; Enstone, Joanne E; Hayward, Andrew; Curran, Martin D; Read, Robert C; Lim, Wei S; Nicholson, Karl G; Nguyen-Van-Tam, Jonathan S
In a multi-center, prospective, observational study over two influenza seasons, we sought to quantify and correlate the amount of virus recovered from the nares of infected subjects with that recovered from their immediate environment in community and hospital settings. We recorded the symptoms of adults and children with A(H1N1)pdm09 infection, took nasal swabs, and sampled touched surfaces and room air. Forty-two infected subjects were followed up. The mean duration of virus shedding was 6.2 days by PCR (Polymerase Chain Reaction) and 4.2 days by culture. Surface swabs were collected from 39 settings; 16 (41%) subject locations were contaminated with virus. Overall, 33 of the 671 (4.9%) surface swabs were PCR positive for influenza, of which two (0.3%) yielded viable virus. On illness Day 3, subjects yielding positive surface samples had significantly higher nasal viral loads (geometric mean ratio 25.7; 95% CI 1.75, 376.0, p=0.021) and a positive correlation (r=0.47, p=0.006) was observed between subject nasal viral loads and viral loads recovered from the surfaces around them. Room air was sampled in the vicinity of 12 subjects, and PCR positive samples were obtained for five (42%) samples. Influenza virus shed by infected subjects did not detectably contaminate the vast majority of surfaces sampled. We question the relative importance of the indirect contact transmission of influenza via surfaces, though our data support the existence of super-spreaders via this route. The air sampling results add to the accumulating evidence that supports the potential for droplet nuclei (aerosol) transmission of influenza.
Ribeiro, Ana Freitas; Pellini, Alessandra Cristina Guedes; Kitagawa, Beatriz Yuko; Marques, Daniel; Madalosso, Geraldine; de Cassia Nogueira Figueira, Gerrita; Fred, João; Albernaz, Ricardo Kerti Mangabeira; Carvalhanas, Telma Regina Marques Pinto; Zanetta, Dirce Maria Trevisan
This case-control study aimed to assess the risk factors for death from influenza A(H1N1)pdm09 in patients with laboratory confirmation, who had severe acute respiratory illness-SARI and were hospitalized between June 28th and August 29th 2009, in the metropolitan regions of São Paulo and Campinas, Brazil. Medical charts of all the 193 patients who died (cases) and the 386 randomly selected patients who recovered (controls) were investigated in 177 hospitals. Household interviews were conducted with those who had survived and the closest relative of those who had died. 73.6% of cases and 38.1% of controls were at risk of developing influenza-related complications. The 18-to-59-year age group (OR = 2.31, 95%CI: 1.31–4.10 (reference up to 18 years of age)), presence of risk conditions for severity of influenza (OR = 1.99, 95%CI: 1.11–3.57, if one or OR = 6.05, 95%CI: 2.76–13.28, if more than one), obesity (OR = 2.73, 95%CI: 1.28–5.83), immunosuppression (OR = 3.43, 95%CI: 1.28–9.19), and search for previous care associated with the hospitalization (OR = 3.35, 95%CI: 1.75–6.40) were risk factors for death. Antiviral treatment performed within 72 hours of the onset of symptoms (OR = 0.17, 95%CI: 0.08–0.37, if within 48hours, and OR = 0.30, 95%CI: 0.11–0.81, if between 48 and 72 hours) was protective against death. The identification of high-risk patients and early treatment are important factors for reducing morbi-mortality from influenza. PMID:25774804
Shapshak, Paul; Chiappelli, Francesco; Somboonwit, Charurut; Sinnott, John
Influenza is a moving target, which evolves in unexpected directions and is recurrent annually. The 2009 influenza A/H1N1 pandemic virus was unlike the 2009 seasonal virus strains and originated in pigs prior to infecting humans. Three strains of viruses gave rise to the pandemic virus by antigenic shift, reassortment, and recombination, which occurred in pigs as 'mixing vessels'. The three strains of viruses had originally been derived from birds, pigs, and humans. The influenza hemagglutinin (HA) and neuraminidase (NA) external proteins are used to categorize and group influenza viruses. The internal proteins (PB1, PB1-F2, PB2, PA, NP, M, and NS) are involved in the pathogenesis of influenza infection. A major difference between the 1918 and 2009 pandemic viruses is the lack of the pathogenic protein PB1-F2 in the 2009 pandemic strains, which was present in the more virulent 1918 pandemic strains. We provide an overview of influenza infection since 1847 and the advent of influenza vaccination since 1944. Vaccines and chemotherapy help reduce the spread of influenza, reduce morbidity and mortality, and are utilized by the global rapid-response organizations associated with the WHO. Immediate identification of impending epidemic and pandemic strains, as well as sustained vigilance and collaboration, demonstrate continued success in combating influenza.
Takemae, Nobuhiro; Harada, Michiyo; Nguyen, Phuong Thanh; Nguyen, Tung; Nguyen, Tien Ngoc; To, Thanh Long; Nguyen, Tho Dang; Pham, Vu Phong; Le, Vu Tri; Do, Hoa Thi; Vo, Hung Van; Le, Quang Vinh Tin; Tran, Tan Minh; Nguyen, Thanh Duy; Thai, Phuong Duy; Nguyen, Dang Hoang; Le, Anh Quynh Thi; Nguyen, Diep Thi; Uchida, Yuko; Saito, Takehiko
Active surveillance of influenza A viruses of swine (IAV-S) involving 262 farms and 10 slaughterhouses in seven provinces in northern and southern Vietnam from 2010 to 2015 yielded 388 isolates from 32 farms; these viruses were classified into H1N1, H1N2, and H3N2 subtypes. Whole-genome sequencing followed by phylogenetic analysis revealed that the isolates represented 15 genotypes, according to the genetic constellation of the eight segments. All of the H1N1 viruses were entirely A(H1N1)pdm09 viruses, whereas all of the H1N2 and H3N2 viruses were reassortants among 5 distinct ancestral viruses: H1 and H3 triple-reassortant (TR) IAV-S that originated from North American pre-2009 human seasonal H1, human seasonal H3N2, and A(H1N1)pdm09 viruses. Notably, 93% of the reassortant IAV-S retained M genes that were derived from A(H1N1)pdm09, suggesting some advantage in terms of their host adaptation. Bayesian Markov chain Monte Carlo analysis revealed that multiple introductions of A(H1N1)pdm09 and TR IAV-S into the Vietnamese pig population have driven the genetic diversity of currently circulating Vietnamese IAV-S. In addition, our results indicate that a reassortant IAV-S with human-like H3 and N2 genes and an A(H1N1)pdm09 origin M gene likely caused a human case in Ho Chi Minh City in 2010. Our current findings indicate that human-to-pig transmission as well as cocirculation of different IAV-S have contributed to diversifying the gene constellations of IAV-S in Vietnam.
Abou-Jaoudé, Georges; Scemla, Anne; Ribaud, Patricia; Mercier-Delarue, Séverine; Caro, Valérie; Enouf, Vincent; Simon, François; Molina, Jean-Michel; van der Werf, Sylvie
Background Resistance of pandemic A(H1N1)2009 (H1N1pdm09) virus to neuraminidase inhibitors (NAIs) has remained limited. A new mutation I223R in the neuraminidase (NA) of H1N1pdm09 virus has been reported along with H275Y in immunocompromised patients. The aim of this study was to determine the impact of I223R on oseltamivir and zanamivir susceptibility. Methods The NA enzymatic characteristics and susceptibility to NAIs of viruses harbouring the mutations I223R and H275Y alone or in combination were analyzed on viruses produced by reverse genetics and on clinical isolates collected from an immunocompromised patient with sustained influenza H1N1pdm09 virus shedding and treated by oseltamivir (days 0–15) and zanamivir (days 15–25 and 70–80). Results Compared with the wild type, the NA of recombinant viruses and clinical isolates with H275Y or I223R mutations had about two-fold reduced affinity for the substrate. The H275Y and I223R isolates showed decreased susceptibility to oseltamivir (246-fold) and oseltamivir and zanamivir (8.9- and 4.9-fold), respectively. Reverse genetics assays confirmed these results and further showed that the double mutation H275Y and I223R conferred enhanced levels of resistance to oseltamivir and zanamivir (6195- and 15.2-fold). In the patient, six days after initiation of oseltamivir therapy, the mutation H275Y conferring oseltamivir resistance and the I223R mutation were detected in the NA. Mutations were detected concomitantly from day 6–69 but molecular cloning did not show any variant harbouring both mutations. Despite cessation of NAI treatment, the mutation I223R persisted along with additional mutations in the NA and the hemagglutinin. Conclusions Reduced susceptibility to both oseltamivir and zanamivir was conferred by the I223R mutation which potentiated resistance to both NAIs when associated with the H275Y mutation in the NA. Concomitant emergence of the I223R and H275Y mutations under oseltamivir treatment underlines
Evans, David; Cauchemez, Simon; Hayden, Frederick G
The availability of immunogenic, licensed H5N1 vaccines and the anticipated development of vaccines against "swine" influenza A(H1N1) have stimulated debate about the possible use of these vaccines for protection of those exposed to potential pandemic influenza viruses and for immunization or "priming" of populations in the so-called "prepandemic" (interpandemic) era. However, the safety of such vaccines is a critical issue in policy development for wide-scale application of vaccines in the interpandemic period. For example, wide-scale interpandemic use of H5N1 vaccines could lead to millions of persons receiving vaccines of uncertain efficacy potentially associated with rare severe adverse events and against a virus that may not cause a pandemic. Here, we first review aspects of the 1976 National Influenza Immunization Programme against "swine flu" and its well-documented association with Guillain-Barré syndrome as a case study illustration of a suspected vaccine-associated severe adverse event in a mass interpandemic immunization setting. This case study is especially timely, given the recent spread of a novel influenza A(H1N1) virus in humans in Mexico and beyond. Following this, we examine available safety data from clinical trials of H5N1 vaccines and briefly discuss how vaccine safety could be monitored in a postmarketing surveillance setting.
Kreijtz, Joost H C M; Osterhaus, Albert D M E; Rimmelzwaan, Guus F
Influenza viruses of the H5N1 subtype cause an ever-increasing number of bird-to-human transmissions and a pandemic outbreak caused by these viruses is imminent. Therefore, the availability of safe and effective vaccines is highly desirable and their development considered a priority. However, using production and use of seasonal influenza vaccine as template for the production of pandemic H5N1 vaccines did not yield effective vaccines. High antigen doses were required to induce appreciable antibody responses. In addition, limited production capacity and long production times are other disadvantages of conventional influenza vaccine preparations. Here, we review recent developments that will contribute to a more rapid availability of sufficient doses of highly efficacious and safe pandemic influenza vaccines. The new developments include the establishment of novel methods to prepare vaccine strains, novel production technologies and the use of novel adjuvants and alternative vaccine formulations.
In the past, influenza pandemics have been occurring every 20 to 30 years. Highly pathogenic avian influenza A(H5N1) has been causing unprecedented global outbreaks since 2003 and many human cases with a high case fatality rate have also been reported. But the virus that caused a pandemic in 2009 was A(H1N1) that was originated from swine influenza. The same subtype, A(H1N1) has been circulating in human population since 1977. This pandemic (H1N1) 2009 is also not as virulent as A(H5N1) in humans. Many aspects of pandemic (H1N1) 2009 are different from what we had been expecting. We should reconsider the concepts and the strategies for influenza pandemic by reviewing current pandemic (H1N1).
Abed, Yacine; Carbonneau, Julie; L'Huillier, Arnaud G; Kaiser, Laurent; Boivin, Guy
The H275Y and E119D neuraminidase (NA) mutations constitute important molecular markers of resistance to NA inhibitors in A(H1N1) pdm09 viruses. We used reverse transcriptase-droplet digital PCR amplification (RT-ddPCR) to analyze quasi-species at codons 275 and 119 of the NA in A(H1N1) pdm09 viruses recovered from an immuncompromised patient who received oseltamivir and zanamivir therapies. RT-ddPCR assays detected and quantified H275Y and E119D mutations with an efficiency that was comparable to that of high throughput sequencing (HiSeq 2500 Illumina, San Diego, CA) technology. With its sensitivity and reproducibility, RT-ddPCR could be a reliable method for accurate detection and quantification of major NAI-resistance mutations in clinical settings. J. Med. Virol. 89:737-741, 2017. © 2016 Wiley Periodicals, Inc.
Elizondo-Montemayor, Leticia; Alvarez, Mario M.; Hernández-Torre, Martín; Ugalde-Casas, Patricia A.; Lam-Franco, Lorena; Bustamante-Careaga, Humberto; Castilleja-Leal, Fernando; Contreras-Castillo, Julio; Moreno-Sánchez, Héctor; Tamargo-Barrera, Daniela; López-Pacheco, Felipe; Freiden, Pamela J.; Schultz-Cherry, Stacey
Summary Objective No serological studies have been performed in Mexico to assess the seroprevalence of influenza A/H1N1/2009 in groups of people according to the potential risk of transmission. The aim of this study was to determine the seroprevalence of antibodies against influenza A/H1N1/2009 in subjects in Mexico grouped by risk of transmission. Methods Two thousand two hundred and twenty-two subjects were categorized into one of five occupation groups according to the potential risk of transmission: (1) students, (2) teachers, (3) healthcare workers, (4) institutional home residents aged >60 years, and (5) general population. Seroprevalence by potential transmission group and by age grouped into decades was determined by a virus-free ELISA method based on the recombinant receptor-binding domain of the hemagglutinin of influenza A/H1N1/2009 virus as antigen (85% sensitivity; 95% specificity). The Wilson score, Chi-square test, and logistic regression models were used for the statistical analyses. Results Seroprevalence for students was 47.3%, for teachers was 33.9%, for older adults was 36.5%, and for the general population was 33.0%, however it was only 24.6% for healthcare workers (p = 0.011). Of the students, 56.6% of those at middle school, 56.4% of those at high school, 52.7% of those at elementary school, and 31.1% of college students showed positive antibodies (p < 0.001). Seroprevalence was 44.6% for college teachers, 31.6% for middle school teachers, and 29.8% for elementary school teachers, but was only 20.3% for high school teachers (p = 0.002). Conclusions The student group was the group most affected by influenza A/H1N1/2009, while the healthcare worker group showed the lowest prevalence. Students represent a key target for preventive measures. PMID:21855383
Charland, Katia M; de Montigny, Luc; Brownstein, John S; Buckeridge, David L
Background Nineteen mass vaccination clinics were established in Montreal, Canada, as part of the 2009 influenza A/H1N1p vaccination campaign. Although approximately 50% of the population was vaccinated, there was a considerable variation in clinic performance and community vaccine coverage. Objective To identify community- and clinic-level predictors of vaccine uptake, while accounting for the accessibility of clinics from the community of residence. Methods All records of influenza A/H1N1p vaccinations administered in Montreal were obtained from a vaccine registry. Multivariable regression models, specifically Bayesian gravity models, were used to assess the relationship between vaccination rates and clinic accessibility, clinic-level factors, and community-level factors. Results Relative risks compare the vaccination rates at the variable's upper quartile to the lower quartile. All else being equal, clinics in areas with high violent crime rates, high residential density, and high levels of material deprivation tended to perform poorly (adjusted relative risk [ARR]: 0·917, 95% CI [credible interval]: 0·915, 0·918; ARR: 0·663, 95% CI: 0·660, 0·666, ARR: 0·649, 95% CI: 0·645, 0·654, respectively). Even after controlling for accessibility and clinic-level predictors, communities with a greater proportion of new immigrants and families living below the poverty level tended to have lower rates (ARR: 0·936, 95% CI: 0·913, 0·959; ARR: 0·918, 95% CI: 0·893, 0·946, respectively), while communities with a higher proportion speaking English or French tended to have higher rates (ARR: 1·034, 95% CI: 1·012, 1·059). Conclusion In planning future mass vaccination campaigns, the gravity model could be used to compare expected vaccine uptake for different clinic location strategies. PMID:24382000
Adnane Berdai, Mohamed; Labib, Smael; Harandou, Mustapha
Introduction Le but de cette étude est de décrire les caractéristiques épidémiologiques, cliniques, paracliniques ainsi que l’évolution des femmes enceintes ou en post partum atteintes de formes graves de Grippe A(H1N1) 2009. Méthodes C’est une étude prospective observationnelle monocentrique, menée au sein de notre service de réanimation mère et enfant au centre hospitalier universitaire Hassan II à Fès, sur une période de 3 mois, allant de novembre 2009 à janvier 2010. Résultats L’âge moyen était de 28 ans, dans 85% des cas la grossesse se situaient au troisième trimestre, le syndrome grippal était constant, la SpO2 initiale était en moyenne de 86%. A la radiographie thoracique, un syndrome alvéolaire bilatéral était toujours présent. L’infection virale était confirmée dans tous les cas par la polymerase chain reaction. Chez 3 patientes la PaO2/FiO2 était inférieure à 300. L’Oseltamivir était l’antiviral utilisé chez toutes les parturientes. Un syndrome de détresse respiratoire aigu a été développé chez 28% des parturientes, elles ont été ventilées artificiellement avec des niveaux de pressions expiratoires positives à 14 +/- 1 cmH2O. L’évolution était favorable dans 71% des cas, cependant, 2 décès ont été déplorés. Conclusion Les résultats rejoignent les données de la littérature, à savoir, un risque accru pour la femme enceinte de développer une forme grave, une présentation clinique similaire au reste de la population, l’intérêt de la vaccination et d’un traitement antiviral précoce et le rôle de l’ECMO dans le traitement des hypoxémies réfractaires. PMID:22514770
Mooney, Alaina J; Tompkins, S Mark
Influenza A viruses continue to emerge and re-emerge, causing outbreaks, epidemics and occasionally pandemics. While the influenza vaccines licensed for public use are generally effective against seasonal influenza, issues arise with production, immunogenicity, and efficacy in the case of vaccines against pandemic and emerging influenza viruses, and highly pathogenic avian influenza virus in particular. Thus, there is need of improved influenza vaccines and vaccination strategies. This review discusses advances in alternative influenza vaccines, touching briefly on licensed vaccines and vaccine antigens; then reviewing recombinant subunit vaccines, virus-like particle vaccines and DNA vaccines, with the main focus on virus-vectored vaccine approaches. PMID:23440999
Singer, Andrew C; Järhult, Josef D; Grabic, Roman; Khan, Ghazanfar A; Fedorova, Ganna; Fick, Jerker; Lindberg, Richard H; Bowes, Michael J; Olsen, Björn; Söderström, Hanna
Antiviral provision remains the focus of many pandemic preparedness plans, however, there is considerable uncertainty regarding antiviral compliance rates. Here we employ a waste water epidemiology approach to estimate oseltamivir (Tamiflu®) compliance. Oseltamivir carboxylate (oseltamivir's active metabolite) was recovered from two waste water treatment plant (WWTP) catchments within the United Kingdom at the peak of the autumnal wave of the 2009 Influenza A (H1N1)pdm09 pandemic. Predictions of oseltamivir consumption from detected levels were compared with two sources of national government statistics to derive compliance rates. Scenario and sensitivity analysis indicated between 3-4 and 120-154 people were using oseltamivir during the study period in the two WWTP catchments and a compliance rate between 45-60%. With approximately half the collected antivirals going unused, there is a clear need to alter public health messages to improve compliance. We argue that a near real-time understanding of drug compliance at the scale of the waste water treatment plant (hundreds to millions of people) can potentially help public health messages become more timely, targeted, and demographically sensitive, while potentially leading to less mis- and un-used antiviral, less wastage and ultimately a more robust and efficacious pandemic preparedness plan.
The history of the 1957/58 Asian flu in Germany is systematically presented for the first time. The focus is on flu vaccination, which is discussed as a yardstick of the perception of the pandemic. International expertise on influenza virology was predominantly based in Anglo-Saxon countries. German microbiologists issued no clear recommendation for preventative vaccination until 1960. Instead, quinine was relied upon as the traditional medicinal prophylaxis. Antibiotics were more frequently administered. In East Germany, little fuss was made over the Asian flu. In line with the authorities' social hygiene orientation, vaccination was accepted as a matter of principle. In the Federal Republic and West Berlin, the population rejected the vaccination largely. It was seen as a scandal that many employees were on sick leave because of the flu, thus adversely affecting the economy.
Yang, Ji-Rong; Kuo, Chuan-Yi; Huang, Hsiang-Yi; Wu, Fu-Ting; Huang, Yi-Lung; Cheng, Chieh-Yu; Su, Yu-Ting; Chang, Feng-Yee; Wu, Ho-Sheng; Liu, Ming-Tsan
New variants of the influenza A(H1N1)pdm09 and A(H3N2) viruses were detected in Taiwan between 2012 and 2013. Some of these variants were not detected in clinical specimens using a common real-time reverse transcription-PCR (RT-PCR) assay that targeted the conserved regions of the viral matrix (M) genes. An analysis of the M gene sequences of the new variants revealed that several newly emerging mutations were located in the regions where the primers or probes of the real-time RT-PCR assay bind; these included three mutations (G225A, T228C, and G238A) in the A(H1N1)pdm09 virus, as well as one mutation (C163T) in the A(H3N2) virus. These accumulated mismatch mutations, together with the previously identified C154T mutation of the A(H1N1)pdm09 virus and the C153T and G189T mutations of the A(H3N2) virus, result in a reduced detection sensitivity for the real-time RT-PCR assay. To overcome the loss of assay sensitivity due to mismatch mutations, we established a real-time RT-PCR assay using degenerate nucleotide bases in both the primers and probe and successfully increased the sensitivity of the assay to detect circulating variants of the human influenza A viruses. Our observations highlight the importance of the simultaneous use of different gene-targeting real-time RT-PCR assays for the clinical diagnosis of influenza.
L'Huillier, Arnaud G.; Abed, Yacine; Petty, Tom J.; Cordey, Samuel; Thomas, Yves; Bouhy, Xavier; Schibler, Manuel; Simon, Audrey; Chalandon, Yves; van Delden, Christian; Zdobnov, Evgeny; Boquete-Suter, Patricia; Boivin, Guy; Kaiser, Laurent
Background. An influenza A(H1N1)pdm09 infection was diagnosed in a hematopoietic stem cell transplant recipient during conditioning regimen. He was treated with oral oseltamivir, later combined with intravenous zanamivir. The H275Y neuraminidase (NA) mutation was first detected, and an E119D NA mutation was identified during zanamivir therapy. Methods. Recombinant wild-type (WT) E119D and E119D/H275Y A(H1N1)pdm09 NA variants were generated by reverse genetics. Susceptibility to NA inhibitors (NAIs) was evaluated with a fluorometric assay using the 2′-(4-methylumbelliferyl)-α-d-N-acetylneuraminic acid (MUNANA) substrate. Susceptibility to favipiravir (T-705) was assessed using plaque reduction assays. The NA affinity and velocity values were determined with NA enzymatic studies. Results. We identified an influenza A(H1N1)pdm09 E119D mutant that exhibited a marked increase in the 50% inhibitory concentrations against all tested NAIs (827-, 25-, 286-, and 702-fold for zanamivir, oseltamivir, peramivir, and laninamivir, respectively). The double E119D/H275Y mutation further increased oseltamivir and peramivir 50% inhibitory concentrations by 790- and >5000-fold, respectively, compared with the WT. The mutant viruses remained susceptible to favipiravir. The NA affinity and velocity values of the E119D variant decreased by 8.1-fold and 4.5-fold, respectively, compared with the WT. Conclusions. The actual emergence of a single NA mutation conferring pan-NAI resistance in the clinical setting reinforces the pressing need to develop new anti-influenza strategies. PMID:25985905
Larrieu, S; Rosine, J; Ledrans, M; Flamand, C; Chappert, J-L; Cassadou, S; Carvalho, L; Blateau, A; Barrau, M; Ardillon, V; Quénel, P
Guadeloupe, French Guiana, Martinique, St. Martin and St. Barthelemy were the French territories most exposed to the new influenza A(H1N1)v, and adequate epidemiological surveillance tools were promptly developed in order to detect its emergence. The first stage, "containment phase", consisted in detection and management of individual cases. Then, when an autochthonous A(H1N1)v circulation was confirmed, its evolution has been monitored within the whole population, mainly through data collected from sentinel doctors' networks and virological surveillance. This allowed to detect very early the occurrence of epidemics, and to follow their evolution until they were over. Like all the other Caribbean countries, the five French overseas territories were hit by an outbreak of influenza A(H1N1)v. Although they had globally similar characteristics, each epidemic had its specificity in terms of scale and severity. They started between August and September 2009 in four of the five territories, while the last one, St. Barthelemy, was not affected until the end of the year. Attack rate estimates varied from 28 to 70 per 1000 inhabitants according to the territory, and hospitalisation rate varied from 4.3 to 10.3 per 1000 cases. Severity rate didn't reach 1 per 1000 cases in any of the territories. Compared to metropolitan France, the surveillance system presented several strengths, including the pre-existence of both an active sentinel network and an expert committee on emerging diseases in each territory. On the other hand, specific difficulties appeared, notably linked with logistical aspects of virological surveillance and the co-circulation of dengue virus in Guadeloupe and St. Barthelemy. Despite these difficulties, the different tools allowed early detection of the epidemics and follow-up of their evolution. All of them lead to very concordant results, suggesting that they are completely appropriate to monitor a potential new epidemic wave.
Seligová, Jana; Belyová, Anna; Culmanová, Andrea; Oleár, Vladimír; Cisláková, Lýdia
Influenza illnesses and positive laboratory tests for the presence of influenza virus in recent years in the districts of Kosice I-IV and surroundings have only occurred during the winter season. In May to July 2010 only one positive laboratory test for the presence of influenza virus A/H1N1-2009 was reported. In 2011, during the same period, a total of 29 positive laboratory tests recorded the presence of influenza virus A/ H1N1-2009 in individuals with typical clinical symptoms of influenza. Of 29 clinical cases, 27 were diagnosed as influenza and 2 as SARI; 4 cases involved children.
Wedde, Marianne; Biere, Barbara; Wolff, Thorsten; Schweiger, Brunhilde
This report describes the evolution of the influenza A(H1N1)pdm09 and A(H3N2) viruses circulating in Germany between 2008-2009 and 2013-2014. The phylogenetic analysis of the hemagglutinin (HA) genes of both subtypes revealed similar evolution of the HA variants that were also seen worldwide with minor exceptions. The analysis showed seven distinct HA clades for A(H1N1)pdm09 and six HA clades for A(H3N2) viruses. Herald strains of both subtypes appeared sporadically since 2008-2009. Regarding A(H1N1)pdm09, herald strains of HA clade 3 and 4 were detected late in the 2009-2010 season. With respect to A(H3N2), we found herald strains of HA clade 3, 4 and 7 between 2009 and 2012. Those herald strains were predominantly seen for minor and not for major HA clades. Generally, amino acid substitutions were most frequently found in the globular domain, including substitutions near the antigenic sites or the receptor binding site. Differences between both influenza A subtypes were seen with respect to the position of the indicated substitutions in the HA. For A(H1N1)pdm09 viruses, we found more substitutions in the stem region than in the antigenic sites. In contrast, in A(H3N2) viruses most changes were identified in the major antigenic sites and five changes of potential glycosylation sites were identified in the head of the HA monomer. Interestingly, we found in seasons with less influenza activity a relatively high increase of substitutions in the head of the HA in both subtypes. This might be explained by the fact that mutations under negative selection are subsequently compensated by secondary mutations to restore important functions e.g. receptor binding properties. A better knowledge of basic evolution strategies of influenza viruses will contribute to the refinement of predictive mathematical models for identifying novel antigenic drift variants.
Takashita, Emi; Fujisaki, Seiichiro; Shirakura, Masayuki; Nakamura, Kazuya; Kishida, Noriko; Kuwahara, Tomoko; Shimazu, Yukie; Shimomura, Takeshi; Watanabe, Shinji; Odagiri, Takato
An influenza A(H1N1)pdm09 virus carrying a G147R substitution in combination with an H275Y substitution in the neuraminidase protein, which confers cross-resistance to oseltamivir and peramivir, was detected from an immunocompromised inpatient in Japan, March 2016. This dual H275Y/G147R mutant virus exhibited enhanced cross-resistance to both drugs compared with the single H275Y mutant virus and reduced susceptibility to zanamivir, although it showed normal inhibition by laninamivir.
