Intellectual property rights and challenges for development of affordable human papillomavirus, rotavirus and pneumococcal vaccines: Patent landscaping and perspectives of developing country vaccine manufacturers.

PubMed

Chandrasekharan, Subhashini; Amin, Tahir; Kim, Joyce; Furrer, Eliane; Matterson, Anna-Carin; Schwalbe, Nina; Nguyen, Aurélia

2015-11-17

The success of Gavi, the Vaccine Alliance depends on the vaccine markets providing appropriate, affordable vaccines at sufficient and reliable quantities. Gavi's current supplier base for new and underutilized vaccines, such as the human papillomavirus (HPV), rotavirus, and the pneumococcal conjugate vaccine is very small. There is growing concern that following globalization of laws on intellectual property rights (IPRs) through trade agreements, IPRs are impeding new manufacturers from entering the market with competing vaccines. This article examines the extent to which IPRs, specifically patents, can create such obstacles, in particular for developing country vaccine manufacturers (DCVMs). Through building patent landscapes in Brazil, China, and India and interviews with manufacturers and experts in the field, we found intense patenting activity for the HPV and pneumococcal vaccines that could potentially delay the entry of new manufacturers. Increased transparency around patenting of vaccine technologies, stricter patentability criteria suited for local development needs and strengthening of IPRs management capabilities where relevant, may help reduce impediments to market entry for new manufacturers and ensure a competitive supplier base for quality vaccines at sustainably low prices. Copyright © 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.

WHO consultation on clinical evaluation of vaccines, 17-18 July 2014, WHO Headquarters, Geneva, Switzerland.

PubMed

Knezevic, Ivana; Moorthy, Vasee; Sheets, Rebecca

2015-04-21

A World Health Organization (WHO) consultation on guidelines for National Regulatory Authorities (NRAs) and vaccine manufacturers on clinical evaluation of vaccines was held from 17 to 18 July 2014, to review key scientific challenges that regulators have been facing since the establishment of the WHO Guidelines on Clinical Evaluation of Vaccines. The guidelines, adopted by the WHO Expert Committee on Biological Standardization (ECBS) in 2001, have served as the basis for setting or updating national requirements for the evaluation and licensing of a broad range of vaccines as well as for WHO vaccine prequalification. Regulators from Australia, Brazil, China, Canada, Germany, India, Republic of Korea, South Africa, United States of America and the United Kingdom were represented. The International Federation for Pharmaceutical Manufacturers' Association (IFPMA) and the Developing Country Vaccine Manufacturers' Network (DCVMN) provided industry representation. The consultation concluded that the guidelines should be revised to address issues that were raised in the context of vaccines that were the subject of clinical development in the past decade. Although the current guidelines have served well over time, it was recognized that an update would further increase their utility and would help regulators, manufacturers, vaccine developers and academia to respond to the challenging questions regarding the safety, immunogenicity, efficacy and effectiveness of vaccines intended for global use. A summary of the main outcomes of the consultation and proposals for the next steps regarding the guidelines and beyond are provided in this report. Copyright © 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.

Technology transfer of oil-in-water emulsion adjuvant manufacturing for pandemic influenza vaccine production in Romania.

PubMed

Fox, Christopher B; Huynh, Chuong; O'Hara, Michael K; Onu, Adrian

2013-03-15

Many developing countries lack or have inadequate pandemic influenza vaccine manufacturing capacity. In the 2009 H1N1 pandemic, this led to delayed and inadequate vaccine coverage in the developing world. Thus, bolstering developing country influenza vaccine manufacturing capacity is urgently needed. The Cantacuzino Institute in Bucharest, Romania has been producing seasonal influenza vaccine since the 1970s, and has the capacity to produce ∼5 million doses of monovalent vaccine in the event of an influenza pandemic. Inclusion of an adjuvant in the vaccine could enable antigen dose sparing, expanding vaccine coverage and potentially allowing universal vaccination of the Romanian population and possibly neighboring countries. However, adjuvant formulation and manufacturing know-how are difficult to access. This manuscript describes the successful transfer of oil-in-water emulsion adjuvant manufacturing and quality control technologies from the Infectious Disease Research Institute in Seattle, USA to the Cantacuzino Institute. By describing the challenges and accomplishments of the project, it is hoped that the knowledge and experience gained will benefit other institutes involved in similar technology transfer projects designed to facilitate increased vaccine manufacturing capacity in developing countries. Copyright © 2012 Elsevier Ltd. All rights reserved.

Viral vaccines and their manufacturing cell substrates: New trends and designs in modern vaccinology.

PubMed

Rodrigues, Ana F; Soares, Hugo R; Guerreiro, Miguel R; Alves, Paula M; Coroadinha, Ana S

2015-09-01

Vaccination is one of the most effective interventions in global health. The worldwide vaccination programs significantly reduced the number of deaths caused by infectious agents. A successful example was the eradication of smallpox in 1979 after two centuries of vaccination campaigns. Since the first variolation administrations until today, the knowledge on immunology has increased substantially. This knowledge combined with the introduction of cell culture and DNA recombinant technologies revolutionized vaccine design. This review will focus on vaccines against human viral pathogens, recent developments on vaccine design and cell substrates used for their manufacture. While the production of attenuated and inactivated vaccines requires the use of the respective permissible cell substrates, the production of recombinant antigens, virus-like particles, vectored vaccines and chimeric vaccines requires the use - and often the development - of specific cell lines. Indeed, the development of novel modern viral vaccine designs combined with, the stringent safety requirements for manufacture, and the better understanding on animal cell metabolism and physiology are increasing the awareness on the importance of cell line development and engineering areas. A new era of modern vaccinology is arriving, offering an extensive toolbox to materialize novel and creative ideas in vaccine design and its manufacture. Copyright © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Challenges in conducting post-authorisation safety studies (PASS): A vaccine manufacturer's view.

PubMed

Cohet, Catherine; Rosillon, Dominique; Willame, Corinne; Haguinet, Francois; Marenne, Marie-Noëlle; Fontaine, Sandrine; Buyse, Hubert; Bauchau, Vincent; Baril, Laurence

2017-05-25

Post-authorisation safety studies (PASS) of vaccines assess or quantify the risk of adverse events following immunisation that were not identified or could not be estimated pre-licensure. The aim of this perspective paper is to describe the authors' experience in the design and conduct of twelve PASS that contributed to the evaluation of the benefit-risk of vaccines in real-world settings. We describe challenges and learnings from selected PASS of rotavirus, malaria, influenza, human papillomavirus and measles-mumps-rubella-varicella vaccines that assessed or identified potential or theoretical risks, which may lead to changes to risk management plans and/or to label updates. Study settings include the use of large healthcare databases and de novo data collection. PASS methodology is influenced by the background incidence of the outcome of interest, vaccine uptake, availability and quality of data sources, identification of the at-risk population and of suitable comparators, availability of validated case definitions, and the frequent need for case ascertainment in large databases. Challenges include the requirement for valid exposure and outcome data, identification of, and access to, adequate data sources, and mitigating limitations including bias and confounding. Assessing feasibility is becoming a key step to confirm that study objectives can be met in a timely manner. PASS provide critical information for regulators, public health agencies, vaccine manufacturers and ultimately, individuals. Collaborative approaches and synergistic efforts between vaccine manufacturers and key stakeholders, such as regulatory and public health agencies, are needed to facilitate access to data, and to drive optimal study design and implementation, with the aim of generating robust evidence. Copyright © 2017 GSK Biologicals SA. Published by Elsevier Ltd.. All rights reserved.

Tracing and control of raw materials sourcing for vaccine manufacturers.

PubMed

Faretra Peysson, Laurence

2010-05-01

The control of the raw materials used to manufacture vaccines is mandatory; therefore, a very clear process must be in place to guarantee that raw materials are traced. Those who make products or supplies used in vaccine manufacture (suppliers of culture media, diagnostic tests, etc.) must apply quality systems proving that they adhere to certain standards. ISO certification, Good Manufacturing Practices for production sites and the registration of culture media with a 'Certificate of Suitability' from the European Directorate for the Quality of Medicines and Healthcare are reliable quality systems pertaining to vaccine production. Suppliers must assure that each lot of raw materials used in a product that will be used in vaccine manufacture adheres to the level of safety and traceability required. Incoming materials must be controlled in a single 'Enterprise Resource Planning' system which is used to document important information, such as the assignment of lot number, expiration date, etc. Ingredients for culture media in particular must conform to certain specifications. The specifications that need to be checked vary according to the ingredient, based on the level of risk. The way a raw material is produced is also important, and any aspect relative to cross-contamination, such as the sanitary measures used in producing and storing the raw material must be checked as well. In addition, suppliers can reduce the risk of viral contamination of raw materials by avoiding purchases in countries where a relevant outbreak is currently declared. 2010 The International Association for Biologicals. Published by Elsevier Ltd. All rights reserved.

Geneva-Seattle collaboration in support of developing country vaccine manufacturing.

PubMed

Stevenson, Michael A

2018-04-01

Vaccines were once produced almost exclusively by state-supported entities. While they remain essential tools for public health protection, the majority of the world's governments have allowed industry to assume responsibility for this function. This is significant because while the international harmonisation of quality assurance standards have effectively increased vaccine safety, they have also reduced the number of developing country vaccine producers, and Northern multinational pharmaceutical companies have shown little interest in offering the range of low-priced products needed in low and middle-income-country contexts. This article examines how public-private collaboration is relevant to contemporary efforts aimed at strengthening developing country manufacturers' capacity to produce high-quality, low-priced vaccines. Specifically, it casts light on the important and largely complimentary roles of the World Health Organization, The Bill and Melinda Gates Foundation, and the Seattle-based non-profit PATH, in this process. The take away message is that external support remains critical to ensuring that developing country vaccine manufacturers have the tools needed to produce for both domestic and global markets, and the United Nations supply chain, and collaboration at the public-private interface is driving organisational innovation focused on meeting these goals.

Perspectives on the manufacture of combination vaccines.

PubMed

Vose, J R

2001-12-15

Evolving regulatory requirements in the United States and Europe create major challenges for manufacturers tasked with production of vaccines that contain > or =9 separate antigens capable of protecting against infectious diseases, such as diphtheria, tetanus, pertussis, polio, hepatitis B, and Haemophilus influenza b, in a single shot. This article describes 10 steps that can facilitate the process of licensing these complex vaccines. It also points out problems associated with the use of animal tests for the crucial step of potency testing for batch release caused by the inherent variability of such tests and the difficulties of interpreting their results.

Genetic and Phenotypic Characterization of Manufacturing Seeds for a Tetravalent Dengue Vaccine (DENVax)

PubMed Central

Huang, Claire Y.-H.; Kinney, Richard M.; Livengood, Jill A.; Bolling, Bethany; Arguello, John J.; Luy, Betty E.; Silengo, Shawn J.; Boroughs, Karen L.; Stovall, Janae L.; Kalanidhi, Akundi P.; Brault, Aaron C.; Osorio, Jorge E.; Stinchcomb, Dan T.

2013-01-01

Background We have developed a manufacturing strategy that can improve the safety and genetic stability of recombinant live-attenuated chimeric dengue vaccine (DENVax) viruses. These viruses, containing the pre-membrane (prM) and envelope (E) genes of dengue serotypes 1–4 in the replicative background of the attenuated dengue-2 PDK-53 vaccine virus candidate, were manufactured under cGMP. Methodology/Principal Findings After deriving vaccine viruses from RNA-transfected Vero cells, six plaque-purified viruses for each serotype were produced. The plaque-purified strains were then analyzed to select one stock for generation of the master seed. Full genetic and phenotypic characterizations of the master virus seeds were conducted to ensure these viruses retained the previously identified attenuating determinants and phenotypes of the vaccine viruses. We also assessed vector competence of the vaccine viruses in sympatric (Thai) Aedes aegypti mosquito vectors. Conclusion/Significance All four serotypes of master vaccine seeds retained the previously defined safety features, including all three major genetic loci of attenuation, small plaques, temperature sensitivity in mammalian cells, reduced replication in mosquito cell cultures, and reduced neurovirulence in new-born mice. In addition, the candidate vaccine viruses demonstrated greatly reduced infection and dissemination in Aedes aegypti mosquitoes, and are not likely to be transmissible by these mosquitoes. This manufacturing strategy has successfully been used to produce the candidate tetravalent vaccine, which is currently being tested in human clinical trials in the United States, Central and South America, and Asia. PMID:23738026

Lessons learned during the development and transfer of technology related to a new Hib conjugate vaccine to emerging vaccine manufacturers.

PubMed

Hamidi, A; Boog, C; Jadhav, S; Kreeftenberg, H

2014-07-16

The incidence of Haemophilus Influenzae type b (Hib) disease in developed countries has decreased since the introduction of Hib conjugate vaccines in their National Immunization Programs (NIP). In countries where Hib vaccination is not applied routinely, due to limited availability and high cost of the vaccines, invasive Hib disease is still a cause of mortality. Through the development of a production process for a Hib conjugate vaccine and related quality control tests and the transfer of this technology to emerging vaccine manufacturers in developing countries, a substantial contribution was made to the availability and affordability of Hib conjugate vaccines in these countries. Technology transfer is considered to be one of the fastest ways to get access to the technology needed for the production of vaccines. The first Hib conjugate vaccine based on the transferred technology was licensed in 2007, since then more Hib vaccines based on this technology were licensed. This paper describes the successful development and transfer of Hib conjugate vaccine technology to vaccine manufacturers in India, China and Indonesia. By describing the lessons learned in this process, it is hoped that other technology transfer projects can benefit from the knowledge and experience gained. Copyright © 2014 Elsevier Ltd. All rights reserved.

Lot-to-lot consistency of live attenuated SA 14-14-2 Japanese encephalitis vaccine manufactured in a good manufacturing practice facility and non-inferiority with respect to an earlier product.

PubMed

Zaman, K; Naser, Abu Mohd; Power, Maureen; Yaich, Mansour; Zhang, Lei; Ginsburg, Amy Sarah; Luby, Stephen P; Rahman, Mahmudur; Hills, Susan; Bhardwaj, Mukesh; Flores, Jorge

2014-10-21

We conducted a four-arm, double-blind, randomized controlled trial among 818 Bangladeshi infants between 10 and 12 months of age to establish equivalence among three lots of live attenuated SA 14-14-2 JE vaccine manufactured by the China National Biotec Group's Chengdu Institute of Biological Products (CDIBP) in a new Good Manufacturing Practice (GMP) facility and to evaluate non-inferiority of the product with a lot of the same vaccine manufactured in CDIBP's original facility. The study took place in two sites in Bangladesh, rural Matlab and Mirpur in urban Dhaka. We collected pre-vaccination (Day 0) and post-vaccination Day 28 (-4 to +14 days) blood samples to assess neutralizing anti-JE virus antibody titers in serum by plaque reduction neutralization tests (PRNT). Seroprotection following vaccination was defined as a PRNT titer ≥1:10 at Day 28 in participants non-immune at baseline. Follow-up for reactogenicity and safety was conducted through home visits at Day 7 and monitoring for serious adverse events through Day 28. Seroprotection rates ranged from 80.2% to 86.3% for all four lots of vaccine. Equivalence of the seroprotection rates between pairs of vaccine lots produced in the new GMP facility was satisfied at the pre-specified 10% margin of the 95% confidence interval (CI) for two of the three pairwise comparisons, but not for the third (-4.3% observed difference with 95% CI of -11.9 to 3.3%). Nevertheless, the aggregate seroprotection rate for all three vaccine lots manufactured in the GMP facility was calculated and found to be within the non-inferiority margin (within 10%) to the vaccine lot produced in the original facility. All four lots of vaccine were safe and well tolerated. These study results should facilitate the use of SA 14-14-2 JE vaccine as a routine component of immunization programs in Asian countries. Copyright © 2014 Elsevier Ltd. All rights reserved.

FluBlok, a next generation influenza vaccine manufactured in insect cells.

PubMed

Cox, Manon M J; Hollister, Jason R

2009-06-01

FluBlok, a recombinant trivalent hemagglutinin (rHA) vaccine produced in insect cell culture using the baculovirus expression system, provides an attractive alternative to the current egg-based trivalent inactivated influenza vaccine (TIV). Its manufacturing process presents the possibility for safe and expeditious vaccine production. FluBlok contains three times more HA than TIV and does not contain egg-protein or preservatives. The high purity of the antigen enables administration at higher doses without a significant increase in side-effects in human subjects. The insect cell-baculovirus production technology is particularly suitable for influenza where annual adjustment of the vaccine is required. The baculovirus-insect expression system is generally considered a safe production system, with limited growth potential for adventitious agents. Still regulators question and challenge the safety of this novel cell substrate as FluBlok continues to advance toward product approval. This review provides an overview of cell substrate characterization for expresSF cell line used for the manufacturing of FluBlok. In addition, this review includes an update on the clinical development of FluBlok. The highly purified protein vaccine, administered at three times higher antigen content than TIV, is well tolerated and results in stronger immunogenicity, a long lasting immune response and provides cross-protection against drift influenza viruses.

System Vaccinology for the Evaluation of Influenza Vaccine Safety by Multiplex Gene Detection of Novel Biomarkers in a Preclinical Study and Batch Release Test

PubMed Central

Mizukami, Takuo; Momose, Haruka; Kuramitsu, Madoka; Takizawa, Kazuya; Araki, Kumiko; Furuhata, Keiko; Ishii, Ken J.; Hamaguchi, Isao; Yamaguchi, Kazunari

2014-01-01

Vaccines are beneficial and universal tools to prevent infectious disease. Thus, safety of vaccines is strictly evaluated in the preclinical phase of trials and every vaccine batch must be tested by the National Control Laboratories according to the guidelines published by each country. Despite many vaccine production platforms and methods, animal testing for safety evaluation is unchanged thus far. We recently developed a systems biological approach to vaccine safety evaluation where identification of specific biomarkers in a rat pre-clinical study evaluated the safety of vaccines for pandemic H5N1 influenza including Irf7, Lgals9, Lgalsbp3, Cxcl11, Timp1, Tap2, Psmb9, Psme1, Tapbp, C2, Csf1, Mx2, Zbp1, Ifrd1, Trafd1, Cxcl9, β2m, Npc1, Ngfr and Ifi47. The current study evaluated whether these 20 biomarkers could evaluate the safety, batch-to-batch and manufacturer-to-manufacturer consistency of seasonal trivalent influenza vaccine using a multiplex gene detection system. When we evaluated the influenza HA vaccine (HAv) from four different manufactures, the biomarker analysis correlated to findings from conventional animal use tests, such as abnormal toxicity test. In addition, sensitivity of toxicity detection and differences in HAvs were higher and more accurate than with conventional methods. Despite a slight decrease in body weight caused by HAv from manufacturer B that was not statistically significant, our results suggest that HAv from manufacturer B is significantly different than the other HAvs tested with regard to Lgals3bp, Tapbp, Lgals9, Irf7 and C2 gene expression in rat lungs. Using the biomarkers confirmed in this study, we predicted batch-to-batch consistency and safety of influenza vaccines within 2 days compared with the conventional safety test, which takes longer. These biomarkers will facilitate the future development of new influenza vaccines and provide an opportunity to develop in vitro methods of evaluating batch-to-batch consistency and

Implementation workshop of WHO guidelines on evaluation of malaria vaccines: Current regulatory concepts and issues related to vaccine quality, Pretoria, South Africa 07 Nov 2014.

PubMed

Ho, Mei Mei; Baca-Estrada, Maria; Conrad, Christoph; Karikari-Boateng, Eric; Kang, Hye-Na

2015-08-26

The current World Health Organization (WHO) guidelines on the quality, safety and efficacy of recombinant malaria vaccines targeting the pre-erythrocytic and blood stages of Plasmodium falciparum were adopted by the WHO Expert Committee on Biological Standardization in 2012 to provide guidance on the quality, nonclinical and clinical aspects of recombinant malaria vaccines. A WHO workshop was organised to facilitate implementation into African (national/regional) regulatory practices, of the regulatory evaluation principles outlined in the guidelines regarding quality aspects. The workshop was used also to share knowledge and experience on regulatory topics of chemistry, manufacturing and control with a focus on vaccines through presentations and an interactive discussion using a case study approach. The basic principles and concepts of vaccine quality including consistency of production, quality control and manufacturing process were presented and discussed in the meeting. By reviewing and practicing a case study, better understanding on the relationship between consistency of production and batch release tests of an adjuvanted pre-erythrocytic recombinant malaria vaccine was reached. The case study exercise was considered very useful to understand regulatory evaluation principles of vaccines and a suggestion was made to WHO to provide such practices also through its Global Learning Opportunities for Vaccine Quality programme. Crown Copyright © 2015. Published by Elsevier Ltd. All rights reserved.

Comprehensive hands-on training for influenza vaccine manufacturing: a WHO-BARDA-BTEC partnership for global workforce development.

PubMed

Ruiz, Jennifer; Gilleskie, Gary L; Brown, Patty; Burnett, Bruce; Carbonell, Ruben G

2014-01-01

The critical need for enhancing influenza pandemic preparedness in many developing nations has led the World Health Organization (WHO) and the Biomedical Advanced Research and Development Authority (BARDA), part of the U.S. Department of Health and Human Services (HHS), to develop an international influenza vaccine capacity-building program. Among the critical limitations faced by many of these nations is lack of access to training programs for staff supporting operations within vaccine production facilities. With support from BARDA, the Biomanufacturing Training and Education Center (BTEC) at North Carolina State University has addressed this need for training by developing and delivering a comprehensive training program, consisting of three courses: Fundamentals of cGMP Influenza Vaccine Manufacturing, Advanced Upstream Processes for Influenza Vaccine Manufacturing, and Advanced Downstream Processes for Influenza Vaccine Manufacturing. The courses cover process design, transfer, and execution at manufacturing scale, quality systems, and regulations covering both manufacturing and approval of pandemic vaccines. The Fundamentals course focuses on the concepts, equipment, applicable regulations, and procedures commonly used to produce influenza vaccine. The two Advanced courses focus on process design, scale up, validation, and new technologies likely to improve efficiency of vaccine production. All three courses rely on a combination of classroom instruction and hands-on training in BTEC's various laboratories. Each course stands alone, and participants may take one or more of the three courses. Overall participant satisfaction with the courses has been high, and follow-up surveys show that participants actively transferred the knowledge they gained to the workplace. Future plans call for BTEC to continue offering the three courses and to create an online version of several modules of the Fundamentals course. Copyright © 2014 Wiley Periodicals, Inc.

Veterinary and human vaccine evaluation methods

PubMed Central

Knight-Jones, T. J. D.; Edmond, K.; Gubbins, S.; Paton, D. J.

2014-01-01

Despite the universal importance of vaccines, approaches to human and veterinary vaccine evaluation differ markedly. For human vaccines, vaccine efficacy is the proportion of vaccinated individuals protected by the vaccine against a defined outcome under ideal conditions, whereas for veterinary vaccines the term is used for a range of measures of vaccine protection. The evaluation of vaccine effectiveness, vaccine protection assessed under routine programme conditions, is largely limited to human vaccines. Challenge studies under controlled conditions and sero-conversion studies are widely used when evaluating veterinary vaccines, whereas human vaccines are generally evaluated in terms of protection against natural challenge assessed in trials or post-marketing observational studies. Although challenge studies provide a standardized platform on which to compare different vaccines, they do not capture the variation that occurs under field conditions. Field studies of vaccine effectiveness are needed to assess the performance of a vaccination programme. However, if vaccination is performed without central co-ordination, as is often the case for veterinary vaccines, evaluation will be limited. This paper reviews approaches to veterinary vaccine evaluation in comparison to evaluation methods used for human vaccines. Foot-and-mouth disease has been used to illustrate the veterinary approach. Recommendations are made for standardization of terminology and for rigorous evaluation of veterinary vaccines. PMID:24741009

Vaccine manufacturing and technology: from biotechnological platforms to syntethic epitopes, current viepoint.

PubMed

Ignateva, G A

2016-01-01

The Purposes: the review take into account short history of vaccination practice and development of vaccine technology. In the review we include data from several monographs about manufacturing of vaccines published by authors from such companies as Merck & Co; Sanofi Pasteur; Dynavax Europe/Rhein Biotech GmbH; Latham Biopharm Group; Aridis Pharmaceuticals LLC; Genentech; Amgen; Shamir Biologics LLC; Biopharm Services US; Novartis Pharma AG, аnd several research centers: Laboratory of Bacterial Polysaccharides, Center for Biologics Evaluation and Research; Purdue University, West Lafayette, IN, US; Department of Pharmaceutical Chemistry, Univ. Of Kansas; Max Planck Institute for dynamics of Complex Technical Systems; Fraunhofer USA Center for Molecular Biotechnology; US Dep. of Agriculture Animal and Plant Health Inspection Service, etc. In historic literature there are data about inoculation practices in antique China, Persia, India, Byzantium, native Americans, some African population. In modern immunology since the end of XIX century the vaccines were produced at the in vivo platforms - in animals (rabbits, mice, cows). Since 1931 due to E. Goodpasture' elaboration most virus vaccines were and are produced at the in ovo platform. In 1949 J.F. Enders elaborated large-scale polio virus production in the primary culture of monkey kidney cells in vitro. Up to day primary culture of chiken embrio fibroblasts are used to large-scale production of vaccine viruses of measles, mumps, rabies. Since 2000-th in Western countries most part of virus vaccines were began to produced via a cultivation in continuous tumor cell lines. The last technology is the most low cost for large-scale production of vaccines. We review several new biotechnological platforms for the production of the recombinant protein or virus-like particles as subunit vaccines: plant system, algae, mushrooms, insect cells, etc. Beside of good purpose of vaccination - prophylactic of several infectious

Performance characteristics of qualified cell lines for isolation and propagation of influenza viruses for vaccine manufacturing.

PubMed

Donis, Ruben O; Davis, C Todd; Foust, Angie; Hossain, M Jaber; Johnson, Adam; Klimov, Alexander; Loughlin, Rosette; Xu, Xiyan; Tsai, Theodore; Blayer, Simone; Trusheim, Heidi; Colegate, Tony; Fox, John; Taylor, Beverly; Hussain, Althaf; Barr, Ian; Baas, Chantal; Louwerens, Jaap; Geuns, Ed; Lee, Min-Shi; Venhuizen, Odewijk; Neumeier, Elisabeth; Ziegler, Thedi

2014-11-12

Cell culture is now available as a method for the production of influenza vaccines in addition to eggs. In accordance with currently accepted practice, viruses recommended as candidates for vaccine manufacture are isolated and propagated exclusively in hens' eggs prior to distribution to manufacturers. Candidate vaccine viruses isolated in cell culture are not available to support vaccine manufacturing in mammalian cell bioreactors so egg-derived viruses have to be used. Recently influenza A (H3N2) viruses have been difficult to isolate directly in eggs. As mitigation against this difficulty, and the possibility of no suitable egg-isolated candidate viruses being available, it is proposed to consider using mammalian cell lines for primary isolation of influenza viruses as candidates for vaccine production in egg and cell platforms. To investigate this possibility, we tested the antigenic stability of viruses isolated and propagated in cell lines qualified for influenza vaccine manufacture and subsequently investigated antigen yields of such viruses in these cell lines at pilot-scale. Twenty influenza A and B-positive, original clinical specimens were inoculated in three MDCK cell lines. The antigenicity of recovered viruses was tested by hemagglutination inhibition using ferret sera against contemporary vaccine viruses and the amino acid sequences of the hemagglutinin and neuraminidase were determined. MDCK cell lines proved to be highly sensitive for virus isolation. Compared to the virus sequenced from the original specimen, viruses passaged three times in the MDCK lines showed up to 2 amino acid changes in the hemagglutinin. Antigenic stability was also established by hemagglutination inhibition titers comparable to those of the corresponding reference virus. Viruses isolated in any of the three MDCK lines grew reasonably well but variably in three MDCK cells and in VERO cells at pilot-scale. These results indicate that influenza viruses isolated in vaccine

Performance characteristics of qualified cell lines for isolation and propagation of influenza viruses for vaccine manufacturing

PubMed Central

Donis, Ruben O.; Chen, i-Mei; Davis, C Todd; Foust, Angie; Hossain, M. Jaber; Johnson, Adam; Klimov, Alexander; Loughlin, Rosette; Xu, Xiyan; Tsai, Theodore; Blayer, Simone; Trusheim, Heidi; Colegate, Tony; Fox, John; Taylor, Beverly; Hussain, Althaf; Barr, Ian; Baas, Chantal; Louwerens, Jaap; Geuns, Ed; Lee, Min-Shi; Venhuizen, odewijk; Neumeier, Elisabeth; Ziegler, Thedi

2018-01-01

Cell culture is now available as a method for the production of influenza vaccines in addition to eggs. In accordance with currently accepted practice, viruses recommended as candidates for vaccine manufacture are isolated and propagated exclusively in hens' eggs prior to distribution to manufacturers. Candidate vaccine viruses isolated in cell culture are not available to support vaccine manufacturing in mammalian cell bioreactors so egg-derived viruses have to be used. Recently influenza A (H3N2) viruses have been difficult to isolate directly in eggs. As mitigation against this difficulty, and the possibility of no suitable egg-isolated candidate viruses being available, it is proposed to consider using mammalian cell lines for primary isolation of influenza viruses as candidates for vaccine production in egg and cell platforms. To investigate this possibility, we tested the antigenic stability of viruses isolated and propagated in cell lines qualified for influenza vaccine manufacture and subsequently investigated antigen yields of such viruses in these cell lines at pilot-scale. Twenty influenza A and B-positive, original clinical specimens were inoculated in three MDCK cell lines. The antigenicity of recovered viruses was tested by hemagglutination inhibition using ferret sera against contemporary vaccine viruses and the amino acid sequences of the hemagglutinin and neuraminidase were determined. MDCK cell lines proved to be highly sensitive for virus isolation. Compared to the virus sequenced from the original specimen, viruses passaged three times in the MDCK lines showed up to 2 amino acid changes in the hemagglutinin. Antigenic stability was also established by hemagglutination inhibition titers comparable to those of the corresponding reference virus. Viruses isolated in any of the three MDCK lines grew reasonably well but variably in three MDCK cells and in VERO cells at pilot-scale. These results indicate that influenza viruses isolated in vaccine

Assessment of safety and immunogenicity of two different lots of diphtheria, tetanus, pertussis, hepatitis B and Haemophilus influenzae type b vaccine manufactured using small and large scale manufacturing process.

PubMed

Sharma, Hitt J; Patil, Vishwanath D; Lalwani, Sanjay K; Manglani, Mamta V; Ravichandran, Latha; Kapre, Subhash V; Jadhav, Suresh S; Parekh, Sameer S; Ashtagi, Girija; Malshe, Nandini; Palkar, Sonali; Wade, Minal; Arunprasath, T K; Kumar, Dinesh; Shewale, Sunil D

2012-01-11

Hib vaccine can be easily incorporated in EPI vaccination schedule as the immunization schedule of Hib is similar to that of DTP vaccine. To meet the global demand of Hib vaccine, SIIL scaled up the Hib conjugate manufacturing process. This study was conducted in Indian infants to assess and compare the immunogenicity and safety of DTwP-HB+Hib (Pentavac(®)) vaccine of SIIL manufactured at large scale with the 'same vaccine' manufactured at a smaller scale. 720 infants aged 6-8 weeks were randomized (2:1 ratio) to receive 0.5 ml of Pentavac(®) vaccine from two different lots one produced at scaled up process and the other at a small scale process. Serum samples obtained before and at one month after the 3rd dose of vaccine from both the groups were tested for IgG antibody response by ELISA and compared to assess non-inferiority. Neither immunological interference nor increased reactogenicity was observed in either of the vaccine groups. All infants developed protective antibody titres to diphtheria, tetanus and Hib disease. For hepatitis B antigen, one child from each group remained sero-negative. The response to pertussis was 88% in large scale group vis-à-vis 87% in small scale group. Non-inferiority was concluded for all five components of the vaccine. No serious adverse event was reported in the study. The scale up vaccine achieved comparable response in terms of the safety and immunogenicity to small scale vaccine and therefore can be easily incorporated in the routine childhood vaccination programme. Copyright © 2011 Elsevier Ltd. All rights reserved.

Preclinical evaluation of a Haemophilus influenzae type b conjugate vaccine process intended for technology transfer.