Weil-Olivier, Catherine; Lina, Bruno
For a number of years now, GEIG, the Groupement d'Expertise et d'Information sur la Grippe (Influenza Expertise and Information Group) has conducted surveys to monitor seasonal trivalent vaccine uptake in France in adults. During the H1N1 pandemic in 2009, this survey was conducted to determine vaccination uptake for both pandemic and seasonal vaccines. An additional specific questionnaire was used to collect data on vaccination in children under 15 years of age. This additional study was carried out because pandemic vaccination (PV) was offered to the French population and children were listed as a priority target group by the national health authorities, whereas seasonal trivalent inactivated vaccines (TIV) are not recommended in children in France. Overall, we collected 2443 questionnaires on children, including children with underlying conditions (9.2%) for whom TIV vaccination was recommended. Overall, 17.9% of children (438/2443) received at least one shot of PV, compared to 3.4% (83/2443) who received at least one shot of TIV. PV uptake was statistically different between non at-risk and at-risk children (366/2218 [16.5%] vs. 71/225 [31.8%], p<0.0001). This difference was even more significant in the subgroup of children with severe underlying diseases (42.7%, p<0.0001). This confirms that despite the low overall PV uptake in the French population (9%), the specific recommendation for PV for children increased vaccine uptake in this specific population, suggesting that the disease burden of influenza in children is recognised by both practitioners and parents. The next few years will tell us whether TIV uptake in children increases as a consequence of the specific recommendations made for children during the 2009 pandemic wave, or whether it will return to the very low level of 3.4% observed before the pandemic.
Fitzgerald, Thomas J.; Kang, Yoonjae; Bridges, Carolyn B.; Talbert, Todd; Vagi, Sara J.; Lamont, Brock; Graitcer, Samuel B.
Background During an influenza pandemic, to achieve early and rapid vaccination coverage and maximize the benefit of an immunization campaign, partnerships between public health agencies and vaccine providers are essential. Immunizing pharmacists represent an important group for expanding access to pandemic vaccination. However, little is known about nationwide coordination between public health programs and pharmacies for pandemic vaccine response planning. Methods To assess relationships and planning activities between public health programs and pharmacies, we analyzed data from Centers for Disease Control and Prevention assessments of jurisdictions that received immunization and emergency preparedness funding from 2012 to 2015. Results Forty-seven (88.7%) of 53 jurisdictions reported including pharmacies in pandemic vaccine distribution plans, 24 (45.3%) had processes to recruit pharmacists to vaccinate, and 16 (30.8%) of 52 established formal relationships with pharmacies. Most jurisdictions plan to allocate less than 10% of pandemic vaccine supply to pharmacies. Discussion While most jurisdictions plan to include pharmacies as pandemic vaccine providers, work is needed to establish formalized agreements between public health departments and pharmacies to improve pandemic preparedness coordination and ensure that vaccinating pharmacists are fully utilized during a pandemic. PMID:27686834
Birrell, Paul J.; Zhang, Xu-Sheng; Pebody, Richard G.; Gay, Nigel J.; de Angelis, Daniela
Understanding how the geographic distribution of and movements within a population influence the spatial spread of infections is crucial for the design of interventions to curb transmission. Existing knowledge is typically based on results from simulation studies whereas analyses of real data remain sparse. The main difficulty in quantifying the spatial pattern of disease spread is the paucity of available data together with the challenge of incorporating optimally the limited information into models of disease transmission. To address this challenge the role of routine migration on the spatial pattern of infection during the epidemic of 2009 pandemic influenza in England is investigated here through two modelling approaches: parallel-region models, where epidemics in different regions are assumed to occur in isolation with shared characteristics; and meta-region models where inter-region transmission is expressed as a function of the commuter flux between regions. Results highlight that the significantly less computationally demanding parallel-region approach is sufficiently flexible to capture the underlying dynamics. This suggests that inter-region movement is either inaccurately characterized by the available commuting data or insignificant once its initial impact on transmission has subsided.
Birrell, Paul J.; Zhang, Xu-Sheng; Pebody, Richard G.; Gay, Nigel J.; De Angelis, Daniela
Understanding how the geographic distribution of and movements within a population influence the spatial spread of infections is crucial for the design of interventions to curb transmission. Existing knowledge is typically based on results from simulation studies whereas analyses of real data remain sparse. The main difficulty in quantifying the spatial pattern of disease spread is the paucity of available data together with the challenge of incorporating optimally the limited information into models of disease transmission. To address this challenge the role of routine migration on the spatial pattern of infection during the epidemic of 2009 pandemic influenza in England is investigated here through two modelling approaches: parallel-region models, where epidemics in different regions are assumed to occur in isolation with shared characteristics; and meta-region models where inter-region transmission is expressed as a function of the commuter flux between regions. Results highlight that the significantly less computationally demanding parallel-region approach is sufficiently flexible to capture the underlying dynamics. This suggests that inter-region movement is either inaccurately characterized by the available commuting data or insignificant once its initial impact on transmission has subsided. PMID:27404957
... for Planning National Pandemic Influenza Plans (2005-2009) Regulations and Laws That May Apply During a Pandemic Surveillance, Epidemiology and Laboratory Community Mitigation Vaccine and Other Medical ...
treatable with two antiviral drugs, oseltamivir ( brand name Tamiflu®) and zanamivir ( brand name Relenza®), though there is no available vaccine. WHO...www.who.int/ csr /disease/swineflu/en/ index.html and CRS Report R40554, The 2009 H1N1 “Swine Flu” Outbreak: An Overview, by Sarah A. Lister and C...the virus 5 See WHO, Swine influenza - update 3, April 27, 2009, http://www.who.int/ csr /don
Pearce, Melissa B; Belser, Jessica A; Gustin, Kortney M; Pappas, Claudia; Houser, Katherine V; Sun, Xiangjie; Maines, Taronna R; Pantin-Jackwood, Mary J; Katz, Jacqueline M; Tumpey, Terrence M
The influenza virus H1N1 pandemic of 1918 was one of the worst medical catastrophes in human history. Recent studies have demonstrated that the hemagglutinin (HA) protein of the 1918 virus and 2009 H1N1 pandemic virus [A(H1N1)pdm09], the latter now a component of the seasonal trivalent inactivated influenza vaccine (TIV), share cross-reactive antigenic determinants. In this study, we demonstrate that immunization with the 2010-2011 seasonal TIV induces neutralizing antibodies that cross-react with the reconstructed 1918 pandemic virus in ferrets. TIV-immunized ferrets subsequently challenged with the 1918 virus displayed significant reductions in fever, weight loss, and virus shedding compared to these parameters in nonimmune control ferrets. Seasonal TIV was also effective in protecting against the lung infection and severe lung pathology associated with 1918 virus infection. Our data demonstrate that prior immunization with contemporary TIV provides cross-protection against the 1918 virus in ferrets. These findings suggest that exposure to A(H1N1)pdm09 through immunization may provide protection against the reconstructed 1918 virus which, as a select agent, is considered to pose both biosafety and biosecurity threats.
Ljungman, Per; de la Camara, Rafael; Perez-Bercoff, Lena; Abecasis, Manuel; Nieto Campuzano, Jose Bartolo; Cannata-Ortiz, M. Jimena; Cordonnier, Catherine; Einsele, Hermann; Gonzalez-Vicent, Marta; Espigado, Ildefonso; Halter, Jörg; Martino, Rodrigo; Mohty, Bilal; Sucak, Gülsan; Ullmann, Andrew J; Vázquez, Lourdes; Ward, Katherine N.; Engelhard, Dan
During 2009, a new strain of A/H1N1 influenza appeared and became pandemic. A prospective study was performed to collect data regarding risk factors and outcome of A/H1N1 in hematopoietic stem cell transplant recipients. Only verified pandemic A/H1N1 influenza strains were included: 286 patients were reported, 222 allogeneic and 64 autologous recipients. The median age was 38.3 years and the median time from transplant was 19.4 months. Oseltamivir was administered to 267 patients and 15 patients received zanamivir. One hundred and twenty-five patients (43.7%) were hospitalized. Ninety-three patients (32.5%) developed lower respiratory tract disease. In multivariate analysis, risk factors were age (OR 1.025; 1.01–1.04; P=0.002) and lymphopenia (OR 2.49; 1.33–4.67; P<0.001). Thirty-three patients (11.5%) required mechanical ventilation. Eighteen patients (6.3%) died from A/H1N1 infection or its complications. Neutropenia (P=0.03) and patient age (P=0.04) were significant risk factors for death. The 2009 A/H1N1 influenza pandemic caused severe complications in stem cell transplant recipients. PMID:21546495
Vaccine hesitancy is often understood and explored on the level of individual decision-making. However, questions surrounding the risk and efficacy of vaccination are evident in wider public discourse; social narratives of vaccination inform and impact on the individual level. This paper takes a narrative analysis approach from the sociology of health to examine data drawn from a wider study on global public health responses to the H1N1 pandemic. The paper concentrates upon criticisms to mass vaccination as recounted within the Council of Europe's debate of the handling of H1N1. It shows that three narratives were particularly dominant: problematizing the use of vaccination as a public health response; criticising the efficacy of the vaccines; and, questioning the safety of the strategy. This debate presents an important case study in understanding the way in which vaccines are problematized within the public discourse.
Ramezanpour, Bahar; Pronker, Esther S.; Kreijtz, Joost H.C.M.; Osterhaus, Albert D.M.E.; Claassen, E.
A quantitative method is presented to rank strengths, weaknesses, opportunities, and threats (SWOT) of modified vaccinia virus Ankara (MVA) as a platform for pre-pandemic and pandemic influenza vaccines. Analytic hierarchy process (AHP) was applied to achieve pairwise comparisons among SWOT factors in order to prioritize them. Key opinion leaders (KOLs) in the influenza vaccine field were interviewed to collect a unique dataset to evaluate the market potential of this platform. The purpose of this study, to evaluate commercial potential of the MVA platform for the development of novel generation pandemic influenza vaccines, is accomplished by using a SWOT and AHP combined analytic method. Application of the SWOT–AHP model indicates that its strengths are considered more important by KOLs than its weaknesses, opportunities, and threats. Particularly, the inherent immunogenicity capability of MVA without the requirement of an adjuvant is the most important factor to increase commercial attractiveness of this platform. Concerns regarding vector vaccines and anti-vector immunity are considered its most important weakness, which might lower public health value of this platform. Furthermore, evaluation of the results of this study emphasizes equally important role that threats and opportunities of this platform play. This study further highlights unmet needs in the influenza vaccine market, which could be addressed by the implementation of the MVA platform. Broad use of MVA in clinical trials shows great promise for this vector as vaccine platform for pre-pandemic and pandemic influenza and threats by other respiratory viruses. Moreover, from the results of the clinical trials seem that MVA is particularly attractive for development of vaccines against pathogens for which no, or only insufficiently effective vaccines, are available. PMID:26048779
Ramezanpour, Bahar; Pronker, Esther S; Kreijtz, Joost H C M; Osterhaus, Albert D M E; Claassen, E
A quantitative method is presented to rank strengths, weaknesses, opportunities, and threats (SWOT) of modified vaccinia virus Ankara (MVA) as a platform for pre-pandemic and pandemic influenza vaccines. Analytic hierarchy process (AHP) was applied to achieve pairwise comparisons among SWOT factors in order to prioritize them. Key opinion leaders (KOLs) in the influenza vaccine field were interviewed to collect a unique dataset to evaluate the market potential of this platform. The purpose of this study, to evaluate commercial potential of the MVA platform for the development of novel generation pandemic influenza vaccines, is accomplished by using a SWOT and AHP combined analytic method. Application of the SWOT-AHP model indicates that its strengths are considered more important by KOLs than its weaknesses, opportunities, and threats. Particularly, the inherent immunogenicity capability of MVA without the requirement of an adjuvant is the most important factor to increase commercial attractiveness of this platform. Concerns regarding vector vaccines and anti-vector immunity are considered its most important weakness, which might lower public health value of this platform. Furthermore, evaluation of the results of this study emphasizes equally important role that threats and opportunities of this platform play. This study further highlights unmet needs in the influenza vaccine market, which could be addressed by the implementation of the MVA platform. Broad use of MVA in clinical trials shows great promise for this vector as vaccine platform for pre-pandemic and pandemic influenza and threats by other respiratory viruses. Moreover, from the results of the clinical trials seem that MVA is particularly attractive for development of vaccines against pathogens for which no, or only insufficiently effective vaccines, are available.
McLean, Kenneth A; Goldin, Shoshanna; Nannei, Claudia; Sparrow, Erin; Torelli, Guido
A global shortage and inequitable access to influenza vaccines has been cause for concern for developing countries who face dire consequences in the event of a pandemic. The Global Action Plan for Influenza Vaccines (GAP) was launched in 2006 to increase global capacity for influenza vaccine production to address these concerns. It is widely recognized that well-developed infrastructure to produce seasonal influenza vaccines leads to increased capacity to produce pandemic influenza vaccines. This article summarizes the results of a survey administered to 44 manufacturers to assess their production capacity for seasonal influenza and pandemic influenza vaccine production. When the GAP was launched in 2006, global production capacity for seasonal and pandemic vaccines was estimated to be 500million and 1.5billion doses respectively. Since 2006 there has been a significant increase in capacity, with the 2013 survey estimating global capacity at 1.5billion seasonal and 6.2billion pandemic doses. Results of the current survey showed that global seasonal influenza vaccine production capacity has decreased since 2013 from 1.504billion doses to 1.467billion doses. However, notwithstanding the overall global decrease in seasonal vaccine capacity there were notable positive changes in the distribution of production capacity with increases noted in South East Asia (SEAR) and the Western Pacific (WPR) regions, albeit on a small scale. Despite a decrease in seasonal capacity, there has been a global increase of pandemic influenza vaccine production capacity from 6.2 billion doses in 2013 to 6.4 billion doses in 2015. This growth can be attributed to a shift towards more quadrivalent vaccine production and also to increased use of adjuvants. Pandemic influenza vaccine production capacity is at its highest recorded levels however challenges remain in maintaining this capacity and in ensuring access in the event of a pandemic to underserved regions.
Stincarelli, Maria; Arvia, Rosaria; De Marco, Maria Alessandra; Clausi, Valeria; Corcioli, Fabiana; Cotti, Claudia; Delogu, Mauro; Donatelli, Isabella; Azzi, Alberta; Giannecchini, Simone
Exploring the reassortment ability of the 2009 pandemic H1N1 (A/H1N1pdm09) influenza virus with other circulating human or avian influenza viruses is the main concern related to the generation of more virulent or new variants having implications for public health. After different coinfection experiments in human A549 cells, by using the A/H1N1pdm09 virus plus one of human seasonal influenza viruses of H1N1 and H3N2 subtype or one of H11, H10, H9, H7 and H1 avian influenza viruses, several reassortant viruses were obtained. Among these, the HA of H1N1 was the main segment of human seasonal influenza virus reassorted in the A/H1N1pdm09 virus backbone. Conversely, HA and each of the three polymerase segments, alone or in combination, of the avian influenza viruses mainly reassorted in the A/H1N1pdm09 virus backbone. Of note, A/H1N1pdm09 viruses that reassorted with HA of H1N1 seasonal human or H11N6 avian viruses or carried different combination of avian origin polymerase segments, exerted a higher replication effectiveness than that of the parental viruses. These results confirm that reassortment of the A/H1N1pdm09 with circulating low pathogenic avian influenza viruses should not be misjudged in the prediction of the next pandemic.
Schwartz, Benjamin; Orenstein, Walter A
Few catastrophes can compare with the global impact of a severe influenza pandemic. The 1918-1919 pandemic was associated with more than 500,000 deaths in the USA and an estimated 20-40 million deaths worldwide, though some place the global total much higher. In an era when infectious disease mortality had been steadily decreasing, the 1918-1919 pandemic caused a large spike in overall population mortality, temporarily reversing decades of progress. The US Department of Health and Human Services, extrapolating from the 1918-1919 pandemic to the current US population size and demographics, has estimated that a comparable pandemic today would result in almost two million deaths. Vaccination is an important component of a pandemic response. Public health measures such as reduction of close contacts with others, improved hygiene, and respiratory protection with facemasks or respirators can reduce the risk of exposure and illness (Germann et al. 2006; Ferguson et al. 2006), but would not reduce susceptibility among the population. Prophylaxis with antiviral medications also may prevent illness but depends on the availability of large antiviral drug stockpiles and also does not provide long-term immunity. By contrast, immunization with a well-matched pandemic vaccine would provide active immunity and represent the most durable pandemic response. However, given current timelines for the development of a pandemic influenza vaccine and its production capacity, vaccine is likely not to be available in sufficient quantities to protect the entire population before pandemic outbreaks occur, and thus potentially limited stocks may need to be prioritized. This chapter reviews information on influenza vaccine production capacity, describes approaches used in the USA to set priorities for vaccination in the setting of limited supply, and presents a proposed strategy for prioritization.
Pratt, Robert J
This second in a two-part unit on swine flu looks at infection control measures for nurses. During late spring and early summer, increasing numbers of people became infected with novel swine origin influenza type A virus (influenza A(H1N1)v 2009) and a global pandemic started. Part 1 of this unit explored the biology of influenza viruses and the origins and characteristics of flu pandemics. This part reviews viral transmission, infection prevention and control and pandemic preparedness.
Goel, M K; Goel, M; Khanna, P; Mittal, K
The world witnessed a the first influenza pandemic in this century and fourth overall since first flu pandemic was reported during the World War I. The past experiences with influenza viruses and this pandemic of H1N1 place a consider-able strain on health services and resulted in serious illnesses and a large number of deaths. Develop-ing countries were declared more likely to be at risk from the pandemic effects, as they faced the dual problem of highly vulnerable populations and limited resources to respond H1N1. The public health experts agreed that vaccination is the most effective ways to mitigate the negative effects of the pandemic. The vaccines for H1N1 virus have been used in over 40 countries and administered to over 200 million people helped in a great way and on August 10, 2010, World Health Organization (WHO) announced H1N1 to be in postpandemic period. But based on knowledge about past pandemics, the H1N1 (2009) virus is expected to continue to circulate as a seasonal virus and may undergo some agenic-variation. As WHO strongly recommends vaccination, vigilance for regular updating of the composition of influenza vaccines, based on an assessment of the future impact of circulating viruses along with safety surveillance of the vaccines is necessary. This review has been done to take a stock of the currently available H1N1 vaccines and their possible use as public health intervention in the postpandemic period.
The I427T neuraminidase (NA) substitution, located outside the NA active site of an influenza A(H1N1)pdm09 variant with reduced susceptibility to NA inhibitors, alters NA properties and impairs viral fitness.
Tu, Véronique; Abed, Yacine; Barbeau, Xavier; Carbonneau, Julie; Fage, Clément; Lagüe, Patrick; Boivin, Guy
Emergence of pan neuraminidase inhibitor (NAI)-resistant variants constitutes a serious clinical concern. An influenza A(H1N1)pdm09 variant containing the I427T/Q313R neuraminidase (NA) substitutions was previously identified in a surveillance study. Although these changes are not part of the NA active site, the variant showed reduced susceptibility to many NAIs. In this study, we investigated the mechanism of resistance for the I427T/Q313R substitution and its impact on the NA enzyme and viral fitness. Recombinant wild-type (WT), I427T/Q313R and I427T A(H1N1)pdm09 viruses were generated by reverse genetics and tested for their drug susceptibilities, enzymatic properties and replication kinetics in vitro as well as their virulence in mice. Molecular dynamics (MD) simulations were performed for NA structural analysis. The I427T substitution, which was responsible for the resistance phenotype observed in the double (I427T/Q313R) mutant, induced 17-, 56-, 7-, and 14-fold increases in IC50 values against oseltamivir, zanamivir, peramivir and laninamivir, respectively. The I427T substitution alone or combined to Q313R significantly reduced NA affinity. The I427T/Q313R and to a lesser extent I427T recombinant viruses displayed reduced viral titers vs WT in vitro. In experimentally-infected mice, the mortality rates were 62.5%, 0% and 14.3% for the WT, I417T/Q313R and I427T viruses, respectively. There were about 2.5- and 2-Log reductions in mean lung viral titers on day 5 post-infection for the I427T/Q313R and I427T mutants, respectively, compared to WT. Results from simulations revealed that the I427T change indirectly altered the stability of the catalytic R368 residue of the NA enzyme causing its reduced binding to the substrate/inhibitor. This study demonstrates that the I427T/Q313R mutant, not only alters NAI susceptibility but also compromises NA properties and viral fitness, which could explain its infrequent detection in clinic.
Lv, Xing; Chen, Ying; Kung, Hsiang-fu; Zee, Benny; Cheng, Xiao-wen; He, Ming-Liang
Much information is available for the 2009 H1N1 influenza immunity response, but little is known about the antibody change in seasonal influenza before and during the novel influenza A pandemic. In this study, we conducted a cross-sectional serological survey of 4 types of major seasonal influenza in March and September 2009 on a full range of age groups, to investigate seasonal influenza immunity response before and during the outbreak of the sH1N1 influenza in Shenzhen – the largest migration city in China. We found that the 0–5 age group had an increased antibody level for all types of seasonal influenza during the pandemic compared to the pre-outbreak level, in contrast with almost all other age groups, in which the antibody level decreased. Also, distinct from the antibodies of A/H3N2, B/Yamagata and B/Victoria that decreased significantly during the 2009 H1N1 pandemic, the antibody of A/H1N1 showed no statistical difference from the pre-outbreak level. The results suggest that the antibodies against the 2009 sH1N1 cross-reacted with seasonal H1N1. Moreover, the 0–5 age group was under attack by both seasonal and 2009 H1N1 influenza during the pandemic, hence vaccination merely against a new strain of flu might not be enough to protect the youngest group. PMID:23382854
Steelfisher, Gillian K; Blendon, Robert J; Bekheit, Mark M; Mitchell, Elizabeth W; Williams, Jennifer; Lubell, Keri; Peugh, Jordon; DiSogra, Charles A
We sought to examine motivators and barriers related to monovalent 2009 influenza A (H1N1) vaccination among pregnant women. We conducted a national poll of pregnant women using a random online sample (237) and opt-in supplement (277). In all, 42% of pregnant women reported getting the vaccine. Vaccination was positively associated with attitudinal factors including believing the vaccine is very safe or benefits the baby, and with provider recommendations. Women in racial/ethnic minority groups, women with less education, and women <35 years were less likely to get the vaccine and had differing views and experiences. Despite H1N1 vaccination rates that are higher than past seasonal influenza rates, barriers like safety concerns may persist in a pandemic. Messaging from providers that encourages women to believe the vaccine is very safe and benefits their baby may be compelling. Messaging and outreach during future pandemics may require customization to increase vaccination among high-risk groups.
Chen, Huazhong; Liu, Shelan; Liu, Jun; Chai, Chengliang; Mao, Haiyan; Yu, Zhao; Tang, Yuming; Zhu, Geqin; Chen, Haixiao X.; Zhu, Chengchu; Shao, Hui; Tan, Shuguang; Wang, Qianli; Bi, Yuhai; Zou, Zhen; Liu, Guang; Jin, Tao; Jiang, Chengyu; Gao, George F.; Peiris, Malik
A nosocomial cluster induced by co-infections with avian influenza A(H7N9) and A(H1N1)pdm09 (pH1N1) viruses occurred in 2 patients at a hospital in Zhejiang Province, China, in January 2014. The index case-patient was a 57-year-old man with chronic lymphocytic leukemia who had been occupationally exposed to poultry. He had co-infection with H7N9 and pH1N1 viruses. A 71-year-old man with polycythemia vera who was in the same ward as the index case-patient for 6 days acquired infection with H7N9 and pH1N1 viruses. The incubation period for the second case-patient was estimated to be <4 days. Both case-patients died of multiple organ failure. Virus genetic sequences from the 2 case-patients were identical. Of 103 close contacts, none had acute respiratory symptoms; all were negative for H7N9 virus. Serum samples from both case-patients demonstrated strong proinflammatory cytokine secretion but incompetent protective immune responses. These findings strongly suggest limited nosocomial co-transmission of H7N9 and pH1N1 viruses from 1 immunocompromised patient to another. PMID:26982379
Chen, Huazhong; Liu, Shelan; Liu, Jun; Chai, Chengliang; Mao, Haiyan; Yu, Zhao; Tang, Yuming; Zhu, Geqin; Chen, Haixiao X; Zhu, Chengchu; Shao, Hui; Tan, Shuguang; Wang, Qianli; Bi, Yuhai; Zou, Zhen; Liu, Guang; Jin, Tao; Jiang, Chengyu; Gao, George F; Peiris, Malik; Yu, Hongjie; Chen, Enfu
A nosocomial cluster induced by co-infections with avian influenza A(H7N9) and A(H1N1)pdm09 (pH1N1) viruses occurred in 2 patients at a hospital in Zhejiang Province, China, in January 2014. The index case-patient was a 57-year-old man with chronic lymphocytic leukemia who had been occupationally exposed to poultry. He had co-infection with H7N9 and pH1N1 viruses. A 71-year-old man with polycythemia vera who was in the same ward as the index case-patient for 6 days acquired infection with H7N9 and pH1N1 viruses. The incubation period for the second case-patient was estimated to be <4 days. Both case-patients died of multiple organ failure. Virus genetic sequences from the 2 case-patients were identical. Of 103 close contacts, none had acute respiratory symptoms; all were negative for H7N9 virus. Serum samples from both case-patients demonstrated strong proinflammatory cytokine secretion but incompetent protective immune responses. These findings strongly suggest limited nosocomial co-transmission of H7N9 and pH1N1 viruses from 1 immunocompromised patient to another.
Håberg, Siri E; Trogstad, Lill; Gunnes, Nina; Wilcox, Allen J.; Gjessing, Håkon K.; Samuelsen, Sven Ove; Skrondal, Anders; Cappelen, Inger; Engeland, Anders; Aavitsland, Preben; Madsen, Steinar; Buajordet, Ingebjørg; Furu, Kari; Nafstad, Per; Vollset, Stein Emil; Berit, Feiring; Nøkleby, Hanne; Magnus, Per; Stoltenberg, Camilla
Background During the 2009 influenza pandemic, pregnant women were at particular risk of serious influenza illness. This concern was further complicated by questions about vaccine safety in pregnant women raised by anecdotal reports of fetal deaths following vaccination. Methods We explored the safety of influenza vaccination of pregnant women by linking Norwegian national registries and medical consultation data to determine influenza diagnosis, vaccination status, birth outcomes, and background information for pregnant women before, during, and after the pandemic. We used Cox regression models to estimate hazard ratios of fetal death, with gestational day as the time metric and vaccination and pandemic exposure as time-dependent exposure variables. Results There were 117,347 eligible pregnancies in Norway in 2009–2010. Fetal mortality was 4.9/1000. 54% of pregnant women in their second or third trimester during the pandemic were vaccinated. Vaccination in pregnancy substantially reduced the risk of influenza diagnosis (adjusted hazard ratio, 0.30; 95% confidence interval [CI], 0.25 to 0.34). A clinical diagnosis of influenza in the mother increased the risk of fetal death (adjusted hazard ratio, 1.91; 95% CI, 1.07 to 3.41). Among pregnant women, the risk of fetal death was lower with vaccination, although this reduction was not statistically significant (adjusted hazard ratio, 0.88; 95% CI, 0.66 to 1.17). Conclusions Pandemic influenza in pregnancy was associated with increased risk of fetal death. Vaccination during pregnancy reduced the risk of influenza diagnosis. Vaccination itself did not increase fetal mortality, and may have reduced the risk of influenza-related fetal death during the pandemic. PMID:23323868
Hadler, James L
In order to consider the ethical issues around vaccine distribution during an influenza pandemic, it is critical to have an understanding of the role of influenza vaccine in a pandemic, the rate at which vaccine is likely to be come available, who will likely produce and "own" the vaccine, how vaccine distribution and administration might be accomplished, and which are the groups that might be deemed highest priority to be vaccinated against influenza. The United States and Connecticut have been considering the more challenging of these issues and have learned from Canada, which previously discussed and made decisions on the challenges related to vaccine distribution. Although there is still some critical advance thinking that needs to be done, planning for the response to an influenza pandemic is now at an advanced stage. The keys to preparedness at this stage are to be aware of the vaccine distribution options, to know the benefits and limitations of each option, and to be flexible but nimble in dealing with a real pandemic.
Gras, Stephanie; Kedzierski, Lukasz; Valkenburg, Sophie A; Laurie, Karen; Liu, Yu Chih; Denholm, Justin T; Richards, Michael J; Rimmelzwaan, Guus F; Kelso, Anne; Doherty, Peter C; Turner, Stephen J; Rossjohn, Jamie; Kedzierska, Katherine
Preexisting T-cell immunity directed at conserved viral regions promotes enhanced recovery from influenza virus infections, with there being some evidence of cross-protection directed at variable peptides. Strikingly, many of the immunogenic peptides derived from the current pandemic A(H1N1)-2009 influenza virus are representative of the catastrophic 1918 "Spanish flu" rather than more recent "seasonal" strains. We present immunological and structural analyses of cross-reactive CD8(+) T-cell-mediated immunity directed at a variable (although highly cross-reactive) immunodominant NP(418-426) peptide that binds to a large B7 family (HLA-B*3501/03/0702) found throughout human populations. Memory CD8(+) T-cell specificity was probed for 12 different NP(418) mutants that emerged over the 9 decades between the 1918 and 2009 pandemics. Although there is evidence of substantial cross-reactivity among seasonal NP(418) mutants, current memory T-cell profiles show no preexisting immunity to the 2009-NP(418) variant or the 1918-NP(418) variant. Natural infection with the A(H1N1)-2009 virus, however, elicits CD8(+) T cells specific for the 2009-NP(418) and 1918-NP(418) epitopes. This analysis points to the potential importance of cross-reactive T-cell populations that cover the possible spectrum of T-cell variants and suggests that the identification of key residues/motifs that elicit cross-reactive T-cell sets could facilitate the evolution of immunization protocols that provide a measure of protection against unpredicted pandemic influenza viruses. Thus, it is worth exploring the potential of vaccines that incorporate peptide variants with a proven potential for broader immunogenicity, especially to those that are not recognized by the current memory T-cell pool generated by exposure to influenza variants that cause successive seasonal epidemics.
Halperin, Beth A; MacKinnon-Cameron, Donna; McNeil, Shelly; Kalil, Jennifer; Halperin, Scott A
This survey study compared pre- and post-pandemic knowledge, attitudes, beliefs, and intended behaviors of pregnant women regarding influenza vaccination (seasonal and/or pandemic) during pregnancy in order to determine key factors influencing their decision to adhere to influenza vaccine recommendations. Only 36% of 662 pre-pandemic respondents knew that influenza was more severe in pregnant women, compared to 62% of the 159 post-pandemic respondents. Of the pre-pandemic respondents, 41% agreed or strongly agreed that that it was safer to wait until after the first 3 months to receive the seasonal influenza vaccine, whereas 23% of the post-pandemic cohort agreed or strongly agreed; 32% of pre-pandemic participants compared to 11% of post-pandemic respondents felt it was best to avoid all vaccines while pregnant. Despite 61% of the pre-pandemic cohort stating that they would have the vaccine while pregnant if their doctor recommended it and 54% citing their doctor/nurse as their primary source of vaccine information, only 20% said their doctor discussed influenza vaccination during their pregnancy, compared to 77% of the post-pandemic respondents who reported having this conversation. Women whose doctors discussed influenza vaccine during pregnancy had higher overall knowledge scores (P < 0.0001; P = 0.005) and were more likely to believe the vaccine is safe in all stages of pregnancy (P < 0.0001; P = 0.001) than those whose doctors did not discuss influenza vaccination. The 2009 H1N1 pandemic experience appeared to change attitudes and behaviours of health care providers and their pregnant patients toward influenza vaccination. PMID:25668670
Sundaram, Neisha; Purohit, Vidula; Schaetti, Christian; Kudale, Abhay; Joseph, Saju; Weiss, Mitchell G
Vaccination is a cornerstone of influenza prevention, but limited vaccine uptake was a problem worldwide during the 2009–2010 pandemic. Community acceptance of a vaccine is a critical determinant of its effectiveness, but studies have been confined to high-income countries. We conducted a cross-sectional, mixed-method study in urban and rural Pune, India in 2012–2013. Semi-structured explanatory model interviews were administered to community residents (n = 436) to study awareness, experience and preference between available vaccines for pandemic influenza. Focus group discussions and in-depth interviews complemented the survey. Awareness of pandemic influenza vaccines was low (25%). Some respondents did not consider vaccines relevant for adults, but nearly all (94.7%), when asked, believed that a vaccine would prevent swine flu. Reported vaccine uptake however was 8.3%. Main themes identified as reasons for uptake were having heard of a death from swine flu, health care provider recommendation or affiliation with the health system, influence of peers and information from media. Reasons for non-use were low perceived personal risk, problems with access and cost, inadequate information and a perceived lack of a government mandate endorsing influenza vaccines. A majority indicated a preference for injectable over nasal vaccines, especially in remote rural areas. Hesitancy from a lack of confidence in pandemic influenza vaccines appears to have been less of an issue than access, complacency and other sociocultural considerations. Recent influenza outbreaks in 2015 highlight a need to reconsider policy for routine influenza vaccination while paying attention to sociocultural factors and community preferences for effective vaccine action. PMID:26110454
Sundaram, Neisha; Purohit, Vidula; Schaetti, Christian; Kudale, Abhay; Joseph, Saju; Weiss, Mitchell G
Vaccination is a cornerstone of influenza prevention, but limited vaccine uptake was a problem worldwide during the 2009-2010 pandemic. Community acceptance of a vaccine is a critical determinant of its effectiveness, but studies have been confined to high-income countries. We conducted a cross-sectional, mixed-method study in urban and rural Pune, India in 2012-2013. Semi-structured explanatory model interviews were administered to community residents (n = 436) to study awareness, experience and preference between available vaccines for pandemic influenza. Focus group discussions and in-depth interviews complemented the survey. Awareness of pandemic influenza vaccines was low (25%). Some respondents did not consider vaccines relevant for adults, but nearly all (94.7%), when asked, believed that a vaccine would prevent swine flu. Reported vaccine uptake however was 8.3%. Main themes identified as reasons for uptake were having heard of a death from swine flu, health care provider recommendation or affiliation with the health system, influence of peers and information from media. Reasons for non-use were low perceived personal risk, problems with access and cost, inadequate information and a perceived lack of a government mandate endorsing influenza vaccines. A majority indicated a preference for injectable over nasal vaccines, especially in remote rural areas. Hesitancy from a lack of confidence in pandemic influenza vaccines appears to have been less of an issue than access, complacency and other sociocultural considerations. Recent influenza outbreaks in 2015 highlight a need to reconsider policy for routine influenza vaccination while paying attention to sociocultural factors and community preferences for effective vaccine action.
Dormitzer, Philip R; Suphaphiphat, Pirada; Gibson, Daniel G; Wentworth, David E; Stockwell, Timothy B; Algire, Mikkel A; Alperovich, Nina; Barro, Mario; Brown, David M; Craig, Stewart; Dattilo, Brian M; Denisova, Evgeniya A; De Souza, Ivna; Eickmann, Markus; Dugan, Vivien G; Ferrari, Annette; Gomila, Raul C; Han, Liqun; Judge, Casey; Mane, Sarthak; Matrosovich, Mikhail; Merryman, Chuck; Palladino, Giuseppe; Palmer, Gene A; Spencer, Terika; Strecker, Thomas; Trusheim, Heidi; Uhlendorff, Jennifer; Wen, Yingxia; Yee, Anthony C; Zaveri, Jayshree; Zhou, Bin; Becker, Stephan; Donabedian, Armen; Mason, Peter W; Glass, John I; Rappuoli, Rino; Venter, J Craig
During the 2009 H1N1 influenza pandemic, vaccines for the virus became available in large quantities only after human infections peaked. To accelerate vaccine availability for future pandemics, we developed a synthetic approach that very rapidly generated vaccine viruses from sequence data. Beginning with hemagglutinin (HA) and neuraminidase (NA) gene sequences, we combined an enzymatic, cell-free gene assembly technique with enzymatic error correction to allow rapid, accurate gene synthesis. We then used these synthetic HA and NA genes to transfect Madin-Darby canine kidney (MDCK) cells that were qualified for vaccine manufacture with viral RNA expression constructs encoding HA and NA and plasmid DNAs encoding viral backbone genes. Viruses for use in vaccines were rescued from these MDCK cells. We performed this rescue with improved vaccine virus backbones, increasing the yield of the essential vaccine antigen, HA. Generation of synthetic vaccine seeds, together with more efficient vaccine release assays, would accelerate responses to influenza pandemics through a system of instantaneous electronic data exchange followed by real-time, geographically dispersed vaccine production.
Background The first cases of influenza A/H1N1 (swine flu) were confirmed in the UK on 27th April 2009, after a novel virus first identified in Mexico rapidly evolved into a pandemic. The swine flu outbreak was the first pandemic in more than 40 years and for many, their first encounter with a major influenza outbreak. This study examines public understandings of the pandemic, exploring how people deciphered the threat and perceived they could control the risks. Methods Purposive sampling was used to recruit seventy three people (61 women and 12 men) to take part in 14 focus group discussions around the time of the second wave in swine flu cases. Results These discussions showed that there was little evidence of the public over-reacting, that people believed the threat of contracting swine flu was inevitable, and that they assessed their own self-efficacy for protecting against it to be low. Respondents assessed a greater risk to their health from the vaccine than from the disease. Such findings could have led to apathy about following the UK Governments recommended health protective behaviours, and a sub-optimal level of vaccine uptake. More generally, people were confused about the difference between seasonal influenza and swine flu and their vaccines. Conclusions This research suggests a gap in public understandings which could hinder attempts to communicate about novel flu viruses in the future. There was general support for the government's handling of the pandemic, although its public awareness campaign was deemed ineffectual as few people changed their current hand hygiene practices. There was less support for the media who were deemed to have over-reported the swine flu pandemic. PMID:21078169
van den Brand, Judith M A; Kreijtz, Joost H C M; Bodewes, Rogier; Stittelaar, Koert J; van Amerongen, Geert; Kuiken, Thijs; Simon, James; Fouchier, Ron A M; Del Giudice, Giuseppe; Rappuoli, Rino; Rimmelzwaan, Guus F; Osterhaus, Albert D M E
Serum antibodies induced by seasonal influenza or seasonal influenza vaccination exhibit limited or no cross-reactivity against the 2009 pandemic swine-origin influenza virus of the H1N1 subtype (pH1N1). Ferrets immunized once or twice with MF59-adjuvanted seasonal influenza vaccine exhibited significantly reduced lung virus titers but no substantial clinical protection against pH1N1-associated disease. However, priming with MF59-adjuvanted seasonal influenza vaccine significantly increased the efficacy of a pandemic MF59-adjuvanted influenza vaccine against pH1N1 challenge. Elucidating the mechanism involved in this priming principle will contribute to our understanding of vaccine- and infection-induced correlates of protection. Furthermore, a practical consequence of these findings is that during an emerging pandemic, the implementation of a priming strategy with an available adjuvanted seasonal vaccine to precede the eventual pandemic vaccination campaign may be useful and life-saving.
Suhardono, Mahendra; Ugiyadi, Dori; Nurnaeni, Ida; Emelia, Imelda
In Indonesia, avian influenza A(H5N1) virus started to spread in humans in June 2005, with an alarming case-fatality rate of more than 80%. Considering that global influenza vaccine production capacity would barely have covered 10% of the world's pandemic vaccine needs, and that countries with no production facilities or prearranged contracts would be without access to a vaccine, the Government of Indonesia embarked on a programme to increase its readiness for a future influenza pandemic. This included the domestic production of influenza vaccine, which was entrusted to Bio Farma. This health security strategy consists of developing trivalent influenza vaccine production capacity in order to be able to convert immediately to monovalent production of up to 20 million pandemic doses for the Indonesian market upon receipt of the seed strain from the World Health Organization (WHO). For this purpose, a dedicated production facility is being constructed within the Bio Farma premises in Bandung. As an initial stage of influenza vaccine development, imported seasonal influenza bulk has been formulated and filled in the Bio Farma facility. Following three consecutive batches and successful clinical trials, the product was licensed by the Indonesian National Regulatory Authority and distributed commercially for the Hajj programme in 2009. With continued support from its technology transfer partners, Bio Farma is now advancing with the development of upstream processes to produce its own bulk for seasonal and pandemic use.
Black, Andrew J.; House, Thomas; Keeling, M. J.; Ross, J. V.
Antiviral treatment offers a fast acting alternative to vaccination; as such it is viewed as a first-line of defence against pandemic influenza in protecting families and households once infection has been detected. In clinical trials, antiviral treatments have been shown to be efficacious in preventing infection, limiting disease and reducing transmission, yet their impact at containing the 2009 influenza A(H1N1)pdm outbreak was limited. To understand this seeming discrepancy, we develop a general and computationally efficient model for studying household-based interventions. This allows us to account for uncertainty in quantities relevant to the 2009 pandemic in a principled way, accounting for the heterogeneity and variability in each epidemiological process modelled. We find that the population-level effects of delayed antiviral treatment and prophylaxis mean that their limited overall impact is quantitatively consistent (at current levels of precision) with their reported clinical efficacy under ideal conditions. Hence, effective control of pandemic influenza with antivirals is critically dependent on early detection and delivery ideally within 24 h. PMID:23389899
Mayet, A; Haus-Cheymol, R; Bouaiti, E A; Decam, C; Simon, F; Mérens, A; Spiegel, A; Meynard, J B; Deparis, X; Migliani, R
French military personnel are subject to a compulsory vaccination schedule. The aim of this study was to describe vaccine adverse events (VAE) reported from 2002 to 2010 in armed forces. VAE are routinely surveyed by the military Centre for epidemiology and public health. For each case, military practitioners fill a notification form, providing patient characteristics, clinical information and vaccines administered. For this study, VAE following influenza A(H1N1)pdm09 vaccination were excluded. Among the 473 cases retained, 442 (93%) corresponded to non-severe VAE,including local, regional and systemic events, while 31 corresponded to severe VAE, with two leading to significant disability. The global VAE reporting rate (RR) was 14.0 per 100,000 injections. While stationary from 2002 to 2008, the RR increased from 2009. The most important observations were a marked increase of VAE attributed to Bacillus Calmette-Guérin (BCG) vaccine from 2005 to 2008, a high RR observed with the inactivated diphtheria-tetanus (toxoids)-poliovirus vaccine combined with acellular pertussis vaccine (dTap-IPV) from 2008 and an increase in RR for seasonal influenza vaccine VAE in 2009. Our RR for severe VAE (1.1 VAEper 100,000) appears comparable with rates observed among United States civilians and military personnel. The increase observed from 2009 could be partly explained by the influenza A(H1N1)pdm09 pandemic which increased practitioner awareness towards VAE. In conclusion, the tolerance of the vaccines used in French armed forces appears acceptable.
Larrauri Cámara, Amparo; Jiménez-Jorge, Silvia; Mateo Ontañón, Salvador de; Pozo Sánchez, Francisco; Ledesma Moreno, Juan; Casas Flecha, Inmaculada
In accordance with European Centre for Disease Prevention and Control recommendations, the Spanish Influenza Surveillance System (SISS) maintained its activity during the summer of 2009, and since July 2009 the pandemic virus activity was monitored by the SISS. In this paper, we describe the epidemiological and virological characteristics of the 2009 pandemic in the Spain through the SISS. Spain experienced a transmission of the new A(H1N1)pdm09 influenza virus during the summer of 2009, which gradually increased, resulting in the pandemic wave in early autumn of that year. The reproductive number R0, estimated during the growth phase of the pandemic wave (1.32; 95% confidence interval [95%CI], 1.29-1.36), showed a transmissibility comparable to preceding pandemics. There was an almost complete replacement of the previous seasonal A(H1N1) influenza virus by the pandemic virus A(H1N1)pdm09. The pandemic virus produced a greater burden of illness than seasonal influenza in children younger than 15 years old, while the incidence in those older than 64 years was lower compared with previous inter-pandemic seasons. Nevertheless, in Spain the 2009 pandemic was characterized as mild, considering the duration of the pandemic period and the influenza detection rate, both in the range of those observed in previous inter-pandemic seasons. Also, the case fatality ratio (CFR) was estimated at 0.58 deaths/1,000 confirmed ILI cases (95%CI, 0.52-0.64), in the range of the two previous pandemics of 1957 and 1968, with the highest CFR observed in the older than 64 years age group. In the 2009 pandemic there was a higher percentage of pandemic confirmed deaths in the younger ages, compared to seasonal influenza, since only 28% of the reported deaths occurred in persons aged 64 years and older.
Altaş, Ayşe Başak; Bayrakdar, Fatma; Korukluoğlu, Gülay
. Predominance of B/Victoria lineage were observed during 2011-2012 season while the rest of the majority were B/Yamagata. The positivity rates of other respiratory viruses which were also analyzed in the scope of sentinel influenza surveillance were similar to influenza positivity for all seasons except 2010-2011. This fact has emphasized that, those viruses were also responsible for influenza-like illness especially during the early and late phases of the season. In conclusion, monitoring of the antigenic and genetic characteristics of influenza viruses by surveillance studies is essential for the early detection of potential pandemic variants as well as to ensure similarities among the circulating strains and the corresponding vaccine strains.
Crank, Michelle C.; Gordon, Ingelise J.; Yamshchikov, Galina V.; Sitar, Sandra; Hu, Zonghui; Enama, Mary E.; Holman, LaSonji A.; Bailer, Robert T.; Pearce, Melissa B.; Koup, Richard A.; Mascola, John R.; Nabel, Gary J.; Tumpey, Terrence M.; Schwartz, Richard M.; Graham, Barney S.; Ledgerwood, Julie E.
Background A novel, swine-origin influenza A (H1N1) virus was detected worldwide in April 2009, and the World Health Organization (WHO) declared a global pandemic that June. DNA vaccine priming improves responses to inactivated influenza vaccines. We describe the rapid production and clinical evaluation of a DNA vaccine encoding the hemagglutinin protein of the 2009 pandemic A/California/04/2009(H1N1) influenza virus, accomplished nearly two months faster than production of A/California/07/2009(H1N1) licensed monovalent inactivated vaccine (MIV). Methods 20 subjects received three H1 DNA vaccinations (4 mg intramuscularly with Biojector) at 4-week intervals. Eighteen subjects received an optional boost when the licensed H1N1 MIV became available. The interval between the third H1 DNA injection and MIV boost was 3–17 weeks. Vaccine safety was assessed by clinical observation, laboratory parameters, and 7-day solicited reactogenicity. Antibody responses were assessed by ELISA, HAI and neutralization assays, and T cell responses by ELISpot and flow cytometry. Results Vaccinations were safe and well-tolerated. As evaluated by HAI, 6/20 developed positive responses at 4 weeks after third DNA injection and 13/18 at 4 weeks after MIV boost. Similar results were detected in neutralization assays. T cell responses were detected after DNA and MIV. The antibody responses were significantly amplified by the MIV boost, however, the boost did not increased T cell responses induced by DNA vaccine. Conclusions H1 DNA vaccine was produced quickly, was well-tolerated, and had modest immunogenicity as a single agent. Other HA DNA prime-MIV boost regimens utilizing one DNA prime vaccination and longer boost intervals have shown significant immunogenicity. Rapid and large-scale production of HA DNA vaccines has the potential to contribute to an efficient response against future influenza pandemics. Trial Registration Clinicaltrials.gov NCT00973895 PMID:25884189
Asay, Garrett R. Beeler; Cho, Bo-Hyun; Lorick, Suchita A.; Tipton, Meredith L.; Dube, Nancy L.; Messonnier, Mark L.
School nurses played a key role in Maine's school-located influenza vaccination (SLV) clinics during the 2009-2010 pandemic season. The objective of this study was to determine, from the school district perspective, the labor hours and costs associated with outside-clinic coordination activities (OCA). The authors defined OCA as labor hours spent…
Lerdsamran, Hatairat; Pittayawonganon, Chakrarat; Pooruk, Phisanu; Mungaomklang, Anek; Iamsirithaworn, Sopon; Thongcharoen, Prasert; Kositanont, Uraiwan; Auewarakul, Prasert; Chokephaibulkit, Kulkanya; Oota, Sineenat; Pongkankham, Warin; Silaporn, Patummal; Komolsiri, Supaloek; Noisumdaeng, Pirom; Chotpitayasunondh, Tawee; Sangsajja, Chariya; Wiriyarat, Witthawat; Louisirirotchanakul, Suda; Puthavathana, Pilaipan
Background Individuals infected with the 2009 pandemic virus A(H1N1) developed serological response which can be measured by hemagglutination-inhibition (HI) and microneutralization (microNT) assays. Methodology/Principal Findings MicroNT and HI assays for specific antibody to the 2009 pandemic virus were conducted in serum samples collected at the end of the first epidemic wave from various groups of Thai people: laboratory confirmed cases, blood donors and health care workers (HCW) in Bangkok and neighboring province, general population in the North and the South, as well as archival sera collected at pre- and post-vaccination from vaccinees who received influenza vaccine of the 2006 season. This study demonstrated that goose erythrocytes yielded comparable HI antibody titer as compared to turkey erythrocytes. In contrast to the standard protocol, our investigation found out the necessity to eliminate nonspecific inhibitor present in the test sera by receptor destroying enzyme (RDE) prior to performing microNT assay. The investigation in pre-pandemic serum samples showed that HI antibody was more specific to the 2009 pandemic virus than NT antibody. Based on data from pre-pandemic sera together with those from the laboratory confirmed cases, HI antibody titers ≥40 for adults and ≥20 for children could be used as the cut-off level to differentiate between the individuals with or without past infection by the 2009 pandemic virus. Conclusions/Significance Based on the cut-off criteria, the infection rates of 7 and 12.8% were estimated in blood donors and HCW, respectively after the first wave of the 2009 influenza pandemic. Among general population, the infection rate of 58.6% was found in children versus 3.1% in adults. PMID:21283570
Wahlen, Mongeon Kari J; Bessette, Richard R; Bernard, Matthew E; Springer, Donna J; Benson, Catherine A
Vaccine distribution is an essential component of any healthcare organization's pandemic influenza plan. Variables surrounding distribution in these circumstances are often difficult to anticipate and require careful consideration. The 2009 H1N1 influenza pandemic provided organizations with an opportunity to test current models and overall organizational readiness for the next influenza pandemic. This article describes the experiences at a large, midwestern, multispecialty medical system in responding to the unique circumstances surrounding distribution of the 2009 H1N1 influenza vaccine. We discuss challenges, variables to consider when choosing a vaccine distribution model, institutional response, and lessons learned.
Naval Health Research Center Safety of the Pandemic H1N1 Influenza Vaccine among Pregnant Women and Their Newborns Ava M.S. Conlin Anna...Safety of the Pandemic H1N1 Influenza Vaccine Among Pregnant U.S. Military Women and Their Newborns Ava Marie S. Conlin, DO, MPH, Anna T. Bukowinski...active-duty U.S. military women who received pandemic H1N1 vaccine during pregnancy as well as adverse health outcomes among the newborns resulting from
Parretta, Elisabetta; Ianniello, Benedetta; Ferrazin, Fernanda; Rossi, Francesco; Capuano, Annalisa
According to European recommendations, the Italian Medicines Agency (AIFA) required close monitoring of the safety of the MF59-adjuvanted H1N1v vaccine, which was the only vaccine available in Italy for prophylaxis of the A/H1N1 (2009) pandemic influenza. From October 2009 to June 2010, the Italian Pharmacovigilance Adverse Event (AE) Spontaneous Reporting System [Rete Nazionale Farmacovigilanza] (RNF) received 1330 reports of AEs temporally related with the pandemic influenza vaccination out of a total of 924,057 doses administered. Among these, 1,162 (87.37%) AE reports were classified 'non serious', 91 (6.84%) 'serious', 3 (0.23%) had a fatal outcome and 74 (5.56%) did not include the degree of seriousness. Among the serious AE reports, some unexpected AEs emerged. Even though some typical vaccine safety issues which emerged should be further explored, such as vaccination in pregnancy, the analysis of all AE reports sent to RNF shows that the vaccine has a well-tolerated safety profile which resembles that of the already available seasonal influenza vaccines. This contrasts with the widespread public concern about its safety, which has been one of the major causes of the low vaccination rate observed in Italy, as well as in other countries.
Gwon, Yong-Dae; Kim, Sehyun; Cho, Yeondong; Heo, Yoonki; Cho, Hansam; Park, Kihoon; Lee, Hee-Jung; Choi, Jiwon; Poo, Haryoung; Kim, Young Bong
An outbreak of influenza H1N1 in 2009, representing the first influenza pandemic of the 21st century, was transmitted to over a million individuals and claimed 18,449 lives. The current status in many countries is to prepare influenza vaccine using cell-based or egg-based killed vaccine. However, traditional influenza vaccine platforms have several limitations. To overcome these limitations, many researchers have tried various approaches to develop alternative production platforms. One of the alternative approach, we reported the efficacy of influenza HA vaccination using a baculoviral DNA vaccine (AcHERV-HA). However, the immune response elicited by the AcHERV-HA vaccine, which only targets the HA antigen, was lower than that of the commercial killed vaccine. To overcome the limitations of this previous vaccine, we constructed a human endogenous retrovirus (HERV) envelope-coated, baculovirus-based, virus-like-particle (VLP)–forming DNA vaccine (termed AcHERV-VLP) against pandemic influenza A/California/04/2009 (pH1N1). BALB/c mice immunized with AcHERV-VLP (1×107 FFU AcHERV-VLP, i.m.) and compared with mice immunized with the killed vaccine or mice immunized with AcHERV-HA. As a result, AcHERV-VLP immunization produced a greater humoral immune response and exhibited neutralizing activity with an intrasubgroup H1 strain (PR8), elicited neutralizing antibody production, a high level of interferon-γ secretion in splenocytes, and diminished virus shedding in the lung after challenge with a lethal dose of influenza virus. In conclusion, VLP-forming baculovirus DNA vaccine could be a potential vaccine candidate capable of efficiently delivering DNA to the vaccinee and VLP forming DNA eliciting stronger immunogenicity than egg-based killed vaccines. PMID:27149064
... Vaccines--Amendment Authority: 42 U.S.C. 247d-6d. ACTION: Notice of amendment to the September 28, 2009... and Emergency Preparedness Act for H5N1, H2, H6, H7, H9 and 2009-H1N1 Vaccines: Whereas there are or... September 28, 2009 declaration extended through February 28, 2010 for vaccines against influenza...
Baras, Benoit; Bouveret, Nancy; Devaster, Jeanne-Marie; Fries, Louis; Gillard, Paul; Sänger, Roland; Hanon, Emmanuel
Vaccination is considered to be one of the most effective tools to decrease morbidity as well as mortality caused by influenza viruses. For the prevention of seasonal influenza, Fluarix and FluLaval have been marketed since 1987 and 1992, respectively. Both vaccines have consistently been shown to meet or exceed the regulatory criteria for immunogenicity against the three strains H1N1, H3N2 and B, have a good safety profile, and are recommended for vaccinating children and adults of all ages. For the prevention of pandemic influenza, GlaxoSmithKline (GSK) has obtained licensure of a pre-pandemic vaccine, Prepandrix. This split-virus H5N1 adjuvanted with AS03, a proprietary oil-in-water emulsion-based adjuvant system, has demonstrated broad immunity against drifted H5N1 strains and has been shown to be effective in preventing mortality and viral shedding in animal studies. The influenza vaccine portfolio of GSK addresses specific medical needs related to seasonal or pandemic influenza viruses, which remain an important public health threat worldwide.