PubMed

Hamidi, Ahd; Verdijk, Pauline; Kreeftenberg, Hans

2014-01-01

Introduction of Haemophilus influenzae type b (Hib) vaccine in low- and middle-income countries has been limited by cost and availability of Hib conjugate vaccines for a long time. It was previously recognized by the Institute for Translational Vaccinology (Intravacc, originating from the former Vaccinology Unit of the National Institute of Public Health [RIVM] and the Netherlands Vaccine Institute [NVI]) that local production of a Hib conjugate vaccine would increase the affordability and sustainability of the vaccine and thereby help to speed up Hib introduction in these countries. A new affordable and a non-infringing production process for a Hib conjugate vaccine was developed, including relevant quality control tests, and the technology was transferred to a number of vaccine manufacturers in India, Indonesia, and China. As part of the Hib technology transfer project managed by Intravacc, a preclinical toxicity study was conducted in the Netherlands to test the safety and immunogenicity of this new Hib conjugate vaccine. The data generated by this study were used by the technology transfer partners to accelerate the clinical development of the new Hib conjugate vaccine. A repeated dose toxicity and local tolerance study in rats was performed to assess the reactogenicity and immunogenicity of a new Hib conjugate vaccine compared to a licensed vaccine. The results showed that the vaccine was well tolerated and immunogenic in rats, no major differences in both safety and immunogenicity in rats were found between the vaccine produced according to the production process developed by Intravacc and the licensed one. Rats may be useful to verify the immunogenicity of Hib conjugate vaccines and for preclinical evaluation. In general, nonclinical evaluation of the new Hib conjugate vaccine, including this proof of concept (safety and immunogenicity study in rats), made it possible for technology transfer partners, having implemented the original process with no changes

Technology transfer and scale-up of the Flublok recombinant hemagglutinin (HA) influenza vaccine manufacturing process.

PubMed

Buckland, Barry; Boulanger, Robert; Fino, Mireli; Srivastava, Indresh; Holtz, Kathy; Khramtsov, Nikolai; McPherson, Clifton; Meghrous, Jamal; Kubera, Paul; Cox, Manon M J

2014-09-22

Multiple different hemagglutinin (HA) protein antigens have been reproducibly manufactured at the 650L scale by Protein Sciences Corporation (PSC) based on an insect cell culture with baculovirus infection. Significantly, these HA protein antigens were produced by the same Universal Manufacturing process as described in the biological license application (BLA) for the first recombinant influenza vaccine approved by the FDA (Flublok). The technology is uniquely designed so that a change in vaccine composition can be readily accommodated from one HA protein antigen to another one. Here we present a vaccine candidate to combat the recently emerged H7N9 virus as an example starting with the genetic sequence for the required HA, creation of the baculovirus and ending with purified protein antigen (or vaccine component) at the 10L scale accomplished within 38 days under GMP conditions. The same process performance is being achieved at the 2L, 10L, 100L, 650L and 2500L scale. An illustration is given of how the technology was transferred from the benchmark 650L scale facility to a retrofitted microbial facility at the 2500L scale within 100 days which includes the time for facility engineering changes. The successful development, technology transfer and scale-up of the Flublok process has major implications for being ready to make vaccine rapidly on a worldwide scale as a defense against pandemic influenza. The technology described does not have the same vulnerability to mutations in the egg adapted strain, and resulting loss in vaccine efficacy, faced by egg based manufacture. Copyright © 2014 Elsevier Ltd. All rights reserved.

Advanced manufacturing of microdisk vaccines for uniform control of material properties and immune cell function.

PubMed

Zeng, Qin; Zhang, Peipei; Zeng, Xiangbin; Tostanoski, Lisa H; Jewell, Christopher M

2017-12-19

The continued challenges facing vaccines in infectious disease and cancer highlight a need for better control over the features of vaccines and the responses they generate. Biomaterials offer unique advantages to achieve this goal through features such as controlled release and co-delivery of antigens and adjuvants. However, many synthesis strategies lead to particles with heterogeneity in diameter, shape, loading level, or other properties. In contrast, advanced manufacturing techniques allow precision control of material properties at the micro- and nano-scale. These capabilities in vaccines and immunotherapies could allow more rational design to speed efficient design and clinical translation. Here we employed soft lithography to generate polymer microdisk vaccines with uniform structures and tunable compositions of vaccine antigens and toll like receptor agonists (TLRas) that serve as molecular adjuvants. Compared to conventional PLGA particles formed by emulsion, microdisks provided a dramatic improvement in the consistency of properties such as diameter. During culture with primary dendritic cells (DCs) from mice, microdisks were internalized by the cells without toxicity, while promoting co-delivery of antigen and TLRa to the same cell. Analysis of DC surface activation markers by flow cytometry revealed microdisk vaccines activated dendritic cells in a manner that depended on the level of TLRa, while antigen processing and presentation depended on the amount of antigen in the microdisks. Together, this work demonstrates the use of advanced manufacturing techniques to produce uniform vaccines that direct DC function depending on the composition in the disks.

Quality vaccines for all people: Report on the 16th annual general meeting of the Developing Countries Vaccine Manufacturers' Network, 05-07th October 2015, Bangkok, Thailand.

PubMed

Pagliusi, Sonia; Ting, Ching-Chia; Khomvilai, Sumana

2016-06-30

The Developing Countries Vaccine Manufacturers Network (DCVMN) assembled high-profile leaders from global health organisations and vaccine manufactures for its 16th Annual General Meeting to work towards a common goal: providing quality vaccines for all people. Vaccines contribute to a healthy community and robust health system; the Ebola outbreak has raised awareness of the threat and damage one single infectious disease can make, and it is clear that the world was not prepared. However, more research to better understand emerging infectious agents might lead to suitable vaccines which help prevent future outbreaks. DCVMN members presented their progress in developing novel vaccines against Dengue, HPV, Chikungunya, Cholera, cell-based influenza and other vaccines, demonstrating the commitment towards eliminating and eradicating preventable diseases worldwide through global collaboration and technology transfer. The successful introduction of novel Sabin-IPV and Oral Cholera vaccine in China and Korea respectively in 2015 was highlighted. In order to achieve global immunisation, local authorities and community leaders play an important role in the decision-making in vaccine introduction and uptake, based on the ability of vaccines to protect vaccinated people and protect non-vaccinated in the community through herd immunity. Reducing the risk of vaccine shortages can also be achieved by increasing regulatory convergence at regional and international levels. Combatting preventable diseases remains challenging, and collective efforts for improving multi-centre clinical trials, creating regional vaccine security strategies, fostering developing vaccine markets and procurement, and building trust in vaccines were discussed. Copyright © 2016 The Authors. Published by Elsevier Ltd.. All rights reserved.

Drug versus vaccine investment: a modelled comparison of economic incentives

PubMed Central

2013-01-01

Background Investment by manufacturers in research and development of vaccines is relatively low compared with that of pharmaceuticals. If current evaluation technologies favour drugs over vaccines, then the vaccines market becomes relatively less attractive to manufacturers. Methods We developed a mathematical model simulating the decision-making process of regulators and payers, in order to understand manufacturers’ economic incentives to invest in vaccines rather than curative treatments. We analysed the objectives and strategies of manufacturers and payers when considering investment in technologies to combat a disease that affects children, and the interactions between them. Results The model confirmed that, for rare diseases, the economically justifiable prices of vaccines could be substantially lower than drug prices, and that, for diseases spread across multiple cohorts, the revenues derived from vaccinating one cohort per year (routine vaccination) could be substantially lower than those generated by treating sick individuals. Conclusions Manufacturers may see higher incentives to invest in curative treatments rather than in routine vaccines. To encourage investment in vaccines, health authorities could potentially revise their incentive schemes by: (1) committing to vaccinate all susceptible cohorts in the first year (catch-up campaign); (2) choosing a long-term horizon for health technology evaluation; (3) committing higher budgets for vaccines than for treatments; and (4) taking into account all intangible values derived from vaccines. PMID:24011090

Taking aim at novel vaccines market.

PubMed

Awasthi, Sita

2009-10-01

The World Vaccine Congress Washington 2009 was held in Chantilly, VA USA April 2O -23rd. The Vaccine congress attracted over 400 participants from across the world, including leading vaccine manufacturers, biotechs, governmental agencies, NGOs, research and academic institutes, venture capital and legal firms, contract service and equipment manufacturers. The speakers covered a wide range of topics, including the role of government and regulatory agencies, funding availability, research and development, manufacturing, packaging and post vaccine evaluations. Past vaccine development efforts have historically focused on infectious diseases. With advancements in the field of immunology, molecular biology and vaccinology, the vaccine field has begun moving in new directions. "Taking aim at novel vaccines market" session chaired by Dr. Una Ryan, Chief Executive Officer of Waltham Technologies, was focused on traditional approaches to novel targets (nosocomial infections), novel approaches to traditional targets (flu and rabies), novel approaches to novel targets (Type 1 diabetes, multiple sclerosis and smoking) and vaccines for developing markets (TB, malaria, rabies). The importance of collaborations among academic institutions, industries, and philanthropic foundations for developing markets was also emphasized.

Evaluation of scanning 2D barcoded vaccines to improve data accuracy of vaccines administered.

PubMed

Daily, Ashley; Kennedy, Erin D; Fierro, Leslie A; Reed, Jenica Huddleston; Greene, Michael; Williams, Warren W; Evanson, Heather V; Cox, Regina; Koeppl, Patrick; Gerlach, Ken

2016-11-11

Accurately recording vaccine lot number, expiration date, and product identifiers, in patient records is an important step in improving supply chain management and patient safety in the event of a recall. These data are being encoded on two-dimensional (2D) barcodes on most vaccine vials and syringes. Using electronic vaccine administration records, we evaluated the accuracy of lot number and expiration date entered using 2D barcode scanning compared to traditional manual or drop-down list entry methods. We analyzed 128,573 electronic records of vaccines administered at 32 facilities. We compared the accuracy of records entered using 2D barcode scanning with those entered using traditional methods using chi-square tests and multilevel logistic regression. When 2D barcodes were scanned, lot number data accuracy was 1.8 percentage points higher (94.3-96.1%, P<0.001) and expiration date data accuracy was 11 percentage points higher (84.8-95.8%, P<0.001) compared with traditional methods. In multivariate analysis, lot number was more likely to be accurate (aOR=1.75; 99% CI, 1.57-1.96) as was expiration date (aOR=2.39; 99% CI, 2.12-2.68). When controlling for scanning and other factors, manufacturer, month vaccine was administered, and vaccine type were associated with variation in accuracy for both lot number and expiration date. Two-dimensional barcode scanning shows promise for improving data accuracy of vaccine lot number and expiration date records. Adapting systems to further integrate with 2D barcoding could help increase adoption of 2D barcode scanning technology. Published by Elsevier Ltd.

Good Manufacturing Practices production and analysis of a DNA vaccine against dental caries.

PubMed

Yang, Ya-ping; Li, Yu-hong; Zhang, Ai-hua; Bi, Lan; Fan, Ming-wen

2009-11-01

To prepare a clinical-grade anti-caries DNA vaccine pGJA-P/VAX and explore its immune effect and protective efficacy against a cariogenic bacterial challenge. A large-scale industrial production process was developed under Good Manufacturing Practices (GMP) by combining and optimizing common unit operations such as alkaline lysis, precipitation, endotoxin removal and column chromatography. Quality controls of the purified bulk and final lyophilized vaccine were conducted according to authoritative guidelines. Mice and gnotobiotic rats were intranasally immunized with clinical-grade pGJA-P/VAX with chitosan. Antibody levels of serum IgG and salivary SIgA were assessed by an enzyme-linked immunosorbent assay (ELISA), and caries activity was evaluated by the Keyes method. pGJA-P/VAX and pVAX1 prepared by a laboratory-scale commercial kit were used as controls. The production process proved to be scalable and reproducible. Impurities including host protein, residual RNA, genomic DNA and endotoxin in the purified plasmid were all under the limits of set specifications. Intranasal vaccination with clinical-grade pGJA-P/VAX induced higher serum IgG and salivary SIgA in both mice and gnotobiotic rats. While in the experimental caries model, the enamel (E), dentinal slight (Ds), and dentinal moderate (Dm) caries lesions were reduced by 21.1%, 33.0%, and 40.9%, respectively. The production process under GMP was efficient in preparing clinical-grade pGJA-P/VAX with high purity and intended effectiveness, thus facilitating future clinical trials for the anti-caries DNA vaccine.

First evaluation of endotoxins in veterinary autogenous vaccines produced in Italy by LAL assay.

PubMed

Antonella, Di Paolo; Katia, Forti; Lucia, Anzalone; Sara, Corneli; Martina, Pellegrini; Giulio, Severi; Monica, Cagiola

2018-06-21

Endotoxin contamination is a serious concern for manufacturers of biological products and vaccines in terms of not only quality but also safety parameters. We evaluated the endotoxin presence in different veterinary autogenous vaccines produced by the Pharmaceutical Unit at the Experimental Zooprophylactic Institute of Umbria and Marche "Togo Rosati" (IZSUM). According to the 3Rs principles (Replace, Reduce, Refine), which aim to progressively reduce animal use in the quality control process, we tested the vaccines obtained from gram-negative bacteria and adjuvants by the limulus amebocyte lysate (LAL) assay. The results revealed low endotoxin concentrations compared to available data in the literature and represent the first report of the application of the 3Rs principles to veterinary autogenous vaccines production in Italy. Copyright © 2018. Published by Elsevier Ltd.

Optimizing manufacturing and composition of a TLR4 nanosuspension: physicochemical stability and vaccine adjuvant activity

PubMed Central

2013-01-01

Background Nanosuspensions are an important class of delivery system for vaccine adjuvants and drugs. Previously, we developed a nanosuspension consisting of the synthetic TLR4 ligand glucopyranosyl lipid adjuvant (GLA) and dipalmitoyl phosphatidylcholine (DPPC). This nanosuspension is a clinical vaccine adjuvant known as GLA-AF. We examined the effects of DPPC supplier, buffer composition, and manufacturing process on GLA-AF physicochemical and biological activity characteristics. Results DPPC from different suppliers had minimal influence on physicochemical and biological effects. In general, buffered compositions resulted in less particle size stability compared to unbuffered GLA-AF. Microfluidization resulted in rapid particle size reduction after only a few passes, and 20,000 or 30,000 psi processing pressures were more effective at reducing particle size and recovering the active component than 10,000 psi. Sonicated and microfluidized batches maintained good particle size and chemical stability over 6 months, without significantly altering in vitro or in vivo bioactivity of GLA-AF when combined with a recombinant malaria vaccine antigen. Conclusions Microfluidization, compared to water bath sonication, may be an effective manufacturing process to improve the scalability and reproducibility of GLA-AF as it advances further in the clinical development pathway. Various sources of DPPC are suitable to manufacture GLA-AF, but buffered compositions of GLA-AF do not appear to offer stability advantages over the unbuffered composition. PMID:24359024

The global capacity for manufacturing vaccines. Prospects for competition and collaboration among producers in the next decade.

PubMed

Robbins, A; Arita, I

1994-01-01

Can the world respond to the demands of the Children's Vaccine Initiative (CVI) to produce large quantities of affordable vaccines that have never been manufactured previously? Vaccines for the world's birth cohort of 150 million will continue to be produced in the countries that use the greatest part of the global vaccine supply. Thus, the CVI will rely on increased self sufficiency in vaccine production in the developing world and "shared development" of new and improved vaccines. The CVI's goal is to direct product development to meet the needs of immunization programs, but it must not neglect production. Thus, from the start, investment at the front end of the development and production sequence requires attention to the ultimate production capacity.

Safe use of vaccines and vaccine compliance with food safety requirements.

PubMed

Grein, K; Papadopoulos, O; Tollis, M

2007-08-01

Advanced technologies and regulatory regimes have contributed to the availability of veterinary vaccines that have high quality and favourable safety profiles in terms of potential risks posed to the target animals, the persons who come into contact with the vaccine, the consumers of food derived from vaccinated animals and the environment. The authorisation process requires that a range of safety studies are provided to evaluate the products. The design and production of vaccines, and their safe use, are primarily assessed by using data gathered from extensive pre-marketing studies performed on target animals and specific quality tests. The current post-marketing safeguards include good manufacturing practices, batch safety testing, inspections and pharmacovigilance. In addition to hazard identification, a full benefit/risk evaluation needs to be undertaken. The outcome of that evaluation will determine options for risk management and affect regulatory decisions on the safety of the vaccine; options might, for example, include special warnings on package inserts and labels.

Japanese encephalitis vaccines: current vaccines and future prospects.

PubMed

Monath, T P

2002-01-01

Vaccination against JE ideally should be practiced in all areas of Asia where the virus is responsible for human disease. The WHO has placed a high priority on the development of a new vaccine for prevention of JE. Some countries in Asia (Japan, South Korea, North Korea, Taiwan, Vietnam, Thailand, and the PRC) manufacture JE vaccines and practice childhood immunization, while other countries suffering endemic or epidemic disease (India, Nepal, Laos, Cambodia, Bangladesh, Myanmar, Malaysia, Indonesia and the Philippines) have no JE vaccine manufacturing or policy for use. With the exception of the PRC, all countries practicing JE vaccination use formalin inactivated mouse brain vaccines, which are relatively expensive and are associated with rare but clinically significant allergic and neurological adverse events. New inactivated JE vaccines manufactured in Vero cells are in advanced preclinical or early clinical development in Japan, South Korea, Taiwan, and the PRC. An empirically derived, live attenuated vaccine (SA14-14-2) is widely used in the PRC. Trials in the PRC have shown SA14-14-2 to be safe and effective when administered in a two-dose regimen, but regulatory concerns over manufacturing and control have restricted international distribution. The genetic basis of attenuation of SA14-14-2 has been partially defined. A new live attenuated vaccine (ChimeriVax-JE) that uses a reliable flavivirus vaccine--yellow fever 17D--as a live vector for the envelope genes of SA14-14-2 virus is in early clinical trials and appears to be well tolerated and immunogenic after a single dose. Vaccinia and avipox vectored vaccines have also been tested clinically, but are no longer being pursued due to restricted effectiveness mediated by anti-vector immunity. Other approaches to JE vaccines--including naked DNA, oral vaccination, and recombinant subunit vaccines--have been reviewed.

The baculovirus expression vector system: A commercial manufacturing platform for viral vaccines and gene therapy vectors.

PubMed

Felberbaum, Rachael S

2015-05-01

The baculovirus expression vector system (BEVS) platform has become an established manufacturing platform for the production of viral vaccines and gene therapy vectors. Nine BEVS-derived products have been approved - four for human use (Cervarix(®), Provenge(®), Glybera(®) and Flublok(®)) and five for veterinary use (Porcilis(®) Pesti, BAYOVAC CSF E2(®), Circumvent(®) PCV, Ingelvac CircoFLEX(®) and Porcilis(®) PCV). The BEVS platform offers many advantages, including manufacturing speed, flexible product design, inherent safety and scalability. This combination of features and product approvals has previously attracted interest from academic researchers, and more recently from industry leaders, to utilize BEVS to develop next generation vaccines, vectors for gene therapy, and other biopharmaceutical complex proteins. In this review, we explore the BEVS platform, detailing how it works, platform features and limitations and important considerations for manufacturing and regulatory approval. To underscore the growth in opportunities for BEVS-derived products, we discuss the latest product developments in the gene therapy and influenza vaccine fields that follow in the wake of the recent product approvals of Glybera(®) and Flublok(®), respectively. We anticipate that the utility of the platform will expand even further as new BEVS-derived products attain licensure. Finally, we touch on some of the areas where new BEVS-derived products are likely to emerge. Copyright © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Trivalent MDCK cell culture-derived influenza vaccine Optaflu (Novartis Vaccines).

PubMed

Doroshenko, Alexander; Halperin, Scott A

2009-06-01

Annual influenza epidemics continue to have a considerable impact in both developed and developing countries. Vaccination remains the principal measure to prevent seasonal influenza and reduce associated morbidity and mortality. The WHO recommends using established mammalian cell culture lines as an alternative to egg-based substrates in the manufacture of influenza vaccine. In June 2007, the EMEA approved Optaflu, a Madin Darby canine kidney cell culture-derived influenza vaccine manufactured by Novartis Vaccines. This review examines the advantages and disadvantages of cell culture-based technology for influenza vaccine production, compares immunogenicity and safety data for Optaflu with that of currently marketed conventional egg-based influenza vaccines, and considers the prospects for wider use of cell culture-based influenza vaccines.

A Promising IFN-Deficient System to Manufacture IFN-Sensitive Influenza Vaccine Virus.

PubMed

Chen, Can; Fan, Wenhui; Li, Jing; Zheng, Weinan; Zhang, Shuang; Yang, Limin; Liu, Di; Liu, Wenjun; Sun, Lei

2018-01-01

Interferon (IFN)-sensitive and replication-incompetent influenza viruses are likely to be the alternatives to inactivated and attenuated virus vaccines. Some IFN-sensitive influenza vaccine candidates with modified non-structural protein 1 (NS1) are highly attenuated in IFN-competent hosts but induce robust antiviral immune responses. However, little research has been done on the manufacturability of these IFN-sensitive vaccine viruses. Here, RIG-I-knockout 293T cells were used to package the IFN-sensitive influenza A/WSN/33 (H1N1) virus expressing the mutant NS1 R38A/K41A. We found that the packaging efficiency of the NS1 R38A/K41A virus in RIG-I-knockout 293T cells was much higher than that in 293T cells. Moreover, the NS1 R38A/K41A virus almost lost its IFN antagonist activity and could no longer replicate in A549, MDCK, and Vero cells after 3-6 passages. This indicated that the replication of NS1 R38A/K41A virus is limited in conventional cells. Therefore, we further established a stable Vero cell line expressing the wild-type (WT) NS1 of the WSN virus, based on the Tet-On 3G system. The NS1 R38A/K41A virus was able to steadily propagate in this IFN-deficient cell line for at least 20 passages. In a mouse model, the NS1 R38A/K41A virus showed more than a 4-log reduction in lung virus titers compared to the WT virus at 3 and 5 days post infection. Furthermore, we observed that the NS1 R38A/K41A virus triggered high-level of IFN-α/β production in lung tissues and was eliminated from the host in a relatively short period of time. Additionally, this virus induced high-titer neutralizing antibodies against the WT WSN, A/Puerto Rico/8/1934 (PR8), or A/California/04/2009 (CA04) viruses and provided 100% protection against the WT WSN virus. Thus, we found that the replication of the NS1 R38A/K41A virus was limited in IFN-competent cells and mice. We also presented a promising IFN-deficient system, involving a RIG-I-knockout 293T cell line to package the IFN

Design, manufacturing and testing of a portable vaccine carrier box employing thermoelectric module and heat pipe.

PubMed

Putra, N

2009-01-01

Vaccination is a highly effective method and a cheap tool for preventing certain infectious diseases. Routine immunization programs protect most of the world's children from diseases that claim millions of lives each year. There are many practical problems impeding vaccine delivery, especially to maintain the cold chain system, which is the means for storing and transporting vaccines in a potent state from the manufacturer to the person being immunized at a temperature of 2-8 degrees C. The development of the solid state thermoelectric cooling system has permitted newly developed packages that are capable of meeting many requirements and applications where environmental concern, size, weight, performance and noise are an issue. This paper describes the development of a vaccine carrier box. A combination of a thermoelectric module and a heat pipe is used for the cooling system. The position of the heat pipe as a heat sink on the hot side of the thermoelectric module will enhance the thermoelectric performance. The minimum temperature in the cabin of the vaccine carrier box reached -10 degrees C, which indicates that the design of the vaccine carrier box can maintain the vaccine at desired temperatures.

Reduction of spiked porcine circovirus during the manufacture of a Vero cell-derived vaccine.

PubMed

Lackner, Cornelia; Leydold, Sandra M; Modrof, Jens; Farcet, Maria R; Grillberger, Leopold; Schäfer, Birgit; Anderle, Heinz; Kreil, Thomas R

2014-04-11

Porcine circovirus-1 (PCV1) was recently identified as a contaminant in live Rotavirus vaccines, which was likely caused by contaminated porcine trypsin. The event triggered the development of new regulatory guidance on the use of porcine trypsin which shall ensure that cell lines and porcine trypsin in use are free from PCV1. In addition, manufacturing processes of biologicals other than live vaccines include virus clearance steps that may prevent and mitigate any potential virus contamination of product. In this work, artificial spiking of down-scaled models for the manufacturing process of an inactivated pandemic influenza virus vaccine were used to investigate inactivation of PCV1 and the physico-chemically related porcine parvovirus (PPV) by formalin and ultraviolet-C (UV-C) treatment as well as removal by the purification step sucrose gradient ultracentrifugation. A PCV1 infectivity assay, using a real-time PCR infectivity readout was established. The formalin treatment (0.05% for 48h) showed substantial inactivation for both PCV1 and PPV with reduction factors of 3.0log10 and 6.8log10, respectively, whereas UV-C treatment resulted in complete PPV (≥5.9log10) inactivation already at a dose of 13mJ/cm but merely 1.7log10 at 24mJ/cm(2) for PCV1. The UV-C inactivation results with PPV were confirmed using minute virus of mice (MVM), indicating that parvoviruses are far more sensitive to UV-C than PCV1. The sucrose density gradient ultracentrifugation also contributed to PCV1 clearance with a reduction factor of 2log10. The low pH treatment during the production of procine trypsin was investigated and showed effective inactivation for both PCV1 (4.5log10) and PPV (6.4log10). In conclusion, PCV1 in general appears to be more resistant to virus inactivation than PPV. Still, the inactivated pandemic influenza vaccine manufacturing process provides for robust virus reduction, in addition to the already implemented testing for PCV1 to avoid any contaminations

Epidemiologic and Molecular Relationship Between Vaccine Manufacture and Autism Spectrum Disorder Prevalence.

PubMed

Deisher, Theresa A; Doan, Ngoc V; Koyama, Kumiko; Bwabye, Sarah

2015-01-01

To assess the public health consequences of fetal cell line manufactured vaccines that contain residual human fetal DNA fragments utilizing laboratory and ecological approaches including statistics, molecular biology and genomics. MMR coverage and autism disorder or autism spectrum disorder prevalence data for Norway, Sweden and the UK were obtained from public and government websites as well as peer reviewed published articles. Biologically, the size and quantity of the contaminating fetal DNA in Meruvax II and Havrix as well as the propensity of various cell lines for cellular and nuclear uptake of primitive human DNA fragments were measured and quantified using gel electrophoresis, fluorescence microscopy and fluorometry. Lastly, genomic analysis identified the specific sites where fetal DNA fragment integration into a child's genome is most likely to occur. The average MMR coverage for the three countries fell below 90% after Dr. Wakefield's infamous 1998 publication but started to recover slowly after 2001 until reaching over 90% coverage again by 2004. During the same time period, the average autism spectrum disorder prevalence in the United Kingdom, Norway and Sweden dropped substantially after birth year 1998 and gradually increased again after birth year 2000. Average single stranded DNA and double stranded DNA in Meruvax II were 142.05 ng/vial and 35.00 ng/vial, respectively, and 276.00 ng/vial and 35.74 ng/vial in Havrix respectively. The size of the fetal DNA fragments in Meruvax II was approximately 215 base pairs. There was spontaneous cellular and nuclear DNA uptake in HFF1 and NCCIT cells. Genes that have been linked to autism (autism associated genes; AAGs) have a more concentrated susceptibility for insults to genomic stability in comparison to the group of all genes contained within the human genome. Of the X chromosome AAGs, 15 of 19 have double strand break motifs less than 100 kilobases away from the center of a meiotic recombination hotspot

Engineering Enhanced Vaccine Cell Lines To Eradicate Vaccine-Preventable Diseases: the Polio End Game

PubMed Central

van der Sanden, Sabine M. G.; Wu, Weilin; Dybdahl-Sissoko, Naomi; Weldon, William C.; Brooks, Paula; O'Donnell, Jason; Jones, Les P.; Brown, Cedric; Tompkins, S. Mark; Karpilow, Jon; Tripp, Ralph A.

2015-01-01

ABSTRACT Vaccine manufacturing costs prevent a significant portion of the world's population from accessing protection from vaccine-preventable diseases. To enhance vaccine production at reduced costs, a genome-wide RNA interference (RNAi) screen was performed to identify gene knockdown events that enhanced poliovirus replication. Primary screen hits were validated in a Vero vaccine manufacturing cell line using attenuated and wild-type poliovirus strains. Multiple single and dual gene silencing events increased poliovirus titers >20-fold and >50-fold, respectively. Host gene knockdown events did not affect virus antigenicity, and clustered regularly interspaced short palindromic repeat (CRISPR)-Cas9-mediated knockout of the top candidates dramatically improved viral vaccine strain production. Interestingly, silencing of several genes that enhanced poliovirus replication also enhanced replication of enterovirus 71, a clinically relevant virus to which vaccines are being targeted. The discovery that host gene modulation can markedly increase virus vaccine production dramatically alters mammalian cell-based vaccine manufacturing possibilities and should facilitate polio eradication using the inactivated poliovirus vaccine. IMPORTANCE Using a genome-wide RNAi screen, a collection of host virus resistance genes was identified that, upon silencing, increased poliovirus and enterovirus 71 production by from 10-fold to >50-fold in a Vero vaccine manufacturing cell line. This report provides novel insights into enterovirus-host interactions and describes an approach to developing the next generation of vaccine manufacturing through engineered vaccine cell lines. The results show that specific gene silencing and knockout events can enhance viral titers of both attenuated (Sabin strain) and wild-type polioviruses, a finding that should greatly facilitate global implementation of inactivated polio vaccine as well as further reduce costs for live-attenuated oral polio vaccines

Engineering Enhanced Vaccine Cell Lines To Eradicate Vaccine-Preventable Diseases: the Polio End Game.

PubMed

van der Sanden, Sabine M G; Wu, Weilin; Dybdahl-Sissoko, Naomi; Weldon, William C; Brooks, Paula; O'Donnell, Jason; Jones, Les P; Brown, Cedric; Tompkins, S Mark; Oberste, M Steven; Karpilow, Jon; Tripp, Ralph A

2016-02-15

Vaccine manufacturing costs prevent a significant portion of the world's population from accessing protection from vaccine-preventable diseases. To enhance vaccine production at reduced costs, a genome-wide RNA interference (RNAi) screen was performed to identify gene knockdown events that enhanced poliovirus replication. Primary screen hits were validated in a Vero vaccine manufacturing cell line using attenuated and wild-type poliovirus strains. Multiple single and dual gene silencing events increased poliovirus titers >20-fold and >50-fold, respectively. Host gene knockdown events did not affect virus antigenicity, and clustered regularly interspaced short palindromic repeat (CRISPR)-Cas9-mediated knockout of the top candidates dramatically improved viral vaccine strain production. Interestingly, silencing of several genes that enhanced poliovirus replication also enhanced replication of enterovirus 71, a clinically relevant virus to which vaccines are being targeted. The discovery that host gene modulation can markedly increase virus vaccine production dramatically alters mammalian cell-based vaccine manufacturing possibilities and should facilitate polio eradication using the inactivated poliovirus vaccine. Using a genome-wide RNAi screen, a collection of host virus resistance genes was identified that, upon silencing, increased poliovirus and enterovirus 71 production by from 10-fold to >50-fold in a Vero vaccine manufacturing cell line. This report provides novel insights into enterovirus-host interactions and describes an approach to developing the next generation of vaccine manufacturing through engineered vaccine cell lines. The results show that specific gene silencing and knockout events can enhance viral titers of both attenuated (Sabin strain) and wild-type polioviruses, a finding that should greatly facilitate global implementation of inactivated polio vaccine as well as further reduce costs for live-attenuated oral polio vaccines. This work

The use of dissolved oxygen-controlled, fed-batch aerobic cultivation for recombinant protein subunit vaccine manufacturing.

PubMed

Farrell, Patrick; Sun, Jacob; Champagne, Paul-Philippe; Lau, Heron; Gao, Meg; Sun, Hong; Zeiser, Arno; D'Amore, Tony

2015-11-27

A simple "off-the-shelf" fed-batch approach to aerobic bacterial cultivation for recombinant protein subunit vaccine manufacturing is presented. In this approach, changes in the dissolved oxygen levels are used to adjust the nutrient feed rate (DO-stat), so that the desired dissolved oxygen level is maintained throughout cultivation. This enables high Escherichia coli cell densities and recombinant protein titers. When coupled to a kLa-matched scale-down model, process performance is shown to be consistent at the 2L, 20L, and 200L scales for two recombinant E. coli strains expressing different protein subunit vaccine candidates. Additionally, by mining historical DO-stat nutrient feeding data, a method to transition from DO-stat to a pre-determined feeding profile suitable for larger manufacturing scales without using feedback control is demonstrated at the 2L, 20L, and 200L scales. Copyright © 2015 Elsevier Ltd. All rights reserved.