Medina, Rafael A; Manicassamy, Balaji; Stertz, Silke; Seibert, Christopher W; Hai, Rong; Belshe, Robert B; Frey, Sharon E; Basler, Christopher F; Palese, Peter; García-Sastre, Adolfo
The 1918 influenza A virus caused the most devastating pandemic, killing approximately 50 million people worldwide. Immunization with 1918-like and classical swine H1N1 virus vaccines results in cross-protective antibodies against the 2009 H1N1 pandemic influenza, indicating antigenic similarities among these viruses. In this study, we demonstrate that vaccination with the 2009 pandemic H1N1 vaccine elicits 1918 virus cross-protective antibodies in mice and humans, and that vaccination or passive transfer of human-positive sera reduced morbidity and conferred full protection from lethal challenge with the 1918 virus in mice. The spread of the 2009 H1N1 influenza virus in the population worldwide, in addition to the large number of individuals already vaccinated, suggests that a large proportion of the population now have cross-protective antibodies against the 1918 virus, greatly alleviating concerns and fears regarding the accidental exposure/release of the 1918 virus from the laboratory and the use of the virus as a bioterrorist agent.
Garg, Shikha; Olsen, Sonja J; Fernandez, Stefan; Muangchana, Charung; Rungrojcharoenkit, Kamonthip; Prapasiri, Prabda; Katz, Jacqueline M; Curlin, Marcel E; Gibbons, Robert V; Holtz, Timothy H; Chitwarakorn, Anupong; Dawood, Fatimah S
Among 368 Thai men who have sex with men with paired serum samples collected before and during the 2009 H1N1 influenza pandemic, we determined influenza A (H1N1)pdm09 seroconversion rates (≥4-fold rise in antibody titers by hemagglutination inhibition or microneutralization assays). Overall, 66 of 232 (28%) participants seroconverted after the first year of A(H1N1)pdm09 activity, and 83 of 234 (35%) participants seroconverted after the second year. Influenza A(H1N1)pdm09 seroconversion did not differ between human immunodeficiency virus (HIV)-infected (55 of 2157 [35%]) and HIV-uninfected (71 of 2211 [34%]) participants (P = .78). Influenza A(H1N1)pdm09 seroconversion occurred in approximately one third of our Thai study population and was similar among HIV-infected and HIV-uninfected participants.
Henrich, Natalie; Holmes, Bev
To prepare for pandemics, countries are creating pandemic preparedness plans. These plans frequently include crisis communication strategies that recommend conducting pre-crisis audience research to increase the effectiveness and relevance of communication with the public. To begin understanding the communication needs of the public and health care workers, 11 focus groups were conducted in Vancouver, Canada, in 2006 and 2007 to identify what information people want to receive and how they want to receive it. In the event of a pandemic, participants want to know their risk of infection and how sick they could become if infected. To make decisions about using vaccines and drugs, they want information that enables them to assess the risks of using the products. The public prefers to receive this information from family doctors, the Internet, and schools. Health care workers prefer to receive information in e-mails and in-services.
Valero-Pacheco, Nuriban; Pérez-Toledo, Marisol; Villasís-Keever, Miguel Ángel; Núñez-Valencia, Adriana; Boscó-Gárate, Ilka; Lozano-Dubernard, Bernardo; Lara-Puente, Horacio; Espitia, Clara; Alpuche-Aranda, Celia; Bonifaz, Laura C; Arriaga-Pizano, Lourdes; Pastelin-Palacios, Rodolfo; Isibasi, Armando; López-Macías, Constantino
The influenza virus is a human pathogen that causes epidemics every year, as well as potential pandemic outbreaks, as occurred in 2009. Vaccination has proven to be sufficient in the prevention and containment of viral spreading. In addition to the current egg-based vaccines, new and promising vaccine platforms, such as cell culture-derived vaccines that include virus-like particles (VLPs), have been developed. VLPs have been shown to be both safe and immunogenic against influenza infections. Although antibody persistence has been studied in traditional egg-based influenza vaccines, studies on antibody response durations induced by VLP influenza vaccines in humans are scarce. Here, we show that subjects vaccinated with an insect cell-derived VLP vaccine, in the midst of the 2009 H1N1 influenza pandemic outbreak in Mexico City, showed antibody persistence up to 24 months post-vaccination. Additionally, we found that subjects that reported being revaccinated with a subsequent inactivated influenza virus vaccine showed higher antibody titres to the pandemic influenza virus than those who were not revaccinated. These findings provide insights into the duration of the antibody responses elicited by an insect cell-derived pandemic influenza VLP vaccine and the possible effects of subsequent influenza vaccination on antibody persistence induced by this VLP vaccine in humans.
Villasís-Keever, Miguel Ángel; Núñez-Valencia, Adriana; Boscó-Gárate, Ilka; Lozano-Dubernard, Bernardo; Lara-Puente, Horacio; Espitia, Clara; Alpuche-Aranda, Celia; Bonifaz, Laura C.; Arriaga-Pizano, Lourdes; Pastelin-Palacios, Rodolfo; Isibasi, Armando; López-Macías, Constantino
The influenza virus is a human pathogen that causes epidemics every year, as well as potential pandemic outbreaks, as occurred in 2009. Vaccination has proven to be sufficient in the prevention and containment of viral spreading. In addition to the current egg-based vaccines, new and promising vaccine platforms, such as cell culture-derived vaccines that include virus-like particles (VLPs), have been developed. VLPs have been shown to be both safe and immunogenic against influenza infections. Although antibody persistence has been studied in traditional egg-based influenza vaccines, studies on antibody response durations induced by VLP influenza vaccines in humans are scarce. Here, we show that subjects vaccinated with an insect cell-derived VLP vaccine, in the midst of the 2009 H1N1 influenza pandemic outbreak in Mexico City, showed antibody persistence up to 24 months post-vaccination. Additionally, we found that subjects that reported being revaccinated with a subsequent inactivated influenza virus vaccine showed higher antibody titres to the pandemic influenza virus than those who were not revaccinated. These findings provide insights into the duration of the antibody responses elicited by an insect cell-derived pandemic influenza VLP vaccine and the possible effects of subsequent influenza vaccination on antibody persistence induced by this VLP vaccine in humans. PMID:26919288
Feltelius, N; Persson, I; Ahlqvist-Rastad, J; Andersson, M; Arnheim-Dahlström, L; Bergman, P; Granath, F; Adori, C; Hökfelt, T; Kühlmann-Berenzon, S; Liljeström, P; Maeurer, M; Olsson, T; Örtqvist, Å; Partinen, M; Salmonson, T; Zethelius, B
In response to the 2009-2010 influenza A(H1N1)pdm09 pandemic, a mass vaccination programme with the AS03-adjuvanted influenza A(H1N1) vaccine Pandemrix was initiated in Sweden. Unexpectedly, there were a number of narcolepsy cases amongst vaccinated children and adolescents reported. In this review, we summarize the results of a joint cross-disciplinary national research effort to investigate the adverse reaction signal from the spontaneous reporting system and to better understand possible causative mechanisms. A three- to fourfold increased risk of narcolepsy in vaccinated children and adolescents was verified by epidemiological studies. Of importance, no risk increase was observed for the other neurological and autoimmune diseases studied. Genetic studies confirmed the association with the allele HLA-DQB1*06:02, which is known to be related to sporadic narcolepsy. Furthermore, a number of studies using cellular and molecular experimental models investigated possible links between influenza vaccination and narcolepsy. Serum analysis, using a peptide microarray platform, showed that individuals who received Pandemrix exhibited a different epitope reactivity pattern to neuraminidase and haemagglutinin, as compared to individuals who were infected with H1N1. Patients with narcolepsy were also found to have increased levels of interferon-gamma production in response to streptococcus-associated antigens. The chain of patient-related events and the study results emerging over time were subjected to intense nationwide media attention. The importance of transparent communication and collaboration with patient representatives to maintain public trust in vaccination programmes is also discussed in the review. Organizational challenges due to this unexpected event delayed the initiation of some of the research projects, still the main objectives of this joint, cross-disciplinary research effort were reached, and important insights were acquired for future, similar
de PAULA, Stéfano Ivani; de PAULA, Gustavo Ivani; CUNEGUNDES, Kelly Simone Almeida; de MORAES-PINTO, Maria Isabel
SUMMARY This study evaluated the adherence to influenza vaccination among medical students in 2010 and 2011. From August to December 2011, a questionnaire was used to record the influenza vaccination in 2010 and 2011, reasons for acceptance of the influenza vaccine and knowledge of healthcare workers about the influenza vaccine recommendation. One hundred and forty-four students from the 2ndto the 6th years of the medical school were interviewed. A great adherence to pandemic influenza vaccine was noted in 2010, (91% of the students), with "self-protection" being the most common reason cited for vaccination. Other determinants for the vaccination during pandemic were "convenient access to vaccine" and "encouragement by peers and teachers in workplaces and at the university". However, there was a great decay in the acceptance to vaccine in the next influenza season (2011). Only 42% of the students received the vaccine. They claimed "lack of time" and "have forgotten to take the vaccine" as the main reasons. The "knowledge on the recommendation of influenza vaccine to healthcare workers" increased when the students come to attend the last year of the medical school, but that was an insufficient motivator for vaccination. Strategies to increase vaccination should be based on the abovementioned aspects for the adoption of effective measures in both, pandemic and seasonal periods. PMID:27828623
Paula, Stéfano Ivani de; Paula, Gustavo Ivani de; Cunegundes, Kelly Simone Almeida; Moraes-Pinto, Maria Isabel de
This study evaluated the adherence to influenza vaccination among medical students in 2010 and 2011. From August to December 2011, a questionnaire was used to record the influenza vaccination in 2010 and 2011, reasons for acceptance of the influenza vaccine and knowledge of healthcare workers about the influenza vaccine recommendation. One hundred and forty-four students from the 2ndto the 6th years of the medical school were interviewed. A great adherence to pandemic influenza vaccine was noted in 2010, (91% of the students), with "self-protection" being the most common reason cited for vaccination. Other determinants for the vaccination during pandemic were "convenient access to vaccine" and "encouragement by peers and teachers in workplaces and at the university". However, there was a great decay in the acceptance to vaccine in the next influenza season (2011). Only 42% of the students received the vaccine. They claimed "lack of time" and "have forgotten to take the vaccine" as the main reasons. The "knowledge on the recommendation of influenza vaccine to healthcare workers" increased when the students come to attend the last year of the medical school, but that was an insufficient motivator for vaccination. Strategies to increase vaccination should be based on the abovementioned aspects for the adoption of effective measures in both, pandemic and seasonal periods.
Comas‐García, Andreu; García‐Sepúlveda, Christian A.; Méndez‐de Lira, José J.; Aranda‐Romo, Saray; Hernández‐Salinas, Alba E.; Noyola, Daniel E.
Please cite this paper as: Comas‐García et al. (2011) Mortality attributable to pandemic influenza A (H1N1) 2009 in San Luis Potosí, Mexico. Influenza and Other Respiratory Viruses 5(2), 76–82. Background Acute respiratory infections are a leading cause of morbidity and mortality worldwide. Starting in 2009, pandemic influenza A(H1N1) 2009 virus has become one of the leading respiratory pathogens worldwide. However, the overall impact of this virus as a cause of mortality has not been clearly defined. Objectives To determine the impact of pandemic influenza A(H1N1) 2009 on mortality in a Mexican population. Methods We assessed the impact of pandemic influenza virus on mortality during the first and second outbreaks in San Luis Potosí, Mexico, and compared it to mortality associated with seasonal influenza and respiratory syncytial virus (RSV) during the previous winter seasons. Results We estimated that, on average, 8·1% of all deaths that occurred during the 2003–2009 seasons were attributable to influenza and RSV. During the first pandemic influenza A(H1N1) 2009 outbreak, there was an increase in mortality in persons 5–59 years of age, but not during the second outbreak (Fall of 2009). Overall, pandemic influenza A (H1N1) 2009 outbreaks had similar effects on mortality to those associated with seasonal influenza virus epidemics. Conclusions The impact of influenza A(H1N1) 2009 virus on mortality during the first year of the pandemic was similar to that observed for seasonal influenza. The establishment of real‐time surveillance systems capable of integrating virological, morbidity, and mortality data may result in the timely identification of outbreaks so as to allow for the institution of appropriate control measures to reduce the impact of emerging pathogens on the population. PMID:21306570
Lecendreux, Michel; Libri, Valentina; Jaussent, Isabelle; Mottez, Estelle; Lopez, Régis; Lavault, Sophie; Regnault, Armelle; Arnulf, Isabelle; Dauvilliers, Yves
Recent advances in the identification of susceptibility genes and environmental exposures (pandemic influenza 2009 vaccination) provide strong support that narcolepsy type 1 is an immune-mediated disease. Considering the limited knowledge regarding the immune mechanisms involved in narcolepsy whether related to flu vaccination or not and the recent progresses in cytokine measurement technology, we assessed 30 cytokines, chemokines and growth factors using the Luminex technology in either peripheral (serum) or central (CSF) compartments in a large population of 90 children and adult patients with narcolepsy type 1 in comparison to 58 non-hypocretin deficient hypersomniacs and 41 healthy controls. Furthermore, we compared their levels in patients with narcolepsy whether exposed to pandemic flu vaccine or not, and analyzed the effect of age, duration of disease and symptom severity. Comparison for sera biomarkers between narcolepsy (n = 84, 54 males, median age: 15.5 years old) and healthy controls (n = 41, 13 males, median age: 20 years old) revealed an increased stimulation of the immune system with high release of several pro- and anti-inflammatory serum cytokines and growth factors with interferon-γ, CCL11, epidermal growth factor, and interleukin-2 receptor being independently associated with narcolepsy. Increased levels of interferon-γ, CCL11, and interleukin-12 were found when close to narcolepsy onset. After several adjustments, only one CSF biomarker differed between narcolepsy (n = 44, 26 males, median age: 15 years old) and non-hypocretin deficient hypersomnias (n = 57, 24 males, median age: 36 years old) with higher CCL 3 levels found in narcolepsy. Comparison for sera biomarkers between patients with narcolepsy who developed the disease post-pandemic flu vaccination (n = 36) to those without vaccination (n = 48) revealed an increased stimulation of the immune system with high release of three cytokines, regulated upon activation normal T-cell expressed
Roh, Hang Sik; Song, Hye Min; Yun, Bo Reum; Kang, Hyun Kyung; Choi, Keum Suk; Park, Yun Ju; Kim, Dong Sub; Kim, Seung Hee; Mo, In Pil; An, Beum-Soo; Ahn, Chi Young
Single radial immunodiffusion (SRID) assay requires a reference antigen and an antibody to the hemagglutinin (HA) of an influenza vaccine. As it takes 2‑3 months to develop the reference antigen, vaccine development is delayed in cases of an influenza pandemic. In the present study, the measurement of the HA content of influenza vaccines was assessed using size exclusion high performance liquid chromatography (SE‑HPLC) for the rapid development of a pandemic vaccine. When the 2009 H1N1 reference antigen, pandemic 2009 H1N1 vaccine and 2010 seasonal influenza vaccines were analyzed by SE‑HPLC, the HA of the reference antigen and vaccines was specifically separated. The presence and specificity of HA were evidenced with immunoprecipitation and ELISA assays. For the influenza vaccines, the chromatogram pattern and retention time of HA were similar among the antigen types (2009 H1N1, 2010 H3N2 and 2010 B). In addition, when SE‑HPLC was applied, the ratio of HA chromatogram to peak area revealed a significant correlation with HA concentration for the reference antigen and vaccine. The result of the HA content calculation based on SE‑HPLC exhibited 99.91‑100% similarity, compared with that of SRID. These findings suggest that the measurement of peak area ratio/HA content using SE‑HPLC may be a substitute for SRID and rapidly measure HA content to enable faster development of a vaccine during an influenza pandemic.
Sullivan, K M; Monto, A S; Foster, D A
Four inactivated influenza vaccines (containing the recommended antigens for the 1985-1986 influenza season) of various antigenic concentration levels were randomly administered to 140 study participants. The effect of the increasing antigen concentration resulted in significantly higher influenza hemagglutination inhibition (HI) antibody levels 3 weeks after vaccination for the A/H1N1 antigen but not for the A/H3N2 or B antigens. Also, at 3 weeks after vaccination, there were significantly lower antibody titer levels associated with increasing age for the A/H1N1 and B antigens (adjusting for the prevaccination antibody titer and antigen content).
Khazeni, Nayer; Hutton, David W; Collins, Ine; Garber, Alan M; Owens, Douglas K
Background 2009 pandemic vaccination occurred late, limiting its benefits. Influenza A (H7N9) is causing high morbidity and mortality in China, and researchers have modified A (H5N1) to transmit via aerosol, again heightening concerns about pandemic influenza preparedness. Objective We sought to determine how much more quickly a vaccination program should be implemented to reduce infections, deaths, and healthcare costs in a pandemic with characteristics similar to influenza A (H7N9) and A (H5N1). Design We used a dynamic transmission model to estimate health and economic consequences of a severe influenza pandemic in a large metropolitan city. Data Sources Literature and expert opinion. Target Population Residents of a U.S. metropolitan city with characteristics similar to New York City. Perspective Societal. Time Horizon Lifetime. Interventions Vaccination of 30% of the population at 4 or 6 months. Outcome Measures Infections and deaths averted, cost-effectiveness. Results of Base Case Analysis 48,254 would die in 12 months; vaccinating at 9 months would avert 2,365 of these deaths. Vaccinating at 6 months would save 5,775 additional lives and $51 million at a city level. Further accelerating delivery to 4 months would save an additional 5,633 lives and $50 million. Results of Sensitivity Analysis In the event of a vaccine delay to 9 months, increasing reductions in contacts via non-pharmaceutical interventions by 8% would yield a similar reduction in infections and deaths as vaccination at 4 months. Limitations The model is not designed to evaluate programs targeting specific populations such as children or individuals with comorbidities. Conclusions Vaccination in an influenza A (H7N9) pandemic would need to be performed far more rapidly than in 2009 to substantially reduce morbidity, mortality, and healthcare costs. Maximizing non-pharmacological interventions can substantially mitigate the pandemic until matched vaccine becomes available. PMID:24842415
Yin, J Kevin; Khandaker, Gulam; Rashid, Harunor; Heron, Leon; Ridda, Iman; Booy, Robert
The emergence of the 2009 H1N1 pandemic has highlighted the need to have immunogenicity and safety data on the new pandemic vaccines. There is already considerable heterogeneity in the types of vaccine available and of study performed around the world. A systematic review and meta-analysis is needed to assess the immunogenicity and safety of pandemic influenza A (H1N1) 2009 vaccines. We searched Medline, EMBASE, the Cochrane Library and other online databases up to 1st October 2010 for studies in any language comparing different pandemic H1N1 vaccines, with or without placebo, in healthy populations aged at least 6 months. The primary outcome was seroprotection according to haemagglutination inhibition (HI). Safety outcomes were adverse events. Meta-analysis was performed for the primary outcome. We identified 18 articles, 1 only on safety and 17 on immunogenicity, although 1 was a duplicate. We included 16 articles in the meta-analysis, covering 17,921 subjects. Adequate seroprotection (≥70%) was almost invariably achieved in all age groups, and even after one dose and at low antigen content (except in children under 3 years receiving one dose of non-adjuvanted vaccine). Non-adjuvanted vaccine from international companies and adjuvanted vaccines containing oil in water emulsion (e.g. AS03, MF59), rather than aluminium, performed better. Two serious vaccination-associated adverse events were reported, both of which resolved fully. No death or case of Guillain-Barré syndrome was reported. The pandemic influenza (H1N1) 2009 vaccine, with or without adjuvant, appears generally to be seroprotective after just one dose and safe among healthy populations aged ≥36 months; very young children (6-35 months) may need to receive two doses of non-adjuvanted vaccine or one dose of AS03(A/B)-adjuvanted product to achieve seroprotection.
McAnerney, Johanna M; Walaza, Sibongile; Tempia, Stefano; Blumberg, Lucille; Treurnicht, Florette K; Madhi, Shabir A; Valley-Omar, Ziyaad; Cohen, Cheryl
Trivalent seasonal influenza vaccine effectiveness during the 2015 season in South Africa was assessed using a test-negative case control study design. Influenza A(H1N1)pdm09 was the dominant circulating strain. Overall influenza vaccine coverage was 3.2% (29/899). The vaccine effectiveness estimate, against any influenza virus infection, adjusted for age, underlying conditions and timing within season was 46.2% (95% CI: -23.5 to 76.5), and 53.6% (95% CI: -62.6 to 80.3) against influenza A(H1N1)pdm09.
Clegg, Christopher H; Roque, Richard; Perrone, Lucy A; Rininger, Joseph A; Bowen, Richard; Reed, Steven G
The ongoing threat from Influenza necessitates the development of new vaccine and adjuvant technologies that can maximize vaccine immunogenicity, shorten production cycles, and increase global vaccine supply. Currently, the most successful adjuvants for Influenza vaccines are squalene-based oil-in-water emulsions. These adjuvants enhance seroprotective antibody titers to homologous and heterologous strains of virus, and augment a significant dose sparing activity that could improve vaccine manufacturing capacity. As an alternative to an emulsion, we tested a simple lipid-based aqueous formulation containing a synthetic TLR4 ligand (GLA-AF) for its ability to enhance protection against H5N1 infection. GLA-AF was very effective in adjuvanting recombinant H5 hemagglutinin antigen (rH5) in mice and was as potent as the stable emulsion, SE. Both adjuvants induced similar antibody titers using a sub-microgram dose of rH5, and both conferred complete protection against a highly pathogenic H5N1 challenge. However, GLA-AF was the superior adjuvant in ferrets. GLA-AF stimulated a broader antibody response than SE after both the prime and boost immunization with rH5, and ferrets were better protected against homologous and heterologous strains of H5N1 virus. Thus, GLA-AF is a potent emulsion-free adjuvant that warrants consideration for pandemic influenza vaccine development.
Vaccines are hugely important tools in minimising the effect pandemic influenza could have on a population. The reforms introduced by the Pandemic Influenza Preparedness Framework are ill-suited to providing sufficient levels of access to vaccines to meet the needs of developing states, and as such developing states will continue to be reliant upon the traditional methods of vaccine procurement to procure the majority of the vaccines they required. Using procurement during 2009-H1N1 as a case study, this paper examines the methods of procurement utilised by states in order to determine if the procurement tools available to developing states are sufficient to procure adequate levels of pandemic influenza vaccines. Particular focus is given to the role Advance Purchase Agreements (APAs) play in the procurement process. By exploring this case study it is possible to argue that these procurement methods are ineffective for developing states, and when the next influenza pandemic occurs, demand will once again outstrip supply globally, due to supply of vaccines being dominated by the developed states with APAs in place.
Porras Gallo, M I
Against the background of the renewed interest aroused in recent years by the influenza pandemic of 1918-1919, and the leading role now played by research analysing the process of innovation in medicine, this paper assesses the role played by serums and vaccines - the new resources of the medical science of the time 0 in the fight against the influenza outbreak of 1918-1919. The paper highlights the dependence on combined scientific, social, economic and professional factors, and also shows the main consequences arising from the fine-tuning and implementation of these therapeutic and prophylactic resources.
Abubakar, A; Malik, M; Pebody, R G; Elkholy, A A; Khan, W; Bellos, A; Mala, P
There are gaps in the knowledge about the burden of severe respiratory disease in the Eastern Mediterranean Region (EMR). This literature review was therefore conducted to describe the burden of epidemicand pandemic-prone acute respiratory infections (ARI) in the Region which may help in the development of evidence-based disease prevention and control policies. Relevant published and unpublished reports were identified from searches of various databases; 83 documents fulfilled the search criteria. The infections identified included: ARI, avian influenza A(H5N1), influenza A(H1N1)pdm09 and Middle East respiratory syndrome coronavirus (MERS-CoV) infection. Pneumonia and ARIs were leading causes of disease and death in the Region. Influenza A(H1N1) was an important cause of morbidity during the 2009 pandemic. This review provides a descriptive summary of the burden of acute respiratory diseases in the Region, but there still remains a lack of necessary data.
Ventura, Roland; Brunner, Livia; Heriyanto, Bambang; de Boer, Otto; O'Hara, Michael; Huynh, Chuong; Suhardono, Mahendra; Collin, Nicolas
With the current enzootic circulation of highly pathogenic avian influenza viruses, the ability to increase global pandemic influenza vaccine production capacity is of paramount importance. This has been highlighted by, and is one of the main pillars of, the WHO Global Action Plan for Influenza Vaccines (GAP). Such capacity expansion is especially relevant in developing countries. The Vaccine Formulation Laboratory at University of Lausanne is engaged in the technology transfer of an antigen-sparing oil-in-water adjuvant in order to empower developing countries vaccine manufacturers to increase pandemic influenza vaccine capacity. In a one-year project funded by United States Department of Health and Human Services, the Vaccine Formulation Laboratory transferred the process know-how and associated equipment for the pilot-scale manufacturing of an oil-in-water adjuvant to Bio Farma, Indonesia's state-owned vaccine manufacturer, for subsequent formulation with H5N1 pandemic influenza vaccines. This paper describes the experience acquired and lessons learnt from this technology transfer project.
Huang, Qiu Sue; Turner, Nikki; Baker, Michael G; Williamson, Deborah A; Wong, Conroy; Webby, Richard; Widdowson, Marc-Alain
The 2009 influenza A(H1N1)pdm09 pandemic highlighted the need for improved scientific knowledge to support better pandemic preparedness and seasonal influenza control. The Southern Hemisphere Influenza and Vaccine Effectiveness Research and Surveillance (SHIVERS) project, a 5-year (2012-2016) multiagency and multidisciplinary collaboration, aimed to measure disease burden, epidemiology, aetiology, risk factors, immunology, effectiveness of vaccination and other prevention strategies for influenza and other respiratory infectious diseases of public health importance. Two active, prospective, population-based surveillance systems were established for monitoring influenza and other respiratory pathogens among those hospitalized patients with acute respiratory illness and those enrolled patients seeking consultations at sentinel general practices. In 2015, a sero-epidemiological study will use a sample of patients from the same practices. These data will provide a full picture of the disease burden and risk factors from asymptomatic infections to severe hospitalized disease and deaths and related economic burden. The results during the first 2 years (2012-2013) provided scientific evidence to (a) support a change to NZ's vaccination policy for young children due to high influenza hospitalizations in these children; (b) contribute to the revision of the World Health Organization's case definition for severe acute respiratory illness for global influenza surveillance; and (c) contribute in part to vaccine strain selection using vaccine effectiveness assessment in the prevention of influenza-related consultations and hospitalizations. In summary, SHIVERS provides valuable international platforms for supporting seasonal influenza control and pandemic preparedness, and responding to other emerging/endemic respiratory-related infections.
Valenciano, Marta; Kissling, Esther; Cohen, Jean-Marie; Oroszi, Beatrix; Barret, Anne-Sophie; Rizzo, Caterina; Nunes, Baltazar; Pitigoi, Daniela; Larrauri Cámara, Amparro; Mosnier, Anne; Horvath, Judith K.; O'Donnell, Joan; Bella, Antonino; Guiomar, Raquel; Lupulescu, Emilia; Savulescu, Camelia; Ciancio, Bruno C.; Kramarz, Piotr; Moren, Alain
Background A multicentre case-control study based on sentinel practitioner surveillance networks from seven European countries was undertaken to estimate the effectiveness of 2009–2010 pandemic and seasonal influenza vaccines against medically attended influenza-like illness (ILI) laboratory-confirmed as pandemic influenza A (H1N1) (pH1N1). Methods and Findings Sentinel practitioners swabbed ILI patients using systematic sampling. We included in the study patients meeting the European ILI case definition with onset of symptoms >14 days after the start of national pandemic vaccination campaigns. We compared pH1N1 cases to influenza laboratory-negative controls. A valid vaccination corresponded to >14 days between receiving a dose of vaccine and symptom onset. We estimated pooled vaccine effectiveness (VE) as 1 minus the odds ratio with the study site as a fixed effect. Using logistic regression, we adjusted VE for potential confounding factors (age group, sex, month of onset, chronic diseases and related hospitalizations, smoking history, seasonal influenza vaccinations, practitioner visits in previous year). We conducted a complete case analysis excluding individuals with missing values and a multiple multivariate imputation to estimate missing values. The multivariate imputation (n = 2902) adjusted pandemic VE (PIVE) estimates were 71.9% (95% confidence interval [CI] 45.6–85.5) overall; 78.4% (95% CI 54.4–89.8) in patients <65 years; and 72.9% (95% CI 39.8–87.8) in individuals without chronic disease. The complete case (n = 1,502) adjusted PIVE were 66.0% (95% CI 23.9–84.8), 71.3% (95% CI 29.1–88.4), and 70.2% (95% CI 19.4–89.0), respectively. The adjusted PIVE was 66.0% (95% CI −69.9 to 93.2) if vaccinated 8–14 days before ILI onset. The adjusted 2009–2010 seasonal influenza VE was 9.9% (95% CI −65.2 to 50.9). Conclusions Our results suggest good protection of the pandemic monovalent vaccine against medically attended pH1N1 and no
Background Influenza A virus (IAV) is a member of the family Orthomyxoviridae and contains eight segments of a single-stranded RNA genome with negative polarity. The first influenza pandemic of this century was declared in April of 2009, with the emergence of a novel H1N1 IAV strain (H1N1pdm) in Mexico and USA. Understanding the extent and causes of biases in codon usage is essential to the understanding of viral evolution. A comprehensive study to investigate the effect of selection pressure imposed by the human host on the codon usage of an emerging, pandemic IAV strain and the trends in viral codon usage involved over the pandemic time period is much needed. Results We performed a comprehensive codon usage analysis of 310 IAV strains from the pandemic of 2009. Highly biased codon usage for Ala, Arg, Pro, Thr and Ser were found. Codon usage is strongly influenced by underlying biases in base composition. When correspondence analysis (COA) on relative synonymous codon usage (RSCU) is applied, the distribution of IAV ORFs in the plane defined by the first two major dimensional factors showed that different strains are located at different places, suggesting that IAV codon usage also reflects an evolutionary process. Conclusions A general association between codon usage bias, base composition and poor adaptation of the virus to the respective host tRNA pool, suggests that mutational pressure is the main force shaping H1N1 pdm IAV codon usage. A dynamic process is observed in the variation of codon usage of the strains enrolled in these studies. These results suggest a balance of mutational bias and natural selection, which allow the virus to explore and re-adapt its codon usage to different environments. Recoding of IAV taking into account codon bias, base composition and adaptation to host tRNA may provide important clues to develop new and appropriate vaccines. PMID:23134595
Ramírez-Martínez, Gustavo; Cruz-Lagunas, Alfredo; Jiménez-Alvarez, Luis; Espinosa, Enrique; Ortíz-Quintero, Blanca; Santos-Mendoza, Teresa; Herrera, María Teresa; Canché-Pool, Elsy; Mendoza, Criselda; Bañales, José L.; García-Moreno, Sara A.; Morán, Juan; Cabello, Carlos; Orozco, Lorena; Aguilar-Delfín, Irma; Hidalgo-Miranda, Alfredo; Romero, Sandra; Suratt, Benjamin T.; Selman, Moisés; Zúñiga, Joaquín
Background Infection with pandemic (pdm) A/H1N1 virus induces high levels of pro-inflammatory mediators in blood and lungs of experimental animals and humans. Methods To compare the involvement of seasonal A/PR/8/34 and pdm A/H1N1 virus strains in the regulation of inflammatory responses, we analyzed the changes in the whole-genome expression induced by these strains in macrophages and A549 epithelial cells. We also focused on the functional implications (cytokine production) of the differential induction of suppressors of cytokine signaling (SOCS)-1, SOCS-3, retinoid-inducible gene (RIG)-I and interferon receptor 1 (IFNAR1) genes by these viral strains in early stages of the infection. Results We identified 130 genes differentially expressed by pdm A/H1N1 and A/PR/8/34 infections in macrophages. mRNA levels of SOCS-1 and RIG-I were up-regulated in macrophages infected with the A/PR/8/34 but not with pdm A/H1N1 virus. mRNA levels of SOCS-3 and IFNAR1 induced by A/PR/8/34 and pdm A/H1N1 strains in macrophages, as well as in A549 cells were similar. We found higher levels of IL-6, TNF-α, IL-10, CCL3, CCL5, CCL4 and CXCL8 (p<0.05) in supernatants from cultures of macrophages infected with the pdm A/H1N1 virus compared to those infected with the A/PR/8/34 strain, coincident with the lack of SOCS-1 and RIG-I expression. In contrast, levels of INF-α were higher in cultures of macrophages 48 h after infection with the A/PR/8/34 strain than with the pdm A/H1N1 virus. Conclusions These findings suggest that factors inherent to the pdm A/H1N1 viral strain may increase the production of inflammatory mediators by inhibiting SOCS-1 and modifying the expression of antiviral immunity-related genes, including RIG-I, in human macrophages. PMID:23434273
Castilla, Jesús; Martínez-Artola, Víctor; Salcedo, Esther; Martínez-Baz, Iván; Cenoz, Manuel García; Guevara, Marcela; Alvarez, Nerea; Irisarri, Fátima; Morán, Julio; Barricarte, Aurelio
We evaluated the 2010-2011 seasonal influenza vaccine effectiveness in preventing hospitalizations. Using healthcare databases we defined the target population for vaccination in Navarre, Spain, consisting of 217,320 people with major chronic conditions or aged 60 years and older. All hospitalized patients with influenza-like illness (ILI) were swabbed for influenza testing. A total of 269 patients with ILI were hospitalized and 61 of them were found positive for influenza virus: 58 for A(H1N1)2009 and 3 for B virus. The incidence rates of hospitalization with laboratory-confirmed influenza were compared by vaccination status. In the Cox regression model adjusted for sex, age, children in the household, urban/rural residence, comorbidity, pandemic vaccination, pneumococcal vaccination, outpatient visits and hospitalization in the previous year, the seasonal vaccine effectiveness was 58% (95% CI: 16-79%). The nested test-negative case-control analysis gave an adjusted estimate of 59% (95% CI: 4-83%). These results suggest a moderate effect of the 2010-2011 seasonal influenza vaccine in preventing hospitalization in a risk population. The close estimates obtained in the cohort and the test-negative case-control analyses suggest good control of biases.
Iskander, John; Strikas, Raymond A; Gensheimer, Kathleen F; Cox, Nancy J; Redd, Stephen C
During the past century, 4 influenza pandemics occurred. After the emergence of a novel influenza virus of swine origin in 1976, national, state, and local US public health authorities began planning efforts to respond to future pandemics. Several events have since stimulated progress in public health emergency planning: the 1997 avian influenza A(H5N1) outbreak in Hong Kong, China; the 2001 anthrax attacks in the United States; the 2003 outbreak of severe acute respiratory syndrome; and the 2003 reemergence of influenza A(H5N1) virus infection in humans. We outline the evolution of US pandemic planning since the late 1970s, summarize planning accomplishments, and explain their ongoing importance. The public health community's response to the 2009 influenza A(H1N1)pdm09 pandemic demonstrated the value of planning and provided insights into improving future plans and response efforts. Preparedness planning will enhance the collective, multilevel response to future public health crises.
Yin, J. Kevin; Khandaker, Gulam; Rashid, Harunor; Heron, Leon; Ridda, Iman; Booy, Robert
Please cite this paper as: Yin et al. (2011) Immunogenicity and safety of pandemic influenza A (H1N1) 2009 vaccine: systematic review and meta‐analysis. Influenza and Other Respiratory Viruses 5(5), 299–305. The emergence of the 2009 H1N1 pandemic has highlighted the need to have immunogenicity and safety data on the new pandemic vaccines. There is already considerable heterogeneity in the types of vaccine available and of study performed around the world. A systematic review and meta‐analysis is needed to assess the immunogenicity and safety of pandemic influenza A (H1N1) 2009 vaccines. We searched Medline, EMBASE, the Cochrane Library and other online databases up to 1st October 2010 for studies in any language comparing different pandemic H1N1 vaccines, with or without placebo, in healthy populations aged at least 6 months. The primary outcome was seroprotection according to haemagglutination inhibition (HI). Safety outcomes were adverse events. Meta‐analysis was performed for the primary outcome. We identified 18 articles, 1 only on safety and 17 on immunogenicity, although 1 was a duplicate. We included 16 articles in the meta‐analysis, covering 17 921 subjects. Adequate seroprotection (≥70%) was almost invariably achieved in all age groups, and even after one dose and at low antigen content (except in children under 3 years receiving one dose of non‐adjuvanted vaccine). Non‐adjuvanted vaccine from international companies and adjuvanted vaccines containing oil in water emulsion (e.g. AS03, MF59), rather than aluminium, performed better. Two serious vaccination‐associated adverse events were reported, both of which resolved fully. No death or case of Guillain–Barré syndrome was reported. The pandemic influenza (H1N1) 2009 vaccine, with or without adjuvant, appears generally to be seroprotective after just one dose and safe among healthy populations aged ≥36 months; very young children (6–35 months) may need to receive two
Hillaire, Marine L B; Vogelzang-van Trierum, Stella E; Kreijtz, Joost H C M; de Mutsert, Gerrie; Fouchier, Ron A M; Osterhaus, Albert D M E; Rimmelzwaan, Guus F
Virus-specific CD8(+) T-cells contribute to protective immunity against influenza A virus (IAV) infections. As the majority of these cells are directed to conserved viral proteins, they may afford protection against IAVs of various subtypes. The present study assessed the cross-reactivity of human CD8(+) T-lymphocytes, induced by infection with seasonal A (H1N1) or A (H3N2) influenza virus, with 2009 pandemic influenza A (H1N1) virus [A(H1N1)pdm09] and swine-origin triple-reassortant A (H3N2) [A(H3N2)v] viruses that are currently causing an increasing number of human cases in the USA. It was demonstrated that CD8(+) T-cells induced after seasonal IAV infections exerted lytic activity and produced gamma interferon upon in vitro restimulation with A(H1N1)pdm09 and A(H3N2)v influenza A viruses. Furthermore, CD8(+) T-cells directed to A(H1N1)pdm09 virus displayed a high degree of cross-reactivity with A(H3N2)v viruses. It was concluded that cross-reacting T-cells had the potential to afford protective immunity against A(H1N1)pdm09 viruses during the pandemic and offer some degree of protection against infection with A(H3N2)v viruses.
Surichan, Somchaiya; Wirachwong, Ponthip; Supachaturas, Wutichai; Utid, Kanchala; Theerasurakarn, Sompone; Langsanam, Pimsuk; Lakornrach, Pattharachai; Nitisaporn, Ladda; Chansikkakorn, Chanpen; Vangkanonta, Wilak; Kaweepornpoj, Ruangchai; Poopipatpol, Kittisak; Thirapakpoomanunt, Sit; Srichainak, Somchai; Artavatkun, Witit; Chokevivat, Vichai; Wibulpolprasert, Suwit
In 2005, a year after highly pathogenic avian influenza outbreaks in Thailand, the Thai Government issued a National Strategy Plan for Pandemic Influenza Preparedness, a major objective of which was the domestic production of seasonal influenza vaccine. It was considered that sustained influenza vaccine production was the best guarantee of a pandemic vaccine in the event of a future pandemic. The Government decided to provide funds to establish an industrial-scale influenza vaccine production plant, and gave responsibility for this challenging project to the Government Pharmaceutical Organization (GPO). In 2007, with support from the World Health Organization (WHO), the GPO started to develop egg-based, trivalent inactivated influenza vaccine (IIV) in a renovated pilot plant. In early 2009, during the second year of the project, the GPO turned its attention to develop a pandemic live attenuated influenza vaccine (PLAIV) against the influenza A (H1N1) virus. By December 2010, the H1N1 PLAIV had successfully completed Phase II clinical trials and was awaiting registration approval from the Thai Food and Drug Administration (TFDA). The GPO has also started to develop an H5N2 PLAIV, which is expected to enter clinical trials in January 2011. The next step in 2011 will be the development and clinical evaluation of seasonal LAIV. To meet the needs of the national seasonal influenza vaccination programme, the GPO aims to produce 2 million doses of trivalent IIV in 2012 and progressively increase production to the maximum annual capacity of 10 million doses. This article relates how influenza vaccine production capacity was developed and how major challenges are being met in an expeditious manner, with strong local and global commitment.
Saito, Masaya M.; Imoto, Seiya; Yamaguchi, Rui; Tsubokura, Masaharu; Kami, Masahiro; Nakada, Haruka; Sato, Hiroki; Miyano, Satoru; Higuchi, Tomoyuki
Vaccination is a preventive measure against influenza that does not require placing restrictions on social activities. However, since the stockpile of vaccine that can be prepared before the arrival of an emerging pandemic strain is generally quite limited, one has to select priority target groups to which the first stockpile is distributed. In this paper, we study a simulation-based priority target selection method with the goal of enhancing the collective immunity of the whole population. To model the region in which the disease spreads, we consider an urban area composed of suburbs and central areas connected by a single commuter train line. Human activity is modelled following an agent-based approach. The degree to which collective immunity is enhanced is judged by the attack rate in unvaccinated people. The simulation results show that if students and office workers are given exclusive priority in the first three months, the attack rate can be reduced from in the baseline case down to 1–2%. In contrast, random vaccination only slightly reduces the attack rate. It should be noted that giving preference to active social groups does not mean sacrificing those at high risk, which corresponds to the elderly in our simulation model. Compared with the random administration of vaccine to all social groups, this design successfully reduces the attack rate across all age groups. PMID:24058445
Kang, Hyunkyung; Roh, Hang Sik; Song, Hyemin; Lee, Kwangmoon; Chung, Seung-Tae; Ban, Sang-ja; Mo, In Pil; An, Beum-Soo; Ahn, Chi-Young
The potency of influenza vaccine is determined based on its hemagglutinin (HA) content. In general, single radial immunodiffusion (SRID) assay has been utilized as the standard method to measure HA content. However, preparation of reagents for SRID such as antigen and antibody takes approximately 2~3 months, which causes delays in the development of influenza vaccine. Therefore, quantification of HA content by other alternative methods is required. In this study, we measured HA contents of H1N1 antigen and H1N1 influenza vaccine by reverse phase-high performance liquid chromatography (RP-HPLC) methods. The presence of HA1 and HA2 was investigated by silver staining and Western blot assay. In addition, accuracy and repeatability of HA measurement by RP-HPLC were evaluated. Comparison of HA concentration by SRID and RP-HPLC revealed a precise correlation between the two methods. Our results suggest that RP-HPLC assay can replace SRID in the event of a pandemic flu outbreak for rapid vaccine development. PMID:27818728
Sigmundsdottir, G; Gudnason, T; Ólafsson, Ö; Baldvinsdottir, G E; Atladottir, A; Löve, A; Danon, L; Briem, H
In a pandemic setting, surveillance is essential to monitor the spread of the disease and assess its impact. Appropriate mitigation and healthcare preparedness strategies depend on fast and accurate epidemic surveillance data. During the 2009 influenza A(H1N1) pandemic, rapid improvements in influenza surveillance were made in Iceland. Here, we describe the improvements made in influenza surveillance during the pandemic , which could also be of great value in outbreaks caused by other pathogens. Following the raised level of pandemic influenza alert in April 2009, influenza surveillance was intensified. A comprehensive automatic surveillance system for influenza-like illness was developed, surveillance of influenza-related deaths was established and laboratory surveillance for influenza was strengthened. School absenteeism reports were also collected and compared with results from the automatic surveillance system. The first case of 2009 pandemic influenza A(H1N1) was diagnosed in Iceland in May 2009, but sustained community transmission was not confirmed until mid-August. The pandemic virus circulated during the summer and early autumn before an abrupt increase in the number of cases was observed in October. There were large outbreaks in elementary schools for children aged 6–15 years throughout the country that peaked in late October. School absenteeism reports from all elementary schools in Iceland gave a similar epidemiological curve as that from data from the healthcare system. Estimates of the proportion of the population infected with the pandemic virus ranged from 10% to 22%. This study shows how the sudden need for improved surveillance in the pandemic led to rapid improvements in data collection in Iceland. This reporting system will be improved upon and expanded to include other notifiable diseases, to ensure accurate and timely collection of epidemiological data.
Dalgıç, Özden O.; Özaltın, Osman Y.; Ciccotelli, William A.; Erenay, Fatih S.
Individuals are prioritized based on their risk profiles when allocating limited vaccine stocks during an influenza pandemic. Computationally expensive but realistic agent-based simulations and fast but stylized compartmental models are typically used to derive effective vaccine allocation strategies. A detailed comparison of these two approaches, however, is often omitted. We derive age-specific vaccine allocation strategies to mitigate a pandemic influenza outbreak in Seattle by applying derivative-free optimization to an agent-based simulation and also to a compartmental model. We compare the strategies derived by these two approaches under various infection aggressiveness and vaccine coverage scenarios. We observe that both approaches primarily vaccinate school children, however they may allocate the remaining vaccines in different ways. The vaccine allocation strategies derived by using the agent-based simulation are associated with up to 70% decrease in total cost and 34% reduction in the number of infections compared to the strategies derived by using the compartmental model. Nevertheless, the latter approach may still be competitive for very low and/or very high infection aggressiveness. Our results provide insights about potential differences between the vaccine allocation strategies derived by using agent-based simulations and those derived by using compartmental models. PMID:28222123
Ormen, Bahar; Türker, Nesrin; Vardar, Ilknur; Kaptan, Figen; El, Sibel; Ural, Serap; Kaya, Fatih; Coşkun, Nejat Ali
The aims of this study were to evaluate the attitudes towards H1N1 vaccination and to determine the safety and side effects following 2009 pandemic influenza A (H1N1) vaccination. Pandemic influenza vaccine had been administered to the healthcare personnel in our research and training hospital in December 2009. The rate being vaccinated was established as 40% (800/2000). Four months following vaccination, the opinions about vaccination were asked to the healthcare workers, and also side effects were questioned to the vaccinated group. Two different questionnaires (for vaccinated and unvaccinated subjects) were delivered to the volunteers who agreed to participate in the study. Demographic features, reasons related to being vaccinated or not, were questioned. The vaccinated group was also questioned for the presence of chronic diseases, previous vaccinations (pandemic/seasonal influenza), local or systemic reactions that develop after vaccination. A total of 332 volunteers participated in the questionnaire. Of them 247 (74.4%) were vaccinated and 85 (25.6%) were unvaccinated. Male/female ratio of the participants was 1.2, and 55.7% of them were older than 30-year-old. Most of the participants (82.8%) were highly educated (high school and faculty-graduated). Vaccination rates were found statistically significant in advanced age group compared to young adults (p= 0.042); in male gender compared to females (p= 0.001) and in parents compared to subjects who didn't have children (p= 0.021). Vaccination rates were observed to be higher (57.5%) in non-medical staff (cleaning employers, administrative personnel, etc.) than the physicians (29.1%) and nurses (13.4%), and the rate was also high (54.7%) in personnel who worked in intensive care units, emergency department and administrative units than the personnel who worked in the clinics of internal medicine (22.3%) and surgery (23.1%) (p= 0.001). The most important causes of rejecting vaccination were being afraid of the
Purpose Adverse events during mass vaccination campaigns have had a profoundly negative impact on vaccine coverage rates. The objective of the study was to identify the characteristics of reported psychogenic illness cases following mass vaccination that needed further interventions of the national immunization program. Materials and Methods We collected documents that were submitted to the Korea Centers for Disease Control and Prevention for vaccine injury compensation, and analyzed cases of psychogenic illness following pandemic influenza A (H1N1) vaccination in 2009 which were confirmed by the Korean Advisory Committee on Vaccine Injury Compensation. Results During the 2009-2010 influenza season, 13 million Koreans were vaccinated against pandemic influenza. Of 28 reported psychogenic illness cases following immunization, 25 were vaccinated through school-located mass immunization. Significant numbers of them were female adolescents (68%) or had underlying vulnerable conditions or emotional life stressors (36%). They required lengthy hospitalization (median, 7 days) and high medical costs (median, US $1,582 per case). Conclusion Health authorities and organizers of future mass vaccinations should be well aware of the possible occurrence of psychogenic illness, acknowledge their detailed characteristics, and take its economic burden into account to mitigate the risk of transmission of infectious diseases efficiently. PMID:28168171
Herbinger, Karl-Heinz; von Sonnenburg, Frank; Nothdurft, Hans Dieter; Perona, Pamela; Borkowski, Astrid; Fragapane, Elena; Nicolay, Uwe; Clemens, Ralf
An investigational tetravalent vaccine combining pre-pandemic, MF59®-adjuvanted A/H5N1 vaccine with non-adjuvanted, trivalent, seasonal influenza vaccine has been developed, which has the potential to be used for pre-pandemic priming and to improve levels of compliance and coverage. It is important to determine whether the safety and immunogenicity of the combination vaccine is equivalent to that of the two separate vaccines when administered concomitantly. Healthy adults (n=601) were randomly assigned to three vaccination groups to receive either: (1) tetravalent vaccine and placebo concomitantly (in separate arms) on Day 1, followed by A/H5N1 vaccine on Day 22; (2) A/H5N1 vaccine and placebo concomitantly on Day 1, followed by tetravalent vaccine on Day 22; or (3) A/H5N1 and seasonal vaccines concomitantly on Day 1, followed by A/H5N1 vaccine on Day 22. Antibody responses were measured using single radial hemolysis (SRH), haemagglutination inhibition (HI), and microneutralization (MN) assays on Days 1, 22, and 43. Solicited adverse reactions were recorded for seven days after vaccination. Spontaneous adverse events were recorded throughout the study. The tetravalent vaccine elicited antibody titers equivalent to those for separate A/H5N1 and seasonal vaccines, and sufficient to meet the European licensure criteria against A/H5N1 and all three seasonal strains. Local and systemic reactions were mainly mild to moderate. No vaccine-related serious adverse events occurred. These findings demonstrate that MF59-adjuvanted A/H5N1 and seasonal influenza vaccines had an acceptable safety profile and could be effectively administered as a tetravalent formulation, supporting the possibility of integrating pre-pandemic priming into seasonal influenza vaccination programs.
Ashbaugh, Andrea R.; Herbert, Christophe F.; Saimon, Elena; Azoulay, Nelson; Olivera-Figueroa, Lening; Brunet, Alain
Background With the release of the H1N1 vaccine, there was much controversy surrounding its use despite strong encouragements to be vaccinated in the media. Though studies have examined factors influencing people's decision to be vaccinated, few have focused on how general beliefs about the world or where an individual gathers information might influence that decision. Methodology/Principal Findings A cross-sectional web-based survey (N = 817) was conducted during the H1N1 outbreak after the vaccine was available. Variables examined included sociodemographic information, health related behaviours, specific beliefs concerning the H1N1 virus and its vaccine, as well as general beliefs, such as fear of contamination, intolerance of uncertainty, emotional states, coping behaviour, and the source of information concerning the virus. Three converging statistical methods were used to examine the associations – analysis of variance, logistic regression, and recursive partition modelling. The most consistent and strongest association was that negative beliefs about the H1N1 vaccine (e.g. fear of its side effects) was related to the decision not to be vaccinated, whereas beliefs about the dangers of the H1N1 virus was related to the decision to be vaccinated. Most notably, having very strong negative beliefs about the vaccine was a more powerful predictor than even strong beliefs about the dangers of the H1N1 virus. Furthermore, obtaining information from the Internet, as compared to more traditional sources of information (e.g., TV, newspapers) was related to the decision not to be vaccinated. Conclusions/Significance These results are consistent with the Health Belief Model. Importantly they suggest that during future pandemics public health officials should not only discuss the dangers of the pandemic but also (i) take additional steps to reassure the public about the safety of vaccines and (ii) monitor the information disseminated over the Internet rather than
Hossain, M. Jaber; Bourgeois, Melissa; Quan, Fu-Shi; Lipatov, Aleksandr S.; Song, Jae-Min; Chen, Li-Mei; Compans, Richard W.; York, Ian; Kang, Sang-Moo; Donis, Ruben O.
Immunization of the world population before an influenza pandemic such as the 2009 H1N1 virus spreads globally is not possible with current vaccine production platforms. New influenza vaccine technologies, such as virus-like-particles (VLPs), offer a promising alternative. Here, we tested the immunogenicity and protective efficacy of a VLP vaccine containing hemagglutinin (HA) and M1 from the 2009 pandemic H1N1 influenza virus (H1N1pdm) in ferrets and compared intramuscular (i.m.) and intranasal (i.n.) routes of immunization. Vaccination of ferrets with VLPs containing the M1 and HA proteins from A/California/04/2009 (H1N1pdm) induced high antibody titers and conferred significant protection against virus challenge. VLP-vaccinated animals lost less weight, shed less virus in nasal washes, and had markedly lower virus titers in all organs tested than naïve controls. A single dose of VLPs, either i.m. or i.n., induced higher levels of antibody than did two doses of commercial split vaccine. Ferrets vaccinated with split vaccine were incompletely protected against challenge; these animals had lower virus titers in olfactory bulbs, tonsils, and intestines, but lost weight and shed virus in nasal washes to a similar extent as naïve controls. Challenge with heterologous A/Brisbane/59/07 (H1N1) virus revealed that the VLPs conferred minimal cross-protection to heterologous infection, as revealed by the lack of reduction in nasal wash and lung virus titers and slightly higher weight loss relative to controls. In summary, these experiments demonstrate the strong immunogenicity and protective efficacy of VLPs compared to the split vaccine and show that i.n. vaccination with VLPs has the potential for highly efficacious vaccination against influenza. PMID:22030367
Kohn, Sivan; Barnett, Daniel J; Leventhal, Alex; Reznikovich, Shmuel; Oren, Meir; Laor, Danny; Grotto, Itamar; Balicer, Ran D
In April 2009, the World Health Organization announced the emergence of a novel influenza A(H1N1-09) virus and in June 2009 declared the outbreak a pandemic. The value of military structures in responding to pandemic influenza has become widely acknowledged in recent years. In 2005, the Israeli Government appointed the Ministry of Defense to be in charge of national preparedness and response for a severe pandemic influenza scenario. The Israeli case offers a unique example of civilian-defense partnership where the interface between the governmental, military and civilian spheres has formed a distinctive structure. The Israeli pandemic preparedness protocols represent an example of a collaboration in which aspects of an inherently medical problem can be managed by the defense sector. Although distinctive concepts of the model are not applicable to all countries, it offers a unique forum for governments and international agencies to evaluate this interface within the context of pandemic influenza.
Ludolph, Ramona; Nobile, Marta; Hartung, Uwe; Castaldi, Silvana; Schulz, Peter J.