Recombinant protein vaccines produced in insect cells.

PubMed

Cox, Manon M J

2012-02-27

The baculovirus-insect cell expression system is a well known tool for the production of complex proteins. The technology is also used for commercial manufacture of various veterinary and human vaccines. This review paper provides an overview of how this technology can be applied to produce a multitude of vaccine candidates. The key advantage of this recombinant protein manufacturing platform is that a universal "plug and play" process may be used for producing a broad range of protein-based prophylactic and therapeutic vaccines for both human and veterinary use while offering the potential for low manufacturing costs. Large scale mammalian cell culture facilities previously established for the manufacturing of monoclonal antibodies that have now become obsolete due to yield improvement could be deployed for the manufacturing of these vaccines. Alternatively, manufacturing capacity could be established in geographic regions that do not have any vaccine production capability. Dependent on health care priorities, different vaccines could be manufactured while maintaining the ability to rapidly convert to producing pandemic influenza vaccine when the need arises. Copyright © 2012 Elsevier Ltd. All rights reserved.

[Immunological surrogate endpoints to evaluate vaccine efficacy].

PubMed

Jin, Pengfei; Li, Jingxin; Zhou, Yang; Zhu, Fengcai

2015-12-01

An immunological surrogate endpoints is a vaccine-induced immune response (either humoral or cellular immune) that predicts protection against clinical endpoints (infection or disease), and can be used to evaluate vaccine efficacy in clinical vaccine trials. Compared with field efficacy trials observing clinical endpoints, immunological vaccine trials could reduce the sample size or shorten the duration of a trial, which promote the license and development of new candidate vaccines. For these reasons, establishing immunological surrogate endpoints is one of 14 Grand Challenges of Global Health of the National Institutes of Health (NIH) and the Bill and Melinda Gates Foundation. From two parts of definition and statistical methods for evaluation of surrogate endpoints, this review provides a more comprehensive description.

Economic value of dengue vaccine in Thailand.

PubMed

Lee, Bruce Y; Connor, Diana L; Kitchen, Sarah B; Bacon, Kristina M; Shah, Mirat; Brown, Shawn T; Bailey, Rachel R; Laosiritaworn, Yongjua; Burke, Donald S; Cummings, Derek A T

2011-05-01

With several candidate dengue vaccines under development, this is an important time to help stakeholders (e.g., policy makers, scientists, clinicians, and manufacturers) better understand the potential economic value (cost-effectiveness) of a dengue vaccine, especially while vaccine characteristics and strategies might be readily altered. We developed a decision analytic Markov simulation model to evaluate the potential health and economic value of administering a dengue vaccine to an individual (≤ 1 year of age) in Thailand from the societal perspective. Sensitivity analyses evaluated the effects of ranging various vaccine (e.g., cost, efficacy, side effect), epidemiological (dengue risk), and disease (treatment-seeking behavior) characteristics. A ≥ 50% efficacious vaccine was highly cost-effective [< 1× per capita gross domestic product (GDP) ($4,289)] up to a total vaccination cost of $60 and cost-effective [< 3× per capita GDP ($12,868)] up to a total vaccination cost of $200. When the total vaccine series was $1.50, many scenarios were cost saving.

Economic Value of Dengue Vaccine in Thailand

PubMed Central

Lee, Bruce Y.; Connor, Diana L.; Kitchen, Sarah B.; Bacon, Kristina M.; Shah, Mirat; Brown, Shawn T.; Bailey, Rachel R.; Laosiritaworn, Yongjua; Burke, Donald S.; Cummings, Derek A. T.

2011-01-01

With several candidate dengue vaccines under development, this is an important time to help stakeholders (e.g., policy makers, scientists, clinicians, and manufacturers) better understand the potential economic value (cost-effectiveness) of a dengue vaccine, especially while vaccine characteristics and strategies might be readily altered. We developed a decision analytic Markov simulation model to evaluate the potential health and economic value of administering a dengue vaccine to an individual (≤ 1 year of age) in Thailand from the societal perspective. Sensitivity analyses evaluated the effects of ranging various vaccine (e.g., cost, efficacy, side effect), epidemiological (dengue risk), and disease (treatment-seeking behavior) characteristics. A ≥ 50% efficacious vaccine was highly cost-effective [< 1× per capita gross domestic product (GDP) ($4,289)] up to a total vaccination cost of $60 and cost-effective [< 3× per capita GDP ($12,868)] up to a total vaccination cost of $200. When the total vaccine series was $1.50, many scenarios were cost saving. PMID:21540387

Casting off vaccine supply charity -- the pace quickens. CVI goal: quality vaccines for all children.

PubMed

1995-10-01

Several proposals are offered for production of high-quality vaccines within developing countries. The World Health Organization's Vaccine Supply and Quality (VSQ) team from the Global Program for Vaccines and Immunization (GPV) visited 10 countries (Bangladesh, Brazil, Egypt, India, Indonesia, Iran, Mexico, Pakistan, Philippines, and South Africa) out of 14 priority countries (China, Russia, Thailand, and Vietnam were not visited) producing vaccines and found only two with a quality control system that was acceptable. Vaccine-producing countries are urged to consider the full costs of production that include necessary infrastructure, an independent national control authority and laboratory, manufacturers with managerial autonomy, and manufacturers with good management, a qualified staff, and adequate technology. UNICEF has urged both private and public sectors to combine forces in bringing down the price of new vaccines for distribution to a very large market. Some imaginative proposals were made by some manufacturers for vaccine production and supply for a range of less traditional vaccines. The Director of the Massachusetts Public Health Biologic Laboratories proposed the formation of a consortium of vaccine manufacturers who would support public health priorities for market-affordable, simple vaccines against the major childhood diseases. The aim would be international validation of high-quality local vaccine production in developing countries, ease of research collaboration, improvement in information exchange between countries, and structured assistance. Lack of political commitment has been blamed for poor quality local production. A small cooperative effort among some Latin American countries, the Pan American Association's Regional Vaccine System for Latin America (SIREVA), is backed by the Children's Vaccine Initiative. SIREVA is a consortium of manufacturers in Brazil, Chile, and Mexico that plans joint development of some vaccines. Donor assistance is

Tomorrow's vector vaccines for small ruminants.

PubMed

Kyriakis, C S

2015-12-14

Inactivated and attenuated vaccines have contributed to the control or even the eradication of significant animal pathogens. However, these traditional vaccine technologies have limitations and disadvantages. Inactivated vaccines lack efficacy against certain pathogens, while attenuated vaccines are not always as safe. New technology vaccines, namely DNA and recombinant viral vector vaccines, are being developed and tested against pathogens of small ruminants. These vaccines induce both humoral and cellular immune responses, are safe to manufacture and use and can be utilized in strategies for differentiation of infected from vaccinated animals. Although there are more strict regulatory requirements for the safety standards of these vaccines, once a vaccine platform is evaluated and established, effective vaccines can be rapidly produced and deployed in the field to prevent spread of emerging pathogens. The present article offers an introduction to these next generation technologies and examples of vaccines that have been tested against important diseases of sheep and goats. Copyright © 2015 Elsevier B.V. All rights reserved.

Influenza virus surveillance, vaccine strain selection, and manufacture.

PubMed

Stöhr, Klaus; Bucher, Doris; Colgate, Tony; Wood, John

2012-01-01

As outlined in other chapters, the influenza virus, existing laboratory diagnostic abilities, and disease epidemiology have several peculiarities that impact on the timing and processes for the annual production of influenza vaccines. The chapter provides an overview on the key biological and other factors that influence vaccine production. They are the reason for an "annual circle race" beginning with global influenza surveillance during the influenza season in a given year to the eventual supply of vaccines 12 months later in time before the next seasonal outbreak and so on. As influenza vaccines are needed for the Northern and Southern Hemisphere outbreaks in fall and spring, respectively, global surveillance and vaccine production has become a year round business. Its highlights are the WHO recommendations on vaccine strains in February and September and the eventual delivery of vaccine doses in time before the coming influenza season. In between continues vaccine strain and epidemiological surveillance, preparation of new high growth reassortments, vaccine seed strain preparation and development of standardizing reagents, vaccine bulk production, fill-finishing and vaccine release, and in some regions, clinical trials for regulatory approval.

Assessment of an optimized manufacturing process for inactivated quadrivalent influenza vaccine: a phase III, randomized, double-blind, safety and immunogenicity study in children and adults.

PubMed

Claeys, Carine; Drame, Mamadou; García-Sicilia, José; Zaman, Khalequ; Carmona, Alfonso; Tran, Phu My; Miranda, Mariano; Martinón-Torres, Federico; Thollot, Franck; Horn, Michael; Schwarz, Tino F; Behre, Ulrich; Merino, José M; Sadowska-Krawczenko, Iwona; Szymański, Henryk; Schu, Peter; Neumeier, Elisabeth; Li, Ping; Jain, Varsha K; Innis, Bruce L

2018-04-18

GSK has modified the licensed monovalent bulk manufacturing process for its split-virion inactivated quadrivalent influenza vaccine (IIV4) to harmonize the process among different strains, resulting in an increased number of finished vaccine doses, while compensating for the change from inactivated trivalent influenza vaccine (IIV3) to IIV4. To confirm the manufacturing changes do not alter the profile of the vaccine, a clinical trial was conducted to compare IIV4 made by the currently licensed process with a vaccine made by the new (investigational) process (IIV4-I). The main objectives were to compare the reactogenicity and safety of IIV4-I versus IIV4 in all age groups, and to demonstrate the non-inferiority of the hemagglutination-inhibition (HI) antibody responses based on the geometric mean titer ratio of IIV4-I versus IIV4 in children. The Phase III, randomized, double-blind, multinational study included three cohorts: adults (18-49 years; N = 120), children (3-17 years; N = 821), and infants (6-35 months; N = 940). Eligible subjects in each cohort were randomized 1:1 to receive IIV4-I or IIV4. Both vaccines contained 15 μg of hemagglutinin antigen for each of the four seasonal virus strains. Adults and vaccine-primed children received one dose of vaccine, and vaccine-unprimed children received two doses of vaccine 28 days apart. All children aged ≥9 years were considered to be vaccine-primed and received one dose of vaccine. The primary immunogenicity objective of the study was met in demonstrating immunogenic non-inferiority of IIV4-I versus IIV4 in children. The IIV4-I was immunogenic against all four vaccine strains in each age cohort. The reactogenicity and safety profile of IIV4-I was similar to IIV4 in each age cohort, and there was no increase in the relative risk of fever (≥38 °C) with IIV4-I versus IIV4 within the 7-day post-vaccination period in infants (1.06; 95% Confidence Interval: 0.75, 1.50; p = 0.786). The study

Method for automatically evaluating a transition from a batch manufacturing technique to a lean manufacturing technique

DOEpatents

Ivezic, Nenad; Potok, Thomas E.

2003-09-30

A method for automatically evaluating a manufacturing technique comprises the steps of: receiving from a user manufacturing process step parameters characterizing a manufacturing process; accepting from the user a selection for an analysis of a particular lean manufacturing technique; automatically compiling process step data for each process step in the manufacturing process; automatically calculating process metrics from a summation of the compiled process step data for each process step; and, presenting the automatically calculated process metrics to the user. A method for evaluating a transition from a batch manufacturing technique to a lean manufacturing technique can comprise the steps of: collecting manufacturing process step characterization parameters; selecting a lean manufacturing technique for analysis; communicating the selected lean manufacturing technique and the manufacturing process step characterization parameters to an automatic manufacturing technique evaluation engine having a mathematical model for generating manufacturing technique evaluation data; and, using the lean manufacturing technique evaluation data to determine whether to transition from an existing manufacturing technique to the selected lean manufacturing technique.

Plant-based vaccines against diarrheal diseases.

PubMed

Tacket, Carol O

2007-01-01

Every year 1.6 million deaths occur due to diarrhea related to unsafe water and inadequate sanitation-the vast majority in children under 5 years old. Safe and effective vaccines against enteric infections could contribute to control of these diseases. However, purification of protective antigens for inclusion in vaccines using traditional expression systems is expensive and unattractive to vaccine manufacturers who see the vaccine market as economically uninviting. Cost is one of the persistent barriers to deployment of new vaccines to populations that need them most urgently. Transgenic plant-derived vaccines offer a new strategy for development of safe, inexpensive vaccines against diarrheal diseases. In phase 1 clinical studies, these vaccines have been safe and immunogenic without the need for a buffer or vehicle other than the plant cell. This paper describes early clinical studies evaluating oral transgenic plant vaccines against enteric infections such as enterotoxigenic E. coli infection and norovirus.

Economic evaluation of vaccines in Canada: A systematic review

PubMed Central

Chit, Ayman; Lee, Jason K. H.; Shim, Minsup; Nguyen, Van Hai; Grootendorst, Paul; Wu, Jianhong; Van Exan, Robert; Langley, Joanne M.

2016-01-01

ABSTRACT Background: Economic evaluations should form part of the basis for public health decision making on new vaccine programs. While Canada's national immunization advisory committee does not systematically include economic evaluations in immunization decision making, there is increasing interest in adopting them. We therefore sought to examine the extent and quality of economic evaluations of vaccines in Canada. Objective: We conducted a systematic review of economic evaluations of vaccines in Canada to determine and summarize: comprehensiveness across jurisdictions, studied vaccines, funding sources, study designs, research quality, and changes over time. Methods: Searches in multiple databases were conducted using the terms “vaccine,” “economics” and “Canada.” Descriptive data from eligible manuscripts was abstracted and three authors independently evaluated manuscript quality using a 7-point Likert-type scale scoring tool based on criteria from the International Society for Pharmacoeconomics and Outcomes Research (ISPOR). Results: 42/175 articles met the search criteria. Of these, Canada-wide studies were most common (25/42), while provincial studies largely focused on the three populous provinces of Ontario, Quebec and British Columbia. The most common funding source was industry (17/42), followed by government (7/42). 38 studies used mathematical models estimating expected economic benefit while 4 studies examined post-hoc data on established programs. Studies covered 10 diseases, with 28/42 addressing pediatric vaccines. Many studies considered cost-utility (22/42) and the majority of these studies reported favorable economic results (16/22). The mean quality score was 5.9/7 and was consistent over publication date, funding sources, and disease areas. Conclusions: We observed diverse approaches to evaluate vaccine economics in Canada. Given the increased complexity of economic studies evaluating vaccines and the impact of results on public

Economic evaluation of vaccines in Canada: A systematic review.

PubMed

Chit, Ayman; Lee, Jason K H; Shim, Minsup; Nguyen, Van Hai; Grootendorst, Paul; Wu, Jianhong; Van Exan, Robert; Langley, Joanne M

2016-05-03

Economic evaluations should form part of the basis for public health decision making on new vaccine programs. While Canada's national immunization advisory committee does not systematically include economic evaluations in immunization decision making, there is increasing interest in adopting them. We therefore sought to examine the extent and quality of economic evaluations of vaccines in Canada. We conducted a systematic review of economic evaluations of vaccines in Canada to determine and summarize: comprehensiveness across jurisdictions, studied vaccines, funding sources, study designs, research quality, and changes over time. Searches in multiple databases were conducted using the terms "vaccine," "economics" and "Canada." Descriptive data from eligible manuscripts was abstracted and three authors independently evaluated manuscript quality using a 7-point Likert-type scale scoring tool based on criteria from the International Society for Pharmacoeconomics and Outcomes Research (ISPOR). 42/175 articles met the search criteria. Of these, Canada-wide studies were most common (25/42), while provincial studies largely focused on the three populous provinces of Ontario, Quebec and British Columbia. The most common funding source was industry (17/42), followed by government (7/42). 38 studies used mathematical models estimating expected economic benefit while 4 studies examined post-hoc data on established programs. Studies covered 10 diseases, with 28/42 addressing pediatric vaccines. Many studies considered cost-utility (22/42) and the majority of these studies reported favorable economic results (16/22). The mean quality score was 5.9/7 and was consistent over publication date, funding sources, and disease areas. We observed diverse approaches to evaluate vaccine economics in Canada. Given the increased complexity of economic studies evaluating vaccines and the impact of results on public health practice, Canada needs improved, transparent and consistent processes

Pricing of new vaccines

PubMed Central

McGlone, Sarah M

2010-01-01

New vaccine pricing is a complicated process that could have substantial long-standing scientific, medical and public health ramifications. Pricing can have a considerable impact on new vaccine adoption and, thereby, either culminate or thwart years of research and development and public health efforts. Typically, pricing strategy consists of the following eleven components: (1) Conduct a target population analysis; (2) Map potential competitors and alternatives; (3) Construct a vaccine target product profile (TPP) and compare it to projected or actual TPPs of competing vaccines; (4) Quantify the incremental value of the new vaccine's characteristics; (5) Determine vaccine positioning in the marketplace; (6) Estimate the vaccine price-demand curve; (7) Calculate vaccine costs (including those of manufacturing, distribution, and research and development); (8) Account for various legal, regulatory, third party payer and competitor factors; (9) Consider the overall product portfolio; (10) Set pricing objectives; (11) Select pricing and pricing structure. While the biomedical literature contains some studies that have addressed these components, there is still considerable room for more extensive evaluation of this important area. PMID:20861678

Pricing of new vaccines.

PubMed

Lee, Bruce Y; McGlone, Sarah M

2010-08-01

New vaccine pricing is a complicated process that could have substantial long-standing scientific, medical, and public health ramifications. Pricing can have a considerable impact on new vaccine adoption and, thereby, either culminate or thwart years of research and development and public health efforts. Typically, pricing strategy consists of the following ten components: 1. Conduct a target population analysis; 2. Map potential competitors and alternatives; 3. Construct a vaccine target product profile (TPP) and compare it to projected or actual TPPs of competing vaccines; 4. Quantify the incremental value of the new vaccine's characteristics; 5. Determine vaccine positioning in the marketplace; 6. Estimate the vaccine price-demand curve; 7. Calculate vaccine costs (including those of manufacturing, distribution, and research and development); 8. Account for various legal, regulatory, third party payer, and competitor factors; 9. Consider the overall product portfolio; 10. Set pricing objectives; 11. Select pricing and pricing structure. While the biomedical literature contains some studies that have addressed these components, there is still considerable room for more extensive evaluation of this important area.

Modern Vaccines/Adjuvants Formulation Session 6: Vaccine &Adjuvant Formulation & Production 15-17 May 2013, Lausanne, Switzerland.

PubMed

Fox, Christopher B

2013-09-01

The Modern Vaccines/Adjuvants Formulation meeting aims to fill a critical gap in current vaccine development efforts by bringing together formulation scientists and immunologists to emphasize the importance of rational formulation design in order to optimize vaccine and adjuvant bioactivity, safety, and manufacturability. Session 6 on Vaccine and Adjuvant Formulation and Production provided three examples of this theme, with speakers emphasizing the need for extensive physicochemical characterization of adjuvant-antigen interactions, the rational formulation design of a CD8+ T cell-inducing adjuvant based on immunological principles, and the development and production of a rabies vaccine by a developing country manufacturer. Throughout the session, the practical importance of sound formulation and manufacturing design accompanied by analytical characterization was highlighted.

Impact of BRICS’ investment in vaccine development on the global vaccine market

PubMed Central

Milstien, Julie; Schmitt, Sarah

2014-01-01

Abstract Brazil, the Russian Federation, India, China and South Africa – the countries known as BRICS – have made considerable progress in vaccine production, regulation and development over the past 20 years. In 1993, all five countries were producing vaccines but the processes used were outdated and non-standardized, there was little relevant research and there was negligible international recognition of the products. By 2014, all five countries had strong initiatives for the development of vaccine technology and had greatly improved their national regulatory capacity. South Africa was then the only BRICS country that was not completely producing vaccines. South Africa is now in the process of re-establishing its own vaccine production and passing beyond the stage of simply importing, formulating and filling vaccine bulks. Changes in the public sector’s price per dose of selected vaccines, the global market share represented by products from specific manufacturers, and the attractiveness, for multinational companies, of partnership and investment opportunities in BRICS companies have all been analysed. The results indicate that the BRICS countries have had a major impact on vaccine price and availability, with much of that impact attributable to the output of Indian vaccine manufacturers. China is expected to have a greater impact soon, given the anticipated development of Chinese vaccine manufacturers in the near future. BRICS’ accomplishments in the field of vaccine development are expected to reshape the global vaccine market and accelerate access to vaccines in the developing world. The challenge is to turn these expectations into strategic actions and practical outcomes. PMID:24940018

Impact of BRICS' investment in vaccine development on the global vaccine market.

PubMed

Kaddar, Miloud; Milstien, Julie; Schmitt, Sarah

2014-06-01

Brazil, the Russian Federation, India, China and South Africa--the countries known as BRICS--have made considerable progress in vaccine production, regulation and development over the past 20 years. In 1993, all five countries were producing vaccines but the processes used were outdated and non-standardized, there was little relevant research and there was negligible international recognition of the products. By 2014, all five countries had strong initiatives for the development of vaccine technology and had greatly improved their national regulatory capacity. South Africa was then the only BRICS country that was not completely producing vaccines. South Africa is now in the process of re-establishing its own vaccine production and passing beyond the stage of simply importing, formulating and filling vaccine bulks. Changes in the public sector's price per dose of selected vaccines, the global market share represented by products from specific manufacturers, and the attractiveness, for multinational companies, of partnership and investment opportunities in BRICS companies have all been analysed. The results indicate that the BRICS countries have had a major impact on vaccine price and availability, with much of that impact attributable to the output of Indian vaccine manufacturers. China is expected to have a greater impact soon, given the anticipated development of Chinese vaccine manufacturers in the near future. BRICS' accomplishments in the field of vaccine development are expected to reshape the global vaccine market and accelerate access to vaccines in the developing world. The challenge is to turn these expectations into strategic actions and practical outcomes.

Vaccine production, distribution, access, and uptake.

PubMed

Smith, Jon; Lipsitch, Marc; Almond, Jeffrey W

2011-07-30

For human vaccines to be available on a global scale, complex production methods, meticulous quality control, and reliable distribution channels are needed to ensure that the products are potent and effective at the point of use. The technologies used to manufacture different types of vaccines can strongly affect vaccine cost, ease of industrial scale-up, stability, and, ultimately, worldwide availability. The complexity of manufacturing is compounded by the need for different formulations in different countries and age-groups. Reliable vaccine production in appropriate quantities and at affordable prices is the cornerstone of developing global vaccination policies. However, to ensure optimum access and uptake, strong partnerships are needed between private manufacturers, regulatory authorities, and national and international public health services. For vaccines whose supply is insufficient to meet demand, prioritisation of target groups can increase the effect of these vaccines. In this report, we draw from our experience of vaccine development and focus on influenza vaccines as an example to consider production, distribution, access, and other factors that affect vaccine uptake and population-level effectiveness. Copyright © 2011 Elsevier Ltd. All rights reserved.

A Sequential Phase 2b Trial Design for Evaluating Vaccine Efficacy and Immune Correlates for Multiple HIV Vaccine Regimens

PubMed Central

Gilbert, Peter B.; Grove, Douglas; Gabriel, Erin; Huang, Ying; Gray, Glenda; Hammer, Scott M.; Buchbinder, Susan P.; Kublin, James; Corey, Lawrence; Self, Steven G.

2012-01-01

Five preventative HIV vaccine efficacy trials have been conducted over the last 12 years, all of which evaluated vaccine efficacy (VE) to prevent HIV infection for a single vaccine regimen versus placebo. Now that one of these trials has supported partial VE of a prime-boost vaccine regimen, there is interest in conducting efficacy trials that simultaneously evaluate multiple prime-boost vaccine regimens against a shared placebo group in the same geographic region, for accelerating the pace of vaccine development. This article proposes such a design, which has main objectives (1) to evaluate VE of each regimen versus placebo against HIV exposures occurring near the time of the immunizations; (2) to evaluate durability of VE for each vaccine regimen showing reliable evidence for positive VE; (3) to expeditiously evaluate the immune correlates of protection if any vaccine regimen shows reliable evidence for positive VE; and (4) to compare VE among the vaccine regimens. The design uses sequential monitoring for the events of vaccine harm, non-efficacy, and high efficacy, selected to weed out poor vaccines as rapidly as possible while guarding against prematurely weeding out a vaccine that does not confer efficacy until most of the immunizations are received. The evaluation of the design shows that testing multiple vaccine regimens is important for providing a well-powered assessment of the correlation of vaccine-induced immune responses with HIV infection, and is critically important for providing a reasonably powered assessment of the value of identified correlates as surrogate endpoints for HIV infection. PMID:23181167

Plant-Based Vaccines Against Diarrheal Diseases

PubMed Central

Tacket, Carol O.

2007-01-01

Every year 1.6 million deaths occur due to diarrhea related to unsafe water and inadequate sanitation—the vast majority in children under 5 years old. Safe and effective vaccines against enteric infections could contribute to control of these diseases. However, purification of protective antigens for inclusion in vaccines using traditional expression systems is expensive and unattractive to vaccine manufacturers who see the vaccine market as economically uninviting. Cost is one of the persistent barriers to deployment of new vaccines to populations that need them most urgently. Transgenic plant-derived vaccines offer a new strategy for development of safe, inexpensive vaccines against diarrheal diseases. In phase 1 clinical studies, these vaccines have been safe and immunogenic without the need for a buffer or vehicle other than the plant cell. This paper describes early clinical studies evaluating oral transgenic plant vaccines against enteric infections such as enterotoxigenic E. coli infection and norovirus. PMID:18528491

Vaccines and Thimerosal

MedlinePlus

... as a vaccine is being prepared for administration. Contamination by germs in a vaccine could cause severe local reactions, serious illness or death. In some vaccines, preservatives, including thimerosal, are added during the manufacturing process to prevent germ growth. The human body ...

Vaccine production, distribution, access and uptake

PubMed Central

Smith, Jon; Lipsitch, Marc; Almond, Jeffrey W.

2011-01-01

Making human vaccines available on a global scale requires the use of complex production methods, meticulous quality control and reliable distribution channels that ensure the products are potent and effective at their point of use. The technologies involved in manufacturing different types of vaccines may strongly influence vaccine cost, ease of industrial scale-up, stability and ultimately world-wide availability. Manufacturing complexity is compounded by the need for different formulations for different countries and age groups. Reliable vaccine production in appropriate quantities and at affordable prices is the cornerstone of developing global vaccination policies. However, ensuring optimal access and uptake also requires strong partnerships between private manufacturers, regulatory authorities and national and international public health services. For vaccines whose supplies are limited, either due to rapidly emerging diseases or longer-term mismatch of supply and demand, prioritizing target groups can increase vaccine impact. Focusing on influenza vaccines as an example that well illustrates many of the relevant points, this article considers current production, distribution, access and other factors that ultimately impact on vaccine uptake and population-level effectiveness. PMID:21664680

Possibilities of vaccine manufacture in human diploid cell strains with a serum replacement factor.

PubMed

Candal, F J; George, V G; Ades, E W

1991-07-01

Cell lines MDCK (canine kidney), BGM (Buffalo green monkey kidney) and human embryonic lung fibroblast will support viral growth efficiently in medium without serum. Both MRC-5 and WI-38 cell strains have been approved by the Food and Drug Administration for manufacturing viral vaccines against cytomegalovirus and varicella-zoster virus. In this study we examine these two cell lines and viruses for their ability to grow in medium containing a serum replacement. The serum substitute used is LPSR-1 (low protein serum replacement). Using LPSR-1 in defined medium, we demonstrate multipassage cell growth and viral cultivation and replication equivalent to those obtained in medium containing fetal bovine serum (FBS). Viral growth after complete elimination of FBS varies and depends on cell line and virus. Serum substitutes can eliminate FBS in the viral growth phase of vaccine production and reduce costs.

DNA Vaccines for Prostate Cancer

PubMed Central

Zahm, Christopher D.; Colluru, Viswa Teja; McNeel, Douglas G.

2017-01-01

DNA vaccines offer many advantages over other anti-tumor vaccine approaches due to their simplicity, ease of manufacturing, and safety. Results from several clinical trials in patients with cancer have demonstrated that DNA vaccines are safe and can elicit immune responses. However, to date few DNA vaccines have progressed beyond phase I clinical trial evaluation. Studies into the mechanism of action of DNA vaccines in terms of antigen-presenting cell types able to directly present or cross-present DNA-encoded antigens, and the activation of innate immune responses due to DNA itself, have suggested opportunities to increase the immunogenicity of these vaccines. In addition, studies into the mechanisms of tumor resistance to anti-tumor vaccination have suggested combination approaches that can increase the antitumor effect of DNA vaccines. This review focuses on these mechanisms of action and mechanisms of resistance using DNA vaccines, and how this information is being used to improve the anti-tumor effect of DNA vaccines. These approaches are then specifically discussed in the context of human prostate cancer, a disease for which DNA vaccines have been and continue to be explored as treatments. PMID:28185916

Avian influenza pandemic preparedness: developing prepandemic and pandemic vaccines against a moving target

PubMed Central

Singh, Neetu; Pandey, Aseem; Mittal, Suresh K.

2010-01-01

The unprecedented global spread of highly pathogenic avian H5N1 influenza viruses within the past ten years and their extreme lethality to poultry and humans has underscored their potential to cause an influenza pandemic. Combating the threat of an impending H5N1 influenza pandemic will require a combination of pharmaceutical and nonpharmaceutical intervention strategies. The emergence of the H1N1 pandemic in 2009 emphasised the unpredictable nature of a pandemic influenza. Undoubtedly, vaccines offer the most viable means to combat a pandemic threat. Current egg-based influenza vaccine manufacturing strategies are unlikely to be able to cater to the huge, rapid global demand because of the anticipated scarcity of embryonated eggs in an avian influenza pandemic and other factors associated with the vaccine production process. Therefore, alternative, egg-independent vaccine manufacturing strategies should be evaluated to supplement the traditional egg-derived influenza vaccine manufacturing. Furthermore, evaluation of dose-sparing strategies that offer protection with a reduced antigen dose will be critical for pandemic influenza preparedness. Development of new antiviral therapeutics and other, nonpharmaceutical intervention strategies will further supplement pandemic preparedness. This review highlights the current status of egg-dependent and egg-independent strategies against an avian influenza pandemic. PMID:20426889

Moving new vaccines for tuberculosis through the regulatory process.

PubMed

Brennan, M J

2000-06-01

The development of novel vaccines for the prevention of tuberculosis is an area of intense interest for scientific researchers, public health agencies, and pharmaceutical manufacturers. Development of effective new vaccines directed against tuberculosis for use in target populations will require close cooperation among several different international organizations, including regulatory agencies responsible for evaluating the safety and effectiveness of new biologics for human use.

Influenza Vaccine Manufacturing: Effect of Inactivation, Splitting and Site of Manufacturing. Comparison of Influenza Vaccine Production Processes

PubMed Central

Kon, Theone C.; Onu, Adrian; Berbecila, Laurentiu; Lupulescu, Emilia; Ghiorgisor, Alina; Kersten, Gideon F.; Cui, Yi-Qing; Amorij, Jean-Pierre; Van der Pol, Leo

2016-01-01

The aim of this study was to evaluate the impact of different inactivation and splitting procedures on influenza vaccine product composition, stability and recovery to support transfer of process technology. Four split and two whole inactivated virus (WIV) influenza vaccine bulks were produced and compared with respect to release criteria, stability of the bulk and haemagglutinin recovery. One clarified harvest of influenza H3N2 A/Uruguay virus prepared on 25.000 fertilized eggs was divided equally over six downstream processes. The main unit operation for purification was sucrose gradient zonal ultracentrifugation. The inactivation of the virus was performed with either formaldehyde in phosphate buffer or with beta-propiolactone in citrate buffer. For splitting of the viral products in presence of Tween®, either Triton™ X-100 or di-ethyl-ether was used. Removal of ether was established by centrifugation and evaporation, whereas removal of Triton-X100 was performed by hydrophobic interaction chromatography. All products were sterile filtered and subjected to a 5 months real time stability study. In all processes, major product losses were measured after sterile filtration; with larger losses for split virus than for WIV. The beta-propiolactone inactivation on average resulted in higher recoveries compared to processes using formaldehyde inactivation. Especially ether split formaldehyde product showed low recovery and least stability over a period of five months. PMID:26959983

Global economic evaluations of rotavirus vaccines: A systematic review.