Background The aim of the study is to assess the long-term secondary effects of personal experience with the H1N1 pandemic of 2009/2010 and the perception of the institutional reaction to it on Italians’ willingness to get vaccinated in case of a novel influenza pandemic. Design and Methods We conducted 140 face-to-face interviews in the Registry Office of the Municipality of Milan, Italy, from October to December 2012. Results Willingness to get vaccinated during a novel influenza pandemic was best predicted by having been vaccinated against the seasonal flu in the past (OR=5.18; 95%CI: 1.40 to 19.13) and fear of losing one’s life in case of an infection with H1N1 (OR=4.09; 95%CI: 1.68 to 9.97). It was unaffected by the assessment of institutional performance. Conclusions The findings of this study do not point to long-term secondary effects of the institutional handling of the H1N1 pandemic. The results highlight the fact that behavioural intention is not the same as behaviour, and that the former cannot simply be taken as an indicator of the latter. Significance for public health Whereas influenza pandemics occurred rather rarely in the last centuries, their frequency can be expected to increase in the future due to the enhanced globalisation and still raising importance of air travelling. Recent examples (Ebola, H1N1, SARS, avian influenza) demonstrate that initially local disease outbreaks often become worldwide health threats of international concern. National and international health authorities are consequently urged to present preparedness plans on how to manage such health crises. However, their success highly depends on their acceptance by the public. To ensure the public compliance with recommended actions, effective communication is needed. Since communication is most successful when it meets the needs of the target audience, a full understanding of the audience is crucial. This study can help public health experts to better understand the
Khazeni, Nayer; Hutton, David W; Garber, Alan M; Owens, Douglas K
Background The pandemic potential of the influenza A (H5N1) virus is among the greatest public health concerns of the 21st century. Objective To determine the effectiveness and cost-effectiveness of alternative pandemic mitigation and response strategies. Design Compartmental epidemic model in conjunction with a Markov model of disease progression. Data Sources Literature and expert opinion. Target Population Residents of a U.S. metropolitan city. Time Horizon Lifetime. Perspective Societal. Interventions One mitigation strategy used non-pharmaceutical interventions, vaccination, and antiviral pharmacotherapy in quantities similar to those available currently in the U.S. stockpile. The second and third strategies used expanded supplies of either antivirals (expanded antiviral prophylaxis strategy) or adjuvanted vaccine (expanded vaccination strategy) in addition to non-pharmaceutical interventions. Outcome Measures Infections and deaths averted, costs, quality-adjusted life-years (QALYs), and incremental cost-effectiveness. Results of Base Case Analysis The stockpiled strategy averted 44% of infections and deaths, gaining 258,342 QALYs at $8,907 per QALY gained relative to no intervention. Expanded antiviral prophylaxis delayed the pandemic, averting 48% of infections and deaths, and gaining 282,329 QALYs, with a less favorable cost-effectiveness ratio than adjuvanted vaccination. Adjuvanted vaccination was the most effective strategy and was cost-effective, averting 68% of infections and deaths, and gaining 404,030 QALYs at $10,844 per QALY gained relative to stockpiled strategy. Results of Sensitivity Analysis Over a wide range of assumptions, the incremental cost-effectiveness ratio of the expanded adjuvanted vaccination strategy was less than $50,000 per QALY gained. Limitations Large groups and frequent contacts may spread the virus more rapidly. The model is not designed to target interventions to specific groups. Conclusions Expanded adjuvanted vaccination
Background Influenza is one of the most common vaccine-preventable diseases in travellers. By performing two cross-sectional questionnaire surveys during winter 2009 and winter 2010 among European travellers to resource-limited destinations, we aimed to investigate knowledge, attitudes and practices (KAP) regarding seasonal influenza vaccination. Methods Questionnaires were distributed in the waiting room to the visitors of the University of Zurich Centre for Travel' Health (CTH) in January and February 2009 and January 2010 prior to travel health counselling (CTH09 and CTH10). Questions included demographic data, travel-related characteristics and KAP regarding influenza vaccination. Data were analysed by using SPSS® version 14.0 for Windows. Differences in proportions were compared using the Chi-square test and the significance level was set at p ≤ 0.05. Predictors for seasonal and pandemic influenza vaccination were determined by multiple logistic regression analyses. Results With a response rate of 96.6%, 906 individuals were enrolled and 868 (92.5%) provided complete data. Seasonal influenza vaccination coverage was 13.7% (n = 119). Only 43 (14.2%) participants were vaccinated against pandemic influenza A/H1N1, mostly having received both vaccines simultaneously, the seasonal and pandemic one. Job-related purposes (44, 37%), age > 64 yrs (25, 21%) and recommendations of the family physician (27, 22.7%) were the most often reported reasons for being vaccinated. In the multiple logistic regression analyses of the pooled data increasing age (OR = 1.03, 95% CI 1.01 - 1.04), a business trip (OR = 0.39, 95% CI 0.17 - 0.92) and seasonal influenza vaccination in the previous winter seasons (OR = 12.91, 95% CI 8.09 - 20.58) were independent predictors for seasonal influenza vaccination in 2009 or 2010. Influenza vaccination recommended by the family doctor (327, 37.7%), travel to regions with known high risk of influenza (305, 35.1%), and influenza vaccination
Song, Min-Suk; Hee Baek, Yun; Kim, Eun-Ha; Park, Su-Jin; Kim, Semi; Lim, Gyo-Jin; Kwon, Hyeok-il; Pascua, Philippe Noriel Q; Decano, Arun G; Lee, Byeong-Jae; Kim, Young-Il; Webby, Richard J; Choi, Young-Ki
Pandemic H1N1 2009 (A[H1N1]pdm09) variants associated with oseltamivir resistance have emerged with a histidine-to-tyrosine substitution in the neuraminidase(NA) at position 274 (H274Y). To determine whether the H274Y variant has increased virulence potential, A(H1N1)pdm09 virus, with or without the H274Y mutation, was adapted by serial lung-to-lung passages in mice. The mouse-adapted H274Y (maCA04H274Y) variants showed increased growth properties and virulence in vitro and in vivo while maintaining high NA inhibitor resistance. Interestingly, most maCA04H274Y and maCA04 viruses acquired common mutations in HA (S183P and D222G) and NP (D101G), while only maCA04H274Y viruses had consensus additional K153E mutation in the HA gene, suggesting a potential association with the H274Y substitution. Collectively, our findings highlight the potential emergence of A(H1N1)pdm09 drug-resistant variants with increased virulence and the need for rapid development of novel antiviral drugs. PMID:23924955
Background To optimize the vaccination coverage rates in the general population, the status of coverage rates and the reasons for non-vaccination need to be understood. Therefore, the objective of this study was to assess the changes in influenza vaccination coverage rates in the general population before and after the 2009 influenza pandemic (2008/2009, 2009/2010, and 2010/2011 seasons), and to determine the reasons for non-vaccination. Methods In January 2011 we conducted a multi-stage sampling, retrospective, cross-sectional survey of individuals in Beijing who were ≥ 18 years of age using self-administered, anonymous questionnaires. The questionnaire consisted of three sections: demographics (gender, age, educational level, and residential district name); history of influenza vaccination in the 2008/2009, 2009/2010, and 2010/2011 seasons; and reasons for non-vaccination in all three seasons. The main outcome was the vaccination coverage rate and vaccination frequency. Differences among the subgroups were tested using a Pearson’s chi-square test. Multivariate logistic regression was used to determine possible determinants of influenza vaccination uptake. Results A total of 13002 respondents completed the questionnaires. The vaccination coverage rates were 16.9% in 2008/2009, 21.8% in 2009/2010, and 16.7% in 2010/2011. Compared to 2008/2009 and 2010/2011, the higher rate in 2009/2010 was statistically significant (χ2=138.96, p<0.001), and no significant difference existed between 2008/2009 and 2010/2011 (χ2=1.296, p=0.255). Overall, 9.4% of the respondents received vaccinations in all three seasons, whereas 70% of the respondents did not get a vaccination during the same period. Based on multivariate analysis, older age and higher level of education were independently associated with increased odds of reporting vaccination in 2009/2010 and 2010/2011. Among participants who reported no influenza vaccinations over the previous three seasons, the most commonly
Girard, Marc P; Katz, Jacqueline M; Pervikov, Yuri; Hombach, Joachim; Tam, John S
On February 17-18, 2011, the World Health Organization convened the 7th meeting on "The Evaluation of Pandemic Influenza Vaccines in Clinical Trials" to review the progress made on pandemic A (H1N1) 2009 vaccines and the evaluation of their effectiveness in the field, especially in children less than 3 years of age and in pregnant women. Other topics to be addressed included a comparison of egg- and cell culture-based influenza vaccines, technical issues related to vaccine strain development and vaccine potency, and the status of development of prototype influenza vaccines using new technologies. Pandemic A (H1N1) vaccines were safe in young children, pregnant women and immunocompromized individuals. Overall effectiveness of inactivated A (H1N1) vaccines for all ages was found to vary between 72% and 100% in different countries and with different vaccine preparations. Effectiveness of pandemic A (H1N1) 2009 live attenuated vaccine was estimated to be approximately 80% in pediatric populations in the USA. A single dose of inactivated vaccine adjuvanted with AS03, MF59 or AF03 induced protective immunity in young children and pregnant women. However, unadjuvanted vaccines as well as low dose adjuvanted vaccines (1.9 μg HA) required two doses to elicit protective antibody levels in these populations. Clinical trials of influenza vaccines developed using new technologies showed they were well tolerated and induced antibody and/or T cell immune responses to viral proteins. Further studies are warranted to validate novel immunological criteria for evaluation and licensing of such new influenza vaccine concepts. On the regulatory side, work should be undertaken to harmonize the results of serological tests used to evaluate the immunogenicity of traditional influenza vaccines.
Callahan, S. Todd; Wolff, Mark; Hill, Heather R.; Edwards, Kathryn M.; Keitel, Wendy; Atmar, Robert; Patel, Shital; Sahly, Hana El; Munoz, Flor; Paul Glezen, W.; Brady, Rebecca; Frenck, Robert; Bernstein, David; Harrison, Christopher; Jackson, Mary Anne; Swanson, Douglas; Newland, Jason; Myers, Angela; Livingston, Robyn A; Walter, Emmanuel; Dolor, Rowena; Schmader, Kenneth; Mulligan, Mark J.; Edupuganti, Srilatha; Rouphael, Nadine; Whitaker, Jennifer; Spearman, Paul; Keyserling, Harry; Shane, Andi; Eckard, Allison Ross; Jackson, Lisa A.; Frey, Sharon E.; Belshe, Robert B.; Graham, Irene; Anderson, Edwin; Englund, Janet A.; Healy, Sara; Winokur, Patricia; Stapleton, Jack; Meier, Jeffrey; Kotloff, Karen; Chen, Wilbur; Hutter, Julia; Stephens, Ina; Wooten, Susan; Wald, Anna; Johnston, Christine; Edwards, Kathryn M.; Buddy Creech, C.; Todd Callahan, S.
Obesity emerged as a risk factor for morbidity and mortality related to 2009 pandemic influenza A (H1N1) infection. However, few studies examine the immune responses to H1N1 vaccine among children and adults of various body mass indices (BMI). Pooling data from 3 trials of unadjuvanted split-virus H1N1 A/California/07/2009 influenza vaccines, we analyzed serologic responses of participants stratified by BMI grouping. A single vaccine dose produced higher hemagglutination inhibition antibody titers at day 21 in obese compared to nonobese adults, but there were no significant differences in responses to H1N1 vaccine among children or adults of various BMI following 2 doses. PMID:24795475
Henriksen Hellyer, Joan M.; DeVries, Aaron S.; Jenkins, Sarah M.; Lackore, Kandace A.; James, Katherine M.; Ziegenfuss, Jeanette Y.; Poland, Gregory A.; Tilburt, Jon C.
Background Though recommended by many and mandated by some, influenza vaccination rates among health care workers, even in pandemics, remain below optimal levels. The objective of this study was to assess vaccination uptake, attitudes, and distinguishing characteristics (including doctor-nurse differences) of health care workers who did and did not receive the pandemic H1N1 influenza vaccine in late 2009. Methodology/Principal Findings In early 2010 we mailed a self-administered survey to 800 physicians and 800 nurses currently licensed and practicing in Minnesota. 1,073 individuals responded (cooperation rate: 69%). 85% and 62% of Minnesota physicians and nurses, respectively, reported being vaccinated. Accurately estimating the risk of vaccine side effects (OR 2.0; 95% CI 1.5–2.7), agreeing with a professional obligation to be vaccinated (OR 10.1; 95% CI 7.1–14.2), an ethical obligation to follow public health authorities' recommendations (OR 9.9; 95% CI 6.6–14.9), and laws mandating pandemic vaccination (OR 3.1; 95% CI 2.3–4.1) were all independently associated with receiving the H1N1 influenza vaccine. Conclusions/Significance While a majority of health care workers in one midwestern state reported receiving the pandemic H1N1 vaccine, physicians and nurses differed significantly in vaccination uptake. Several key attitudes and perceptions may influence health care workers' decisions regarding vaccination. These data inform how states might optimally enlist health care workers' support in achieving vaccination goals during a pandemic. PMID:22216290
Morales-Suárez-Varela, María; González-Candelas, Fernando; Astray, Jenaro; Alonso, Jordi; Castro, Ady; Cantón, Rafael; Galán, Juan Carlos; Garin, Olatz; Soldevila, Núria; Baricot, Maretva; Castilla, Jesús; Godoy, Pere; Delgado-Rodríguez, Miguel; Martín, Vicente; Mayoral, José María; Pumarola, Tomás; Quintana, José Maria; Tamames, Sonia; Llopis-González, Agustín; Domínguez, Angela
The aim of this study was to investigate the main characteristics of non-vaccinated pregnant women who were hospitalised for influenza A (H1N1) pdm09 pandemic versus pregnant women hospitalised for non-influenza-related reasons in Spain, and to characterise the clinical presentation of the disease in this population to facilitate early diagnosis and future action programmes. Understanding influenza infection during pregnancy is important as pregnant women are a high-risk population for increased morbidity from influenza infection. We investigated the socio-demographic and clinical features of 51 non-vaccinated, pregnant women infected with the pandemic influenza A (H1N1) virus in Spain (cases) and compared them to 114 controls (non-vaccinated and non-infected pregnant women) aged 15-44 years. Substantial and significant odd ratios (ORs) for pandemic influenza A (H1N1) were found for the pregnant women who were obese compared with controls (body mass index > 30) (OR 3.03; 95% confidence intervals 1.13-8.11). The more prevalent symptoms observed in pandemic influenza-infected pregnant women were high temperature, cough (82.4%), malaise (80.5%), myalgia (56.1%), and headaches (54.9%). Our results suggest that the initial symptoms and risk factors for infection of pregnant women with the influenza A (H1N1) pdm09 virus are similar to the symptoms and risk factors for seasonal influenza, which make early diagnosis difficult, and reinforces the need to identify and protect high-risk groups.
Ertek, Mustafa; Sevencan, Funda; Kalaycıoğlu, Handan; Gözalan, Ayşegül; Simşek, Ciğdem; Culha, Gönül; Dorman, Vedat; Ozlü, Ahmet; Arıkan, Füsun; Aktaş, Dilber; Akın, Levent; Korukluoğlu, Gülay; Sevindi, Demet Furkan
In this study, it was aimed to determine the frequency of the symptoms of influenza-like illness during influenza A (H1N1)v pandemic in two provinces where sentinel influenza surveillance was conducted and also to obtain opinions about H1N1 influenza and vaccination, H1N1 vaccination status and factors affecting vaccination. This cross-sectional study was conducted in the provinces of Ankara (capital city, located at Central Anatolia) and Diyarbakır (located at southeastern Anatolia). It was planned to include 455 houses in Ankara and 276 houses in Diyarbakır. The household participation rate in the study was 78.9% and 53.6% for Ankara and Diyarbakır, respectively. Our study was carried out between January-February 2010, with 1164 participants from Ankara and 804 from Diyarbakır, including every household subjects except for infants younger than 11 months and patients with primary/secondary immunodeficiency diseases. Data was collected by site teams consisting of a physician and a healthcare staff with informed consent. Of the participants 45.5% from Ankara and 35.3% from Diyarbakır stated that they had gone through an influenza-like illness. The most frequently indicated clinical symptoms were fatigue/weakness, rhinitis, sore throat and cough. The rates of admission to a physician with influenza like illness complaints were 50.6% and 58.7%; rates of hospitalization due to influenza-like illness were 1% and 1.5%, and rates of antiviral drug use were 3.8% and 1.9%, in Ankara ve Diyarbakır participants, respectively. The rate of personal precautions taken by the subjects for prevention from pandemic influenza were 59% and 53.3%, in Ankara and Diyarbakır, respectively. These precautions most frequently were "hand washing" and "avoiding crowded public areas". H1N1 influenza vaccine was applied in 9.3% of the participants in Ankara and in 3.7% of the participants in Diyarbakır. Vaccination rate was higher in both of the provinces in adults over 25 years old than
Determann, Domino; Korfage, Ida J; Fagerlin, Angela; Steyerberg, Ewout W; Bliemer, Michiel C; Voeten, Helene A; Richardus, Jan Hendrik; Lambooij, Mattijs S; de Bekker-Grob, Esther W
This study aims to quantify and compare preferences of citizens from different European countries for vaccination programme characteristics during pandemics, caused by pathogens which are transmitted through respiratory droplets. Internet panel members, nationally representative based on age, sex, educational level and region, of four European Union Member States (Netherlands, Poland, Spain, and Sweden, n = 2,068) completed an online discrete choice experiment. These countries, from different geographical areas of Europe, were chosen because of the availability of high-quality Internet panels and because of the cooperation between members of the project entitled Effective Communication in Outbreak Management: development of an evidence-based tool for Europe (ECOM). Data were analysed using panel latent class regression models. In the case of a severe pandemic scenario, vaccine effectiveness was the most important characteristic determining vaccination preference in all countries, followed by the body that advises on vaccination. In Sweden, the advice of family and/or friends and the advice of physicians strongly affected vaccine preferences, in contrast to Poland and Spain, where the advice of (international) health authorities was more decisive. Irrespective of pandemic scenario or vaccination programme characteristics, the predicted vaccination uptakes were lowest in Sweden, and highest in Poland. To increase vaccination uptake during future pandemics, the responsible authorities should align with other important stakeholders in the country and communicate in a coordinated manner.
This article explores the decisive role of British military medicine in shaping official approaches to the 1918 influenza pandemic. It contends that British approaches were defined through a system of military pathology, which had been established by the War Office as part of the mobilization of medicine for the First World War. Relying on the bacteriological laboratory for the identification and control of pathogenic agents, military pathology delivered therapeutic and preventive measures against a range of battlefield diseases, and military and civilian authorities trusted that it could do the same with influenza. This article traces how it shaped efforts to establish the etiology of the pandemic and to produce a general influenza vaccine. It highlights the challenges involved in both strategies. Understanding the central role of military pathology helps make sense of the nature, direction, scale, and limitations of medical mobilization against the pandemic in Britain and the authority accorded to specific medical bodies for elaborating and coordinating strategies. Crucially, it demands that we rethink the relationship between the war and pandemic as one about the social organization of medical knowledge and institutions.
Mereckiene, J; Cotter, S; Nicoll, A; Lopalco, P; Noori, T; Weber, Jt; D'Ancona, F; Levy-Bruhl, D; Dematte, L; Giambi, C; Valentiner-Branth, P; Stankiewicz, I; Appelgren, E; O Flanagan, D
Since 2008, annual surveys of influenza vaccination policies, practices and coverage have been undertaken in 29 European Union (EU)/ European Economic Area (EEA) countries. After 2009, this monitored the impact of European Council recommendation to increase vaccination coverage to 75% among risk groups. This paper summarises the results of three seasonal influenza seasons: 2008/09, 2009/10 and 2010/11. In 2008/09, 27/29 countries completed the survey; in 2009/10 and 2010/11, 28/29 completed it. All or almost all countries recommended vaccination of older people (defined as those aged ≥50, ≥55, ≥59, ≥60 or ≥65 years), and people aged ≥6 months with clinical risk and healthcare workers. A total of 23 countries provided vaccination coverage data for older people, but only 7 and 10 had data for the clinical risk groups and healthcare workers, respectively. The number of countries recommending vaccination for some or all pregnant women increased from 10 in 2008/09 to 22 in 2010/11. Only three countries could report coverage among pregnant women. Seasonal influenza vaccination coverage during and after the pandemic season in older people and clinical groups remained unchanged in countries with higher coverage. However, small decreases were seen in most countries during this period. The results of the surveys indicate that most EU/EEA countries recommend influenza vaccination for the main target groups; however, only a few countries have achieved the target of 75% coverage among risk groups. Coverage among healthcare workers remained low.
Dauvilliers, Yves; Arnulf, Isabelle; Lecendreux, Michel; Monaca Charley, Christelle; Franco, Patricia; Drouot, Xavier; d'Ortho, Marie-Pia; Launois, Sandrine; Lignot, Séverine; Bourgin, Patrice; Nogues, Béatrice; Rey, Marc; Bayard, Sophie; Scholz, Sabine; Lavault, Sophie; Tubert-Bitter, Pascale; Saussier, Cristel; Pariente, Antoine
An increased incidence of narcolepsy in children was detected in Scandinavian countries where pandemic H1N1 influenza ASO3-adjuvanted vaccine was used. A campaign of vaccination against pandemic H1N1 influenza was implemented in France using both ASO3-adjuvanted and non-adjuvanted vaccines. As part of a study considering all-type narcolepsy, we investigated the association between H1N1 vaccination and narcolepsy with cataplexy in children and adults compared with matched controls; and compared the phenotype of narcolepsy with cataplexy according to exposure to the H1N1 vaccination. Patients with narcolepsy-cataplexy were included from 14 expert centres in France. Date of diagnosis constituted the index date. Validation of cases was performed by independent experts using the Brighton collaboration criteria. Up to four controls were individually matched to cases according to age, gender and geographic location. A structured telephone interview was performed to collect information on medical history, past infections and vaccinations. Eighty-five cases with narcolepsy-cataplexy were included; 23 being further excluded regarding eligibility criteria. Of the 62 eligible cases, 59 (64% males, 57.6% children) could be matched with 135 control subjects. H1N1 vaccination was associated with narcolepsy-cataplexy with an odds ratio of 6.5 (2.1-19.9) in subjects aged<18 years, and 4.7 (1.6-13.9) in those aged 18 and over. Sensitivity analyses considering date of referral for diagnosis or the date of onset of symptoms as the index date gave similar results, as did analyses focusing only on exposure to ASO3-adjuvanted vaccine. Slight differences were found when comparing cases with narcolepsy-cataplexy exposed to H1N1 vaccination (n=32; mostly AS03-adjuvanted vaccine, n=28) to non-exposed cases (n=30), including shorter delay of diagnosis and a higher number of sleep onset rapid eye movement periods for exposed cases. No difference was found regarding history of infections. In
Baras, Benoît; Stittelaar, Koert J.; Simon, James H.; Thoolen, Robert J. M. M.; Mossman, Sally P.; Pistoor, Frank H. M.; van Amerongen, Geert; Wettendorff, Martine A.; Hanon, Emmanuel; Osterhaus, Albert D. M. E.
Background Unprecedented spread between birds and mammals of highly pathogenic avian influenza viruses (HPAI) of the H5N1 subtype has resulted in hundreds of human infections with a high fatality rate. This has highlighted the urgent need for the development of H5N1 vaccines that can be produced rapidly and in sufficient quantities. Potential pandemic inactivated vaccines will ideally induce substantial intra-subtypic cross-protection in humans to warrant the option of use, either prior to or just after the start of a pandemic outbreak. In the present study, we evaluated a split H5N1 A/H5N1/Vietnam/1194/04, clade 1 candidate vaccine, adjuvanted with a proprietary oil-in- water emulsion based Adjuvant System proven to be well-tolerated and highly immunogenic in the human (Leroux-Roels et al. (2007) The Lancet 370:580–589), for its ability to induce intra-subtypic cross-protection against clade 2 H5N1/A/Indonesia/5/05 challenge in ferrets. Methodology and Principal Findings All ferrets in control groups receiving non-adjuvanted vaccine or adjuvant alone failed to develop specific or cross-reactive neutralizing antibodies and all died or had to be euthanized within four days of virus challenge. Two doses of adjuvanted split H5N1 vaccine containing ≥1.7 µg HA induced neutralizing antibodies in the majority of ferrets to both clade 1 (17/23 (74%) responders) and clade 2 viruses (14/23 (61%) responders), and 96% (22/23) of vaccinees survived the lethal challenge. Furthermore lung virus loads and viral shedding in the upper respiratory tract were reduced in vaccinated animals relative to controls suggesting that vaccination might also confer a reduced risk of viral transmission. Conclusion These protection data in a stringent challenge model in association with an excellent clinical profile highlight the potential of this adjuvanted H5N1 candidate vaccine as an effective tool in pandemic preparedness. PMID:18167560
Quinn, Sandra Crouse; Kumar, Supriya; Freimuth, Vicki S; Kidwell, Kelley; Musa, Donald
On April 26, 2009, the United States declared a public health emergency in response to a growing but uncertain threat from H1N1 influenza, or swine flu. In June, the World Health Organization declared a pandemic. In the U.S., hospitalizations due to swine flu numbered 6,506 on August 6, 2009, with 436 deaths; all 50 states have reported cases. The declaration of a public health emergency, followed by the approval of multiple Emergency Use Authorizations (EUAs) by the Food and Drug Administration, allowed the distribution of unapproved drugs or the off-label use of approved drugs to the public. Thus far, there are 2 antiviral medications available to the public as EUA drugs. It is possible that an H1N1 vaccine will be initially released as an EUA in the fall in the first large-scale use of the EUA mechanism. This study explores the public's willingness to use a drug or vaccine under the conditions stipulated in the FDA's nonbinding guidance regarding EUAs. Using Knowledge Networks' panel, we conducted an internet survey with 1,543 adults from a representative sample of the U.S. population with 2 over samples of African Americans and Spanish-speaking Hispanics. Our completion rate was 62%. We examined willingness to accept an EUA drug or an H1N1 vaccine, the extent of worry associated with taking either, the conditions under which respondents would accept an EUA drug or vaccine, and the impact of language from the EUA fact sheets on people's willingness to accept a drug for themselves or their children. We also examined the association among these variables and race/ethnicity, education level, trust in government, previous vaccine acceptance, and perceived personal consequences from H1N1 influenza. These results provide critical insights into the challenges of communicating about EUA drugs and vaccine in our current pandemic.
Blanchon, Thierry; Geffrier, Félicité; Turbelin, Clément; Daviaud, Isabelle; Laouénan, Cédric; Duval, Xavier; Lambert, Bruno; Hanslik, Thomas; Mosnier, Anne; Leport, Catherine
Background In a context of controversy about influenza antiviral treatments, this study assessed primary health care physicians’ prescription of neuraminidase inhibitors (NIs) in France during pandemic and seasonal influenza between 2009 and 2013. Methods This observational study, using data recorded in three national databases, estimated the rate of NIs’ prescription among influenza like-illness (ILI) patients seen in GPs’ and paediatricians’ consultations, and determined factors associated with this prescription according to a multivariate analysis. NIs’ delivery by pharmacists was also evaluated. Results Rates of NIs’ prescription were estimated to 61.1% among ILI patients with a severe influenza risk factor seen in GPs’ consultation during the A(H1N1)pdm2009 pandemic versus an average rate of 25.9% during the three following seasonal influenza epidemics. Factors associated with NIs’ prescription were a chronic disease in patients under 65 years (OR, 14.85; 95%CI, 13.00–16.97) and in those aged ≥ 65 and older (OR, 7.54; 5.86–9.70), an age 65 years in patients without chronic disease (OR, 1.35; 1.04–1.74), a pregnancy (OR, 10.63; 7.67–15.76), obesity (OR, 4.67; 3.50–6.22), and a consultation during the pandemic A(H1N1)pdm2009 (OR, 3.19; 2.93–3.48). The number of antiviral treatments delivered by pharmacists during the A(H1N1)pdm2009 pandemic was 835 per 100 000 inhabitants, and an average of 275 per 100 000 inhabitants during the three following seasonal influenza epidemics. Conclusions Although physicians seem to follow the recommended indications for NIs in primary health care practice, this study confirms the low rate of NIs prescription to ILI patients with a severe influenza risk factor, especially during seasonal epidemics. PMID:25687219
McLachlan, Hugh V
The current UK policy for the distribution of scarce vaccination in an influenza pandemic is ethically dubious. It is based on the planned outcome of the maximum health benefit in terms of the saving of lives and the reduction of illness. To that end, the population is classified in terms of particular priority groups. An alternative policy with a non-consequentialist rationale is proposed in the present work. The state should give the vaccination, in the first instance, to those who are at risk of catching the pandemic flu in the line of their duties of public employment. Thereafter, if there is not sufficient vaccine to give all citizens equally an effective dose, the state should give all citizens an equal chance of receiving an effective dose. This would be the just thing to do because the state has a duty to treat each and all of its citizens impartially and they have a corresponding right to such impartial treatment. Although this article specifically refers to the UK, it is considered that the suggested alternative policy would be applicable generally. The duty to act justly is not merely a local one.