PubMed

Kotirum, Surachai; Vutipongsatorn, Naaon; Kongpakwattana, Khachen; Hutubessy, Raymond; Chaiyakunapruk, Nathorn

2017-06-08

World Health Organization (WHO) recommends Rotavirus vaccines to prevent and control rotavirus infections. Economic evaluations (EE) have been considered to support decision making of national policy. Summarizing global experience of the economic value of rotavirus vaccines is crucial in order to encourage global WHO recommendations for vaccine uptake. Therefore, a systematic review of economic evaluations of rotavirus vaccine was conducted. We searched Medline, Embase, NHS EED, EconLit, CEA Registry, SciELO, LILACS, CABI-Global Health Database, Popline, World Bank - e-Library, and WHOLIS. Full economic evaluations studies, published from inception to November 2015, evaluating Rotavirus vaccines preventing Rotavirus infections were included. The methods, assumptions, results and conclusions of the included studies were extracted and appraised using WHO guide for standardization of EE of immunization programs. 104 relevant studies were included. The majority of studies were conducted in high-income countries. Cost-utility analysis was mostly reported in many studies using incremental cost-effectiveness ratio per DALY averted or QALY gained. Incremental cost per QALY gained was used in many studies from high-income countries. Mass routine vaccination against rotavirus provided the ICERs ranging from cost-saving to highly cost-effective in comparison to no vaccination among low-income countries. Among middle-income countries, vaccination offered the ICERs ranging from cost-saving to cost-effective. Due to low- or no subsidized price of rotavirus vaccines from external funders, being not cost-effective was reported in some high-income settings. Mass vaccination against rotavirus was generally found to be cost-effective, particularly in low- and middle-income settings according to the external subsidization of vaccine price. On the other hand, it may not be a cost-effective intervention at market price in some high-income settings. This systematic review provides

Evaluating the Safety of New Vaccines: Summary of a Workshop

PubMed Central

Ellenberg, Susan S.; Foulkes, Mary A.; Midthun, Karen; Goldenthal, Karen L.

2005-01-01

Public concerns about the safety of vaccines arise on a regular basis. In November 2000, a workshop titled “Evaluation of New Vaccines: How Much Safety Data?” was convened by US Public Health Service agencies, including the Food and Drug Administration, the National Institutes of Health, the Centers for Disease Control and Prevention, and the Health Resources and Services Administration, to discuss appropriate methods for evaluating the safety of new vaccines. Workshop presentations addressed the current standards and approaches for new vaccine evaluation and postlicensure surveillance, as well as public views about vaccine safety and alternative approaches that could be considered. The advantages and disadvantages of conducting large controlled trials before licensure or widespread use of a new vaccine were discussed. We summarize these presentations and discussions. PMID:15855455

Vaccines: Shaping global health.

PubMed

Pagliusi, Sonia; Ting, Ching-Chia; Lobos, Fernando

2017-03-14

The Developing Countries Vaccine Manufacturers' Network (DCVMN) gathered leaders in immunization programs, vaccine manufacturing, representatives of the Argentinean Health Authorities and Pan American Health Organization, among other global health stakeholders, for its 17th Annual General Meeting in Buenos Aires, to reflect on how vaccines are shaping global health. Polio eradication and elimination of measles and rubella from the Americas is a result of successful collaboration, made possible by timely supply of affordable vaccines. After decades of intense competition for high-value markets, collaboration with developing countries has become critical, and involvement of multiple manufacturers as well as public- and private-sector investments are essential, for developing new vaccines against emerging infectious diseases. The recent Zika virus outbreak and the accelerated Ebola vaccine development exemplify the need for international partnerships to combat infectious diseases. A new player, Coalition for Epidemic Preparedness Innovations (CEPI) has made its entrance in the global health community, aiming to stimulate research preparedness against emerging infections. Face-to-face panel discussions facilitated the dialogue around challenges, such as risks of viability to vaccine development and regulatory convergence, to improve access to sustainable vaccine supply. It was discussed that joint efforts to optimizing regulatory pathways in developing countries, reducing registration time by up to 50%, are required. Outbreaks of emerging infections and the global Polio eradication and containment challenges are reminders of the importance of vaccines' access, and of the importance of new public-private partnerships. Copyright © 2017.

Detection of bovine viral diarrhoea virus nucleic acid, but not infectious virus, in bovine serum used for human vaccine manufacture.

PubMed

Laassri, Majid; Mee, Edward T; Connaughton, Sarah M; Manukyan, Hasmik; Gruber, Marion; Rodriguez-Hernandez, Carmen; Minor, Philip D; Schepelmann, Silke; Chumakov, Konstantin; Wood, David J

2018-06-22

Bovine viral diarrhoea virus (BVDV) is a cattle pathogen that has previously been reported to be present in bovine raw materials used in the manufacture of biological products for human use. Seven lots of trivalent measles, mumps and rubella (MMR) vaccine and 1 lot of measles vaccine from the same manufacturer, together with 17 lots of foetal bovine serum (FBS) from different vendors, 4 lots of horse serum, 2 lots of bovine trypsin and 5 lots of porcine trypsin were analysed for BVDV using recently developed techniques, including PCR assays for BVDV detection, a qRT-PCR and immunofluorescence-based virus replication assays, and deep sequencing to identify and genotype BVDV genomes. All FBS lots and one lot of bovine-derived trypsin were PCR-positive for the presence of BVDV genome; in contrast all vaccine lots and the other samples were negative. qRT-PCR based virus replication assay and immunofluorescence-based infection assay detected no infectious BVDV in the PCR-positive samples. Complete BVDV genomes were generated from FBS samples by deep sequencing, and all were BVDV type 1. These data confirmed that BVDV nucleic acid may be present in bovine-derived raw materials, but no infectious virus or genomic RNA was detected in the final vaccine products. Copyright © 2018 International Alliance for Biological Standardization. All rights reserved.

Partnering for Vaccine Emerging Markets--Berlin, June 10-11, 2013: balancing vaccine quality, capacity, and cost-of-goods in emerging markets.

PubMed

Onraedt, Annelies

2013-09-01

Phacilitates 1st Partnering event for Vaccine Emerging Markets brought together approximately 100 attendees from developed and developing world vaccine manufacturers, leading non-profit organizations and industry suppliers. The goal was to discuss the vaccine needs in the developing world and how these needs can be met by leveraging collaboration and partnership models, by improving access to existing, new and next generation vaccines, by using novel technologies to drive competitive advantage and economics of vaccine manufacturing and by investing in localized capacity, including capacity for pandemic vaccines. The present article summarizes insights out of 30 oral contributions on how quality and capacity requirements can be balanced with cost by using novel manufacturing technologies and operating models.

Evaluation of intradermal vaccination at the anti rabies vaccination OPD.

PubMed

Mankeshwar, R; Silvanus, V; Akarte, S

2014-09-01

Rabies is a virtually 100% fatal acute viral encephalitis caused by an RNA virus belonging to family Rhabdoviridae and genus Lyssavirus. The virus can infect all warm blooded animals. The disease is transmitted to humans by the bite, lick or scratch of an infected animal. More than 99% of all human rabies deaths occur in the developing world. It is preventable with timely and proper usage of modern immunobiologicals (vaccines and immunoglobulins). Once exposure occurs, modern prophylaxis entails immediate wound care, local infiltration of rabies immune globulin and parenteral administration of modern cell culture vaccines in multiple doses. The annual medicinal (vaccines and other drugs) cost for animal bite treatment is Rs. 2 billion approximately (2004). The objective of the present study is to evaluate the performance of the Intradermal (i.d.) route visa vis the Intramuscular (i.m.) route in our clinical setting the Antirabies Vaccination (ARV) OPD, Sir J.J. Hospital, Mumbai. A total of 1460 patients were administered the Antirabies vaccine by the Intradermal route over the 1 year period as compared to 1075 patients who were administered the Antirabies vaccine by the Intramuscular route in the previous year. 1230 (84.2) of the patients who were administered the vaccine by the i.d. route completed the schedule and 230 (15.8%) partially completed the schedule. Four hundred thirty two (40%) of the patients who were administered the vaccine by the Intramuscular route completed the schedule and 643 (59.8%) partially completed the schedule. The vaccine cost for i.d. was Rs. 2,80,600. The vaccine cost for the intramuscular (i.m.) assuming 84% compliance was estimated as Rs. 15, 64, 000. Assuming 40% compliance the cost was estimated as Rs. 7, 82, 230. Thus a saving of Rs. 5, 01, 630 to Rs. 12, 83, 400 was effected. In our setting, the Intradermal regime was cost effective and increased patient adherence and enrolment. It has now been routinely adopted at the clinic.

Cell culture-derived influenza vaccines from Vero cells: a new horizon for vaccine production.

PubMed

Montomoli, Emanuele; Khadang, Baharak; Piccirella, Simona; Trombetta, Claudia; Mennitto, Elisa; Manini, Ilaria; Stanzani, Valerio; Lapini, Giulia

2012-05-01

In the 20th century, three influenza pandemics killed approximately 100 million people. The traditional method of influenza vaccine manufacturing is based on using chicken eggs. However, the necessity of the availability of millions of fertile eggs in the event of a pandemic has led research to focus on the development of cell culture-derived vaccines, which offer shorter lead-in times and greater flexibility of production. So far, the cell substrates being evaluated and in use include Vero, Madin-Darby canine kidney, PER.C6 and insect cells. However, Vero cells are the most widely accepted among others. This review introduces briefly the concepts of advanced cell culture-derived influenza vaccine production and highlights the advantages of these vaccines in terms of efficiency, speed and immunogenicity based on the clinical data obtained from different studies.

An international technology platform for influenza vaccines.

PubMed

Hendriks, Jan; Holleman, Marit; de Boer, Otto; de Jong, Patrick; Luytjes, Willem

2011-07-01

Since 2008, the World Health Organization has provided seed grants to 11 manufacturers in low- and middle-income countries to establish or improve their pandemic influenza vaccine production capacity. To facilitate this ambitious project, an influenza vaccine technology platform (or "hub") was established at the Netherlands Vaccine Institute for training and technology transfer to developing countries. During its first two years of operation, a robust and transferable monovalent pilot process for egg-based inactivated whole virus influenza A vaccine production was established under international Good Manufacturing Practice standards, as well as in-process and release assays. A course curriculum was designed, including a two-volume practical handbook on production and quality control. Four generic hands-on training courses were successfully realized for over 40 employees from 15 developing country manufacturers. Planned extensions to the curriculum include cell-culture based technology for viral vaccine production, split virion influenza production, and generic adjuvant formulation. We conclude that technology transfer through the hub model works well, significantly builds vaccine manufacturing capacity in developing countries, and thereby increases global and equitable access to vaccines of high public health relevance. Copyright © 2011 Elsevier Ltd. All rights reserved.

Application of a risk analysis method to different technologies for producing a monoclonal antibody employed in hepatitis B vaccine manufacturing.

PubMed

Milá, Lorely; Valdés, Rodolfo; Tamayo, Andrés; Padilla, Sigifredo; Ferro, Williams

2012-03-01

CB.Hep-1 monoclonal antibody (mAb) is used for a recombinant Hepatitis B vaccine manufacturing, which is included in a worldwide vaccination program against Hepatitis B disease. The use of this mAb as immunoligand has been addressed into one of the most efficient steps of active pharmaceutical ingredient purification process. Regarding this, Quality Risk Management (QRM) provides an excellent framework for the risk management use in pharmaceutical manufacturing and quality decision-making applications. Consequently, this study sought applying a prospective risk analysis methodology Failure Mode Effects Analysis (FMEA) as QRM tool for analyzing different CB.Hep-1 mAb manufacturing technologies. As main conclusions FMEA was successfully used to assess risks associated with potential problems in CB.Hep-1 mAb manufacturing processes. The severity and occurrence of risks analysis evidenced that the percentage of very high severe risks ranged 31.0-38.7% of all risks and the huge majority of risks have a very low occurrence level (61.9-83.3%) in all assessed technologies. Finally, additive Risk Priority Number, was descending ordered as follow: transgenic plants (2636), ascites (2577), transgenic animals (2046) and hollow fiber bioreactors (1654), which also corroborated that in vitro technology, should be the technology of choice for CB.Hep-1 mAb manufacturing in terms of risks and mAb molecule quality. Copyright © 2011 The International Alliance for Biological Standardization. Published by Elsevier Ltd. All rights reserved.

Vaccine provision: Delivering sustained & widespread use.

PubMed

Preiss, Scott; Garçon, Nathalie; Cunningham, Anthony L; Strugnell, Richard; Friedland, Leonard R

2016-12-20

The administration of a vaccine to a recipient is the final step in a development and production process that may have begun several decades earlier. Here we describe the scale and complexity of the processes that brings a candidate vaccine through clinical development to the recipient. These challenges include ensuring vaccine quality (between 100 and 500 different Quality Control tests are performed during production to continually assess safety, potency and purity); making decisions about optimal vaccine presentation (pre-filled syringes versus multi-dose vials) that affect capacity and supply; and the importance of maintaining the vaccine cold chain (most vaccines have stringent storage temperature requirements necessary to maintain activity and potency). The ultimate aim is to make sure that an immunogenic product matching the required specifications reaches the recipient. The process from concept to licensure takes 10-30years. Vaccine licensure is based on a file submitted to regulatory agencies which contains the comprehensive compilation of chemistry, manufacturing information, assay procedures, preclinical and clinical trial results, and proposals for post-licensure effectiveness and safety data collection. Expedited development and licensure pathways may be sought in emergency settings: e.g., the 2009 H1N1 influenza pandemic, the 2014 West African Ebola outbreak and meningococcal serogroup B meningitis outbreaks in the United States and New Zealand. Vaccines vary in the complexity of their manufacturing process. Influenza vaccines are particularly challenging to produce and delays in manufacturing may occur, leading to vaccine shortages during the influenza season. Shortages can be difficult to resolve due to long manufacturing lead times and stringent, but variable, local regulations. New technologies are driving the development of new vaccines with simplified manufacturing requirements and with quality specifications that can be confirmed with fewer

Vaccines against poverty

PubMed Central

MacLennan, Calman A.; Saul, Allan

2014-01-01

With the 2010s declared the Decade of Vaccines, and Millennium Development Goals 4 and 5 focused on reducing diseases that are potentially vaccine preventable, now is an exciting time for vaccines against poverty, that is, vaccines against diseases that disproportionately affect low- and middle-income countries (LMICs). The Global Burden of Disease Study 2010 has helped better understand which vaccines are most needed. In 2012, US$1.3 billion was spent on research and development for new vaccines for neglected infectious diseases. However, the majority of this went to three diseases: HIV/AIDS, malaria, and tuberculosis, and not neglected diseases. Much of it went to basic research rather than development, with an ongoing decline in funding for product development partnerships. Further investment in vaccines against diarrheal diseases, hepatitis C, and group A Streptococcus could lead to a major health impact in LMICs, along with vaccines to prevent sepsis, particularly among mothers and neonates. The Advanced Market Commitment strategy of the Global Alliance for Vaccines and Immunisation (GAVI) Alliance is helping to implement vaccines against rotavirus and pneumococcus in LMICs, and the roll out of the MenAfriVac meningococcal A vaccine in the African Meningitis Belt represents a paradigm shift in vaccines against poverty: the development of a vaccine primarily targeted at LMICs. Global health vaccine institutes and increasing capacity of vaccine manufacturers in emerging economies are helping drive forward new vaccines for LMICs. Above all, partnership is needed between those developing and manufacturing LMIC vaccines and the scientists, health care professionals, and policy makers in LMICs where such vaccines will be implemented. PMID:25136089

Hepatitis E virus: Current epidemiology and vaccine.

PubMed

Wu, Xing; Chen, Pan; Lin, Huijuan; Hao, Xiaotian; Liang, Zhenglun

2016-10-02

Hepatitis E virus infections have been continuously reported in Indian subcontinent, Africa, southeast and central Asia, posing great health threats to the public, especially to pregnant women. Hecolin® is the only licensed HEV vaccine developed by Xiamen Innovax Biotech Co., Ltd. Extensive characterizations on antigenicity, physicochemical properties, efficacy in clinical trials, and manufacturing capability have made Hecolin® a promising vaccine for HEV control. However, there are many obstacles in large scale application of Hecolin®. Efforts are needed to further evaluate safety and efficacy in HEV risk populations, and to complement HEV standards for quality control. Passing World Health Organization prequalification and licensing outside China are priorities as these are also hindering Hecolin® promotion. Multilateral cooperation among Chinese vaccine manufacturers, Chinese National Regulatory Authorization (NRA) and WHO will expedite the entrance of Hecolin® into international market, so that Hecolin® could play its due role in global hepatitis E control.

Considerations for sustainable influenza vaccine production in developing countries.

PubMed

Nannei, Claudia; Chadwick, Christopher; Fatima, Hiba; Goldin, Shoshanna; Grubo, Myriam; Ganim, Alexandra

2016-10-26

Through its Global Action Plan for Influenza Vaccines (GAP), the World Health Organization (WHO) in collaboration with the United States Department of Health and Human Services has produced a checklist to support policy-makers and influenza vaccine manufacturers in identifying key technological, political, financial, and logistical issues affecting the sustainability of influenza vaccine production. This checklist highlights actions in five key areas that are beneficial for establishing successful local vaccine manufacturing. These five areas comprise: (1) the policy environment and health-care systems; (2) surveillance systems and influenza evidence; (3) product development and manufacturing; (4) product approval and regulation; and (5) communication to support influenza vaccination. Incorporating the checklist into national vaccine production programmes has identified the policy gaps and next steps for countries involved in GAP's Technology Transfer Initiative. Lessons learnt from country experiences provide context and insight that complement the checklist's goal of simplifying the complexities of influenza prevention, preparedness, and vaccine manufacturing. Copyright © 2016 The Authors. Published by Elsevier Ltd.. All rights reserved.

Evaluation of a vaccine passport to improve vaccine coverage in people living with HIV.

PubMed

Chadwick, D R; Corbett, K; Mann, S; Teruzzi, B; Horner, S

2018-01-01

An increased risk of vaccine-preventable infections (VPIs) is seen in people living with HIV (PLWH), and current vaccine coverage and immunity is variable. Vaccine passports have the potential to improve vaccine coverage. The objective was to assess how successful a vaccine passport was in improving vaccine coverage in PLWH. Baseline immunity to VPIs was established in PLWH attending a single HIV clinic and vaccinations required were determined based on the BHIVA Vaccination Guidelines (2015). The passport was completed and the PLWH informed about additional vaccines they should obtain from primary care. After 6-9 months the passport was reviewed including confirmation if vaccines were given. PLWH satisfaction with the system was evaluated by a survey. Seventy-three PLWH provided sufficient data for analysis. At baseline significant proportions of PLWH were not immune/unvaccinated to the main VPIs, especially human papillomavirus, pneumococcus and measles. After the passport was applied immunity improved significantly (56% overall, p < 0.01) for most VPIs; however, full coverage was not achieved. The system was popular with PLWH. The passport was successful in increasing vaccination coverage although full or near-full coverage was not achieved. A more successful service would probably be achieved by commissioning English HIV clinics to provide all vaccines.

Evaluation of vaccines in the EU TB Vaccine Cluster using a guinea pig aerosol infection model of tuberculosis.

PubMed

Williams, Ann; Hatch, Graham J; Clark, Simon O; Gooch, Karen E; Hatch, Kim A; Hall, Graham A; Huygen, Kris; Ottenhoff, Tom H M; Franken, Kees L M C; Andersen, Peter; Doherty, T Mark; Kaufmann, Stefan H E; Grode, Leander; Seiler, Peter; Martin, Carlos; Gicquel, Brigitte; Cole, Stewart T; Brodin, Priscille; Pym, Alexander S; Dalemans, Wilfried; Cohen, Joe; Lobet, Yves; Goonetilleke, Nilu; McShane, Helen; Hill, Adrian; Parish, Tanya; Smith, Debbie; Stoker, Neil G; Lowrie, Douglas B; Källenius, Gunilla; Svenson, Stefan; Pawlowski, Andrzej; Blake, Karen; Marsh, Philip D

2005-01-01

The TB Vaccine Cluster project funded by the EU Fifth Framework programme aims to provide novel vaccines against tuberculosis that are suitable for evaluation in humans. This paper describes the studies of the protective efficacy of vaccines in a guinea pig aerosol-infection model of primary tuberculosis. The objective was to conduct comparative evaluations of vaccines that had previously demonstrated efficacy in other animal models. Groups of 6 guinea pigs were immunized with vaccines provided by the relevant EU Vaccine Cluster partners. Survival over 17 or 26 weeks was used as the principal measure of vaccine efficacy following aerosol challenge with H37Rv. Counts of mycobacteria in lungs and spleens, and histopathological changes in the lungs, were also used to provide evidence of protection. A total of 24 vaccines were evaluated in 4 experiments each of a different design. A heterologous prime-boost strategy of DNA and MVA, each expressing Ag85A and a fusion protein of ESAT-6 and Ag85B in adjuvant, protected the guinea pigs to the same extent as BCG. Genetically modified BCG vaccines and boosted BCG strategies also protected guinea pigs to the same extent as BCG but not statistically significantly better. A relatively high aerosol-challenge dose and evaluation over a protracted time post-challenge allowed superior protection over BCG to be demonstrated by BCG boosted with MVA and fowl pox vectors expressing Ag85A.

A novel enzyme-linked immuno-sorbent assay (ELISA) for the quantification of total and free polysaccharide in Haemophilus influenzae b-Tetanus toxoid conjugate vaccines in monovalent and combined vaccine formulations.

PubMed

Saydam, Manolya; Rigsby, Peter; Mawas, Fatme

2014-01-01

Current Haemophilus influenzae b conjugate vaccines (Hib), which are made of purified capsular polysaccharide (poly-ribosyl-ribitol-phosphate; PRP) conjugated to a carrier protein, are almost completely evaluated by physico-chemical methods to ensure the integrity and stability of the vaccine and consistency of manufacture of batches. The absence of a potency assay makes the quantification of total PRP content (in SI units) and of % free polysaccharide in final fills or bulk components of Hib vaccines critical release tests for both manufacturers and national control authorities. Here we describe a simple and sensitive Enzyme-Linked Immuno-sorbent Assay (ELISA) which has been developed to quantify total and free PRP content in Hib-TT vaccine alone or when in combination with other vaccines. The assay is robust, specific and highly sensitive. Copyright © 2013 The International Alliance for Biological Standardization. Published by Elsevier Ltd. All rights reserved.

Improving birth dose coverage of hepatitis B vaccine.

PubMed Central

Hipgrave, David B.; Maynard, James E.; Biggs, Beverley-Ann

2006-01-01

Administration of a birth dose of hepatitis B vaccine (HepB vaccine) to neonates is recommended to prevent mother-to-infant transmission and chronic infection with the hepatitis B virus (HBV). Although manufacturers recommend HepB vaccine distribution and storage at 2-8 degrees C, recognition of the heat stability of hepatitis B surface antigen stimulated research into its use after storage at, or exposure to, ambient or high temperatures. Storage of HepB vaccine at ambient temperatures would enable birth dosing for neonates delivered at home in remote areas or at health posts lacking refrigeration. This article reviews the current evidence on the thermostability of HepB vaccine when stored outside the cold chain (OCC). The reports reviewed show that the vaccines studied were safe and effective whether stored cold or OCC. Field and laboratory data also verifies the retained potency of the vaccine after exposure to heat. The attachment of a highly stable variety of a vaccine vial monitor (measuring cumulative exposure to heat) on many HepB vaccines strongly supports policies allowing their storage OCC, when this will benefit birth dose coverage. We recommend that this strategy be introduced to improve birth dose coverage, especially in rural and remote areas. Concurrent monitoring and evaluation should be undertaken to affirm the safe implementation of this strategy, and assess its cost, feasibility and effect on reducing HBV infection rates. Meanwhile, release of manufacturer data verifying the potency of currently available HepB vaccines after exposure to heat will increase confidence in the use of vaccine vial monitors as a managerial tool during storage of HepB vaccine OCC. PMID:16501717

A double blind, randomized, active controlled study to assess the safety, tolerability and immunogenicity of measles, mumps rubella, and varicella vaccine (MMRV) manufactured using an alternative process

PubMed Central

Marshall, Gary S.; Senders, Shelly D.; Shepard, Julie; Twiggs, Jerry D.; Gardner, Julie; Hille, Darcy; Hartzel, Jonathan; Valenzuela, Rowan; Stek, Jon E.; Helmond, Frans A.

2016-01-01

ABSTRACT Vaccination against measles, mumps, rubella, and varicella is recommended for all children in the US. Limitations manufacturing Oka/Merck strain varicella-zoster virus have hampered the availability of the combination vaccine (MMRV) against these 4 viruses, which drove the need to investigate an alternative manufacturing process. Healthy children 12-to-23 months of age at 71 US sites were randomized (1:1) to receive MMRV manufactured using an alternative process (MMRVAMP) or the currently licensed MMRV. Subjects received 2 0.5 mL doses 3 months apart. Sera were collected before and 6 weeks after Dose-1. Adverse experiences (AEs) were collected for 42 d after each dose and serious AEs and events of special interest for 180 d after Dose-2. Overall, 706 subjects were randomized to MMRVAMP and 706 to MMRV and 698 and 702 received at least 1 dose of study vaccine, respectively. The risk difference in response rates and geometric mean concentrations of antibody to measles, mumps, rubella, and varicella viruses 6 weeks after Dose-1 met non-inferiority criteria for MMRVAMP versus, MMRV. Response rates met acceptability criteria for each virus, and the seroconversion rate to varicella-zoster virus was 99.5% in both groups. Vaccine-related AEs were mostly mild-to-moderate in intensity and somewhat more common after MMRVAMP. Febrile seizures occurred at similar rates in both groups during the first 42 d after each vaccine dose. MMRVAMP is non-inferior to MMRV and represents an important advancement in maintaining an adequate supply of vaccines against these diseases. PMID:27149048

Potency assays for therapeutic live whole cell cancer vaccines.

PubMed

Petricciani, John; Egan, William; Vicari, Giuseppe; Furesz, John; Schild, Geoffrey

2007-04-01

Therapeutic cancer vaccines are under development with the goal of enhancing the body's immune response to cancer cells sufficient to arrest cancer cell growth. Among the various approaches being used are those based on whole tumor cells. Developing a suitable measure of the potency of such vaccines presents a significant challenge because neither cellular associated markers nor in vivo biological responses that are correlated with efficacy have been identified; nevertheless, manufacturers and regulatory agencies will need to develop methods to evaluate these products. At this moment, the challenge for manufacturers who are developing whole cell vaccines is to demonstrate batch-to-batch consistency for the vaccine used in clinical studies and to show that comparable vaccine batches have the same capacity to achieve an acceptable level of biological activity that may be related to efficacy. This is particularly challenging in that animal models to test that activity do not exist and direct serological or immunological correlates of clinical protection are not available because protection has not yet been established in clinical trials. In the absence of well-defined biological markers and tests for manufacturing consistency, manufacturers and regulators will need to rely heavily on a highly reproducible manufacturing process--the consistency of the process therefore becomes critical. In developing regulatory approaches to whole cell cancer vaccines, the experience from the field of infectious disease vaccines should be examined for general guidance. A framework that draws heavily on the field of infectious disease vaccines is presented and suggests that at this point in the development of this new class of products, it is reasonable to develop data on quantitative antigen expression as a measure of potency with the expectation that when clinical efficacy has been established it will confirm the appropriateness of this approach. But because this will not be known

Identifying ethical issues in the development of vaccines and in vaccination.

PubMed

Johari, Veena

2017-01-01

Vaccines are a widely accepted public health intervention. They are also a profitable tool for pharmaceutical companies manufacturing vaccines. There are many vaccines in the pipeline, for various diseases, or as combination vaccines for several diseases. However, there is also a growing concern about vaccines and the manner in which they are developed and approved by the authorities. Approvals are fast tracked and adverse events and serious adverse events following vaccination are seldom reported once the vaccine gets its marketing approval. Thus, vaccines have been clouded with many controversies and their use as a public health tool to prevent diseases is constantly under challenge.

Vaccination policies and programs: the federal government's role in making the system work.

PubMed

Schwartz, B; Orenstein, W A

2001-12-01

Government agencies play a key role, from preclinical development to postlicensure monitoring, in making vaccinations one of the leading public health interventions. Important steps in this process include development and testing of vaccine antigens, evaluation of clinical and manufacturing data leading to licensure, formulation of recommendations, vaccine purchase, defining strategies to improve coverage, compensation of those injured by vaccine adverse reactions, and monitoring vaccine impact and safety. Using examples of newly recommended vaccines, this article describes the infrastructure that underlies a safe and effective program and highlights some of the opportunities and threats likely to impact the system in coming years.

Evaluation of an Intervention Providing HPV Vaccine in Schools

PubMed Central

Stubbs, Brenda W.; Panozzo, Catherine A.; Moss, Jennifer L.; Reiter, Paul L.; Whitesell, Dianne H.; Brewer, Noel T.

2014-01-01

Objectives To conduct outcome and process evaluations of school-located HPV vaccination clinics in partnership with a local health department. Methods Temporary clinics provided the HPV vaccine to middle school girls in Guilford County, North Carolina, in 2009–2010. Results HPV vaccine initiation was higher among girls attending host schools than satellite schools (6% vs. 1%, OR = 6.56, CI = 3.99–10.78). Of the girls who initiated HPV vaccine, 80% received all 3 doses. Private insurance or federal programs paid for most vaccine doses. Conclusions Lessons learned for creating more effective school-health department partnerships include focusing on host schools and delivering several vaccines to adolescents, not just HPV vaccine alone. PMID:24034684

Methodological Challenges to Economic Evaluations of Vaccines: Is a Common Approach Still Possible?

PubMed

Jit, Mark; Hutubessy, Raymond

2016-06-01

Economic evaluation of vaccination is a key tool to inform effective spending on vaccines. However, many evaluations have been criticised for failing to capture features of vaccines which are relevant to decision makers. These include broader societal benefits (such as improved educational achievement, economic growth and political stability), reduced health disparities, medical innovation, reduced hospital beds pressures, greater peace of mind and synergies in economic benefits with non-vaccine interventions. Also, the fiscal implications of vaccination programmes are not always made explicit. Alternative methodological frameworks have been proposed to better capture these benefits. However, any broadening of the methodology for economic evaluation must also involve evaluations of non-vaccine interventions, and hence may not always benefit vaccines given a fixed health-care budget. The scope of an economic evaluation must consider the budget from which vaccines are funded, and the decision-maker's stated aims for that spending to achieve.

A double blind, randomized, active controlled study to assess the safety, tolerability and immunogenicity of measles, mumps rubella, and varicella vaccine (MMRV) manufactured using an alternative process.

PubMed

Marshall, Gary S; Senders, Shelly D; Shepard, Julie; Twiggs, Jerry D; Gardner, Julie; Hille, Darcy; Hartzel, Jonathan; Valenzuela, Rowan; Stek, Jon E; Helmond, Frans A

2016-08-02

Vaccination against measles, mumps, rubella, and varicella is recommended for all children in the US. Limitations manufacturing Oka/Merck strain varicella-zoster virus have hampered the availability of the combination vaccine (MMRV) against these 4 viruses, which drove the need to investigate an alternative manufacturing process. Healthy children 12-to-23 months of age at 71 US sites were randomized (1:1) to receive MMRV manufactured using an alternative process (MMRV AMP ) or the currently licensed MMRV. Subjects received 2 0.5 mL doses 3 months apart. Sera were collected before and 6 weeks after Dose-1. Adverse experiences (AEs) were collected for 42 d after each dose and serious AEs and events of special interest for 180 d after Dose-2. Overall, 706 subjects were randomized to MMRV AMP and 706 to MMRV and 698 and 702 received at least 1 dose of study vaccine, respectively. The risk difference in response rates and geometric mean concentrations of antibody to measles, mumps, rubella, and varicella viruses 6 weeks after Dose-1 met non-inferiority criteria for MMRV AMP versus, MMRV. Response rates met acceptability criteria for each virus, and the seroconversion rate to varicella-zoster virus was 99.5% in both groups. Vaccine-related AEs were mostly mild-to-moderate in intensity and somewhat more common after MMRV AMP . Febrile seizures occurred at similar rates in both groups during the first 42 d after each vaccine dose. MMRV AMP is non-inferior to MMRV and represents an important advancement in maintaining an adequate supply of vaccines against these diseases.

Recommendations for safe vaccination in children at the risk of taking allergic reactions to vaccine components

PubMed

2018-04-01

Vaccines are one of the most important advances in medicine as a public health tool for the control of immunopreventable diseases. Occasionally, adverse reactions may occur. If a child has a reaction to a vaccine, it is likely to disrupt his immunization schedule with risks to himself and the community. This establishes the importance of correctly diagnosing a possible allergy and defining appropriate behavior. Allergic reactions to vaccines may be due to the immunogenic component, to the residual proteins in the manufacturing process and to antimicrobial agents, stabilizers, preservatives and any other element used in the manufacturing process. Vaccination should be a priority in the entire child population, so this document describes particular situations of allergic children to minimize the risk of immunizations and achieve safe vaccination.

Obstacles to developing vaccines for the Third World.

PubMed

Robbins, A; Freeman, P

1988-11-01

Despite the tremendous strides in global immunization in less developed countries (LDCs) in the last 25 years, much remains to be done and the momentum has slowed. Vaccination programs continue to prove that they are less expensive, easier to implement, and in some cases more effective than other public health programs. Therefore it is imperative to produce and deliver new or improved vaccines to LDCs to prevent many infectious diseases and save the lives of children. Yet economic and political obstacles impede the development of these vaccines, even though the scientific know-how already exists. Manufacturers of vaccines that have been around for a long time and used widely in developed nations have often sold these vaccines to international agencies, such as WHO, at production cost. They do this because they have already recouped research & development (R&D) costs. When it comes to R&D of new vaccines, however, manufacturers are generally unwilling to invest time and money into R&D since they may not recoup their costs and make a profit. International agencies do not have the money to pay the high prices charged by manufacturers. Instead of the public health community in LDCs deciding on the development of new vaccines, the decision is left almost entirely in the hands of a few institutes or commercial manufacturers in the developed world. Other than continuing with the status quo, however, possible solutions do exist. For example, the UN could create an institute to develop and manufacture its own vaccines. Another possibility is that R&D and production of vaccines for diseases prevalent in an LDC or region could take place within that specified area.

[Clinical effectiveness and economical evaluation of preventive vaccination].

PubMed

Vaz Carneiro, António; Belo, Ana Isabel; Gouveia, Miguel; Costa, João; Borges, Margarida

2011-01-01

The value of mass vaccination as a preventive measure for infectious diseases is one of the most important advances of modern Medicine. The impact on incidence of several infectious diseases, until recently responsible for significant morbidity and mortality at world level, is well proved in a series of high quality epidemiological studies. In this scientific review we aimed firstly to briefly resume the history of mass vaccination and its scientists, responsible for synthesis and marketing of these drugs. In second place we present a group of a few disease preventable by vaccines as well as the Portuguese National Vaccination Plan and its benefits. In third place we identified groups of subjects in which a well structured vaccination plan is particularly important, as well as the correspondent diseases to be covered by vaccination. Fourthly, we discussed the ethical considerations of vaccination, and its tensions between subject autonomy and society advantages in com pulsive programs. Fifthly, we analyzed clinical effectiveness of vaccines through the concept of herd immunity, clinical evaluation of immune response to vaccines and some examples of systematic reviews on three relevant diseases (influenza, meningococcal and pneumococcal infections). In sixth place we discussed vaccine safety presenting monitoring methods of vaccination risks, as well as discussing the public myths concerning vaccines. Finally we present a economic analysis of preventive vaccination with a review of some published literature on specific diseases. We conclude that mass vaccination is a efficacious preventive measure, as well as a economic rational choice, and that this public health intervention should be a pillar of a modern preventive system.

Evaluation of travel medicine practice by yellow fever vaccination centers in England, Wales, and Northern Ireland.

PubMed

Boddington, Nicola L; Simons, Hilary; Launders, Naomi; Gawthrop, Mary; Stillwell, Alexandra; Wong, Claire; Mathewson, John; Hill, David R

2012-01-01

The National Travel Health Network and Centre (NaTHNaC) introduced a program of registration, training, standards, and audit for yellow fever vaccination centers (YFVCs) in England, Wales, and Northern Ireland (EWNI) in 2005. Prior to rolling out the program, NaTHNaC surveyed YFVCs in England. To reassess the practice of YFVCs in 2009, 4 years after the institution of the NaTHNaC program, to identify areas for ongoing support, and to assess the impact of the program. In 2009, all YFVCs in EWNI were asked to complete a questionnaire on type of practice, administration of travel vaccines, staff training, vaccine storage and patient record keeping, use of travel health information, evaluation of NaTHNaC yellow fever (YF) training, and resource and training needs. Data were analyzed using Microsoft Excel® and STATA 9®. The questionnaire was completed by 1,438 YFVCs (41.5% of 3,465 YFVCs). Most YFVCs were based in General Practice (87.4%). In nearly all YFVCs (97.0%), nurses advised travelers and administered YF vaccine. An annual median of 50 doses of YF vaccine was given by each YFVC. A total of 96.7% of nurses had received training in travel medicine, often through study days run by vaccine manufacturers. The internet was frequently used for information during travel consultations (84.8%) and NaTHNaC's on-line and telephone advice resources were highly rated. Following YF training, 95.8% of attendees expressed improved confidence regarding YF vaccination issues. There was excellent adherence to vaccination standards: ≥ 94% correctly stored vaccines, recorded refrigerator temperatures, and maintained YF vaccination records. In the 4 years since institution of the NaTHNaC program for YFVCs, there has been improved adherence to basic standards of immunization practice and increased confidence of health professionals in YF vaccination. The NaTHNaC program could be a model for other national public health bodies, as they establish a program for YF centers. © 2012

Development of a scaled-down aerobic fermentation model for scale-up in recombinant protein vaccine manufacturing.

PubMed

Farrell, Patrick; Sun, Jacob; Gao, Meg; Sun, Hong; Pattara, Ben; Zeiser, Arno; D'Amore, Tony

2012-08-17

A simple approach to the development of an aerobic scaled-down fermentation model is presented to obtain more consistent process performance during the scale-up of recombinant protein manufacture. Using a constant volumetric oxygen mass transfer coefficient (k(L)a) for the criterion of a scale-down process, the scaled-down model can be "tuned" to match the k(L)a of any larger-scale target by varying the impeller rotational speed. This approach is demonstrated for a protein vaccine candidate expressed in recombinant Escherichia coli, where process performance is shown to be consistent among 2-L, 20-L, and 200-L scales. An empirical correlation for k(L)a has also been employed to extrapolate to larger manufacturing scales. Copyright © 2012 Elsevier Ltd. All rights reserved.

Vaccines are different: A systematic review of budget impact analyses of vaccines.

PubMed

Loze, Priscilla Magalhaes; Nasciben, Luciana Bertholim; Sartori, Ana Marli Christovam; Itria, Alexander; Novaes, Hillegonda Maria Dutilh; de Soárez, Patrícia Coelho

2017-05-15

Several countries require manufacturers to present a budget impact analysis (BIA), together with a cost-effectiveness analysis, to support national funding requests. However, guidelines for conducting BIA of vaccines are scarce. To analyze the methodological approaches used in published budget impact analysis (BIA) of vaccines, discussing specific methodological issues related to vaccines. This systematic review of the literature on BIA of vaccines was carried out in accordance with the Centre for Reviews and Dissemination - CRD guidelines. We searched multiple databases: MedLine, Embase, Biblioteca Virtual de Saúde (BVS), Cochrane Library, DARE Database, NHS Economic Evaluation Database (NHS EED), HTA Database (via Centre for Reviews and Dissemination - CRD), and grey literature. Two researchers, working independently, selected the studies and extracted the data. The methodology quality of individual studies was assessed using the ISPOR 2012 Budget Impact Analysis Good Practice II Task Force. A qualitative narrative synthesis was conducted. Twenty-two studies were reviewed. The most frequently evaluated vaccines were pneumococcal (41%), influenza (23%) and rotavirus (18%). The target population was stated in 21 studies (95%) and the perspective was clear in 20 (91%). Only 36% reported the calculations used to complete the BIA, 27% informed the total and disaggregated costs for each time period, and 9% showed the change in resource use for each time period. More than half of the studies (55%, n=12) reported less than 50% of the items recommended in the checklist. The production of BIA of vaccines has increased from 2009. The report of the methodological steps was unsatisfactory, making it difficult to assess the validity of the results presented. Vaccines specific issues should be discussed in international guidelines for BIA of vaccines, to improve the quality of the studies. Copyright © 2017 Elsevier Ltd. All rights reserved.

Development of a recombinant toxin fragment vaccine for Clostridium difficile infection.

PubMed

Karczewski, Jerzy; Zorman, Julie; Wang, Su; Miezeiewski, Matthew; Xie, Jinfu; Soring, Keri; Petrescu, Ioan; Rogers, Irene; Thiriot, David S; Cook, James C; Chamberlin, Mihaela; Xoconostle, Rachel F; Nahas, Debbie D; Joyce, Joseph G; Bodmer, Jean-Luc; Heinrichs, Jon H; Secore, Susan

2014-05-19

Clostridium difficile infection (CDI) is the major cause of antibiotic-associated diarrhea and pseudomembranous colitis, a disease associated with significant morbidity and mortality. The disease is mostly of nosocomial origin, with elderly patients undergoing anti-microbial therapy being particularly at risk. C. difficile produces two large toxins: Toxin A (TcdA) and Toxin B (TcdB). The two toxins act synergistically to damage and impair the colonic epithelium, and are primarily responsible for the pathogenesis associated with CDI. The feasibility of toxin-based vaccination against C. difficile is being vigorously investigated. A vaccine based on formaldehyde-inactivated Toxin A and Toxin B (toxoids) was reported to be safe and immunogenic in healthy volunteers and is now undergoing evaluation in clinical efficacy trials. In order to eliminate cytotoxic effects, a chemical inactivation step must be included in the manufacturing process of this toxin-based vaccine. In addition, the large-scale production of highly toxic antigens could be a challenging and costly process. Vaccines based on non-toxic fragments of genetically engineered versions of the toxins alleviate most of these limitations. We have evaluated a vaccine assembled from two recombinant fragments of TcdB and explored their potential as components of a novel experimental vaccine against CDI. Golden Syrian hamsters vaccinated with recombinant fragments of TcdB combined with full length TcdA (Toxoid A) developed high titer IgG responses and potent neutralizing antibody titers. We also show here that the recombinant vaccine protected animals against lethal challenge with C. difficile spores, with efficacy equivalent to the toxoid vaccine. The development of a two-segment recombinant vaccine could provide several advantages over toxoid TcdA/TcdB such as improvements in manufacturability. Copyright © 2014 Elsevier Ltd. All rights reserved.

Generalized herd effects and vaccine evaluation: impact of live influenza vaccine on off-target bacterial colonisation.

PubMed

Mina, Michael J

2017-06-01

Interactions between pathogens and commensal microbes are major contributors to health and disease. Infectious diseases however are most often considered independent, viewed within a one-host one-pathogen paradigm and, by extension, the interventions used to treat and prevent them are measured and evaluated within this same paradigm. Vaccines, especially live vaccines, by stimulating immune responses or directly interacting with other microbes can alter the environment in which they act, with effects that span across pathogen species. Live attenuated infl uenza vaccines for example, while safe, increase upper respiratory tract bacterial carriage density of important human commensal pathogens like Streptococcus pneumoniae and Staphylococcus aureus. Further, by altering the ecological niche and dynamics of phylogenetically distinct microbes within the host, vaccines may unintentionally affect transmission of non-vaccine targeted pathogens. Thus, vaccine effects may span across species and across scales, from the individual to the population level. In keeping with traditional vaccine herd-effects that indirectly protect even unvaccinated individuals by reducing population prevalence of vaccine-targeted pathogens, we call these cross-species cross-scale effects "generalized herd-effects". As opposed to traditional herd-effects, "generalized" relaxes the assumption that the effect occurs at the level of the vaccine-target pathogen and "herd effect" implies, as usual, that the effects indirectly impact the population at large, including unvaccinated bystanders. Unlike traditional herd-effects that decrease population prevalence of the vaccine-target, generalized herd-effects may decrease or increase prevalence and disease by the off-target pathogen. LAIV, for example, by increasing pneumococcal density in the upper respiratory tract of vaccine recipients, especially children, may increase pneumococcal transmission and prevalence, leading to excess pneumococcal invasive

Challenges for the registration of vaccines in emerging countries: Differences in dossier requirements, application and evaluation processes.

PubMed

Dellepiane, Nora; Pagliusi, Sonia

2018-06-07

The divergence of regulatory requirements and processes in developing and emerging countries contributes to hamper vaccines' registration, and therefore delay access to high-quality, safe and efficacious vaccines for their respective populations. This report focuses on providing insights on the heterogeneity of registration requirements in terms of numbering structure and overall content of dossiers for marketing authorisation applications for vaccines in different areas of the world. While it also illustrates the divergence of regulatory processes in general, as well as the need to avoid redundant reviews, it does not claim to provide a comprehensive view of all processes nor existing facilitating mechanisms, nor is it intended to touch upon the differences in assessments made by different regulatory authorities. This report describes the work analysed by regulatory experts from vaccine manufacturing companies during a meeting held in Geneva in May 2017, in identifying and quantifying differences in the requirements for vaccine registration in three aspects for comparison: the dossier numbering structure and contents, the application forms, and the evaluation procedures, in different countries and regions. The Module 1 of the Common Technical Document (CTD) of 10 countries were compared. Modules 2-5 of the CTDs of two regions and three countries were compared to the CTD of the US FDA. The application forms of eight countries were compared and the registration procedures of 134 importing countries were compared as well. The analysis indicates a high degree of divergence in numbering structure and content requirements. Possible interventions that would lead to significant improvements in registration efficiency include alignment in CTD numbering structure, a standardised model-application form, and better convergence of evaluation procedures. Copyright © 2018.

Partnering for Vaccine Emerging Markets—Berlin, June 10–11, 2013

PubMed Central

Onraedt, Annelies

2013-01-01

Phacilitates 1st Partnering event for Vaccine Emerging Markets brought together approximately 100 attendees from developed and developing world vaccine manufacturers, leading non-profit organizations and industry suppliers. The goal was to discuss the vaccine needs in the developing world and how these needs can be met by leveraging collaboration and partnership models, by improving access to existing, new and next generation vaccines, by using novel technologies to drive competitive advantage and economics of vaccine manufacturing and by investing in localized capacity, including capacity for pandemic vaccines. The present article summarizes insights out of 30 oral contributions on how quality and capacity requirements can be balanced with cost by using novel manufacturing technologies and operating models. PMID:23966097

Vaccine supply, demand, and policy: a primer.

PubMed

Muzumdar, Jagannath M; Cline, Richard R

2009-01-01

To provide an overview of supply and demand issues in the vaccine industry and the policy options that have been implemented to resolve these issues. Medline, Policy File, and International Pharmaceutical Abstracts were searched to locate academic journal articles. Other sources reviewed included texts on the topics of vaccine history and policy, government agency reports, and reports from independent think tanks. Keywords included vaccines, immunizations, supply, demand, and policy. Search criteria were limited to English language and human studies. Articles pertaining to vaccine demand, supply, and public policy were selected and reviewed for inclusion. By the authors. Vaccines are biologic medications, therefore making their development and production more difficult and costly compared with "small-molecule" drugs. Research and development costs for vaccines can exceed $800 million, and development may require 10 years or more. Strict manufacturing regulations and facility upgrades add to these costs. Policy options to increase and stabilize the supply of vaccines include those aimed at increasing supply, such as government subsidies for basic vaccine research, liability protection for manufacturers, and fast-track approval for new vaccines. Options to increase vaccine demand include advance purchase commitments, government stockpiles, and government financing for select populations. High development costs and multiple barriers to entry have led to a decline in the number of vaccine manufacturers. Although a number of vaccine policies have met with mixed success in increasing the supply of and demand for vaccines, a variety of concerns remain, including developing vaccines for complex pathogens and increasing immunization rates with available vaccines. New policy innovations such as advance market commitments and Medicare Part D vaccine coverage have been implemented and may aid in resolving some of the problems in the vaccine industry.

Why does the world need another rotavirus vaccine?

PubMed Central

Ward, Richard L; McNeal, Monica M; Steele, A Duncan

2008-01-01

A “Meeting on Upstream Rotavirus Vaccines and Emerging Vaccine Producers” was held at the World Health Organization in Geneva, Switzerland on March 28–30, 2006. The purpose was to discuss, evaluate, and weigh the importance of additional rotavirus vaccine candidates following the successful international licensure of rotavirus vaccines by two major pharmaceutical companies (GlaxoSmithKline and Merck) that had been in development for many years. Both licensed vaccines are composed of live rotaviruses that are delivered orally as have been all candidate rotavirus vaccines evaluated in humans. Each is built on the experience gained with previous candidates whose development had either been discontinued or, in the case of the previously licensed rhesus rotavirus reassortant vaccine (Rotashield), was withdrawn by its manufacturer after the discovery of a rare association with intussusception. Although which alternative candidate vaccines should be supported for development and where this should be done are controversial topics, there was general agreement expressed at the Geneva meeting that further development of alternative candidates is a high priority. This development will help insure that the most safe, effective and economic vaccines are available to children in Third World nations where the vast majority of the >600,000 deaths due to rotavirus occur each year. This review is intended to provide the history and present status of rotavirus vaccines as well as a perspective on the future development of candidate vaccines as a means of promulgating plans suggested at the Geneva meeting. PMID:18728720

The role of vaccines and vaccine decision-making to achieve the goals of the Grand Convergence in public health.

PubMed

Kaslow, David C; Kalil, Jorge; Bloom, David; Breghi, Gianluca; Colucci, Anna Maria; De Gregorio, Ennio; Madhavan, Guru; Meier, Genevieve; Seabrook, Richard; Xu, Xiaoning

2017-01-20

On 17 and 18 July 2015, a meeting in Siena jointly sponsored by ADITEC and GlaxoSmithKline (GSK) was held to review the goals of the Global Health 2035 Grand Convergence, to discuss current vaccine evaluation methods, and to determine the feasibility of reaching consensus on an assessment framework for comprehensively and accurately capturing the full benefits of vaccines. Through lectures and workshops, participants reached a consensus that Multi-Criteria-Decision-Analysis is a method suited to systematically account for the many variables needed to evaluate the broad benefits of vaccination, which include not only health system savings, but also societal benefits, including benefits to the family and increased productivity. Participants also agreed on a set of "core values" to be used in future assessments of vaccines for development and introduction. These values include measures of vaccine efficacy and safety, incident cases prevented per year, the results of cost-benefit analyses, preventable mortality, and the severity of the target disease. Agreement on this set of core assessment parameters has the potential to increase alignment between manufacturers, public health agencies, non-governmental organizations (NGOs), and policy makers (see Global Health 2035 Mission Grand Convergence [1]). The following sections capture the deliberations of a workshop (Working Group 4) chartered to: (1) review the list of 24 parameters selected from SMART vaccines (see the companion papers by Timmis et al. and Madhavan et al., respectively) to determine which represent factors (see Table 1) that should be taken into account when evaluating the role of vaccines in maximizing the success of the Global Health 2035 Grand Convergence; (2) develop 3-5 "core values" that should be taken into account when evaluating vaccines at various stages of development; and (3) determine how vaccines can best contribute to the Global Health 2035 Grand Convergence effort. Copyright © 2016.

Stability of live attenuated rotavirus vaccine with selected preservatives and primary containers.

PubMed

Lal, Manjari; Jarrahian, Courtney; Zhu, Changcheng; Hosken, Nancy A; McClurkan, Chris L; Koelle, David M; Saxon, Eugene; Roehrig, Andrew; Zehrung, Darin; Chen, Dexiang

2016-05-11

Rotavirus infection, which can be prevented by vaccination, is responsible for a high burden of acute gastroenteritis disease in children, especially in low-income countries. An appropriate formulation, packaging, and delivery device for oral rotavirus vaccine has the potential to reduce the manufacturing cost of the vaccine and the logistical impact associated with introduction of a new vaccine, simplify the vaccination procedure, and ensure that the vaccine is safely and accurately delivered to children. Single-dose prefilled presentations can be easy to use; however, they are typically more expensive, can be a bottleneck during production, and occupy a greater volume per dose vis-à-vis supply chain storage and medical waste disposal, which is a challenge in low-resource settings. Multi-dose presentations used thus far have other issues, including increased wastage of vaccine and the need for separate delivery devices. In this study, the goals were to evaluate both the technical feasibility of using preservatives to develop a liquid multi-dose formulation and the primary packaging alternatives for orally delivered, liquid rotavirus vaccines. The feasibility evaluation included evaluation of commonly used preservatives for compatibility with rotavirus vaccines and stability testing of rotavirus vaccine in various primary containers, including Lameplast's plastic tubes, BD's oral dispenser version of Uniject™ (Uniject DP), rommelag's blow-fill-seal containers, and MEDInstill's multi-dose vial and pouch. These presentations were compared to a standard glass vial. The results showed that none of the preservatives tested were compatible with a live attenuated rotavirus vaccine because they had a detrimental effect on the viability of the virus. In the presence of preservatives, vaccine virus titers declined to undetectable levels within 1 month. The vaccine formulation without preservatives maintained a stability profile over 12 months in all primary containers

Utility of two modified-live virus canine distemper vaccines in wild-caught fishers (Martes pennanti).

PubMed

Peper, Steven T; Peper, Randall L; Mitcheltree, Denise H; Kollias, George V; Brooks, Robert P; Stevens, Sadie S; Serfass, Thomas L

2016-12-01

Canine distemper virus (CDV) infects families in the order Carnivora. As a preventive measure, vaccinations against CDV are frequently given to mustelids in captive environments. Our objectives were to compare the utility between two modified-live virus canine distemper vaccines (MLV CDV's), Fervac-D® (no longer manufactured) and Galaxy-D® (now manufactured by MSD Animal Health as part of a multivalent vaccine), in developing an immune response in wild-caught fishers. The Pennsylvania Fisher Reintroduction Project (PFRP) used 14 wild-caught fishers during one year of the project to evaluate the utility of vaccinations against CDV as part of any reintroduction project. Fishers were injected subcutaneously in the nape of the neck with their designated vaccine. Fervac-D® did not effectively stimulate development of a serologic antibody response, whereas Galaxy-D® had adequate seroconversion or rise of titer levels to suggest that the general use of MLV CDV may be suitable in fishers pending further studies. We recommend that future studies be conducted, evaluating the use of currently produced vaccines in fishers. Future research should also focus on the length of days required between administration of primary and booster vaccines to achieve sufficient immune response. If only primary doses are required, then hard-release reintroduction projects for fishers could be recommended. If primary and booster vaccines are required then soft-release reintroduction projects should be recommended that include captive management periods, allowing for appropriate vaccination intervals needed to maximize the probability of protection against CDV.

Technical Transformation of Biodefense Vaccines

PubMed Central

Lu, Shan; Wang, Shixia

2013-01-01

Biodefense vaccines are developed against a diverse group of pathogens. Vaccines were developed for some of these pathogens a long time ago but they are facing new challenges to move beyond the old manufacturing technologies. New vaccines to be developed against other pathogens have to determine whether to follow traditional vaccination strategies or to seek new approaches. Advances in basic immunology and recombinant DNA technology have fundamentally transformed the process of formulating a vaccine concept, optimizing protective antigens, and selecting the most effective vaccine delivery approach for candidate biodefense vaccines. PMID:19837293

Vaccines today, vaccines tomorrow: a perspective.

PubMed

Loucq, Christian

2013-01-01

Vaccines are considered as one of the major contributions of the 20th century and one of the most cost effective public health interventions. The International Vaccine Institute has as a mission to discover, develop and deliver new and improved vaccines against infectious diseases that affects developing nations. If Louis Pasteur is known across the globe, vaccinologists like Maurice Hilleman, Jonas Salk and Charles Mérieux are known among experts only despite their contribution to global health. Thanks to a vaccine, smallpox has been eradicated, polio has nearly disappeared, Haemophilus influenzae B, measles and more recently meningitis A are controlled in many countries. While a malaria vaccine is undergoing phase 3, International Vaccine Institute, in collaboration with an Indian manufacturer has brought an oral inactivated cholera vaccine to pre-qualification. The field of vaccinology has undergone major changes thanks to philanthropists such as Bill and Melinda Gates, initiatives like the Decade of Vaccines and public private partnerships. Current researches on vaccines have more challenging targets like the dengue viruses, malaria, human immunodeficiency virus, the respiratory syncytial virus and nosocomial diseases. Exciting research is taking place on new adjuvants, nanoparticles, virus like particles and new route of administration. An overcrowded infant immunization program, anti-vaccine groups, immunizing a growing number of elderlies and delivering vaccines to difficult places are among challenges faced by vaccinologists and global health experts.

Propelling novel vaccines directed against tuberculosis through the regulatory process.

PubMed

Brennan, M J; Collins, F M; Morris, S L

1999-01-01

The development of novel vaccines for use in the prevention and immunotherapy of tuberculosis is an area of intense interest for scientific researchers, public health agencies and pharmaceutical manufacturers. Development of effective anti-tuberculosis vaccines for use in specific target populations will require close cooperation among several different international organizations including agencies responsible for evaluating the safety and effectiveness of new biologics for human use. In this review, the major issues that are addressed by regulatory agencies to ensure that vaccines are pure, potent, safe, and effective are discussed. It is hoped that the comments provided here will help accelerate the development of new effective vaccines for the prevention and treatment of tuberculosis.

Egg-Independent Influenza Vaccines and Vaccine Candidates

PubMed Central

Manini, Ilaria; Pozzi, Teresa; Rossi, Stefania; Montomoli, Emanuele

2017-01-01

Vaccination remains the principal way to control seasonal infections and is the most effective method of reducing influenza-associated morbidity and mortality. Since the 1940s, the main method of producing influenza vaccines has been an egg-based production process. However, in the event of a pandemic, this method has a significant limitation, as the time lag from strain isolation to final dose formulation and validation is six months. Indeed, production in eggs is a relatively slow process and production yields are both unpredictable and highly variable from strain to strain. In particular, if the next influenza pandemic were to arise from an avian influenza virus, and thus reduce the egg-laying hen population, there would be a shortage of embryonated eggs available for vaccine manufacturing. Although the production of egg-derived vaccines will continue, new technological developments have generated a cell-culture-based influenza vaccine and other more recent platforms, such as synthetic influenza vaccines. PMID:28718786

Innovations in vaccine development: can regulatory authorities keep up?

PubMed

Cox, Manon M J; Onraedt, Annelies

2012-10-01

Vaccine Production Summit San Francisco, CA, USA, 4-6 June 2012 IBC's 3rd Vaccine Production Summit featured 28 presentations discussing regulatory challenges in vaccine development, including the use of adjuvants, vaccine manufacturing and technology transfer, process development for vaccines and the role of quality by design, how to address vaccine stability, and how vaccine development timelines can be improved. The conference was run in parallel with the single-use applications for Biopharmaceutical Manufacturing conference. Approximately 250 attendees from large pharmaceutical companies, large and small biotech companies, vendors and a more limited number from academia were allowed to access sessions of either conference, including one shared session. This article summarizes the recurring themes across various presentations.

Epidemiological Studies to Support the Development of Next Generation Influenza Vaccines.

PubMed

Petrie, Joshua G; Gordon, Aubree

2018-03-26

The National Institute of Allergy and Infectious Diseases recently published a strategic plan for the development of a universal influenza vaccine. This plan focuses on improving understanding of influenza infection, the development of influenza immunity, and rational design of new vaccines. Epidemiological studies such as prospective, longitudinal cohort studies are essential to the completion of these objectives. In this review, we discuss the contributions of epidemiological studies to our current knowledge of vaccines and correlates of immunity, and how they can contribute to the development and evaluation of the next generation of influenza vaccines. These studies have been critical in monitoring the effectiveness of current influenza vaccines, identifying issues such as low vaccine effectiveness, reduced effectiveness among those who receive repeated vaccination, and issues related to egg adaptation during the manufacturing process. Epidemiological studies have also identified population-level correlates of protection that can inform the design and development of next generation influenza vaccines. Going forward, there is an enduring need for epidemiological studies to continue advancing knowledge of correlates of protection and the development of immunity, to evaluate and monitor the effectiveness of next generation influenza vaccines, and to inform recommendations for their use.

Size of clinical trials and Introductory prices of prophylactic vaccine series

PubMed Central

Weinberg, Steven H.; Butchart, Amy T.; Davis, Matthew M.

2012-01-01

Costs of completing the recommended immunization schedule have increased over the last decade. Access to prophylactic vaccines may become limited due to financing obstacles within current delivery systems. Vaccine prices reflect research and development expenses incurred by vaccine manufacturers, including costs associated with evaluating candidate vaccines in human subjects. If the number of subjects in clinical trials is increasing over time and associated with vaccine price, this may help explain increases in prices of vaccine series. We examined whether: (A) the initial public- and private-sector prices for recommended prophylactic vaccine series licensed and recommended in the US increased from 2000–2011, (B) the number of human subjects per licensed vaccine increased during the time period, and (C) the number of human subjects was associated with the initial public–and private–sector prices of the vaccine series. In regression analyses of 13 vaccines, approval year was not significantly associated with the number of human subjects, initial public-sector prices, or initial private-sector prices. While the number of phase II subjects was not significantly associated with prices, the numbers of phase III and combined late phase (phases II + III) subjects were significantly associated with initial public- and private-sector series prices (p < 0.05). The association between number of subjects and initial prices demonstrated diminishing marginal increases in price with increasing numbers of subjects. These findings may help guide the number of subjects required by the FDA in clinical trials, in order to reduce expenses for manufacturers and thereby help mitigate increases in initial vaccine series prices. PMID:22854668

Size of clinical trials and Introductory prices of prophylactic vaccine series.

PubMed

Weinberg, Steven H; Butchart, Amy T; Davis, Matthew M

2012-08-01

Costs of completing the recommended immunization schedule have increased over the last decade. Access to prophylactic vaccines may become limited due to financing obstacles within current delivery systems. Vaccine prices reflect research and development expenses incurred by vaccine manufacturers, including costs associated with evaluating candidate vaccines in human subjects. If the number of subjects in clinical trials is increasing over time and associated with vaccine price, this may help explain increases in prices of vaccine series. We examined whether: (A) the initial public- and private-sector prices for recommended prophylactic vaccine series licensed and recommended in the US increased from 2000-2011, (B) the number of human subjects per licensed vaccine increased during the time period, and (C) the number of human subjects was associated with the initial public-and private-sector prices of the vaccine series. In regression analyses of 13 vaccines, approval year was not significantly associated with the number of human subjects, initial public-sector prices, or initial private-sector prices. While the number of phase II subjects was not significantly associated with prices, the numbers of phase III and combined late phase (phases II + III) subjects were significantly associated with initial public- and private-sector series prices (p < 0.05). The association between number of subjects and initial prices demonstrated diminishing marginal increases in price with increasing numbers of subjects. These findings may help guide the number of subjects required by the FDA in clinical trials, in order to reduce expenses for manufacturers and thereby help mitigate increases in initial vaccine series prices.

The Human Hookworm Vaccine.

PubMed

Hotez, Peter J; Diemert, David; Bacon, Kristina M; Beaumier, Coreen; Bethony, Jeffrey M; Bottazzi, Maria Elena; Brooker, Simon; Couto, Artur Roberto; Freire, Marcos da Silva; Homma, Akira; Lee, Bruce Y; Loukas, Alex; Loblack, Marva; Morel, Carlos Medicis; Oliveira, Rodrigo Correa; Russell, Philip K

2013-04-18

Hookworm infection is one of the world's most common neglected tropical diseases and a leading cause of iron deficiency anemia in low- and middle-income countries. A Human Hookworm Vaccine is currently being developed by the Sabin Vaccine Institute and is in phase 1 clinical testing. The candidate vaccine is comprised of two recombinant antigens known as Na-GST-1 and Na-APR-1, each of which is an important parasite enzyme required for hookworms to successfully utilize host blood as a source of energy. The recombinant proteins are formulated on Alhydrogel(®) and are being tested in combination with a synthetic Toll-like receptor 4 agonist. The aim of the vaccine is to induce anti-enzyme antibodies that will reduce both host blood loss and the number of hookworms attached to the gut. Transfer of the manufacturing technology to the Oswaldo Cruz Foundation (FIOCRUZ)/Bio-Manguinhos (a Brazilian public sector developing country vaccine manufacturer) is planned, with a clinical development plan that could lead to registration of the vaccine in Brazil. The vaccine would also need to be introduced in the poorest regions of Africa and Asia, where hookworm infection is highly endemic. Ultimately, the vaccine could become an essential tool for achieving hookworm control and elimination, a key target in the 2012 London Declaration on Neglected Tropical Diseases. Copyright © 2012 Elsevier Ltd. All rights reserved.