Bonaccorsi, Guglielmo; Lorini, Chiara; Santomauro, Francesca; Guarducci, Silvia; Pellegrino, Elettra; Puggelli, Francesco; Balli, Marta; Bonanni, Paolo
Assessing the beliefs and attitudes of Health Care Workers (HCW) to influenza and influenza vaccination can be useful in overcoming low compliance rates. The purpose of our study is to evaluate the opinion of HCW and students regarding influenza, influenza vaccine and the factors associated with vaccination compliance. A survey was conducted between October 2010 and April 2011 in the Florence metropolitan area. A questionnaire was administered to HCW in three local healthcare units and at Careggi University Teaching Hospital. Students matriculating in health degree programs at Florence University were also surveyed. The coverage with vaccination against seasonal and pandemic influenza is generally low, and it is lower in students than in HCW (12.5% vs 15% for the seasonal vaccination, 8.5% vs 18% for the pandemic vaccination). Individuals comply with vaccination offer mainly to protect themselves and their contacts. Individuals not receiving vaccination did not consider themselves at risk, had never been vaccinated before or believed that pandemic influenza was not a public health concern. Physicians had the highest compliance to vaccination and women were less frequently vaccinated than men. HCW do not appear to perceive their possible influenza infections as a risk for patients: HCW receive vaccination mainly as a form of personal protection. Low compliance to vaccination is determined by various factors and therefore requires a multi-faceted strategy of response. This should include short-term actions to overcome organizational barriers, in addition to long-term interventions to raise HCW's level of knowledge about influenza and influenza vaccination.
Solórzano, Alicia; Ye, Jianqiang; Pérez, Daniel R
Human influenza is a seasonal disease associated with significant morbidity and mortality. Influenza vaccination is the most effective means for disease prevention. We have previously shown that mutations in the PB1 and PB2 genes of the live-attenuated influenza vaccine (LAIV) from the cold-adapted (ca) influenza virus A/Ann Arbor/6/60 (H2N2) could be transferred to avian influenza viruses and produce partially attenuated viruses. We also demonstrated that avian influenza viruses carrying the PB1 and PB2 mutations could be further attenuated by stably introducing a hemagglutinin (HA) epitope tag in the PB1 gene. In this work, we wanted to determine whether these modifications would also result in attenuation of a so-called triple reassortant (TR) swine influenza virus (SIV). Thus, the TR influenza A/swine/Wisconsin/14094/99 (H3N2) virus was generated by reverse genetics and subsequently mutated in the PB1 and PB2 genes. Here we show that a combination of mutations in this TR backbone results in an attenuated virus in vitro and in vivo. Furthermore, we show the potential of our TR backbone as a vaccine that provides protection against the 2009 swine-origin pandemic influenza H1N1 virus (S-OIV) when carrying the surface of a classical swine strain. We propose that the availability of alternative backbones to the conventional ca A/Ann Arbor/6/60 LAIV strain could also be useful in epidemic and pandemic influenza and should be considered for influenza vaccine development. In addition, our data provide evidence that the use of these alternative backbones could potentially circumvent the effects of original antigenic sin (OAS) in certain circumstances.
Adisasmito, Wiku; Hunter, Benjamin M; Krumkamp, Ralf; Latief, Kamal; Rudge, James W; Hanvoravongchai, Piya; Coker, Richard J
The failure to contain pandemic influenza A(H1N1) 2009 in Mexico has shifted global attention from containment to mitigation. Limited surveillance and reporting have, however, prevented detailed assessment of mitigation during the pandemic, particularly in low- and middle-income countries. To assess pandemic influenza case management capabilities in a resource-limited setting, the authors used a health system questionnaire and density-dependent, deterministic transmission model for Bali, Indonesia, determining resource gaps. The majority of health resources were focused in and around the provincial capital, Denpasar; however, gaps are found in every district for nursing staff, surgical masks, and N95 masks. A relatively low pathogenicity pandemic influenza virus would see an overall surplus for physicians, antivirals, and antimicrobials; however, a more pathogenic virus would lead to gaps in every resource except antimicrobials. Resources could be allocated more evenly across Bali. These, however, are in short supply universally and therefore redistribution would not fill resource gaps.
Bencharitiwong, Ramon; Leonard, Stephanie; Tsai, Theodore; Nowak-Węgrzyn, Anna
A licensed inactivated MF59-adjuvanted seasonal influenza vaccine (Optaflu) produced in canine kidney cells (MDCK 33016-PF) contained no egg proteins and did not trigger degranulation in rat basophilic leukemia (RBL) cells passively sensitized with human anti-dog IgE, supporting its safe use in dog-allergic individuals. The cell-derived pandemic H1N1 influenza vaccine was also adjuvanted with the emulsion adjuvant MF59, and support for its similar safe use was sought. We sought to evaluate in vitro allergenicity of the MF59-adjuvanted cell-derived pandemic H1N1 influenza vaccine in subjects with dog allergy, with a mediator release assay. RBL-2H3 cells transfected with human Fcε receptor type 1 were sensitized with sera from adult dog-allergic subjects and stimulated with serial dilutions of pandemic H1N1 influenza vaccine and dog dander extract. β-N-hexosaminidase release (NHR) was used as a marker of RBL degranulation.. Median dog dander-specific IgE in 30 dog-allergic subjects was 27.7 kU(A)/L (range 10.1; > 100); and in 5 dog non-allergic subjects was < 0.35 kU(A)/L (UniCAP system). Median (range) maximum NHR in dog-allergic subjects was: pandemic H1N1 influenza vaccine 1.1% (0; 4.4) and dog dander 6.9% (0.7; 37.3), P < 0.001. In conclusion, MF59-adjuvanted pandemic H1N1 influenza vaccine produced in continuous canine kidney cells did not trigger degranulation in RBL cells passively sensitized with human anti-dog IgE, supporting its safe use in dog-allergic individuals.
Chen, Shan-Hui; Wu, Meng-Na; Qian, Yan-Hua; Ma, Guang-Yuan; Wang, Guo-Lin; Yang, Yang; Zhao, Teng; Lu, Bing; Ma, Mai-Juan; Cao, Wu-Chun
We firstly report a patient who presented with severe complications after infection with influenza A(H1N1) pdm2009, more than 1 year after recovery from severe H7N9 virus infections. The population of patients who recovered from severe H7N9 infections might be at a higher risk to suffer severe complications after seasonal influenza infections, and they should be included in the high-risk populations recommended to receive seasonal influenza vaccination. PMID:27757100
Anderson, Christopher S.; DeDiego, Marta L.; Thakar, Juilee; Topham, David J.
Recently, an avian influenza virus, H5NX subclade 22.214.171.124, emerged and spread to North America. This subclade has frequently reassorted, leading to multiple novel viruses capable of human infection. Four cases of human infections, three leading to death, have already occurred. Existing vaccine strains do not protect against these new viruses, raising a need to identify new vaccine candidate strains. We have developed a novel sequence-based mapping (SBM) tool capable of visualizing complex protein sequence data sets using a single intuitive map. We applied SBM on the complete set of avian H5 viruses in order to better understand hemagglutinin protein variance amongst H5 viruses and identify any patterns associated with this variation. The analysis successfully identified the original reassortments that lead to the emergence of this new subclade of H5 viruses, as well as their known unusual ability to re-assort among neuraminidase subtypes. In addition, our analysis revealed distinct clusters of 126.96.36.199 variants that would not be covered by existing strains in the H5 vaccine stockpile. The results suggest that our method may be useful for pandemic candidate vaccine virus selection. PMID:27494186
Archer, Brett N.; Timothy, Geraldine A.; Cohen, Cheryl; Tempia, Stefano; Huma, Mmampedi; Blumberg, Lucille; Naidoo, Dhamari; Cengimbo, Ayanda; Schoub, Barry D.
Background. We documented the introduction of 2009 pandemic influenza A virus subtype H1N1 (A[H1N1]pdm09) into South Africa and describe its clinical presentation, epidemiology, and transmissibility. Methods. We conducted a prospective descriptive study of the first 100 laboratory-confirmed cases of A(H1N1)pdm09 infections identified through active case finding and surveillance. Infected patients and the attending clinicians were interviewed, and close contacts were followed up to investigate household transmission. Findings. The first case was confirmed on 14 June 2009, and by 15 July 2009, 100 cases were diagnosed. Forty-two percent of patients reported international travel within 7 days prior to onset of illness. Patients ranged in age from 4 to 70 years (median age, 21.5 years). Seventeen percent of household contacts developed influenza-like illness, and 10% of household contacts had laboratory-confirmed A(H1N1)pdm09 infection. We found a mean serial interval (± SD) of 2.3 ± 1.3 days (range, 1–5 days) between successive laboratory-confirmed cases in the transmission chain. Conclusions. A(H1N1)pdm09 established itself rapidly in South Africa. Transmissibility of the virus was comparable to observations from outside of Africa and to seasonal influenza virus strains. PMID:23169962
Stavaru, Crina; Onu, Adrian; Lupulescu, Emilia; Tucureanu, Catalin; Rasid, Orhan; Vlase, Ene; Coman, Cristin; Caras, Iuliana; Ghiorghisor, Alina; Berbecila, Laurentiu; Tofan, Vlad; Bowen, Richard A.; Marlenee, Nicole; Hartwig, Airn; Bielefeldt-Ohmann, Helle; Baldwin, Susan L.; Van Hoeven, Neal; Vedvick, Thomas S.; Huynh, Chuong; O'Hara, Michael K.; Noah, Diana L.; Fox, Christopher B.
abstract Millions of seasonal and pandemic influenza vaccine doses containing oil-in-water emulsion adjuvant have been administered in order to enhance and broaden immune responses and to facilitate antigen sparing. Despite the enactment of a Global Action Plan for Influenza Vaccines and a multi-fold increase in production capabilities over the past 10 years, worldwide capacity for pandemic influenza vaccine production is still limited. In developing countries, where routine influenza vaccination is not fully established, additional measures are needed to ensure adequate supply of pandemic influenza vaccines without dependence on the shipment of aid from other, potentially impacted first-world countries. Adaptation of influenza vaccine and adjuvant technologies by developing country influenza vaccine manufacturers may enable antigen sparing and corresponding increases in global influenza vaccine coverage capacity. Following on previously described work involving the technology transfer of oil-in-water emulsion adjuvant manufacturing to a Romanian vaccine manufacturing institute, we herein describe the preclinical evaluation of inactivated split virion H5N1 influenza vaccine with emulsion adjuvant, including immunogenicity, protection from virus challenge, antigen sparing capacity, and safety. In parallel with the evaluation of the bioactivity of the tech-transferred adjuvant, we also describe the impact of concurrent antigen manufacturing optimization activities. Depending on the vaccine antigen source and manufacturing process, inclusion of adjuvant was shown to enhance and broaden functional antibody titers in mouse and rabbit models, promote protection from homologous virus challenge in ferrets, and facilitate antigen sparing. Besides scientific findings, the operational lessons learned are delineated in order to facilitate adaptation of adjuvant technologies by other developing country institutes to enhance global pandemic influenza preparedness. PMID:26618392
Technology transfer of oil-in-water emulsion adjuvant manufacturing for pandemic influenza vaccine production in Romania: Preclinical evaluation of split virion inactivated H5N1 vaccine with adjuvant.
Stavaru, Crina; Onu, Adrian; Lupulescu, Emilia; Tucureanu, Catalin; Rasid, Orhan; Vlase, Ene; Coman, Cristin; Caras, Iuliana; Ghiorghisor, Alina; Berbecila, Laurentiu; Tofan, Vlad; Bowen, Richard A; Marlenee, Nicole; Hartwig, Airn; Bielefeldt-Ohmann, Helle; Baldwin, Susan L; Van Hoeven, Neal; Vedvick, Thomas S; Huynh, Chuong; O'Hara, Michael K; Noah, Diana L; Fox, Christopher B
Millions of seasonal and pandemic influenza vaccine doses containing oil-in-water emulsion adjuvant have been administered in order to enhance and broaden immune responses and to facilitate antigen sparing. Despite the enactment of a Global Action Plan for Influenza Vaccines and a multi-fold increase in production capabilities over the past 10 years, worldwide capacity for pandemic influenza vaccine production is still limited. In developing countries, where routine influenza vaccination is not fully established, additional measures are needed to ensure adequate supply of pandemic influenza vaccines without dependence on the shipment of aid from other, potentially impacted first-world countries. Adaptation of influenza vaccine and adjuvant technologies by developing country influenza vaccine manufacturers may enable antigen sparing and corresponding increases in global influenza vaccine coverage capacity. Following on previously described work involving the technology transfer of oil-in-water emulsion adjuvant manufacturing to a Romanian vaccine manufacturing institute, we herein describe the preclinical evaluation of inactivated split virion H5N1 influenza vaccine with emulsion adjuvant, including immunogenicity, protection from virus challenge, antigen sparing capacity, and safety. In parallel with the evaluation of the bioactivity of the tech-transferred adjuvant, we also describe the impact of concurrent antigen manufacturing optimization activities. Depending on the vaccine antigen source and manufacturing process, inclusion of adjuvant was shown to enhance and broaden functional antibody titers in mouse and rabbit models, promote protection from homologous virus challenge in ferrets, and facilitate antigen sparing. Besides scientific findings, the operational lessons learned are delineated in order to facilitate adaptation of adjuvant technologies by other developing country institutes to enhance global pandemic influenza preparedness.
Goldman, G S
The aim of this study was to compare the number of inactivated-influenza vaccine-related spontaneous abortion and stillbirth (SB) reports in the Vaccine Adverse Event Reporting System (VAERS) database during three consecutive flu seasons beginning 2008/2009 and assess the relative fetal death reports associated with the two-vaccine 2009/2010 season. The VAERS database was searched for reports of fetal demise following administration of the influenza vaccine/vaccines to pregnant women. Utilization of an independent surveillance survey and VAERS, two-source capture-recapture analysis estimated the reporting completeness in the 2009/2010 flu season. Capture-recapture demonstrated that the VAERS database captured about 13.2% of the total 1321 (95% confidence interval (CI): 815-2795) estimated reports, yielding an ascertainment-corrected rate of 590 fetal-loss reports per million pregnant women vaccinated (or 1 per 1695). The unadjusted fetal-loss report rates for the three consecutive influenza seasons beginning 2008/2009 were 6.8 (95% CI: 0.1-13.1), 77.8 (95% CI: 66.3-89.4), and 12.6 (95% CI: 7.2-18.0) cases per million pregnant women vaccinated, respectively. The observed reporting bias was too low to explain the magnitude increase in fetal-demise reporting rates in the VAERS database relative to the reported annual trends. Thus, a synergistic fetal toxicity likely resulted from the administration of both the pandemic (A-H1N1) and seasonal influenza vaccines during the 2009/2010 season.
Pahlman, I; Tohmo, H; Gylling, H
The 2009 influenza A/H1N1 pandemic seems to be only moderately severe. In the future, a pandemic influenza with high lethality, such as the Spanish influenza in 1918-1919 or even worse, may emerge. In this kind of scenario, lethality rates ranging roughly from 2% to 30% have been proposed. Legal and ethical issues should be discussed before the incident. This article aims to highlight the legal, ethical and professional aspects that might be relevant to anaesthesiologists in the case of a high-lethality infectious disease such as a severe pandemic influenza. The epidemiology, the role of anaesthesiologists and possible threats to the profession and colleagueship within medical specialties relevant to anaesthesiologists are reviewed. During historical plague epidemics, some doctors have behaved like 'deserters'. However, during the Spanish influenza, physicians remained at their jobs, although many perished. In surveys, more than half of the health-care workers have reported their willingness to work in the case of severe pandemics. Physicians have the same human rights as all citizens: they have to be effectively protected against infectious disease. However, they have a duty to treat. Fair and responsible colleagueship among the diverse medical specialties should be promoted. Until disaster threatens humanity, volunteering to work during a pandemic might be the best way to ensure that physicians and other health-care workers stay at their workplace. Broad discussion in society is needed.
Carter, C J Chris
Cross-reactive immunity occurs when infection with or vaccination against one virus protects against another related family member. A search for homologues of the HIV-1 envelope glycoprotein revealed that it is composed of thousands of intercalating and overlapping viral matches of pentapeptide or longer gapped consensi, belonging to over 70% of the currently sequenced virome, infecting all kingdoms from bacteria to man. It was also highly homologous to proteins from the Visna/Maedi and other ovine viruses, while other proteins (nef/tat/gag/pol) were homologous to proteins from the equine infectious anaemia virus and HTLV-2/HTLV-3 viruses. This phenomenon suggests that horizontal gene transfer from coinfecting RNA and DNA viruses to retroviruses is extensive, providing a route for the subsequent insertion of non-retroviral genes into human and other genomes via retroviral integration. This homology includes all viruses for which vaccines already exist. Cross-reactive immunity may be operative in AIDS, as Vaccinia vaccination decreases viral replication in HIV-1 infected patients' cells, for the CCR5 tropic form. Measles, Dengue virus, or GB virus C infections also decrease the HIV-1 viral load. A resumption of Vaccinia/smallpox vaccination might be expected to have a significant effect on the AIDS pandemic, and a careful study of the potential uses of other existing viral and bacterial vaccines merits close attention. This phenomenon may also be relevant to other recalcitrant viruses, bacteria, and parasites for which no vaccine exists and the armory of existing vaccines may have a role to play in diseases other than those for which they were designed.
Zheng, Haixue; Lian, Kaiqi; Yang, Fan; Jin, Ye; Zhu, Zixiang; Guo, Jianhong; Cao, Weijun; Liu, Huanan; He, Jijun; Zhang, Keshan; Li, Dan; Liu, Xiangtao
Foot-and-mouth disease (FMD) is a highly contagious vesicular disease that affects domestic and wild cloven-hoofed animals worldwide. Recently, a series of outbreaks of type A FMDV occurred in Southeast Asian countries, China, the Russia Federation, Mongolia, Kazakhstan and South Korea. The FMD virus (A/GDMM/CHA/2013) from China's Guangdong province (2013) is representative of those responsible for the latest epidemic, and has low amino acid identity (93.9%) in VP1 protein with the epidemic strain A/WH/CHA/09 from Wuhan, China in 2009. Both of isolates belong to the Sea-97 genotype of ASIA topotype. Therefore, the application of a new vaccine strain with cross-protective efficacy is of fundamental importance to control the spread of the two described pandemic strains. A chimeric strain rA/P1-FMDV constructed by our lab previously through replacing the P1 gene in the vaccine strain O/CHA/99 with that from the epidemic stain A/WH/CHA/09, has been demonstrated to exhibit good growth characteristics in culture, and the rA/P1-FMDV inactivated vaccine can provide protection against epidemic strain A/WH/CHA/09 in cattle. However, it is still unclear whether the vaccine produces efficient protection against the new pandemic strain (A/GDMM/CHA/2013). Here, vaccine matching and pig 50% protective dose (PD50) tests were performed to assess the vaccine potency. The vaccine matching test showed cross-reactivity of sera from full dose vaccine vaccinated pigs with A/WH/CHA/09 and A/GDMM/CHA/2013 isolates, with average r1 values of 0.94±0.12 and 0.68±0.06 (r1≥0.3), which indicates that the rA/P1-FMDV vaccine is likely to confer good cross-protection against the two isolates. When challenged with two pandemic isolates A/WH/CHA/09 and A/GDMM/CHA/2013 strain, the vaccine achieved 12.51 PD50 and 10.05 PD50 per dose (2.8μg), respectively. The results indicated that the rA/P1-FMDV inactivated vaccine could protect pigs against both A/WH/CHA/09 and A/GDMM/CHA/2013 pandemic isolates.
Kulkarni, Prasad S; Raut, Sidram K; Dhere, Rajeev M
A live attenuated pandemic H1N1 influenza vaccine was developed in India. A post marketing surveillance was conducted retrospectively in healthy individuals (³ 3 years) who were vaccinated intranasally around one year before. After consent, the subjects recorded adverse events developing within 42 days. Among 7565 individuals (3 - 85 years), a total of 81 solicited adverse reactions (1%) were reported in 49 subjects (0.65%). The reactions included mild to moderate respiratory symptoms. No H1N1 case was encountered during one year postvaccination. The data show the safety of the live attenuated influenza vaccine platform developed in India.
Narciso, Heather E; Pathela, Preeti; Morgenthau, Beth Maldin; Kansagra, Susan M; May, Linda; Scaccia, Allison; Zucker, Jane R
In the spring of 2009, New York City (NYC) experienced the emergence and rapid spread of pandemic influenza A H1N1 virus (pH1N1), which had a high attack rate in children and caused many school closures. During the 2009 fall wave of pH1N1, a school-located vaccination campaign for elementary schoolchildren was conducted in order to reduce infection and transmission in the school setting, thereby reducing the impact of pH1N1 that was observed earlier in the year. In this paper, we describe the planning and outcomes of the NYC school-located vaccination campaign. We compared consent and vaccination data for three vaccination models (school nurse alone, school nurse plus contract nurse, team). Overall, >1,200 of almost 1,600 eligible schools participated, achieving 26.8% consent and 21.5% first-dose vaccination rates, which did not vary significantly by vaccination model. A total of 189,902 doses were administered during two vaccination rounds to 115,668 students at 998 schools included in the analysis; vaccination rates varied by borough, school type, and poverty level. The team model achieved vaccination of more children per day and required fewer vaccination days per school. NYC's campaign is the largest described school-located influenza vaccination campaign to date. Despite substantial challenges, school-located vaccination is feasible in large, urban settings, and during a public health emergency.
Lohiniva, Anna-Leena; Barakat, Amal; Dueger, Erica; Restrepo, Suzanne; El Aouad, Rajae
Vaccination uptake of pregnant women in Morocco during the A (H1N1) pdm09 pandemic was lower than expected. A qualitative study using open-ended questions was developed to explore the main determinants of acceptance and non-acceptance of the monovalent A (H1N1) pdm09 vaccine among pregnant women in Morocco and to identify information sources that influenced their decision-making process. The study sample included 123 vaccinated and unvaccinated pregnant women who were in their second or third trimester between December 2009 and March 2010. They took part in 14 focus group discussions and eight in-depth interviews in the districts of Casablanca and Kenitra. Thematic qualitative analysis identified reasons for vaccine non-acceptance: (1) fear of the monovalent A (H1N1) pdm09 vaccine, (2) belief in an A (H1N1) pdm09 pandemic conspiracy, (3) belief in the inapplicability of the monovalent A (H1N1) pdm09 vaccine to Moroccans, (4) lack of knowledge of the monovalent A (H1N1) pdm09 vaccine, and (5) challenges of vaccination services/logistics. Reasons for vaccine acceptance included: (1) perceived benefits and (2) modeling. Decision-making was strongly influenced by family, community, mass media, religious leaders and health providers suggesting that broad communication efforts should also be used to advocate for vaccination. Meaningful communication for future vaccine campaigns must consider these context-specific findings. As cultural and religious values are shared across many Arab countries, these findings may also provide valuable insights for seasonal influenza vaccine planning in the Middle East and North Africa region at large. PMID:25313555
Yang, Jihyun; Shim, Sang-Mu; Nguyen, Thi Quyen; Kim, Eun-Ha; Kim, Kwang; Lim, Yong Taik; Sung, Moon-Hee; Webby, Richard; Poo, Haryoung
In 2009, the global outbreak of an influenza pandemic emphasized the need for an effective vaccine adjuvant. In this study, we examined the efficacy of poly-γ-glutamic acid/chitosan (PC) nanogel as an adjuvant for the influenza vaccine. PC nanogel significantly enhanced antigen-specific cross-presentation and cytotoxic T lymphocyte (CTL) activity. Compared with alum, the protective efficacy of the pandemic H1N1 influenza (pH1N1) vaccine was substantially increased by PC nanogel, with increased hemagglutination-inhibition titers, CTL activity, and earlier virus clearance after homologous and heterosubtypic [A/Philippines/2/82 (H3N2)] virus challenges. However, CD8+ T cell-depleted mice displayed no protection against the heterosubtypic virus challenge after immunization with PC nanogel-adjuvanted pH1N1 vaccine. We also observed that using PC nanogel as a vaccine adjuvant had a dose-sparing effect and significantly enhanced the long-lasting protection of the pH1N1 vaccine. Together, these results suggest that PC nanogel is a promising vaccine adjuvant that could broadly prevent influenza virus infection. PMID:28322289
Manzoli, Lamberto; Ioannidis, John P A; Flacco, Maria Elena; De Vito, Corrado; Villari, Paolo
Fifteen meta-analyses have been published between 1995 and 2011 to evaluate the efficacy/effectiveness and harms of diverse influenza vaccines--seasonal, H5N1 and 2009 (H1N1)--in various age-classes (healthy children, adults or elderly). These meta-analyses have often adopted different analyses and study selection criteria. Because it is difficult to have a clear picture of vaccine benefits and harms examining single systematic reviews, we compiled the main findings and evaluated which could be the most reasonable explanations for some differences in findings (or their interpretation) across previously published meta-analyses. For each age group, we performed analyses that included all trials that had been included in at least one relevant meta-analysis, also exploring whether effect sizes changed over time. Although we identified several discrepancies among the meta-analyses on seasonal vaccines for children and elderly, overall most seasonal influenza vaccines showed statistically significant efficacy/effectiveness, which was acceptable or high for laboratory-confirmed cases and of modest magnitude for clinically-confirmed cases. The available evidence on parenteral inactivated vaccines for children aged < 2 y remains scarce. Pre-pandemic "avian" H5N1 and pandemic 2009 (H1N1) vaccines can achieve satisfactory immunogenicity, but no meta-analysis has addressed H1N1 vaccination impact on clinical outcomes. Data on harms are overall reassuring, but their value is diminished by inconsistent reporting.
Basta, Nicole E; Chao, Dennis L; Halloran, M Elizabeth; Matrajt, Laura; Longini, Ira M
Vaccinating school-aged children against influenza can reduce age-specific and population-level illness attack rates. Using a stochastic simulation model of influenza transmission, the authors assessed strategies for vaccinating children in the United States, varying the vaccine type, coverage level, and reproductive number R (average number of secondary cases produced by a typical primary case). Results indicated that vaccinating children can substantially reduce population-level illness attack rates over a wide range of scenarios. The greatest absolute reduction in influenza illness cases per season occurred at R values ranging from 1.2 to 1.6 for a given vaccine coverage level. The indirect, total, and overall effects of vaccinating children were strong when transmission intensity was low to intermediate. The indirect effects declined rapidly as transmission intensity increased. In a mild influenza season (R = 1.1), approximately 19 million influenza cases could be prevented by vaccinating 70% of children. At most, nearly 100 million cases of influenza illness could be prevented, depending on the proportion of children vaccinated and the transmission intensity. Given the current worldwide threat of novel influenza A (H1N1), with an estimated R of 1.4-1.6, health officials should consider strategies for vaccinating children against novel influenza A (H1N1) as well as seasonal influenza.
Cosby, Michael T.; Pimentel, Guillermo; Nevin, Remington L.; Fouad Ahmed, Salwa; Klena, John D.; Amir, Ehab; Younan, Mary; Browning, Robert; Sebeny, Peter J.