The Human Hookworm Vaccine

PubMed Central

Hotez, Peter J.; Diemert, David; Bacon, Kristina M.; Beaumier, Coreen; Bethony, Jeffrey M.; Bottazzi, Maria Elena; Brooker, Simon; Couto, Artur Roberto; da Silva Freire, Marcos; Homma, Akira; Lee, Bruce Y.; Loukas, Alex; Loblack, Marva; Morel, Carlos Medicis; Oliveira, Rodrigo Correa; Russell, Philip K.

2013-01-01

Hookworm infection is one of the world's most common neglected tropical diseases and a leading cause of iron deficiency anemia in low- and middle-income countries. A Human Hookworm Vaccine is currently being developed by the Sabin Vaccine Institute and is in phase 1 clinical testing. The candidate vaccine is comprised of two recombinant antigens known as Na-GST-1 and Na-APR-1, each of which is an important parasite enzyme required for hookworms to successfully utilize host blood as a source of energy. The recombinant proteins are formulated on Alhydrogel® and are being tested in combination with a synthetic Toll-like receptor 4 agonist. The aim of the vaccine is to induce anti-enzyme antibodies that will reduce both host blood loss and the number of hookworms attached to the gut. Transfer of the manufacturing technology to the Oswaldo Cruz Foundation (FIOCRUZ)/Bio-Manguinhos (a Brazilian public sector developing country vaccine manufacturer) is planned, with a clinical development plan that could lead to registration of the vaccine in Brazil. The vaccine would also need to be introduced in the poorest regions of Africa and Asia, where hookworm infection is highly endemic. Ultimately, the vaccine could become an essential tool for achieving hookworm control and elimination, a key target in the 2012 London Declaration on Neglected Tropical Diseases. PMID:23598487

Evaluation of two vaccine education interventions to improve pertussis vaccination among pregnant African American women: A randomized controlled trial.

PubMed

Kriss, Jennifer L; Frew, Paula M; Cortes, Marielysse; Malik, Fauzia A; Chamberlain, Allison T; Seib, Katherine; Flowers, Lisa; Ault, Kevin A; Howards, Penelope P; Orenstein, Walter A; Omer, Saad B

2017-03-13

Vaccination coverage with tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis (Tdap) vaccine in pregnancy or immediately postpartum has been low. Limited data exist on rigorously evaluated interventions to increase maternal vaccination, including Tdap. Tailored messaging based on the Elaboration Likelihood Model (ELM) framework has been successful in improving uptake of some public health interventions. We evaluated the effect of two ELM-based vaccine educational interventions on Tdap vaccination among pregnant African American women, a group of women who tend to have lower vaccine uptake compared with other groups. We conducted a prospective randomized controlled trial to pilot test two interventions - an affective messaging video and a cognitive messaging iBook - among pregnant African American women recruited during routine prenatal care visits. We measured Tdap vaccination during the perinatal period (during pregnancy and immediately postpartum), reasons for non-vaccination, and intention to receive Tdap in the next pregnancy. Among the enrolled women (n=106), 90% completed follow-up. Tdap vaccination in the perinatal period was 18% in the control group; 50% in the iBook group (Risk Ratio [vs. control group]: 2.83; 95% CI, 1.26-6.37), and 29% in the video group (RR: 1.65; 95% CI, 0.66-4.09). From baseline to follow-up, women's reported intention to receive Tdap during the next pregnancy improved in all three groups. Among unvaccinated women, the most common reason reported for non-vaccination was lack of a recommendation for Tdap by the woman's physician. Education interventions that provide targeted information for pregnant women in an interactive manner may be useful to improve Tdap vaccination during the perinatal period. However, larger studies including multiple racial and ethnic groups are needed to evaluate robustness of our findings. clinicaltrials.gov Identifier: NCT01740310. Copyright © 2017 Elsevier Ltd. All rights reserved.

Live-attenuated tetravalent dengue vaccines: The needs and challenges of post-licensure evaluation of vaccine safety and effectiveness.

PubMed

Wichmann, Ole; Vannice, Kirsten; Asturias, Edwin J; de Albuquerque Luna, Expedito José; Longini, Ira; Lopez, Anna Lena; Smith, Peter G; Tissera, Hasitha; Yoon, In-Kyu; Hombach, Joachim

2017-10-09

Since December 2015, the first dengue vaccine has been licensed in several Asian and Latin American countries for protection against disease from all four dengue virus serotypes. While the vaccine demonstrated an overall good safety and efficacy profile in clinical trials, some key research questions remain which make risk-benefit-assessment for some populations difficult. As for any new vaccine, several questions, such as very rare adverse events following immunization, duration of vaccine-induced protection and effectiveness when used in public health programs, will be addressed by post-licensure studies and by data from national surveillance systems after the vaccine has been introduced. However, the complexity of dengue epidemiology, pathogenesis and population immunity, as well as some characteristics of the currently licensed vaccine, and potentially also future, live-attenuated dengue vaccines, poses a challenge for evaluation through existing monitoring systems, especially in low and middle-income countries. Most notable are the different efficacies of the currently licensed vaccine by dengue serostatus at time of first vaccination and by dengue virus serotype, as well as the increased risk of dengue hospitalization among young vaccinated children observed three years after the start of vaccination in one of the trials. Currently, it is unknown if the last phenomenon is restricted to younger ages or could affect also seronegative individuals aged 9years and older, who are included in the group for whom the vaccine has been licensed. In this paper, we summarize scientific and methodological considerations for public health surveillance and targeted post-licensure studies to address some key research questions related to live-attenuated dengue vaccines. Countries intending to introduce a dengue vaccine should assess their capacities to monitor and evaluate the vaccine's effectiveness and safety and, where appropriate and possible, enhance their surveillance

A review of typhoid fever transmission dynamic models and economic evaluations of vaccination.

PubMed

Watson, Conall H; Edmunds, W John

2015-06-19

Despite a recommendation by the World Health Organization (WHO) that typhoid vaccines be considered for the control of endemic disease and outbreaks, programmatic use remains limited. Transmission models and economic evaluation may be informative in decision making about vaccine programme introductions and their role alongside other control measures. A literature search found few typhoid transmission models or economic evaluations relative to analyses of other infectious diseases of similar or lower health burden. Modelling suggests vaccines alone are unlikely to eliminate endemic disease in the short to medium term without measures to reduce transmission from asymptomatic carriage. The single identified data-fitted transmission model of typhoid vaccination suggests vaccines can reduce disease burden substantially when introduced programmatically but that indirect protection depends on the relative contribution of carriage to transmission in a given setting. This is an important source of epidemiological uncertainty, alongside the extent and nature of natural immunity. Economic evaluations suggest that typhoid vaccination can be cost-saving to health services if incidence is extremely high and cost-effective in other high-incidence situations, when compared to WHO norms. Targeting vaccination to the highest incidence age-groups is likely to improve cost-effectiveness substantially. Economic perspective and vaccine costs substantially affect estimates, with disease incidence, case-fatality rates, and vaccine efficacy over time also important determinants of cost-effectiveness and sources of uncertainty. Static economic models may under-estimate benefits of typhoid vaccination by omitting indirect protection. Typhoid fever transmission models currently require per-setting epidemiological parameterisation to inform their use in economic evaluation, which may limit their generalisability. We found no economic evaluation based on transmission dynamic modelling, and no

Evaluation of introduction of the Haemophilus influenzae vaccine in Côte d’Ivoire

PubMed

Yohou, Kévin Sylvestre; Aka, Nicaise Lepri; Noufe, Soualihou; Douba, Alfred; Assi Assi, Bernard; Dagnan, Simplice N Cho

2016-11-25

Introduction: Côte d’Ivoire introduced the Haemophilus influenzae type b vaccine into the EPI in March 2009. Following this introduction, an evaluation was conducted in 2012 in order to evaluate the vaccine introduction process. Methods: Data collection methods consisted of document review, structured interviews and direct observation. This study collected information from six health region officials, 12 health districts and 36 healthcare institutions. Seventy-two mothers or child carers were also interviewed. Collected data were processed and analysed by Excel, Epi Info and SPSS. Results: A vaccine introduction plan was developed, but was not communicated at the operational level. The planned training for district health care providers was conducted eighteen months after introduction of the vaccine. None of the vaccinating centres had communication support about the new vaccine. Temperature recording was regularly performed in 92% of district deposits and 68% of vaccinating centres. Deteriorated vaccines were observed in 6% of vaccinating centres. Only 3.5% of parents had been informed about introduction of the vaccine. Increased immunization coverage for the third dose of pentavalent vaccine was observed in one half of health districts. Conclusion: Evaluation of the introduction of Haemophilus influenzae type b vaccine highlightsthe strengths and weaknesses of the health system and provides lessons for the introduction of other vaccines into the expanded programme on immunization.

Pharmaceutical companies' role in state vaccination policymaking: the case of human papillomavirus vaccination.

PubMed

Mello, Michelle M; Abiola, Sara; Colgrove, James

2012-05-01

We sought to investigate roles that Merck & Co Inc played in state human papillomavirus (HPV) immunization policymaking, to elicit key stakeholders' perceptions of the appropriateness of these activities, and to explore implications for relationships between health policymakers and industry. We used a series of state case studies combining data from key informant interviews with analysis of media reports and archival materials. We interviewed 73 key informants in 6 states that were actively engaged in HPV vaccine policy deliberations. Merck promoted school-entry mandate legislation by serving as an information resource, lobbying legislators, drafting legislation, mobilizing female legislators and physician organizations, conducting consumer marketing campaigns, and filling gaps in access to the vaccine. Legislators relied heavily on Merck for scientific information. Most stakeholders found lobbying by vaccine manufacturers acceptable in principle, but perceived that Merck had acted too aggressively and nontransparently in this case. Although policymakers acknowledge the utility of manufacturers' involvement in vaccination policymaking, industry lobbying that is overly aggressive, not fully transparent, or not divorced from financial contributions to lawmakers risks undermining the prospects for legislation to foster uptake of new vaccines.

Considerations for setting the specifications of vaccines.

PubMed

Minor, Philip

2012-05-01

The specifications of vaccines are determined by the particular product and its method of manufacture, which raise issues unique to the vaccine in question. However, the general principles are shared, including the need to have sufficient active material to immunize a very high proportion of recipients, an acceptable level of safety, which may require specific testing or may come from the production process, and an acceptable low level of contamination with unwanted materials, which may include infectious agents or materials used in production. These principles apply to the earliest smallpox vaccines and the most recent recombinant vaccines, such as those against HPV. Manufacturing development includes more precise definitions of the product through improved tests and tighter control of the process parameters. Good manufacturing practice plays a major role, which is likely to increase in importance in assuring product quality almost independent of end-product specifications.

Analysis on critical success factors for agile manufacturing evaluation in original equipment manufacturing industry-an AHP approach

NASA Astrophysics Data System (ADS)

Ajay Guru Dev, C.; Senthil Kumar, V. S.

2016-09-01

Manufacturing industries are facing challenges in the implementation of agile manufacturing in their products and processes. Agility is widely accepted as a new competitive concept in the manufacturing sector in fulfilling varying customer demand. Thus, evaluation of agile manufacturing in industries has become a necessity. The success of an organisation depends on its ability to manage finding the critical success factors and give them special and continued attention in order to bring about high performance. This paper proposes a set of critical success factors (CSFs) for evaluating agile manufacturing considered appropriate for the manufacturing sector. The analytical hierarchy process (AHP) method is applied for prioritizing the success factors, by summarizing the opinions of experts. It is believed that the proposed CSFs enable and assist manufacturing industries to achieve a higher performance in agile manufacturing so as to increase competitiveness.

A comparative study on the immunogenicity, safety and tolerance of purified duck embryo vaccine (PDEV) manufactured in India (Vaxirab) and Switzerland (Lyssavac-N): a randomized simulated post-exposure study in healthy volunteers.

PubMed

Mahendra, Bangalore Jayakrishnappa; Madhusudana, Shampur Narayan; Ashwathnarayana, Doddabele Hanumanthaiah; Sampath, Gadey; datta, Soma Subhra; Sudarshan, Mysore Kalappa; Venkatesh, Gonibeedu Manjunatah; Muhamuda, Kader; Bilagumba, Gangaboraiah; Shamanna, Manjula

2007-12-05

Purified duck embryo vaccine (PDEV, Vaxirab) for rabies prophylaxis is now indigenously manufactured in India under technology transfer from Berna Biotech who made the original PDEV (Lyssavac). In the present study we have compared the two vaccines in terms of safety, immunogenicity and tolerance. The study was conducted in 220 adult healthy volunteers. It was observed that both vaccines produced neutralizing antibody titers (as determined by rapid fluorescent focus inhibition test, RFFIT) more than 0.5 IU/mL (minimum level for seroconversion) on all days tested but the titers on days 90 and 180 were significantly higher with Lyssavac. The adverse reactions produced were slightly more with Lysssavac but both vaccines were well tolerated. In conclusion, the indigenously produced PDEV (Vaxirab) was found to be equally safe and immunogenic as the original PDEV (Lyssavac) manufactured at Switzerland.

[Seasonal flu vaccination for older people: Evaluation of the adjuvanted vaccine. Positioning report].

PubMed

López Mongil, Rosa; López Trigo, José Antonio; Mariano Lázaro, Alberto; Mato Chaín, Gloria; Ramos Cordero, Primitivo; Salleras Sanmartí, Luis

2017-11-01

Flu is a major public health problem, particularly for older people, and creates an important clinical and economic burden. A high mortality rate was reported in Spain during the period 2015 to 2016; 3,101 serious cases were hospitalised with a confirmed diagnosis of flu, of which 11% died (352 cases). Furthermore, financial and health costs are greatly increased by the complications of flu; people aged over 65 years represent approximately 64% of the total costs. Seasonal flu vaccination is the fundamental strategy, as demonstrated by cost-benefit and cost-effectiveness studies. A priority objective is to improve the vaccine's immune response and the search for and inclusion of adjuvants and immunostimulants in vaccines is a major line of research. This positioning report evaluates vaccination for older people and the importance of the adjuvanted vaccine in the elderly in strengthening immunogenicity, by means of a critical review of the literature based on the best evidence available on its immunogenicity and effectiveness, and an economic assessment. Copyright © 2017 Sociedad Española de Geriatría y Gerontología. Publicado por Elsevier España, S.L.U. All rights reserved.

Tularemia vaccine: Safety, reactogenicity, "Take" skin reactions, and antibody responses following vaccination with a new lot of the Francisella tularensis live vaccine strain - A phase 2 randomized clinical Trial.

PubMed

Mulligan, Mark J; Stapleton, Jack T; Keitel, Wendy A; Frey, Sharon E; Chen, Wilbur H; Rouphael, Nadine; Edupuganti, Srilatha; Beck, Allison; Winokur, Patricia L; El Sahly, Hana M; Patel, Shital M; Atmar, Robert L; Graham, Irene; Anderson, Edwin; El-Kamary, Samer S; Pasetti, Marcela F; Sztein, Marcelo B; Hill, Heather; Goll, Johannes B

2017-08-24

Tularemia is caused by Francisella tularensis, a gram-negative bacterium that has been weaponized as an aerosol. For protection of personnel conducting biodefense research, the United States Army required clinical evaluation of a new lot of tularemia live vaccine strain manufactured in accordance with Current Good Manufacturing Practices. A phase 2 randomized clinical trial compared the new lot (DVC-LVS) to the existing vaccine that has been in use for decades (USAMRIID-LVS). The vaccines were delivered by scarification to 228 participants. Safety, reactogenicity, take and/or antibody levels were assessed on days 0, 1, 2, 8, 14, 28, 56, and 180. Both vaccines were safe and had acceptable reactogenicity profiles during six months of follow-up. There were no serious or grade 3 and 4 laboratory adverse events. Moderate systemic reactogenicity (mostly headache or feeling tired) was reported by ∼23% of participants receiving either vaccine. Injection site reactogenicity was mostly mild itchiness and pain. The frequencies of vaccine take skin reactions were 73% (95% CI, 64, 81) for DVC-LVS and 80% (95% CI, 71, 87) for USAMRIID-LVS. The 90% CI for the difference in proportions was -6.9% (-16.4, 2.6). The rates of seroconversion measured by microagglutination assay on days 28 or 56 were 94% (95% CI, 88, 98; n=98/104) for DVC-LVS and 94% (95% CI, 87, 97; n=103/110) for USAMRIID-LVS (p=1.00). Day 14 sera revealed more rapid seroconversion for DVC-LVS relative to USAMRIID-LVS: 82% (95% CI, 73, 89) versus 55% (95% CI, 45, 65), respectively (p<0.0001). The DVC-LVS vaccine had similar safety, reactogenicity, take and antibody responses compared to the older USAMRIID vaccine, and was superior for early (day 14) antibody production. Vaccination take was not a sensitive surrogate for seroconversion in a multi-center study where personnel at five research clinics performed assessments. ClinicalTrials.gov identifier NCT01150695. Copyright © 2017 The Authors. Published by Elsevier

Evaluation of vaccine competition using HVT vector vaccines

USDA-ARS?s Scientific Manuscript database

Turkey herpesvirus (HVT) has been widely used as a vaccine for Marek’s disease (MD) since the 1970s. Because HVT is a safe vaccine that is poorly sensitive to interference from maternally derived antibodies, it has seen rising use as a vector for vaccines developed for protection against other comm...

New Vaccines for the World's Poorest People.

PubMed

Hotez, Peter J; Bottazzi, Maria Elena; Strych, Ulrich

2016-01-01

The 2000 Millennium Development Goals helped stimulate the development of life-saving childhood vaccines for pneumococcal and rotavirus infections while greatly expanding coverage of existing vaccines. However, there remains an urgent need to develop new vaccines for HIV/AIDS, malaria, and tuberculosis, as well as for respiratory syncytial virus and those chronic and debilitating (mostly parasitic) infections known as neglected tropical diseases (NTDs). The NTDs represent the most common diseases of people living in extreme poverty and are the subject of this review. The development of NTD vaccines, including those for hookworm infection, schistosomiasis, leishmaniasis, and Chagas disease, is being led by nonprofit product development partnerships (PDPs) working in consortia of academic and industrial partners, including vaccine manufacturers in developing countries. NTD vaccines face unique challenges with respect to their product development and manufacture, as well as their preclinical and clinical testing. We emphasize global efforts to accelerate the development of NTD vaccines and some of the hurdles to ensuring their availability to the world's poorest people.

A critical literature review of health economic evaluations of rotavirus vaccination

PubMed Central

Aballéa, Samuel; Millier, Aurélie; Quilici, Sibilia; Caroll, Stuart; Petrou, Stavros; Toumi, Mondher

2013-01-01

Two licensed vaccines are available to prevent RVGE in infants. A worldwide critical review of economic evaluations of these vaccines was conducted. The objective was to describe differences in methodologies, assumptions and inputs and determine the key factors driving differences in conclusions. 68 economic evaluations were reviewed. RV vaccination was found to be cost-effective in developing countries, while conclusions varied between studies in developed countries. Many studies found that vaccination was likely to be cost-effective under some scenarios, such as lower prices scenarios, inclusion of herd protection, and/or adoption of a societal perspective. Other reasons for variability included uncertainty around healthcare visits incidence and lack of consensus on quality of life (QoL) valuation for infants and caregivers. New evidence on the vaccination effectiveness in real-world, new ways of modeling herd protection and assessments of QoL in children could help more precisely define the conditions under which RV vaccination would be cost-effective in developed countries. PMID:23571226

Economic evaluation of vaccination programme of mumps vaccine to the birth cohort in Japan.

PubMed

Hoshi, Shu-ling; Kondo, Masahide; Okubo, Ichiro

2014-07-16

The most common preventative measure against mumps is vaccination with mumps vaccine. In most parts of the world, mumps vaccine is routinely delivered through live attenuated Measles-Mumps-Rubella (MMR) vaccine. In Japan, receiving mumps vaccine is voluntary and vaccine uptake rate is less than 30%. The introduction of mumps vaccine into routine vaccination schedule has become one of the current topics in health policy and has raised the need to evaluate efficient ways in protecting children from mumps-related diseases in Japan. We conducted a cost-effectiveness analysis with Markov model and calculated incremental cost effectiveness ratios (ICERs) of 11 different programmes; a single-dose programme at 12-16 months and 10 two-dose programmes with second dose uptakes at ages 2, 3, 4, 5, 6, 7, 8, 9, 10 and 11. Our base-case analyse set the cost per shot at ¥6951 (US$72; 1US$=96.8). Results show that single-dose programme dominates status quo. On the other hand, ICERs of all 10 two-dose programmes are under ¥6,300,000 (US$65,082) per QALY from payer's perspective while it ranged from cost-saving to <¥7,000,000 (US$72,314) per QALY from societal perspective. By adopting WHO's classification that an intervention is cost-effective if ICER (in QALY) is between one and three times of GDP as a criterion, either of the vaccination programme is concluded as cost-effective from payer's or societal perspectives. Likewise, to uptake second dose at 3-5 years old is more favourable than an uptake at any other age because of lower incremental cost-effectiveness ratios. Copyright © 2014 Elsevier Ltd. All rights reserved.

Public Health Law and Institutional Vaccine Skepticism.

PubMed

Parasidis, Efthimios

2016-12-01

Vaccine-hesitant parents are often portrayed as misinformed dilettantes clinging to unscientific Internet chatter and a debunked study that linked the MMR vaccine and autism. While this depiction may be an accurate portrayal of a small (but vocal) subset, scholars have unearthed a more complex picture that casts vaccine hesitancy in the context of broader notions of lack of trust in government and industry. At the same time, commentators have highlighted limitations of the vaccine injury compensation program and US Supreme Court Justices Sonia Sotomayor and Ruth Bader Ginsburg have argued that preemption laws that provide vaccine manufacturers with broad legal immunities create "a regulatory vacuum in which no one ensures that vaccine manufacturers adequately take account of scientific and technological advancements when designing or distributing their products." In short, the discussions surrounding vaccine hesitancy that dominate public discourse detract from serious debate as to whether amendments to vaccine-related laws can address the limitations of the existing framework governing immunizations. This commentary examines these issues through a public health law lens. Copyright © 2016 by Duke University Press.

Glycoconjugate Vaccines: The Regulatory Framework.

PubMed

Jones, Christopher

2015-01-01

Most vaccines, including the currently available glycoconjugate vaccines, are administered to healthy infants, to prevent future disease. The safety of a prospective vaccine is a key prerequisite for approval. Undesired side effects would not only have the potential to damage the individual infant but also lead to a loss of confidence in the respective vaccine-or vaccines in general-on a population level. Thus, regulatory requirements, particularly with regard to safety, are extremely rigorous. This chapter highlights regulatory aspects on carbohydrate-based vaccines with an emphasis on analytical approaches to ensure the consistent quality of successive manufacturing lots.

Analytics for vaccine economics and pricing: insights and observations.

PubMed

Robbins, Matthew J; Jacobson, Sheldon H

2015-04-01

Pediatric immunization programs in the USA are a successful and cost-effective public health endeavor, profoundly reducing mortalities caused by infectious diseases. Two important issues relate to the success of the immunization programs, the selection of cost-effective vaccines and the appropriate pricing of vaccines. The recommended childhood immunization schedule, published annually by the CDC, continues to expand with respect to the number of injections required and the number of vaccines available for selection. The advent of new vaccines to meet the growing requirements of the schedule results: in a large, combinatorial number of possible vaccine formularies. The expansion of the schedule and the increase in the number of available vaccines constitutes a challenge for state health departments, large city immunization programs, private practices and other vaccine purchasers, as a cost-effective vaccine formulary must be selected from an increasingly large set of possible vaccine combinations to satisfy the schedule. The pediatric vaccine industry consists of a relatively small number of pharmaceutical firms engaged in the research, development, manufacture and distribution of pediatric vaccines. The number of vaccine manufacturers has dramatically decreased in the past few decades for a myriad of reasons, most notably due to low profitability. The contraction of the industry negatively impacts the reliable provision of pediatric vaccines. The determination of appropriate vaccine prices is an important issue and influences a vaccine manufacturer's decision to remain in the market. Operations research is a discipline that applies advanced analytical methods to improve decision making; analytics is the application of operations research to a particular problem using pertinent data to provide a practical result. Analytics provides a mechanism to resolve the challenges facing stakeholders in the vaccine development and delivery system, in particular, the selection

Immunological Evaluation of Recent MUC1 Glycopeptide Cancer Vaccines

PubMed Central

Hossain, Md Kamal; Wall, Katherine A.

2016-01-01

Aberrantly glycosylated mucin 1 (MUC1) is a recognized tumor-specific antigen on epithelial cell tumors. A wide variety of MUC1 glycopeptide anti-cancer vaccines have been formulated by many research groups. Some researchers have used MUC1 alone as an immunogen whereas other groups used different antigenic carrier proteins such as bovine serum albumin or keyhole limpet hemocyanin for conjugation with MUC1 glycopeptide. A variety of adjuvants have been used with MUC1 glycopeptides to improve their immunogenicity. Fully synthetic multicomponent vaccines have been synthesized by incorporating different T helper cell epitopes and Toll-like receptor agonists. Some vaccine formulations utilized liposomes or nanoparticles as vaccine delivery systems. In this review, we discuss the immunological evaluation of different conjugate or synthetic MUC1 glycopeptide vaccines in different tumor or mouse models that have been published since 2012. PMID:27472370

A systematic review of health economic evaluations of vaccines in Brazil.

PubMed

Sartori, Ana Marli Christovam; Rozman, Luciana Martins; Decimoni, Tassia Cristina; Leandro, Roseli; Novaes, Hillegonda Maria Dutilh; de Soárez, Patrícia Coelho

2017-06-03

In Brazil, since 2005, the Ministry of Health requires Health Economic Evaluation (HEE) of vaccines for introduction into the National Immunization Program. To describe and analyze the full HEE on vaccines conducted in Brazil from 1980 to 2013. Systematic review of the literature. We searched multiple databases. Two researchers independently selected the studies and extracted the data. The methodological quality of individual studies was evaluated using CHEERS items. Twenty studies were reviewed. The most evaluated vaccines were pneumococcal (25%) and HPV (15%). The most used types of HEE were cost-effectiveness analysis (45%) and cost-utility analysis (20%). The research question and compared strategies were stated in all 20 studies and the target population was clear in 95%. Nevertheless, many studies did not inform the perspective of analysis or data sources. HEE of vaccines in Brazil has increased since 2008. However, the studies still have methodological deficiencies.

Manufacturer evaluations of endograft modifications.

PubMed

Waninger, Matthew S; Whirley, Robert G; Smith, Louis J; Wolf, Ben S

2013-03-01

The motivation to modify the design of a vascular device can arise from a number of sources. Clinical experience with the unmodified device could suggest new design modifications to improve device performance or clinical outcomes. Similarly, clinical success with a device often suggests modifications that could broaden the applicability of the device to enable treatment of different or more advanced disease states. As a specific example, both of these scenarios have arisen during the last decade in the evolution of endovascular grafts for the treatment of abdominal aortic aneurysms, with modifications enabling the treatment of patients with shorter infrarenal necks, more angulated anatomy, and smaller access vessels. These modifications have been made by manufacturers and additionally by physicians who create branched and fenestrated devices. The experience to date with the use of fenestrated devices and the development of chimney, snorkel, and periscope techniques suggests that modifications to off-the-shelf devices may provide some clinical benefit. This experience provides additional motivation for manufacturers to develop devices to address the clinical needs not met with their current product lines. For manufacturers, the device development process includes an assessment of the new device design to determine the appropriate evaluation strategy to support the safety and effectiveness of the modified device. This report provides a high-level overview of the process generally followed by device manufacturers to evaluate a proposed device modification before market release, in accordance with local country regulations and recognized international standards such as the International Organization of Standardization (ISO) standards for endovascular grafts (ISO 25539 Part 1). Copyright © 2013 Society for Vascular Surgery. Published by Mosby, Inc. All rights reserved.

Self-amplifying mRNA vaccines.

PubMed

Brito, Luis A; Kommareddy, Sushma; Maione, Domenico; Uematsu, Yasushi; Giovani, Cinzia; Berlanda Scorza, Francesco; Otten, Gillis R; Yu, Dong; Mandl, Christian W; Mason, Peter W; Dormitzer, Philip R; Ulmer, Jeffrey B; Geall, Andrew J

2015-01-01

This chapter provides a brief introduction to nucleic acid-based vaccines and recent research in developing self-amplifying mRNA vaccines. These vaccines promise the flexibility of plasmid DNA vaccines with enhanced immunogenicity and safety. The key to realizing the full potential of these vaccines is efficient delivery of nucleic acid to the cytoplasm of a cell, where it can amplify and express the encoded antigenic protein. The hydrophilicity and strong net negative charge of RNA impedes cellular uptake. To overcome this limitation, electrostatic complexation with cationic lipids or polymers and physical delivery using electroporation or ballistic particles to improve cellular uptake has been evaluated. This chapter highlights the rapid progress made in using nonviral delivery systems for RNA-based vaccines. Initial preclinical testing of self-amplifying mRNA vaccines has shown nonviral delivery to be capable of producing potent and robust innate and adaptive immune responses in small animals and nonhuman primates. Historically, the prospect of developing mRNA vaccines was uncertain due to concerns of mRNA instability and the feasibility of large-scale manufacturing. Today, these issues are no longer perceived as barriers in the widespread implementation of the technology. Currently, nonamplifying mRNA vaccines are under investigation in human clinical trials and can be produced at a sufficient quantity and quality to meet regulatory requirements. If the encouraging preclinical data with self-amplifying mRNA vaccines are matched by equivalently positive immunogenicity, potency, and tolerability in human trials, this platform could establish nucleic acid vaccines as a versatile new tool for human immunization. Copyright © 2015 Elsevier Inc. All rights reserved.

A Safe Foot-and-Mouth Disease Vaccine Platform with Two Negative Markers for Differentiating Infected from Vaccinated Animals

PubMed Central

Uddowla, Sabena; Hollister, Jason; Pacheco, Juan M.; Rodriguez, Luis L.

2012-01-01

Vaccination of domestic animals with chemically inactivated foot-and-mouth disease virus (FMDV) is widely practiced to control FMD. Currently, FMD vaccine manufacturing requires the growth of large volumes of virulent FMDV in biocontainment-level facilities. Here, two marker FMDV vaccine candidates (A24LL3DYR and A24LL3BPVKV3DYR) featuring the deletion of the leader coding region (Lpro) and one of the 3B proteins were constructed and evaluated. These vaccine candidates also contain either one or two sets of mutations to create negative antigenic markers in the 3D polymerase (3Dpol) and 3B nonstructural proteins. Two mutations in 3Dpol, H27Y and N31R, as well as RQKP9-12→PVKV substitutions, in 3B2 abolish reactivity with monoclonal antibodies targeting the respective sequences in 3Dpol and 3B. Infectious cDNA clones encoding the marker viruses also contain unique restriction endonuclease sites flanking the capsid-coding region that allow for easy derivation of custom designed vaccine candidates. In contrast to the parental A24WT virus, single A24LL3DYR and double A24LL3BPVKV3DYR mutant viruses were markedly attenuated upon inoculation of cattle using the natural aerosol or direct tongue inoculation. Likewise, pigs inoculated with live A24LL3DYR virus in the heel bulbs showed no clinical signs of disease, no fever, and no FMD transmission to in-contact animals. Immunization of cattle with chemically inactivated A24LL3DYR and A24LL3BPVKV3DYR vaccines provided 100% protection from challenge with parental wild-type virus. These attenuated, antigenically marked viruses provide a safe alternative to virulent strains for FMD vaccine manufacturing. In addition, a competitive enzyme-linked immunosorbent assay targeted to the negative markers provides a suitable companion test for differentiating infected from vaccinated animals. PMID:22915802

A safe foot-and-mouth disease vaccine platform with two negative markers for differentiating infected from vaccinated animals.

PubMed

Uddowla, Sabena; Hollister, Jason; Pacheco, Juan M; Rodriguez, Luis L; Rieder, Elizabeth

2012-11-01

Vaccination of domestic animals with chemically inactivated foot-and-mouth disease virus (FMDV) is widely practiced to control FMD. Currently, FMD vaccine manufacturing requires the growth of large volumes of virulent FMDV in biocontainment-level facilities. Here, two marker FMDV vaccine candidates (A(24)LL3D(YR) and A(24)LL3B(PVKV)3D(YR)) featuring the deletion of the leader coding region (L(pro)) and one of the 3B proteins were constructed and evaluated. These vaccine candidates also contain either one or two sets of mutations to create negative antigenic markers in the 3D polymerase (3D(pol)) and 3B nonstructural proteins. Two mutations in 3D(pol), H(27)Y and N(31)R, as well as RQKP(9-12)→PVKV substitutions, in 3B(2) abolish reactivity with monoclonal antibodies targeting the respective sequences in 3D(pol) and 3B. Infectious cDNA clones encoding the marker viruses also contain unique restriction endonuclease sites flanking the capsid-coding region that allow for easy derivation of custom designed vaccine candidates. In contrast to the parental A(24)WT virus, single A(24)LL3D(YR) and double A(24)LL3B(PVKV)3D(YR) mutant viruses were markedly attenuated upon inoculation of cattle using the natural aerosol or direct tongue inoculation. Likewise, pigs inoculated with live A(24)LL3D(YR) virus in the heel bulbs showed no clinical signs of disease, no fever, and no FMD transmission to in-contact animals. Immunization of cattle with chemically inactivated A(24)LL3D(YR) and A(24)LL3B(PVKV)3D(YR) vaccines provided 100% protection from challenge with parental wild-type virus. These attenuated, antigenically marked viruses provide a safe alternative to virulent strains for FMD vaccine manufacturing. In addition, a competitive enzyme-linked immunosorbent assay targeted to the negative markers provides a suitable companion test for differentiating infected from vaccinated animals.

Communicating vaccine safety during the development and introduction of vaccines.

PubMed

Kochhar, Sonali

2015-01-01

Vaccines are the best defense available against infectious diseases. Vaccine safety is of major focus for regulatory bodies, vaccine manufacturers, public health authorities, health care providers and the public as vaccines are often given to healthy children and adults as well as to pregnant woman. Safety assessment is critical at all stages of vaccine development. Effective, clear and consistent communication of the risks and benefits of vaccines and advocacy during all stages of clinical research (including the preparation, approvals, conduct of clinical trials through the post marketing phase) is critically important. This needs to be done for all major stakeholders (e.g. community members, Study Team, Health Care Providers, Ministry of Health, Regulators, Ethics Committee members, Public Health Authorities and Policy Makers). Improved stakeholder alignment would help to address some of the concerns that may affect the clinical research, licensing of vaccines and their wide-spread use in immunization programs around the world.

Using Innovative Technologies for Manufacturing and Evaluating Rocket Engine Hardware

NASA Technical Reports Server (NTRS)

Betts, Erin M.; Hardin, Andy

2011-01-01

Many of the manufacturing and evaluation techniques that are currently used for rocket engine component production are traditional methods that have been proven through years of experience and historical precedence. As we enter into a new space age where new launch vehicles are being designed and propulsion systems are being improved upon, it is sometimes necessary to adopt new and innovative techniques for manufacturing and evaluating hardware. With a heavy emphasis on cost reduction and improvements in manufacturing time, manufacturing techniques such as Direct Metal Laser Sintering (DMLS) and white light scanning are being adopted and evaluated for their use on J-2X, with hopes of employing both technologies on a wide variety of future projects. DMLS has the potential to significantly reduce the processing time and cost of engine hardware, while achieving desirable material properties by using a layered powdered metal manufacturing process in order to produce complex part geometries. The white light technique is a non-invasive method that can be used to inspect for geometric feature alignment. Both the DMLS manufacturing method and the white light scanning technique have proven to be viable options for manufacturing and evaluating rocket engine hardware, and further development and use of these techniques is recommended.

Vaccine process technology.

PubMed

Josefsberg, Jessica O; Buckland, Barry

2012-06-01

The evolution of vaccines (e.g., live attenuated, recombinant) and vaccine production methods (e.g., in ovo, cell culture) are intimately tied to each other. As vaccine technology has advanced, the methods to produce the vaccine have advanced and new vaccine opportunities have been created. These technologies will continue to evolve as we strive for safer and more immunogenic vaccines and as our understanding of biology improves. The evolution of vaccine process technology has occurred in parallel to the remarkable growth in the development of therapeutic proteins as products; therefore, recent vaccine innovations can leverage the progress made in the broader biotechnology industry. Numerous important legacy vaccines are still in use today despite their traditional manufacturing processes, with further development focusing on improving stability (e.g., novel excipients) and updating formulation (e.g., combination vaccines) and delivery methods (e.g., skin patches). Modern vaccine development is currently exploiting a wide array of novel technologies to create safer and more efficacious vaccines including: viral vectors produced in animal cells, virus-like particles produced in yeast or insect cells, polysaccharide conjugation to carrier proteins, DNA plasmids produced in E. coli, and therapeutic cancer vaccines created by in vitro activation of patient leukocytes. Purification advances (e.g., membrane adsorption, precipitation) are increasing efficiency, while innovative analytical methods (e.g., microsphere-based multiplex assays, RNA microarrays) are improving process understanding. Novel adjuvants such as monophosphoryl lipid A, which acts on antigen presenting cell toll-like receptors, are expanding the previously conservative list of widely accepted vaccine adjuvants. As in other areas of biotechnology, process characterization by sophisticated analysis is critical not only to improve yields, but also to determine the final product quality. From a regulatory

Immunogenicity of HPV prophylactic vaccines: Serology assays and their use in HPV vaccine evaluation and development.

PubMed

Pinto, Ligia A; Dillner, Joakim; Beddows, Simon; Unger, Elizabeth R

2018-01-17

When administered as standard three-dose schedules, the licensed HPV prophylactic vaccines have demonstrated extraordinary immunogenicity and efficacy. We summarize the immunogenicity of these licensed vaccines and the most commonly used serology assays, with a focus on key considerations for one-dose vaccine schedules. Although immune correlates of protection against infection are not entirely clear, both preclinical and clinical evidence point to neutralizing antibodies as the principal mechanism of protection. Thus, immunogenicity assessments in vaccine trials have focused on measurements of antibody responses to the vaccine. Non-inferiority of antibody responses after two doses of HPV vaccines separated by 6 months has been demonstrated and this evidence supported the recent WHO recommendations for two-dose vaccination schedules in both boys and girls 9-14 years of age. There is also some evidence suggesting that one dose of HPV vaccines may provide protection similar to the currently recommended two-dose regimens but robust data on efficacy and immunogenicity of one-dose vaccine schedules are lacking. In addition, immunogenicity has been assessed and reported using different methods, precluding direct comparison of results between different studies and vaccines. New head-to-head vaccine trials evaluating one-dose immunogenicity and efficacy have been initiated and an increase in the number of trials relying on immunobridging is anticipated. Therefore, standardized measurement and reporting of immunogenicity for the up to nine HPV types targeted by the current vaccines is now critical. Building on previous HPV serology assay standardization and harmonization efforts initiated by the WHO HPV LabNet in 2006, new secondary standards, critical reference reagents and testing guidelines will be generated as part of a new partnership to facilitate harmonization of the immunogenicity testing in new HPV vaccine trials. Copyright © 2018 Elsevier Ltd. All rights

A brief history of vaccines & vaccination in India.

PubMed

Lahariya, Chandrakant

2014-04-01

The challenges faced in delivering lifesaving vaccines to the targeted beneficiaries need to be addressed from the existing knowledge and learning from the past. This review documents the history of vaccines and vaccination in India with an objective to derive lessons for policy direction to expand the benefits of vaccination in the country. A brief historical perspective on smallpox disease and preventive efforts since antiquity is followed by an overview of 19 th century efforts to replace variolation by vaccination, setting up of a few vaccine institutes, cholera vaccine trial and the discovery of plague vaccine. The early twentieth century witnessed the challenges in expansion of smallpox vaccination, typhoid vaccine trial in Indian army personnel, and setting up of vaccine institutes in almost each of the then Indian States. In the post-independence period, the BCG vaccine laboratory and other national institutes were established; a number of private vaccine manufacturers came up, besides the continuation of smallpox eradication effort till the country became smallpox free in 1977. The Expanded Programme of Immunization (EPI) (1978) and then Universal Immunization Programme (UIP) (1985) were launched in India. The intervening events since UIP till India being declared non-endemic for poliomyelitis in 2012 have been described. Though the preventive efforts from diseases were practiced in India, the reluctance, opposition and a slow acceptance of vaccination have been the characteristic of vaccination history in the country. The operational challenges keep the coverage inequitable in the country. The lessons from the past events have been analysed and interpreted to guide immunization efforts.

A brief history of vaccines & vaccination in India

PubMed Central

Lahariya, Chandrakant

2014-01-01

The challenges faced in delivering lifesaving vaccines to the targeted beneficiaries need to be addressed from the existing knowledge and learning from the past. This review documents the history of vaccines and vaccination in India with an objective to derive lessons for policy direction to expand the benefits of vaccination in the country. A brief historical perspective on smallpox disease and preventive efforts since antiquity is followed by an overview of 19th century efforts to replace variolation by vaccination, setting up of a few vaccine institutes, cholera vaccine trial and the discovery of plague vaccine. The early twentieth century witnessed the challenges in expansion of smallpox vaccination, typhoid vaccine trial in Indian army personnel, and setting up of vaccine institutes in almost each of the then Indian States. In the post-independence period, the BCG vaccine laboratory and other national institutes were established; a number of private vaccine manufacturers came up, besides the continuation of smallpox eradication effort till the country became smallpox free in 1977. The Expanded Programme of Immunization (EPI) (1978) and then Universal Immunization Programme (UIP) (1985) were launched in India. The intervening events since UIP till India being declared non-endemic for poliomyelitis in 2012 have been described. Though the preventive efforts from diseases were practiced in India, the reluctance, opposition and a slow acceptance of vaccination have been the characteristic of vaccination history in the country. The operational challenges keep the coverage inequitable in the country. The lessons from the past events have been analysed and interpreted to guide immunization efforts. PMID:24927336

A systematic review of health economic evaluations of vaccines in Brazil

PubMed Central

2017-01-01

ABSTRACT Background: In Brazil, since 2005, the Ministry of Health requires Health Economic Evaluation (HEE) of vaccines for introduction into the National Immunization Program. Objectives: To describe and analyze the full HEE on vaccines conducted in Brazil from 1980 to 2013. Methods: Systematic review of the literature. We searched multiple databases. Two researchers independently selected the studies and extracted the data. The methodological quality of individual studies was evaluated using CHEERS items. Results: Twenty studies were reviewed. The most evaluated vaccines were pneumococcal (25%) and HPV (15%). The most used types of HEE were cost-effectiveness analysis (45%) and cost-utility analysis (20%). The research question and compared strategies were stated in all 20 studies and the target population was clear in 95%. Nevertheless, many studies did not inform the perspective of analysis or data sources. Conclusions: HEE of vaccines in Brazil has increased since 2008. However, the studies still have methodological deficiencies. PMID:28129026

Influenza vaccines in low and middle income countries: a systematic review of economic evaluations.

PubMed

Ott, Jördis J; Klein Breteler, Janna; Tam, John S; Hutubessy, Raymond C W; Jit, Mark; de Boer, Michiel R

2013-07-01

Economic evaluations on influenza vaccination from low resource settings are scarce and have not been evaluated using a systematic approach. Our objective was to conduct a systematic review on the value for money of influenza vaccination in low- and middle-income countries. PubMed and EMBASE were searched for economic evaluations published in any language between 1960 and 2011. Main outcome measures were costs per influenza outcome averted, costs per quality-adjusted life years gained or disability-adjusted life years averted, costs per benefit in monetary units or cost-benefit ratios. Nine economic evaluations on seasonal influenza vaccine met the inclusion criteria. These were model- or randomized-controlled-trial (RCT)-based economic evaluations from middle-income countries. Influenza vaccination provided value for money for elderly, infants, adults and children with high-risk conditions. Vaccination was cost-effective and cost-saving for chronic obstructive pulmonary disease patients and in elderly above 65 y from model-based evaluations, but conclusions from RCTs on elderly varied. Economic evaluations from middle income regions differed in population studied, outcomes and definitions used. Most findings are in line with evidence from high-income countries highlighting that influenza vaccine is likely to provide value for money. However, serious methodological limitations do not allow drawing conclusions on cost-effectiveness of influenza vaccination in middle income countries. Evidence on cost-effectiveness from low-income countries is lacking altogether, and more information is needed from full economic evaluations that are conducted in a standardized manner.

Evaluation of vaccination efficiency against HBV among Syrian multitransfused patients.

PubMed

Yazji, Wadad; Habal, Wafaa; Menem, Fawza

2018-03-05

This cross-sectional study estimates HBV prevalence and evaluates vaccination efficiency among multitransfused patients. 159 patients with various hemoglobinopathies were tested for HBsAg, anti-HBs, and anti-HBc, using enzyme-linked immunosorbent assay (ELISA). The serological results were then compared with the relevant documentation in medical records. Seropositivity of HBV was detected in 1/8 of recruited patients. Serological immunity was found in only half of patients, while the other half were either infected or non-immune. The vaccination against HBV appeared inefficient in almost half of vaccinated patients and was not documented in the medical records of 1/6 of patients. Thus, multitransfused patients are at risk of acquiring hepatitis B infection. Applying prophylactic vaccination, documenting vaccine doses, and monitoring immune response are highly recommended.

Economic evaluations of varicella vaccination programmes: a review of the literature.

PubMed

Thiry, Nancy; Beutels, Philippe; Van Damme, Pierre; Van Doorslaer, Eddy

2003-01-01

Chickenpox infections are generally mild but due to their very high incidence among healthy children they give rise to considerable morbidity and occasional mortality. With the development of a varicella vaccine in the early 1970s and its progressive licensing in many countries, interest in the efficiency of varicella immunisation programmes grew. The objective of this review was to discuss the methodological aspects and results of published economic evaluations of varicella vaccination. From this, we attempted to make recommendations. A computerised search was carried out; 17 full economic evaluations of varicella vaccination were retrieved. The review identified the methodological divergences and similarities between the articles in four areas: study design, epidemiological data, economic data and model characteristics. We assessed to what extent the applied methods conform to general guidelines for the economic evaluation of healthcare interventions and compared the studies' results. The desirability of a universal vaccination programme depends on whose perspective is taken. Despite variability in data and model assumptions, the studies suggest that universal vaccination of infants is attractive to society because large savings occur from averted unproductive days for parents. For the healthcare payer, universal vaccination of infants does not generate savings. Vaccination of susceptible adolescents has been proposed by some authors as a viable alternative; the attractiveness of this is highly dependent on the negative predictive value of anamnestic screening. Targeted vaccination of healthcare workers and immunocompromised individuals appears relatively cost effective. Findings for other target groups are either contradictory or provide insufficient evidence for any unequivocal recommendations to be made. High sensitivity to vaccine price was reported in most studies. This review highlights that some aspects of these studies need to be further improved before

Vaccines, inspiring innovation in health.

PubMed

Pagliusi, Sonia; Dennehy, Maureen; Kim, Hun

2018-05-19

This report covers the topics of pandemics, epidemics and partnerships, including regulatory convergence initiatives, new technologies and novel vaccines, discussed by leading public and private sector stakeholders at the 18th Annual General Meeting (AGM) of the Developing Countries Vaccine Manufacturers' Network (DCVMN). Contributions of Gavi and the vaccine industry from emerging countries to the growing global vaccine market, by improving the supply base from manufacturers in developing countries and contributing to 58% of doses, were highlighted. The Coalition for Epidemic Preparedness Innovations (CEPI), the International Vaccine Institute (IVI) and others reported on new strategies to ensure speedy progress in preclinical and clinical development of innovative vaccines for future MERS, Zika or other outbreak response. Priorities for vaccine stockpiling, to assure readiness during emergencies and to prevent outbreaks due to re-emerging diseases such as yellow fever, cholera and poliomyelitis, were outlined. The role of partnerships in improving global vaccine access, procurement and immunization coverage, and shared concerns were reviewed. The World Health Organization (WHO) and other international collaborating partners provided updates on the Product, Price and Procurement database, the prequalification of vaccines, the control of neglected tropical diseases, particularly the new rabies elimination initiative, and regulatory convergence proposals to accelerate vaccine registration in developing countries. Updates on supply chain innovations and novel vaccine platforms were presented. The discussions enabled members and partners to reflect on efficiency of research & development, supply chain tools and trends in packaging technologies improving delivery of existing vaccines, and allowing a deeper understanding of the current public-health objectives, industry financing, and global policies, required to ensure optimal investments, alignment and stability of

Herpes zoster vaccine: A health economic evaluation for Switzerland.

PubMed

Blank, Patricia R; Ademi, Zanfina; Lu, Xiaoyan; Szucs, Thomas D; Schwenkglenks, Matthias

2017-07-03

Herpes zoster (HZ) or "shingles" results from a reactivation of the varicella zoster virus (VZV) acquired during primary infection (chickenpox) and surviving in the dorsal root ganglia. In about 20% of cases, a complication occurs, known as post-herpetic neuralgia (PHN). A live attenuated vaccine against VZV is available for the prevention of HZ and subsequent PHN. The present study aims to update an earlier evaluation estimating the cost-effectiveness of the HZ vaccine from a Swiss third party payer perspective. It takes into account updated vaccine prices, a different age cohort, latest clinical data and burden of illness data. A Markov model was developed to simulate the lifetime consequences of vaccinating 15% of the Swiss population aged 65-79 y. Information from sentinel data, official statistics and published literature were used. Endpoints assessed were number of HZ and PHN cases, quality-adjusted life years (QALYs), costs of hospitalizations, consultations and prescriptions. Based on a vaccine price of CHF 162, the vaccination strategy accrued additional costs of CHF 17,720,087 and gained 594 QALYs. The incremental cost-effectiveness ratio (ICER) was CHF 29,814 per QALY gained. Sensitivity analyses showed that the results were most sensitive to epidemiological inputs, utility values, discount rates, duration of vaccine efficacy, and vaccine price. Probabilistic sensitivity analyses indicated a more than 99% chance that the ICER was below 40,000 CHF per QALY. Findings were in line with existing cost-effectiveness analyses of HZ vaccination. This updated study supports the value of an HZ vaccination strategy targeting the Swiss population aged 65-79 y.

Evaluation Studies of the DEN-2/S-1 Vaccine.

DTIC Science & Technology

1981-08-01

1.0 3.0, L o 1 .0 I11 125 11111 1.4 n .6_t _ MICROCOPY RESOLUTION TEST CHART NATIONAL WII ALI 0 MF S’ANDAkLT, ,’I, A ;40- AD EVALUATION STUDIES OF THE...monkeys Vaccination DEN-2/S-l Vaccine /AE TlhACT ( i - ,ewr e e1 If .,ceweu7 amd Iderdtlfy by block number) A dengue-2 live virus vaccine was tested in...viremia was detected in control animals. Serological tests were pi.r- formed on sera taken on post infection days 30,56 and 90. HI tests revealed sero

Evaluating Childhood Vaccination Coverage of NIP Vaccines: Coverage Survey versus Zhejiang Provincial Immunization Information System

PubMed Central

Hu, Yu; Chen, Yaping

2017-01-01

Vaccination coverage in Zhejiang province, east China, is evaluated through repeated coverage surveys. The Zhejiang provincial immunization information system (ZJIIS) was established in 2004 with links to all immunization clinics. ZJIIS has become an alternative to quickly assess the vaccination coverage. To assess the current completeness and accuracy on the vaccination coverage derived from ZJIIS, we compared the estimates from ZJIIS with the estimates from the most recent provincial coverage survey in 2014, which combined interview data with verified data from ZJIIS. Of the enrolled 2772 children in the 2014 provincial survey, the proportions of children with vaccination cards and registered in ZJIIS were 94.0% and 87.4%, respectively. Coverage estimates from ZJIIS were systematically higher than the corresponding estimates obtained through the survey, with a mean difference of 4.5%. Of the vaccination doses registered in ZJIIS, 16.7% differed from the date recorded in the corresponding vaccination cards. Under-registration in ZJIIS significantly influenced the coverage estimates derived from ZJIIS. Therefore, periodic coverage surveys currently provide more complete and reliable results than the estimates based on ZJIIS alone. However, further improvement of completeness and accuracy of ZJIIS will likely allow more reliable and timely estimates in future. PMID:28696387

Evaluating Childhood Vaccination Coverage of NIP Vaccines: Coverage Survey versus Zhejiang Provincial Immunization Information System.

PubMed

Hu, Yu; Chen, Yaping

2017-07-11

Vaccination coverage in Zhejiang province, east China, is evaluated through repeated coverage surveys. The Zhejiang provincial immunization information system (ZJIIS) was established in 2004 with links to all immunization clinics. ZJIIS has become an alternative to quickly assess the vaccination coverage. To assess the current completeness and accuracy on the vaccination coverage derived from ZJIIS, we compared the estimates from ZJIIS with the estimates from the most recent provincial coverage survey in 2014, which combined interview data with verified data from ZJIIS. Of the enrolled 2772 children in the 2014 provincial survey, the proportions of children with vaccination cards and registered in ZJIIS were 94.0% and 87.4%, respectively. Coverage estimates from ZJIIS were systematically higher than the corresponding estimates obtained through the survey, with a mean difference of 4.5%. Of the vaccination doses registered in ZJIIS, 16.7% differed from the date recorded in the corresponding vaccination cards. Under-registration in ZJIIS significantly influenced the coverage estimates derived from ZJIIS. Therefore, periodic coverage surveys currently provide more complete and reliable results than the estimates based on ZJIIS alone. However, further improvement of completeness and accuracy of ZJIIS will likely allow more reliable and timely estimates in future.

Evaluation of pneumococcal vaccination rates after vaccine protocol changes and nurse education in a tertiary care teaching hospital.

PubMed

Smith, Jennifer G; Metzger, Nicole L

2011-11-01

Pneumococcal vaccination in eligible patients is recommended by the Infectious Disease Society of America and the Centers for Disease Control (CDC) Advisory Committee on Immunization Practices. Because hospitalization provides an opportunity to vaccinate patients at high risk for developing serious pneumonia complications, eligibility screening and administration of the pneumococcal vaccine prior to discharge in qualified patients are evaluated by the Joint Commission and the Centers for Medicare Medicaid Services (CMS) as part of pneumococcal vaccination core quality measures. Among patients with an inpatient diagnosis of pneumonia in 2008, 56% in our 580-bed tertiary care teaching hospital, compared with 84% nationwide, received pneumococcal vaccination. To improve pneumococcal vaccination rates for all patients in the study facility and not just those with pneumonia, a multifaceted intervention including a revised nurse screening tool, rescheduling of the vaccine order, storage of the vaccine in automated dispensing cabinets on the nursing unit, and creation of a vaccine tracking system was developed and implemented between August 2009 and October 2009. To determine the impact of a multifaceted intervention on pneumococcal vaccine screening and administration rates in eligible patients according to the CDC recommendations who were admitted to an internal medicine unit of a tertiary care teaching hospital. All patients aged 18 years or older from 2 internal medicine units were identified during 4-month time intervals before (pre-intervention, April through July 2009) and after (post-intervention, November 2009 through February 2010) implementation of the multifaceted pneumococcal vaccine protocol. Of these, 150 patients from each 4-month period were randomly selected for electronic medical record review. Eligibility for pneumococcal vaccination was derived from the CDC recommendations and consensus of the vaccine steering committee at the study institution; the

Herpes zoster vaccine: A health economic evaluation for Switzerland

PubMed Central

Blank, Patricia R.; Ademi, Zanfina; Lu, Xiaoyan; Szucs, Thomas D.; Schwenkglenks, Matthias

2017-01-01

ABSTRACT Herpes zoster (HZ) or “shingles” results from a reactivation of the varicella zoster virus (VZV) acquired during primary infection (chickenpox) and surviving in the dorsal root ganglia. In about 20% of cases, a complication occurs, known as post-herpetic neuralgia (PHN). A live attenuated vaccine against VZV is available for the prevention of HZ and subsequent PHN. The present study aims to update an earlier evaluation estimating the cost-effectiveness of the HZ vaccine from a Swiss third party payer perspective. It takes into account updated vaccine prices, a different age cohort, latest clinical data and burden of illness data. A Markov model was developed to simulate the lifetime consequences of vaccinating 15% of the Swiss population aged 65–79 y. Information from sentinel data, official statistics and published literature were used. Endpoints assessed were number of HZ and PHN cases, quality-adjusted life years (QALYs), costs of hospitalizations, consultations and prescriptions. Based on a vaccine price of CHF 162, the vaccination strategy accrued additional costs of CHF 17,720,087 and gained 594 QALYs. The incremental cost-effectiveness ratio (ICER) was CHF 29,814 per QALY gained. Sensitivity analyses showed that the results were most sensitive to epidemiological inputs, utility values, discount rates, duration of vaccine efficacy, and vaccine price. Probabilistic sensitivity analyses indicated a more than 99% chance that the ICER was below 40,000 CHF per QALY. Findings were in line with existing cost-effectiveness analyses of HZ vaccination. This updated study supports the value of an HZ vaccination strategy targeting the Swiss population aged 65–79 y. PMID:28481678

[Evaluating efficiency of influenza vaccinal prevention among oil and gas industry workers].

PubMed

Bulanov, V E; Ivanov, A V; Shostak, G R

2013-01-01

Explore information about the incidence of employees of enterprises of the oil and gas industry with the influenza (SARS). The degree of influence of vaccination on the incidence of influenza, the number and structure of complications as a result of vaccination and their impact on efficiency. Evaluation of the cost-effectiveness of vaccination.

Influenza Vaccines: Unmet Needs and Recent Developments

PubMed Central

Noh, Ji Yun

2013-01-01

Influenza is a worldwide public health concern. Since the introduction of trivalent influenza vaccine in 1978, vaccination has been the primary means of prevention and control of influenza. Current influenza vaccines have moderate efficacy, good safety, and acceptable tolerability; however, they have unsatisfactory efficacy in older adults, are dependent on egg supply for production, and are time-consuming to manufacture. This review outlines the unmet medical needs of current influenza vaccines. Recent developments in influenza vaccines are also described. PMID:24475351

Seasonal influenza vaccine dose distribution in 195 countries (2004-2013): Little progress in estimated global vaccination coverage.

PubMed

Palache, Abraham; Oriol-Mathieu, Valerie; Fino, Mireli; Xydia-Charmanta, Margarita

2015-10-13

Seasonal influenza is an important disease which results in 250,000-500,000 annual deaths worldwide. Global targets for vaccination coverage rates (VCRs) in high-risk groups are at least 75% in adults ≥65 years and increased coverage in other risk groups. The International Federation of Pharmaceutical Manufacturers and Associations Influenza Vaccine Supply (IFPMA IVS) International Task Force developed a survey methodology in 2008, to assess the global distribution of influenza vaccine doses as a proxy for VCRs. This paper updates the previous survey results on absolute numbers of influenza vaccine doses distributed between 2004 and 2013 inclusive, and dose distribution rates per 1000 population, and provides a qualitative assessment of the principal enablers and barriers to seasonal influenza vaccination. The two main findings from the quantitative portion of the survey are the continued negative trend for dose distribution in the EURO region and the perpetuation of appreciable differences in scale of dose distribution between WHO regions, with no observed convergence in the rates of doses distributed per 1000 population over time. The main findings from the qualitative portion of the survey were that actively managing the vaccination program in real-time and ensuring political commitment to vaccination are important enablers of vaccination, whereas insufficient access to vaccination and lack of political commitment to seasonal influenza vaccination programs are likely contributing to vaccination target failures. In all regions of the world, seasonal influenza vaccination is underutilized as a public health tool. The survey provides evidence of lost opportunity to protect populations against potentially serious influenza-associated disease. We call on the national and international public health communities to re-evaluate their political commitment to the prevention of the annual influenza disease burden and to develop a systematic approach to improve vaccine

Economic evaluations of influenza vaccination in healthy working-age adults. Employer and society perspective.

PubMed

Wood, S C; Nguyen, V H; Schmidt, C

2000-08-01

To determine what benefits to the employer and to society are associated with influenza (flu) vaccination in healthy adults. We performed a literature review concerning cost-benefit and cost-effectiveness evaluations of influenza vaccination in healthy, working-age adults. Up to the end of 1999, we found 6 published economic evaluations on the use of influenza vaccine in healthy, working-age adults: 3 prospective studies, 1 retrospective evaluation and 2 model-based simulations. Evaluations were performed from the perspective of an employer or society. Costs were reported in the local currency used in the published evaluation, with conversions into US dollars (when not provided in the article), for comparative purposes only, according to the exchange rates of June 8 1998. Estimations of the cost-benefit of vaccination, compared with a no vaccination strategy, varied widely from a net loss of $US106.59 per infection averted in one study to savings of varying sizes in the 5 others (savings ranged from $US2.58 per dollar invested to $US46.85 per vaccinee). Studies differed in the definition of illness and the measurement of costs associated with vaccination or illness. Decision makers have not yet extended existing vaccine recommendations to cover healthy, working-age adults, partly because of the disparity among economic studies in their methods of estimating costs and measuring effects. However, the published studies seem to suggest that influenza vaccination in the healthy, working adult would be a cost-effective health intervention, at least from the perspective of an employer.

[Comparative evaluation of neurovirulence of domestic and foreign live mumps vaccine].

PubMed

Maksimova, O A; Popov, V F; Bektimirov, T A; Grigor'eva, L V; Iunasova, T N; Kaplunova, O P; Sharova, O K

2001-01-01

Morphological and immunofluorescent study of changes in the central nervous system of monkeys with mumps was carried out in order to determine the criteria of neurovirulence of different mumps virus strains. Quantitative evaluation showed a lower residual neurovirulence of L-3 strain vs. Jeryl Lynn and Urabe Am9 strains. Use of new methodological approaches to evaluation of mumps vaccine strain neurovirulence will improve the safety control of live mumps vaccines.

Vaccine Rejecting Parents' Engagement With Expert Systems That Inform Vaccination Programs.

PubMed

Attwell, Katie; Leask, Julie; Meyer, Samantha B; Rokkas, Philippa; Ward, Paul

2017-03-01

In attempting to provide protection to individuals and communities, childhood immunization has benefits that far outweigh disease risks. However, some parents decide not to immunize their children with some or all vaccines for reasons including lack of trust in governments, health professionals, and vaccine manufacturers. This article employs a theoretical analysis of trust and distrust to explore how twenty-seven parents with a history of vaccine rejection in two Australian cities view the expert systems central to vaccination policy and practice. Our data show how perceptions of the profit motive generate distrust in the expert systems pertaining to vaccination. Our participants perceived that pharmaceutical companies had a pernicious influence over the systems driving vaccination: research, health professionals, and government. Accordingly, they saw vaccine recommendations in conflict with the interests of their child and "the system" underscored by malign intent, even if individual representatives of this system were not equally tainted. This perspective was common to parents who declined all vaccines and those who accepted some. We regard the differences between these parents-and indeed the differences between vaccine decliners and those whose Western medical epistemology informs reflexive trust-as arising from the internalization of countering views, which facilitates nuance.

Conflicts of interest in vaccine safety research.

PubMed

DeLong, Gayle

2012-01-01

Conflicts of interest (COIs) cloud vaccine safety research. Sponsors of research have competing interests that may impede the objective study of vaccine side effects. Vaccine manufacturers, health officials, and medical journals may have financial and bureaucratic reasons for not wanting to acknowledge the risks of vaccines. Conversely, some advocacy groups may have legislative and financial reasons to sponsor research that finds risks in vaccines. Using the vaccine-autism debate as an illustration, this article details the conflicts of interest each of these groups faces, outlines the current state of vaccine safety research, and suggests remedies to address COIs. Minimizing COIs in vaccine safety research could reduce research bias and restore greater trust in the vaccine program.

Systematic review of economic evaluation analyses of available vaccines in Spain from 1990 to 2012.

PubMed

Cortés, Isabel; Pérez-Camarero, Santiago; Del Llano, Juan; Peña, Luz María; Hidalgo-Vega, Alvaro

2013-08-02

The objective of this survey was to describe the evolution of economic evaluation studies on vaccines available in Spain. We conducted a systematic review of the economic evaluations published by Spanish researchers in major bibliographic databases available online from 1990 to 2012. For all references identified, we limited them to full economic evaluation carried out in Spanish vaccine programs. The following variables were analyzed: type of study, year of publication, vaccine evaluated, the herd immunity and the main methodological aspects proposed by international guidelines. The type of vaccines studied were Hepatitis A and B, Rotavirus, Influenza, Varicella, Tetanus, Measles, Human papillomavirus, Streptococcus pneumoniae infection and Neisseria meningitides serogroup C infection. A total of 34 references was included in the study. The number of economic evaluations has been increasing over the years by 86%. For many of the vaccines there were no economic evaluations, while others such as the vaccine against S. pneumoniae infection took up most of the studies. The non-vaccinated comparison was the most used strategy. The cost-effectiveness model was selected in 60% of cases. The most common health outcome was "cost per case prevented" and in 82% of the studies did not consider herd immunity. The results showed a cost-effectiveness ratio which was below breakeven. It is clear that the existence of a huge gap in this kind of work compared to other countries. Although the quality of the work discussed here was significant, we found many areas which could be improved. The reviewed literature exposed the great benefit of vaccination for society by analysing the health outcomes achieved for decades since its implementation. However, the evidence on the efficiency and effectiveness vaccination is not very high, and there are few studies about economic evaluation. Copyright © 2013 Elsevier Ltd. All rights reserved.