Background Influenza pandemics have significant operational impact on deployed military personnel working in areas throughout the world. The US Department of Defense global influenza-like illness (ILI) surveillance network serves an important role in establishing baseline trends and can be leveraged to respond to outbreaks of respiratory illness. Objective We identified and characterized an operationally unique outbreak of H3N2 influenza at Camp Lemonnier, Djibouti occurring simultaneously with the H1N1 pandemic of 2009 [A(H1N1)pdm09]. Methods Enhanced surveillance for ILI was conducted at Camp Lemonnier in response to local reports of a possible outbreak during the A(H1N1)pdm09 pandemic. Samples were collected from consenting patients presenting with ILI (utilizing a modified case definition) and who completed a case report form. Samples were cultured and analyzed using standard real-time reverse transcriptase PCR (rt-RT-PCR) methodology and sequenced genetic material was phylogenetically compared to other published strains. Results rt-RT-PCR and DNA sequencing revealed that 25 (78%) of the 32 clinical samples collected were seasonal H3N2 and only 2 (6%) were A(H1N1)pdm09 influenza. The highest incidence of H3N2 occurred during the month of May and 80% of these were active duty military personnel. Phylogenetic analysis revealed that sequenced H3N2 strains were genetically similar to 2009 strains from the United States of America, Australia, and South east Asia. Conclusions This outbreak highlights challenges in the investigation of influenza among deployed military populations and corroborates the public health importance of maintaining surveillance systems for ILI that can be enhanced locally when needed. PMID:24339995
Hu, Weibin; Chen, Aizhong; Miao, Yi; Xia, Shengli; Ling, Zhiyang; Xu, Ke; Wang, Tongyan; Xu, Ying; Cui, Jun; Wu, Hongqiang; Hu, Guiyu; Tian, Lin; Wang, Lingling; Shu, Yuelong; Ma, Xiaowei; Xu, Bianli; Zhang, Jin; Lin, Xiaojun; Bian, Chao; Sun, Bing
Whether the 2009 pandemic H1N1 influenza vaccine can induce heterosubtypic cross-protective anti-hemagglutinin (HA) neutralizing antibodies is an important issue. We obtained a panel of fully human monoclonal antibodies from the memory B cells of a 2009 pandemic H1N1 influenza vaccine recipient. Most of the monoclonal antibodies targeted the HA protein but not the HA1 fragment. Among the analyzed antibodies, seven mAbs exhibited neutralizing activity against several influenza A viruses of different subtypes. The conserved linear epitope targeted by the neutralizing mAbs (FIEGGWTGMVDGWYGYHH) is part of the fusion peptide on HA2. Our work suggests that a heterosubtypic neutralizing antibody response primarily targeting the HA stem region exists in recipients of the 2009 pandemic H1N1 influenza vaccine. The HA stem region contains various conserved neutralizing epitopes with the fusion peptide as an important one. This work may aid in the design of a universal influenza A virus vaccine.
Pena, Lindomar; Vincent, Amy L; Ye, Jianqiang; Ciacci-Zanella, Janice R; Angel, Matthew; Lorusso, Alessio; Gauger, Philip C; Janke, Bruce H; Loving, Crystal L; Perez, Daniel R
On 11 June 2009, the World Health Organization (WHO) declared that the outbreaks caused by novel swine-origin influenza A (H1N1) virus had reached pandemic proportions. The pandemic H1N1 (H1N1pdm) virus is the predominant influenza virus strain in the human population. It has also crossed the species barriers and infected turkeys and swine in several countries. Thus, the development of a vaccine that is effective in multiple animal species is urgently needed. We have previously demonstrated that the introduction of temperature-sensitive mutations into the PB2 and PB1 genes of an avian H9N2 virus, combined with the insertion of a hemagglutinin (HA) tag in PB1, resulted in an attenuated (att) vaccine backbone for both chickens and mice. Because the new pandemic strain is a triple-reassortant (TR) virus, we chose to introduce the double attenuating modifications into a swine-like TR virus isolate, A/turkey/OH/313053/04 (H3N2) (ty/04), with the goal of producing live attenuated influenza vaccines (LAIV). This genetically modified backbone had impaired polymerase activity and restricted virus growth at elevated temperatures. In vivo characterization of two H1N1 vaccine candidates generated using the ty/04 att backbone demonstrated that this vaccine is highly attenuated in mice, as indicated by the absence of signs of disease, limited replication, and minimum histopathological alterations in the respiratory tract. A single immunization with the ty/04 att-based vaccines conferred complete protection against a lethal H1N1pdm virus infection in mice. More importantly, vaccination of pigs with a ty/04 att-H1N1 vaccine candidate resulted in sterilizing immunity upon an aggressive intratracheal challenge with the 2009 H1N1 pandemic virus. Our studies highlight the safety of the ty/04 att vaccine platform and its potential as a master donor strain for the generation of live attenuated vaccines for humans and livestock.
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Strikas, Raymond A.; Gensheimer, Kathleen F.; Cox, Nancy J.; Redd, Stephen C.
During the past century, 4 influenza pandemics occurred. After the emergence of a novel influenza virus of swine origin in 1976, national, state, and local US public health authorities began planning efforts to respond to future pandemics. Several events have since stimulated progress in public health emergency planning: the 1997 avian influenza A(H5N1) outbreak in Hong Kong, China; the 2001 anthrax attacks in the United States; the 2003 outbreak of severe acute respiratory syndrome; and the 2003 reemergence of influenza A(H5N1) virus infection in humans. We outline the evolution of US pandemic planning since the late 1970s, summarize planning accomplishments, and explain their ongoing importance. The public health community’s response to the 2009 influenza A(H1N1)pdm09 pandemic demonstrated the value of planning and provided insights into improving future plans and response efforts. Preparedness planning will enhance the collective, multilevel response to future public health crises. PMID:23731839
Schultz-Cherry, S; Webby, R J; Webster, R G; Kelso, A; Barr, I G; McCauley, J W; Daniels, R S; Wang, D; Shu, Y; Nobusawa, E; Itamura, S; Tashiro, M; Harada, Y; Watanabe, S; Odagiri, T; Ye, Z; Grohmann, G; Harvey, R; Engelhardt, O; Smith, D; Hamilton, K; Claes, F; Dauphin, G
In recent years, controversy has arisen regarding the risks and benefits of certain types of gain-of-function (GOF) studies involving avian influenza viruses. In this article, we provide specific examples of how different types of data, including information garnered from GOF studies, have helped to shape the influenza vaccine production process-from selection of candidate vaccine viruses (CVVs) to the manufacture and stockpiling of safe, high-yield prepandemic vaccines for the global community. The article is not written to support a specific pro- or anti-GOF stance but rather to inform the scientific community about factors involved in vaccine virus selection and the preparation of prepandemic influenza vaccines and the impact that some GOF information has had on this process.
Eichelberger, Maryna; Golding, Hana; Hess, Maureen; Weir, Jerry; Subbarao, Kanta; Luke, Catherine J; Friede, Martin; Wood, David
The goals of the workshop were to identify gaps in our knowledge and abilities to address the unique challenges encountered in the development of vaccines intended to protect against pandemic influenza and to facilitate implementation of a global research agenda to improve efficacy assessment of pandemic influenza vaccines. This workshop included discussions on: (i) current knowledge regarding immune correlates of protection against seasonal influenza; (ii) human immune responses to avian influenza infection and vaccines for novel influenza viruses; (iii) limitations of currently available assays to evaluate vaccine immunogenicity; and (iv) potential insights from animal models for correlates of protection against avian influenza.
Weinberg, Adriana; Muresan, Petronella; Richardson, Kelly M.; Fenton, Terence; Dominguez, Teresa; Bloom, Anthony; Watts, D. Heather
Influenza infections have high frequency and morbidity in HIV-infected pregnant women, underscoring the importance of vaccine-conferred protection. To identify the factors that determine vaccine immunogenicity in this group, we characterized the relationship of B- and T-cell responses to pandemic H1N1 (pH1N1) vaccine with HIV-associated immunologic and virologic characteristics. pH1N1 and seasonal-H1N1 (sH1N1) antibodies were measured in 119 HIV-infected pregnant women after two double-strength pH1N1 vaccine doses. pH1N1-IgG and IgA B-cell FluoroSpot, pH1N1- and sH1N1-interferon γ (IFNγ) and granzyme B (GrB) T-cell FluoroSpot, and flow cytometric characterization of B- and T-cell subsets were performed in 57 subjects. pH1N1-antibodies increased after vaccination, but less than previously described in healthy adults. pH1N1-IgG memory B cells (Bmem) increased, IFNγ-effector T-cells (Teff) decreased, and IgA Bmem and GrB Teff did not change. pH1N1-antibodies and Teff were significantly correlated with each other and with sH1N1-HAI and Teff, respectively, before and after vaccination. pH1N1-antibody responses to the vaccine significantly increased with high proportions of CD4+, low CD8+ and low CD8+HLADR+CD38+ activated (Tact) cells. pH1N1-IgG Bmem responses increased with high proportions of CD19+CD27+CD21- activated B cells (Bact), high CD8+CD39+ regulatory T cells (Treg), and low CD19+CD27-CD21- exhausted B cells (Bexhaust). IFNγ-Teff responses increased with low HIV plasma RNA, CD8+HLADR+CD38+ Tact, CD4+FoxP3+ Treg and CD19+IL10+ Breg. In conclusion, pre-existing antibody and Teff responses to sH1N1 were associated with increased responses to pH1N1 vaccination in HIV-infected pregnant women suggesting an important role for heterosubtypic immunologic memory. High CD4+% T cells were associated with increased, whereas high HIV replication, Tact and Bexhaust were associated with decreased vaccine immunogenicity. High Treg increased antibody responses but decreased
Kang, Eun Kyeong; Eun, Byung Wook; Kim, Nam Hee; Kim, Yun Kyung; Lim, Jung Sub; Kim, Dong Ho
This study aimed to assess the 1-y immunogenicity of influenza vaccines and the association between immunogenicity at 1 m and further influenza infections in children aged 6 m to 18 y. Serum hemagglutination inhibition (HI) antibody titers and GMTs were determined for the recommended influenza strains 0, 1, 6, and 12 m post-vaccination. The serological evidence of influenza infections were defined as the increase of HI titer (HI ≥1:40 and 4-fold rise). The seroprotection rates for strains A(H1N1), A(H3N2), and B were 91.2%, 87.6%, and 87.6%, respectively, at 1 month (n = 174). These rates were 76.5%, 64.7%, and 54.6%, respectively, at 12 m. The seroprotection rates and GMTs for influenza A(H1N1) and A(H3N2) were higher at 12 m than at 0 m (p < 0.05) but not for B. There were 39 subjects (42 cases) of serological influenza infections. Subjects with seroprotection at 1 m post-vaccination had showed fewer serologic A(H1N1) (10.1 vs 54.5%) and A(H3N2) (7.2 vs 38.1%) infections than the ones with HI titer <1:40 during follow-up (P < 0.01). In conclusion, influenza vaccines used during the 2008-09 season induced adequate 1-y immunogenicity for A(H1N1) and A(H3N2). The immunogenicity at one month after vaccination influenced further serological influenza infections.
Souza, Thiago Moreno L; Santini-Oliveira, Marilia; Martorelli, Andressa; Luz, Paula M; Vasconcellos, Mauricio T L; Giacoia-Gripp, Carmem B W; Morgado, Mariza; Nunes, Estevão P; Lemos, Alberto S; Ferreira, Ana C G; Moreira, Ronaldo I; Veloso, Valdiléa G; Siqueira, Marilda; Grinsztejn, Beatriz; Camacho, Luiz A B
HIV-infected individuals have a higher risk of serious illnesses following infection by infection with influenza. Although anti-influenza vaccination is recommended, immunosuppression may limit their response to active immunization. We followed-up a cohort of HIV-infected individuals vaccinated against influenza to assess the immunogenicity and sustainability of the immune response to vaccination. Individuals were vaccinated 2011 with inactivated triple influenza vaccine (TIV), and they had received in 2010 the monovalent anti-A(H1N1)pdm09 vaccine. The sustainability of the immune response to A(H1N1)pdm09 at 12 months after monovalent vaccination fell, both in individuals given two single or two double doses. For these individuals, A(H1N1)pdm09 component from TIV acted as a booster, raising around 40% the number of seroprotected individuals. Almost 70% of the HIV-infected individuals were already seroprotected to A/H3N2 at baseline. Again, TIV boosted over 90% the seroprotection to A/H3N2. Anti-A/H3N2 titers dropped by 20% at 6 months after vaccination. Pre-vaccination seroprotection rate to influenza B (victoria lineage) was the lowest among those tested, seroconversion rates were higher after vaccination. Seroconversion/protection after TIV vaccination did not differ significantly across categories of clinical and demographic variables. Anti-influenza responses in Brazilian HIV-infected individuals reflected both the previous history of virus circulation in Brazil and vaccination.
Freitas, André Ricardo Ribas; Francisco, Priscila M. S. Bergamo; Donalisio, Maria Rita
The impact of the seasonal influenza and 2009 AH1N1 pandemic influenza on mortality is not yet completely understood, particularly in tropical and subtropical countries. The trends of influenza related mortality rate in different age groups and different outcomes on a area in tropical and subtropical climate with more than 41 million people (State of São Paulo, Brazil), were studied from 2002 to 2011 were studied. Serfling-type regression analysis was performed using weekly mortality registries and virological data obtained from sentinel surveillance. The prepandemic years presented a well-defined seasonality during winter and a clear relationship between activity of AH3N2 and increase of mortality in all ages, especially in individuals older than 60 years. The mortality due to pneumonia and influenza and respiratory causes associated with 2009 pandemic influenza in the age groups 0–4 years and older than 60 was lower than the previous years. Among people aged 5–19 and 20–59 years the mortality was 2.6 and 4.4 times higher than that in previous periods, respectively. The mortality in all ages was higher than the average of the previous years but was equal mortality in epidemics of AH3N2. The 2009 pandemic influenza mortality showed significant differences compared to other years, especially considering the age groups most affected. PMID:23844285
Keeling, Matt J.; White, Peter J.
The emergence of a novel strain of H1N1 influenza virus in Mexico in 2009, and its subsequent worldwide spread, has focused attention to the question of optimal deployment of mass vaccination campaigns. Here, we use three relatively simple models to address three issues of primary concern in the targeting of any vaccine. The advantages of such simple models are that the underlying assumptions and effects of individual parameters are relatively clear, and the impact of uncertainty in the parametrization can be readily assessed in the early stages of an outbreak. In particular, we examine whether targeting risk-groups, age-groups or spatial regions could be optimal in terms of reducing the predicted number of cases or severe effects; and how these targeted strategies vary as the epidemic progresses. We examine the conditions under which it is optimal to initially target vaccination towards those individuals within the population who are most at risk of severe effects of infection. Using age-structured mixing matrices, we show that targeting vaccination towards the more epidemiologically important age groups (5–14 year olds and then 15–24 year olds) leads to the greatest reduction in the epidemic growth and hence reduces the total number of cases. Finally, we consider how spatially targeting the vaccine towards regions of country worst affected could provide an advantage. We discuss how all three of these priorities change as both the speed at which vaccination can be deployed and the start of the vaccination programme is varied. PMID:20943682
Morgan, Sophie B.; Hemmink, Johanneke D.; Porter, Emily; Harley, Ross; Shelton, Holly; Aramouni, Mario; Everett, Helen E.; Brookes, Sharon M.; Bailey, Michael; Townsend, Alain M.; Charleston, Bryan
Influenza A viruses are a major health threat to livestock and humans, causing considerable mortality, morbidity, and economic loss. Current inactivated influenza vaccines are strain specific and new vaccines need to be produced at frequent intervals to combat newly arising influenza virus strains, so that a universal vaccine is highly desirable. We show that pandemic H1N1 influenza virus in which the hemagglutinin signal sequence has been suppressed (S-FLU), when administered to pigs by aerosol can induce CD4 and CD8 T cell immune responses in blood, bronchoalveolar lavage (BAL), and tracheobronchial lymph nodes. Neutralizing Ab was not produced. Detection of a BAL response correlated with a reduction in viral titer in nasal swabs and lungs, following challenge with H1N1 pandemic virus. Intratracheal immunization with a higher dose of a heterologous H5N1 S-FLU vaccine induced weaker BAL and stronger tracheobronchial lymph node responses and a lesser reduction in viral titer. We conclude that local cellular immune responses are important for protection against influenza A virus infection, that these can be most efficiently induced by aerosol immunization targeting the lower respiratory tract, and that S-FLU is a promising universal influenza vaccine candidate. PMID:27183611
Madan, Anuradha; Segall, Nathan; Ferguson, Murdo; Frenette, Louise; Kroll, Robin; Friel, Damien; Soni, Jyoti; Li, Ping; Innis, Bruce L.; Schuind, Anne
Background. Almost 700 cases of human infection with avian influenza A/H7N9 have been reported since 2013. Pandemic preparedness strategies include H7N9 vaccine development. Methods. We evaluated an inactivated H7N9 vaccine in an observer-blind study in healthy adults aged 18–64 years. Participants (420) were randomized to receive 1 of 4 AS03-adjuvanted vaccines (low or medium dose of hemagglutinin with AS03A or AS03B), one nonadjuvanted vaccine, or placebo. The coprimary immunogenicity objective determined whether adjuvanted vaccines elicited an immune response against the vaccine-homologous virus, 21 days after the second vaccine dose per US and European licensure criteria in the per-protocol cohort (n = 389). Results. All adjuvanted vaccines met regulatory acceptance criteria. In groups receiving adjuvanted formulations, seroconversion rates were ≥85.7%, seroprotection rates ≥91.1%, and geometric mean titers ≥92.9% versus 23.2%, 28.6%, and 17.2 for the nonadjuvanted vaccine. The AS03 adjuvant enhanced immune response at antigen-sparing doses. Injection site pain occurred more frequently with adjuvanted vaccines (in ≤98.3% of vaccinees) than with the nonadjuvanted vaccine (40.7%) or placebo (20.0%). None of the 20 serious adverse events reported were related to vaccination. Conclusions. Two doses of AS03-adjuvanted H7N9 vaccine were well tolerated and induced a robust antibody response at antigen-sparing doses in healthy adults. Clinical Trials Registration. NCT01999842. PMID:27609809
Mosterín Höpping, Ana; Fonville, Judith M; Russell, Colin A; James, Sarah; Smith, Derek J
Epidemics of seasonal influenza viruses cause considerable morbidity and mortality each year. Various types and subtypes of influenza circulate in humans and evolve continuously such that individuals at risk of serious complications need to be vaccinated annually to keep protection up to date with circulating viruses. The influenza vaccine in most parts of the world is a trivalent vaccine, including an antigenically representative virus of recently circulating influenza A/H3N2, A/H1N1, and influenza B viruses. However, since the 1970s influenza B has split into two antigenically distinct lineages, only one of which is represented in the annual trivalent vaccine at any time. We describe a lineage selection strategy that optimizes protection against influenza B using the standard trivalent vaccine as a potentially cost effective alternative to quadrivalent vaccines.
Yokomichi, Hiroshi; Kurihara, Shintaro; Yokoyama, Tetsuji; Inoue, Eisuke; Tanaka-Taya, Keiko; Kono, Shigeru; Yamagata, Zentaro
Background Evidence regarding the mortality rate after administration of the pandemic influenza A (H1N1) 2009 vaccine on patients with underlying diseases is currently scarce. We conducted a case-control study in Japan to compare the mortality rates of patients with idiopathic interstitial pneumonia after the vaccines were administered and were not administered. Methods Between October 2009 and March 2010, we collected clinical records in Japan and conducted a 1∶1 matched case-control study. Patients with idiopathic interstitial pneumonia who died during this period were considered case patients, and those who survived were considered control patients. We determined and compared the proportion of each group that received the pandemic influenza A (H1N1) 2009 vaccine and estimated the odds ratio. Finally, we conducted simulations that compensated for the shortcomings of the study associated with adjusted severity of idiopathic interstitial pneumonia. Results The case and control groups each comprised of 75 patients with idiopathic interstitial pneumonia. The proportion of patients who received the pandemic influenza A (H1N1) 2009 vaccine was 30.7% and 38.7% for the case and control groups, respectively. During that winter, the crude conditional odds ratio of mortality was 0.63 (95% confidence interval, 0.25–1.47) and the adjusted conditional odds ratio was 1.18 (95% confidence interval, 0.33–4.49); neither was significant. The simulation study showed more accurate conditional odds ratios of 0.63–0.71. Conclusions In our study, we detected no evidence that the influenza A (H1N1) 2009 vaccine increased the mortality rate of patients with idiopathic interstitial pneumonia. The results, however, are limited by the small sample size and low statistical power. A larger-scale study is required. PMID:24586445
Busquets, Núria; Segalés, Joaquim; Córdoba, Lorena; Mussá, Tufaria; Crisci, Elisa; Martín-Valls, Gerard E; Simon-Grifé, Meritxell; Pérez-Simó, Marta; Pérez-Maíllo, Monica; Núñez, Jose I; Abad, Francesc X; Fraile, Lorenzo; Pina, Sonia; Majó, Natalia; Bensaid, Albert; Domingo, Mariano; Montoya, María
The recent pandemic caused by human influenza virus A(H1N1) 2009 contains ancestral gene segments from North American and Eurasian swine lineages as well as from avian and human influenza lineages. The emergence of this A(H1N1) 2009 poses a potential global threat for human health and the fact that it can infect other species, like pigs, favours a possible encounter with other influenza viruses circulating in swine herds. In Europe, H1N1, H1N2 and H3N2 subtypes of swine influenza virus currently have a high prevalence in commercial farms. To better assess the risk posed by the A(H1N1) 2009 in the actual situation of swine farms, we sought to analyze whether a previous infection with a circulating European avian-like swine A/Swine/Spain/53207/2004 (H1N1) influenza virus (hereafter referred to as SwH1N1) generated or not cross-protective immunity against a subsequent infection with the new human pandemic A/Catalonia/63/2009 (H1N1) influenza virus (hereafter referred to as pH1N1) 21 days apart. Pigs infected only with pH1N1 had mild to moderate pathological findings, consisting on broncho-interstitial pneumonia. However, pigs inoculated with SwH1N1 virus and subsequently infected with pH1N1 had very mild lung lesions, apparently attributed to the remaining lesions caused by SwH1N1 infection. These later pigs also exhibited boosted levels of specific antibodies. Finally, animals firstly infected with SwH1N1 virus and latter infected with pH1N1 exhibited undetectable viral RNA load in nasal swabs and lungs after challenge with pH1N1, indicating a cross-protective effect between both strains.
Chauvat, A; Benhamouda, N; Loison, E; Gougeon, M L; Gey, A; Levionnois, E; Ravel, P; Abitbol, V; Roncelin, S; Marcheteau, E; Quintin-Colonna, F; Fridman, W H; Launay, O; Tartour, E
Monitoring T cells in combination with humoral response may be of value to predict clinical protection and cross-protective immunity after influenza vaccination. Elispot technique which measures cytokine produced after antigen-specific T cell stimulation is used routinely to detect and characterize anti-viral T cells. We found that the preservative thimerosal present in most H1N1 pandemic vaccines, induced in vitro abortive activation of T cells followed by cell death leading to false-positive results with the Elispot technique. The size of the spots, usually not measured in routine analysis, appears to be a discriminative criterion to detect this bias. Multi-dose vials of vaccine containing thimerosal remain important for vaccine delivery and our results alert about false-positive results of Elispot to monitor the clinical efficacy of these vaccines. We showed that this finding extends for other T cell monitoring techniques based on cytokine production such as ELISA. Although measuring in vitro immune response using the whole vaccine used for human immunization directly reflects in vivo global host response to the vaccine, the present study strongly supports the use of individual vaccine components for immune monitoring due to the presence of contaminants, such as thimerosal, leading to a bias in interpretation of the results.
McLachlan, Hugh V
Wardrope argues against my proposed non-consequentialist policy for the distribution of scarce influenza vaccine in the face of a pandemic. According to him, even if one accepts what he calls my deontological ethical theory, it does not follow that we are required to agree with my proposed randomised allocation of doses of vaccine by means of a lottery. He argues in particular that I fail to consider fully the prophylactic role of vaccination whereby it serves to protect from infection more people than are vaccinated. He concludes that: 'The benefits and burdens of vaccination are provided impartially and far more effectively by targeted vaccination than impartial lotteries.' He has shown convincingly that this conclusion can be established in the case of his particular envisaged scenario. However, Wardrope gives no reason to suppose that, in the circumstances that we actually face, targeted vaccination would constitute impartial treatment of citizens in the UK. I readily agree with Wardrope that if it should treat its citizens justly and impartially, it does not necessarily follow that the state should distribute vaccinations of the basis of a lottery. That will be a reasonable thing to do only if certain assumptions are made. These assumptions will not always be reasonable. However, they are reasonable ones to make in the actual circumstances that currently apply.
Molina Hazan, Vered; Balicer, Ran D; Groto, Itamar; Zarka, Salman; Ankol, Omer E; Bar-Zeev, Yael; Levine, Hagai; Ash, Nachman
Pandemic influenza is a major challenge to emergency preparedness agencies and health systems throughout the world. It requires preparation for a situation of widespread morbidity due to flu and its complications which will lead to a huge burden on the health system in the community and in hospitals, and work absenteeism, also among health care personnel. This may require major involvement of the army in both preparedness and measures to be taken to tackle such an event. This article reviews the different roles armies could take in such a crisis, and presents the Israeli test case. Defense systems are characterized by a number of attributes that may be major advantages during pandemic influenza: crisis management capacities, ability to deal with varied tasks in sub-optimal conditions, logistic resources (fuel, food and water), widespread deployment in the country and sometimes in the world, and the ability to activate people in risky situations, even against their will. The army roles during pandemic outbreaks could include: taking national and regional command of the event, assigning workforce for essential civilian missions, use of logistic and military resources, maintaining public order and implementing public health measures such as isolation and quarantine. In addition, the army must continue its primary role of maintaining the security and guarding the borders of the state, especially in times of global geopolitical changes due to pandemic. Since March 2009, the influenza A/H1N1 2009 virus spread throughout the world, leading the WHO to declare a state of pandemic influenza. According to Israeli preparedness plans, the management of the event was supposed to pass to the defense system. However, due to the moderate severity of the illness, it was decided to leave the management of the event to the health system. In view of the necessity of maintaining military combat capabilities, and the possibility of outbreaks in combat units, which actually occurred, the
Development of a candidate influenza vaccine based on virus-like particles displaying influenza M2e peptide into the immunodominant region of hepatitis B core antigen: Broad protective efficacy of particles carrying four copies of M2e.
Tsybalova, Liudmila M; Stepanova, Liudmila A; Kuprianov, Victor V; Blokhina, Elena A; Potapchuk, Marina V; Korotkov, Alexander V; Gorshkov, Andrey N; Kasyanenko, Marina A; Ravin, Nikolai V; Kiselev, Oleg I
A long-term objective when designing influenza vaccines is to create one with broad cross-reactivity that will provide effective control over influenza, no matter which strain has caused the disease. Here we summarize the results from an investigation into the immunogenic and protective capacities inherent in variations of a recombinant protein, HBc/4M2e. This protein contains four copies of the ectodomain from the influenza virus protein M2 (M2e) fused within the immunodominant loop of the hepatitis B virus core antigen (HBc). Variations of this basic design include preparations containing M2e from the consensus human influenza virus; the M2e from the highly pathogenic avian A/H5N1 virus and a combination of two copies from human and two copies from avian influenza viruses. Intramuscular delivery in mice with preparations containing four identical copies of M2e induced high IgG titers in blood sera and bronchoalveolar lavages. It also provoked the formation of memory T-cells and antibodies were retained in the blood sera for a significant period of time post immunization. Furthermore, these preparations prevented the death of 75-100% of animals, which were challenged with lethal doses of virus. This resulted in a 1.2-3.5 log10 decrease in viral replication within the lungs. Moreover, HBc particles carrying only "human" or "avian" M2e displayed cross-reactivity in relation to human (A/H1N1, A/H2N2 and A/H3N2) or A/H5N1 and A(H1N1)pdm09 viruses, respectively; however, with the particles carrying both "human" and "avian" M2e this effect was much weaker, especially in relation to influenza virus A/H5N1. It is apparent from this work that to quickly produce vaccine for a pandemic it would be necessary to have several variations of a recombinant protein, containing four copies of M2e (each one against a group of likely influenza virus strains) with these relevant constructs housed within a comprehensive collection Escherichia coli-producers and maintained ready for use.
Leroux-Roels, Isabel; Bernhard, Roger; Gérard, Pascal; Dramé, Mamadou; Hanon, Emmanuel; Leroux-Roels, Geert
Background The availability of H5N1 vaccines that can elicit a broad cross-protective immunity against different currently circulating clade 2 H5N1 viruses is a pre-requisite for the development of a successful pre-pandemic vaccination strategy. In this regard, it has recently been shown that adjuvantation of a recombinant clade 1 H5N1 inactivated split-virion vaccine with an oil-in-water emulsion-based adjuvant system al