Balancing Vaccine Science and National Policy Objectives: Lessons From the National Vaccine Injury Compensation Program Omnibus Autism Proceedings

PubMed Central

Keelan, Jennifer

2011-01-01

The US Court of Federal Claims, which adjudicates cases for the National Vaccine Injury Compensation Program, has been confronted with more than 5000 cases submitted on behalf of children with autism spectrum disorders, seeking to link the condition to vaccination. Through a test case process, the Omnibus Autism Proceedings have in every instance found no association between autism spectrum disorders and vaccines. However, vaccine advocates have criticized the courts for having an overly permissive evidentiary test for causation and for granting credence to insupportable accusations of vaccine harm. In fact, the courts have functioned as intended and have allowed for a fair hearing of vaccine concerns while maintaining confidence in vaccines and providing protection to vaccine manufacturers. PMID:21940934

Secreted HSP Vaccine for Malaria Prophylaxis

DTIC Science & Technology

2015-10-01

Award Number: W81XWH-13-2-0098 TITLE: Secreted HSP Vaccine for Malaria Prophylaxis PRINCIPAL INVESTIGATOR: Dr. Natasa Strbo CONTRACTING...REPORT DATE October 2015 2. REPORT TYPE Annual 3. DATES COVERED 30 Sep 2014 - 29 Sep 2015 4. TITLE AND SUBTITLE Secreted HSP Vaccine for Malaria ...We have also started manufacturing GMP-grade vaccine material for use in non-human primate studies . 15. SUBJECT TERMS- Malaria , Plasmodium

Testing of a palatable bait and compatible vaccine carrier for the oral vaccination of European badgers (Meles meles) against tuberculosis.

PubMed

Gowtage, Sonya; Williams, Gareth A; Henderson, Ray; Aylett, Paul; MacMorran, Duncan; Palmer, Si; Robertson, Andy; Lesellier, Sandrine; Carter, Stephen P; Chambers, Mark A

2017-02-07

The oral vaccination of wild badgers (Meles meles) with live Bacillus Calmette-Guérin (BCG) is one of the tools being considered for the control of bovine tuberculosis (caused by Mycobacterium bovis) in the UK. The design of a product for oral vaccination requires that numerous, and often competing, conditions are met. These include the need for a highly palatable, but physically stable bait that will meet regulatory requirements, and one which is also compatible with the vaccine formulation; in this case live BCG. In collaboration with two commercial bait companies we have developed a highly attractive and palatable bait recipe designed specifically for European badgers (Meles meles) that meets these requirements. The palatability of different batches of bait was evaluated against a standardised palatable control bait using captive badgers. The physical properties of the bait are described e.g. firmness and colour. The microbial load in the bait was assessed against European and US Pharmacopoeias. The bait was combined with an edible vaccine carrier made of hydrogenated peanut oil in which BCG vaccine was stable during bait manufacture and cold storage, demonstrating <0.5 log 10 reduction in titre after 117weeks' storage at -20°C. BCG stability in bait was also evaluated at +4°C and under simulated environmental conditions (20°C, 98% Relative Humidity; RH). Finally, iophenoxic acid biomarkers were utilised as a surrogate for the BCG vaccine, to test variants of the vaccine-bait design for their ability to deliver biomarker to the gastrointestinal tract of individual animals. These data provide the first detailed description of a bait-vaccine delivery system developed specifically for the oral vaccination of badgers against Mycobacterium bovis using live BCG. Crown Copyright © 2016. Published by Elsevier Ltd. All rights reserved.

Cost Evaluation of a Government-Conducted Oral Cholera Vaccination Campaign-Haiti, 2013.

PubMed

Routh, Janell A; Sreenivasan, Nandini; Adhikari, Bishwa B; Andrecy, Lesly L; Bernateau, Margarette; Abimbola, Taiwo; Njau, Joseph; Jackson, Ernsley; Juin, Stanley; Francois, Jeannot; Tohme, Rania A; Meltzer, Martin I; Katz, Mark A; Mintz, Eric D

2017-10-01

The devastating 2010 cholera epidemic in Haiti prompted the government to introduce oral cholera vaccine (OCV) in two high-risk areas of Haiti. We evaluated the direct costs associated with the government's first vaccine campaign implemented in August-September 2013. We analyzed data for major cost categories and assessed the efficiency of available campaign resources to vaccinate the target population. For a target population of 107,906 persons, campaign costs totaled $624,000 and 215,295 OCV doses were dispensed. The total vaccine and operational cost was $2.90 per dose; vaccine alone cost $1.85 per dose, vaccine delivery and administration $0.70 per dose, and vaccine storage and transport $0.35 per dose. Resources were greater than needed-our analyses suggested that approximately 2.5-6 times as many persons could have been vaccinated during this campaign without increasing the resources allocated for vaccine delivery and administration. These results can inform future OCV campaigns in Haiti.

An overview of the regulation of influenza vaccines in the United States.

PubMed

Weir, Jerry P; Gruber, Marion F

2016-09-01

Influenza virus vaccines are unique among currently licensed viral vaccines. The vaccines designed to protect against seasonal influenza illness must be updated periodically in an effort to match the vaccine strain with currently circulating viruses, and the vaccine manufacturing timeline includes multiple, overlapping processes with a very limited amount of flexibility. In the United States (U.S.), over 150 million doses of seasonal trivalent and quadrivalent vaccine are produced annually, a mammoth effort, particularly in the context of a vaccine with components that usually change on a yearly basis. In addition, emergence of an influenza virus containing an HA subtype that has not recently circulated in humans is an ever present possibility. Recently, pandemic influenza vaccines have been licensed, and the pathways for licensure of pandemic vaccines and subsequent strain updating have been defined. Thus, there are formidable challenges for the regulation of currently licensed influenza vaccines, as well as for the regulation of influenza vaccines under development. This review describes the process of licensing influenza vaccines in the U.S., the process and steps involved in the annual updating of seasonal influenza vaccines, and some recent experiences and regulatory challenges faced in development and evaluation of novel influenza vaccines. © 2016 The Authors. Influenza and Other Respiratory Viruses Published by John Wiley & Sons Ltd.

Designing pediatric vaccine formularies and pricing pediatric combination vaccines using operations research models and algorithms.

PubMed

Jacobson, Sheldon H; Sewell, Edward C; Allwine, Daniel A; Medina, Enrique A; Weniger, Bruce G

2003-02-01

The National Immunization Program, housed within the Centers for Disease Control and Prevention in the USA, has identified several challenges that must be faced in childhood immunization programs to deliver and procure vaccines that immunize children from the plethora of childhood diseases. The biomedical issues cited include how drug manufacturers can combine and formulate vaccines, how such vaccines are scheduled and administered and how economically sound vaccine procurement can be achieved. This review discusses how operations research models can be used to address the economics of pediatric vaccine formulary design and pricing, as well as how such models can be used to address a new set of pediatric formulary problems that will surface with the introduction of pediatric combination vaccines into the US pediatric immunization market.

A DOG TEST FOR MEASURING THE IMMUNIZING POTENCY OF ANTIRABIES VACCINES

PubMed Central

Webster, Leslie T.; Casals, J.

1940-01-01

1. A quantitative method is described for testing the immunizing potency of antirabies vaccines in dogs. 2. Phenolized, single-injection, canine vaccines from seven manufacturers, when administered to dogs according to directions, failed to protect them against the least measurable amount of test virus fatal to 50 per cent or more of controls. Chloroformized vaccines from two of three manufacturers, under the same conditions, gave equivocal or suggestive results. 3. Commercial chloroformized vaccines in 10 cc. doses, injected intraperitoneally rather than subcutaneously into dogs, conferred a significant degree of immunity but proved temporarily irritative to the peritoneum. 4. These results of canine vaccines in dogs parallel closely those already reported in mice. PMID:19870993

Rotavirus vaccine effectiveness in low-income settings: An evaluation of the test-negative design.

PubMed

Schwartz, Lauren M; Halloran, M Elizabeth; Rowhani-Rahbar, Ali; Neuzil, Kathleen M; Victor, John C

2017-01-03

The test-negative design (TND), an epidemiologic method currently used to measure rotavirus vaccine (RV) effectiveness, compares the vaccination status of rotavirus-positive cases and rotavirus-negative controls meeting a pre-defined case definition for acute gastroenteritis. Despite the use of this study design in low-income settings, the TND has not been evaluated to measure rotavirus vaccine effectiveness. This study builds upon prior methods to evaluate the use of the TND for influenza vaccine using a randomized controlled clinical trial database. Test-negative vaccine effectiveness (VE-TND) estimates were derived from three large randomized placebo-controlled trials (RCTs) of monovalent (RV1) and pentavalent (RV5) rotavirus vaccines in sub-Saharan Africa and Asia. Derived VE-TND estimates were compared to the original RCT vaccine efficacy estimates (VE-RCTs). The core assumption of the TND (i.e., rotavirus vaccine has no effect on rotavirus-negative diarrhea) was also assessed. TND vaccine effectiveness estimates were nearly equivalent to original RCT vaccine efficacy estimates. Neither RV had a substantial effect on rotavirus-negative diarrhea. This study supports the TND as an appropriate epidemiologic study design to measure rotavirus vaccine effectiveness in low-income settings. Copyright © 2016 The Author(s). Published by Elsevier Ltd.. All rights reserved.

Human anthelminthic vaccines: Rationale and challenges.

PubMed

Hotez, Peter J; Strych, Ulrich; Lustigman, Sara; Bottazzi, Maria Elena

2016-06-24

Helminth infections are the most common afflictions of humankind, affecting almost every single person living in profound poverty. Through mass drug administration (MDA) we have seen sharp declines in the global prevalence of some helminth infections, including lymphatic filariasis, onchocerciasis, and ascariasis. However, since 1990, there has been no appreciable decrease in the global prevalence of hookworm infection, schistosomiasis, or food-borne trematodiases. Through the activities of a non-profit product development partnerships and two research institutes, a total of five human anthelmintic vaccines for hookworm infection (two) and schistosomiasis (three) have advanced from discovery through manufacture and are now in Phase 1 clinical testing. At least three additional antigens, including two for onchocerciasis and one for schistosomiasis, are also advancing through preclinical development with the intention of moving into the clinic soon. These preventive human anthelmintic vaccines could be used as stand-alone technologies administered to infants as part of the Expanded Program on Immunization (EPI), or together with anthelmintic drugs in programs linked to MDA. Significant hurdles though could hinder the advancement of these vaccines into later-stage clinical and product development and licensure. They include the absence of a major pharma partner (and the resultant access to adjuvants and industrial scale manufacturing expertise), an uncharted roadmap for how to introduce anthelmintic vaccines into appropriate health systems, uncertain global access and regulatory strategies that might need to rely on developing country vaccine manufacturers and national regulatory authorities, and the lack of innovative financing schemes. However, the public health and economic benefits of introducing these vaccines could be massive and therefore deserve international attention and support. Copyright © 2016 Elsevier Ltd. All rights reserved.

Next generation vaccines.

PubMed

Riedmann, Eva M

2011-07-01

In February this year, about 100 delegates gathered for three days in Vienna (Austria) for the Next Generation Vaccines conference. The meeting held in the Vienna Hilton Hotel from 23rd-25th February 2011 had a strong focus on biotech and industry. The conference organizer Jacob Fleming managed to put together a versatile program ranging from the future generation of vaccines to manufacturing, vaccine distribution and delivery, to regulatory and public health issues. Carefully selected top industry experts presented first-hand experience and shared solutions for overcoming the latest challenges in the field of vaccinology. The program also included several case study presentations on novel vaccine candidates in different stages of development. An interactive pre-conference workshop as well as interactive panel discussions during the meeting allowed all delegates to gain new knowledge and become involved in lively discussions on timely, interesting and sometimes controversial topics related to vaccines.

Safety, Tolerability and Immunogenicity of Pentavalent Rotavirus Vaccine Manufactured by a Modified Process.

PubMed

Martinón-Torres, Federico; Greenberg, David; Varman, Meera; Killar, John A; Hille, Darcy; Strable, Erica L; Stek, Jon E; Kaplan, Susan S

2017-04-01

Rotavirus is the leading cause of severe diarrhea in infants and young children. The current formulation of pentavalent rotavirus vaccine (RV5) must be stored refrigerated at 2-8°C. A modified formulation of RV5 (RV5mp) has been developed with stability at 37°C for 7 days and an expiry extended to 36 months when stored at 2-8°C. This study (ClinicalTrials.gov identifier: NCT01600092; EudraCT number: 2012-001611-23) evaluated the safety, tolerability and immunogenicity of RV5mp versus the currently marketed RV5 in infants. To maintain blinding, both vaccine formulations were stored refrigerated at 2-8°C for the duration of the study. Immunogenicity endpoints were (1) serum neutralizing antibody titers to human rotavirus serotypes G1, G2, G3, G4 and P1A[8] and (2) proportion of subjects with a ≥3-fold rise from baseline for serum neutralizing antibody to human rotavirus serotypes G1, G2, G3, G4 and P1A[8] and serum antirotavirus immunoglobulin A. The RV5mp group (n = 505) and RV5 group (n = 509) had comparable safety profiles. There were no deaths and no vaccine-related serious adverse events in this study. With respect to immunogenicity, RV5mp was noninferior compared with RV5. Serum neutralizing antibody responses by country and breast-feeding status were generally consistent with the overall results. RV5mp enhances storage requirements while maintaining the immunogenicity and safety profile of the currently licensed RV5. A vaccine that is stable at room temperature may be more convenient for vaccinators, particularly in places where the cold chain is unreliable, and ultimately will permit more widespread use.

The Australian model of immunization advice and vaccine funding.

PubMed

Nolan, Terry M

2010-04-19

The Australian Government has implemented new arrangements for public funding of vaccines over the past 5 years. By utilising the standard Pharmaceutical Benefits Advisory Committee (PBAC) application process, whether for funding under the National Immunisation Program Schedule (NIP) or under the Pharmaceutical Benefits Scheme (PBS), a predictable and transparent process for vaccine funding recommendations has been established. This process uses the high-level technical resources available through the Australian Technical Advisory Group on Immunisation (ATAGI) to ensure that both vaccine manufacturers and the PBAC are optimally informed about all relevant aspects of population benefits and delivery of vaccines. ATAGI has a long-standing and mutually beneficial dialogue with State and Territory Governments, providers, and vaccine manufacturers to ensure that pipeline awareness, supply issues, and all relevant scientific and clinical details are well understood. Copyright © 2010 Elsevier Ltd. All rights reserved.

Hepatitis B vaccine freezing in the Indonesian cold chain: evidence and solutions.

PubMed

Nelson, Carib M; Wibisono, Hariadi; Purwanto, Hary; Mansyur, Isa; Moniaga, Vanda; Widjaya, Anton

2004-02-01

To document and characterize freezing temperatures in the Indonesian vaccine cold chain and to evaluate the feasibility of changes designed to reduce the occurrence of freezing. Data loggers were used to measure temperatures of shipments of hepatitis B vaccine from manufacturer to point of use. Baseline conditions and three intervention phases were monitored. During each of the intervention phases, vaccines were removed progressively from the standard 2-8 degrees C cold chain. Freezing temperatures were recorded in 75% of baseline shipments. The highest rates of freezing occurred during transport from province to district, storage in district-level ice-lined refrigerators, and storage in refrigerators in health centres. Interventions reduced freezing, without excessive heat exposure. Inadvertent freezing of freeze-sensitive vaccines is widespread in Indonesia. Simple strategies exist to reduce freezing - for example, selective transport and storage of vaccines at ambient temperatures. The use of vaccine vial monitors reduces the risk associated with heat-damaged vaccines in these scenarios. Policy changes that allow limited storage of freeze-sensitive vaccines at temperatures >2-8 degrees C would enable flexible vaccine distribution strategies that could reduce vaccine freezing, reduce costs, and increase capacity.

Evaluation of European tick-borne encephalitis virus vaccine against recent Siberian and far-eastern subtype strains.

PubMed

Hayasaka, D; Goto, A; Yoshii, K; Mizutani, T; Kariwa, H; Takashima, I

2001-09-14

To evaluate the efficacy of the European TBE vaccine in east-Siberian and far-eastern regions of Russia, we examined the immune responses of the vaccine against recent TBE virus Siberian (Irkutsk) and far-eastern (Khabarovsk and Vladivostok) isolates. The sera of vaccinated humans showed efficient neutralizing antibody titers (> or =20) against Siberian and far-eastern strains. To evaluate the efficacy of the vaccine in vivo, mice were vaccinated and challenged with lethal doses of the viruses. All vaccinated mice survived each virus challenge. These results suggest that the European vaccine can prevent the TBE virus infection in east-Siberian and far-eastern regions of Russia.

Evaluation of novel oral vaccine candidates and validation of a caprine model of Johne's disease

PubMed Central

Hines, Murray E.; Turnquist, Sue E.; Ilha, Marcia R. S.; Rajeev, Sreekumari; Jones, Arthur L.; Whittington, Lisa; Bannantine, John P.; Barletta, Raúl G.; Gröhn, Yrjö T.; Katani, Robab; Talaat, Adel M.; Li, Lingling; Kapur, Vivek

2014-01-01

Johne's disease (JD) caused by Mycobacterium avium subspecies paratuberculosis (MAP) is a major threat to the dairy industry and possibly some cases of Crohn's disease in humans. A MAP vaccine that reduced of clinical disease and/or reduced fecal shedding would aid in the control of JD. The objectives of this study were (1) to evaluate the efficacy of 5 attenuated strains of MAP as vaccine candidates compared to a commercial control vaccine using the protocol proposed by the Johne's Disease Integrated Program (JDIP) Animal Model Standardization Committee (AMSC), and (2) to validate the AMSC Johne's disease goat challenge model. Eighty goat kids were vaccinated orally twice at 8 and 10 weeks of age with an experimental vaccine or once subcutaneously at 8 weeks with Silirum® (Zoetis), or a sham control oral vaccine at 8 and 10 weeks. Kids were challenged orally with a total of approximately 1.44 × 109 CFU divided in two consecutive daily doses using MAP ATCC-700535 (K10-like bovine isolate). All kids were necropsied at 13 months post-challenge. Results indicated that the AMSC goat challenge model is a highly efficient and valid model for JD challenge studies. None of the experimental or control vaccines evaluated prevented MAP infection or eliminated fecal shedding, although the 329 vaccine lowered the incidence of infection, fecal shedding, tissue colonization and reduced lesion scores, but less than the control vaccine. Based on our results the relative performance ranking of the experimental live-attenuated vaccines evaluated, the 329 vaccine was the best performer, followed by the 318 vaccine, then 316 vaccine, 315 vaccine and finally the 319 vaccine was the worst performer. The subcutaneously injected control vaccine outperformed the orally-delivered mutant vaccine candidates. Two vaccines (329 and 318) do reduce presence of JD gross and microscopic lesions, slow progression of disease, and one vaccine (329) reduced fecal shedding and tissue colonization. PMID

Vaccine safety evaluation: Practical aspects in assessing benefits and risks.

PubMed

Di Pasquale, Alberta; Bonanni, Paolo; Garçon, Nathalie; Stanberry, Lawrence R; El-Hodhod, Mostafa; Tavares Da Silva, Fernanda

2016-12-20

Vaccines are different from most medicines in that they are administered to large and mostly healthy populations including infants and children, so there is a low tolerance for potential risks or side-effects. In addition, the long-term benefits of immunisation in reducing or eliminating infectious diseases may induce complacency due to the absence of cases. However, as demonstrated in recent measles outbreaks in Europe and United States, reappearance of the disease occurs as soon as vaccine coverage falls. Unfounded vaccine scares such as those associating the combined measles-mumps-rubella vaccine with autism, and whole-cell pertussis vaccines with encephalopathy, can also have massive impacts, resulting in reduced vaccine uptake and disease resurgence. The safety assessment of vaccines is exhaustive and continuous; beginning with non-clinical evaluation of their individual components in terms of purity, stability and sterility, continuing throughout the clinical development phase and entire duration of use of the vaccine; including post-approval. The breadth and depth of safety assessments conducted at multiple levels by a range of independent organizations increases confidence in the rigour with which any potential risks or side-effects are investigated and managed. Industry, regulatory agencies, academia, the medical community and the general public all play a role in monitoring vaccine safety. Within these stakeholder groups, the healthcare professional and vaccine provider have key roles in the prevention, identification, investigation and management of adverse events following immunisation (AEFI). Guidelines and algorithms aid in determining whether AEFI may have been caused by the vaccine, or whether it is coincidental to it. Healthcare providers are encouraged to rigorously investigate AEFIs and to report them via local reporting processes. The ultimate objective for all parties is to ensure vaccines have a favourable benefit-risk profile. Copyright �

The Vaccine Formulation Laboratory: a platform for access to adjuvants.

PubMed

Collin, Nicolas; Dubois, Patrice M

2011-07-01

Adjuvants are increasingly used by the vaccine research and development community, particularly for their ability to enhance immune responses and for their dose-sparing properties. However, they are not readily available to the majority of public sector vaccine research groups, and even those with access to suitable adjuvants may still fail in the development of their vaccines because of lack of knowledge on how to correctly formulate the adjuvants. This shortcoming led the World Health Organization to advocate for the establishment of the Vaccine Formulation Laboratory at the University of Lausanne, Switzerland. The primary mission of the laboratory is to transfer adjuvants and formulation technology free of intellectual property rights to academic institutions, small biotechnology companies and developing countries vaccine manufacturers. In this context, the transfer of an oil-in-water emulsion to Bio Farma, an Indonesian vaccine manufacturer, was initiated to increase domestic pandemic influenza vaccine production capacity as part of the national pandemic influenza preparedness plan. Copyright © 2011 Elsevier Ltd. All rights reserved.

Universal Vaccines and Vaccine Platforms to Protect against Influenza Viruses in Humans and Agriculture

PubMed Central

Rajão, Daniela S.; Pérez, Daniel R.

2018-01-01

Influenza virus infections pose a significant threat to public health due to annual seasonal epidemics and occasional pandemics. Influenza is also associated with significant economic losses in animal production. The most effective way to prevent influenza infections is through vaccination. Current vaccine programs rely heavily on the vaccine's ability to stimulate neutralizing antibody responses to the hemagglutinin (HA) protein. One of the biggest challenges to an effective vaccination program lies on the fact that influenza viruses are ever-changing, leading to antigenic drift that results in escape from earlier immune responses. Efforts toward overcoming these challenges aim at improving the strength and/or breadth of the immune response. Novel vaccine technologies, the so-called universal vaccines, focus on stimulating better cross-protection against many or all influenza strains. However, vaccine platforms or manufacturing technologies being tested to improve vaccine efficacy are heterogeneous between different species and/or either tailored for epidemic or pandemic influenza. Here, we discuss current vaccines to protect humans and animals against influenza, highlighting challenges faced to effective and uniform novel vaccination strategies and approaches. PMID:29467737

Evaluation of the efficacy of an autogenous Escherichia coli vaccine in broiler breeders.

PubMed

Li, Lili; Thøfner, Ida; Christensen, Jens Peter; Ronco, Troels; Pedersen, Karl; Olsen, Rikke H

2017-06-01

In poultry production Escherichia coli autogenous vaccines are often used. However, the efficacy of autogenous E. coli vaccinations has not been evaluated experimentally in chickens after start of lay. The aim of the present study was to evaluate the protective effect of an autogenous E. coli vaccine in broiler breeders. Three groups of 28-week-old broiler breeders (unvaccinated, vaccinated once and twice, respectively) were challenged with a homologous E. coli strain (same strain as included in the vaccine) or a heterologous challenge strain in an experimental ascending model. The clinical outcome was most pronounced in the unvaccinated group; however, the vast majority of chickens in the vaccinated groups had severe pathological manifestations similar to findings in the unvaccinated group after challenge with a homologous as well as a heterologous E. coli strain. Although significant titre rises in IgY antibodies were observed in the twice vaccinated group, antibodies did not confer significant protection in terms of pathological impact. Neither could transfer of maternal-derived antibodies to offspring be demonstrated. In conclusion, with the use of the present model for ascending infection, significant protection of an autogenous E. coli vaccine against neither a homologous nor a heterologous E. coli challenge could not be documented.

Evaluation of the persistence of vaccine-induced protection with human vaccines.

PubMed

Vidor, E

2010-01-01

The persistence of protection induced by vaccines is a key aspect of the implementation of human vaccination policies, particularly for ageing populations. At the time of initial licensure, the duration of protection induced by a vaccine is generally only documented by longitudinal follow up of cohorts of subjects enrolled in the pre-licensure trials over a period of 1-5 years. The follow up of these cohorts provides two types of data: antibody kinetics (or another clinically relevant immunological parameter) over time and the disease incidence. Generally, the latter trials, if implemented during the pre-licensure period, are designed to follow-up cohorts in order to demonstrate vaccine efficacy above the minimal level required for the license. For vaccines already licensed, additional tools exist. The use of immunological surrogate markers of protection is a practical way to monitor the duration of protection. Measuring the persistence of circulating antibodies is widely used in human vaccines. For several vaccines, observed data have allowed the creation of mathematical models to predict the antibody persistence over periods of time longer than those effectively documented. Clinical trials assessing the capacity of the immune system to mount a quick anamnestic response upon re-stimulation a long time after initial priming (measurement of immune memory) is also a tool employed to document the duration of protection. The waning of protection can also be demonstrated by an increase of disease incidence in the subsequent 'time-to-last-vaccine administration' age segments. Seroprevalence studies in a given age group of people that were vaccinated under real-life conditions are another way to document the persistence of protection. Finally, case-control studies in outbreak situations or in situations of persisting endemicity can also be used to document the persistence of the vaccine efficacy. All of these tools are used in the development of new vaccines, and also

Global Foot-and-Mouth Disease Research Update and Gap Analysis: 3 - Vaccines.

PubMed

Robinson, L; Knight-Jones, T J D; Charleston, B; Rodriguez, L L; Gay, C G; Sumption, K J; Vosloo, W

2016-06-01

This study assessed research knowledge gaps in the field of FMDV (foot-and-mouth disease virus) vaccines. The study took the form of a literature review (2011-15) combined with research updates collected in 2014 from 33 institutes from across the world. Findings were used to identify priority areas for future FMD vaccine research. Vaccines play a vital role in FMD control, used both to limit the spread of the virus during epidemics in FMD-free countries and as the mainstay of disease management in endemic regions, particularly where sanitary controls are difficult to apply. Improvements in the performance or cost-effectiveness of FMD vaccines will allow more widespread and efficient disease control. FMD vaccines have changed little in recent decades, typically produced by inactivation of whole virus, the quantity and stability of the intact viral capsids in the final preparation being key for immunogenicity. However, these are exciting times and several promising novel FMD vaccine candidates have recently been developed. This includes the first FMD vaccine licensed for manufacture and use in the USA; this adenovirus-vectored FMD vaccine causes in vivo expression of viral capsids in vaccinated animals. Another promising vaccine candidate comprises stabilized empty FMDV capsids produced in vitro in a baculovirus expression system. Recombinant technologies are also being developed to improve otherwise conventionally produced inactivated vaccines, for example, by creating a chimeric vaccine virus to increase capsid stability and by inserting sequences into the vaccine virus for desired antigen expression. Other important areas of ongoing research include enhanced adjuvants, vaccine quality control procedures and predicting vaccine protection from immune correlates, thus reducing dependency on animal challenge studies. Globally, the degree of independent vaccine evaluation is highly variable, and this is essential for vaccine quality. Previously neglected, the

An open-label, single arm, phase III clinical study to evaluate the efficacy and safety of CJ smallpox vaccine in previously vaccinated healthy adults.

PubMed

Kim, Nak-Hyun; Kang, Yu Min; Kim, Gayeon; Choe, Pyoeng Gyun; Song, Jin Su; Lee, Kwang-Hee; Seong, Baik-Lin; Park, Wan Beom; Kim, Nam Joong; Oh, Myoung-don

2013-10-25

The increased possibility of bioterrorism has led to reinitiation of smallpox vaccination. In Korea, more than 30 years have passed since the last smallpox vaccinations, and even people who were previously vaccinated are not regarded as adequately protected against smallpox. We evaluated the efficacy and safety of CJ-50300, a newly developed cell culture-derived smallpox vaccine, in healthy adults previously vaccinated against smallpox. We conducted an open label, single arm, phase III clinical trial to evaluate the efficacy and safety of CJ-50300. Healthy volunteers, previously vaccinated against smallpox, born between 1950 and 1978 were enrolled. CJ-50300 was administered with a bifurcated needle over the deltoid muscle according to the recommended method. The rate of the cutaneous take reaction, humoral immunogenicity, and safety of the vaccine was assessed. Of 145 individuals enrolled for vaccination, 139 completed the study. The overall rates of cutaneous take reactions and humoral immunogenicity were 95.0% (132/139) and 88.5% (123/139), respectively. Although 95.9% (139/145) reported adverse events related to vaccination, no serious adverse reactions were observed. CJ-50300 can be used safely and effectively in healthy adults previously vaccinated against smallpox. Copyright © 2013 The Authors. Published by Elsevier Ltd.. All rights reserved.

Improving global access to new vaccines: intellectual property, technology transfer, and regulatory pathways.

PubMed

Crager, Sara Eve

2014-11-01

The 2012 World Health Assembly Global Vaccine Action Plan called for global access to new vaccines within 5 years of licensure. Current approaches have proven insufficient to achieve sustainable vaccine pricing within such a timeline. Paralleling the successful strategy of generic competition to bring down drug prices, a clear consensus is emerging that market entry of multiple suppliers is a critical factor in expeditiously bringing down prices of new vaccines. In this context, key target objectives for improving access to new vaccines include overcoming intellectual property obstacles, streamlining regulatory pathways for biosimilar vaccines, and reducing market entry timelines for developing-country vaccine manufacturers by transfer of technology and know-how. I propose an intellectual property, technology, and know-how bank as a new approach to facilitate widespread access to new vaccines in low- and middle-income countries by efficient transfer of patented vaccine technologies to multiple developing-country vaccine manufacturers.

[Improving global access to new vaccines: intellectual property, technology transfer, and regulatory pathways].

PubMed

Crager, Sara Eve

2015-01-01

The 2012 World Health Assembly Global Vaccine Action Plan called for global access to new vaccines within 5 years of licensure. Current approaches have proven insufficient to achieve sustainable vaccine pricing within such a timeline. Paralleling the successful strategy of generic competition to bring down drug prices, a clear consensus is emerging that market entry of multiple suppliers is a critical factor in expeditiously bringing down prices of new vaccines. In this context, key target objectives for improving access to new vaccines include overcoming intellectual property obstacles, streamlining regulatory pathways for biosimilar vaccines, and reducing market entry timelines for developing-country vaccine manufacturers by transfer of technology and know-how. I propose an intellectual property, technology, and know-how bank as a new approach to facilitate widespread access to new vaccines in low- and middle-income countries by efficient transfer of patented vaccine technologies to multiple developing-country vaccine manufacturers.

Making vaccines “on demand”

PubMed Central

De Groot, Anne S; Einck, Leo; Moise, Leonard; Chambers, Michael; Ballantyne, John; Malone, Robert W; Ardito, Matthew; Martin, William

2013-01-01

The integrated US Public Health Emergency Medical Countermeasures Enterprise (PHEMCE) has made great strides in strategic preparedness and response capabilities. There have been numerous advances in planning, biothreat countermeasure development, licensure, manufacturing, stockpiling and deployment. Increased biodefense surveillance capability has dramatically improved, while new tools and increased awareness have fostered rapid identification of new potential public health pathogens. Unfortunately, structural delays in vaccine design, development, manufacture, clinical testing and licensure processes remain significant obstacles to an effective national biodefense rapid response capability. This is particularly true for the very real threat of “novel pathogens” such as the avian-origin influenzas H7N9 and H5N1, and new coronaviruses such as hCoV-EMC. Conventional approaches to vaccine development, production, clinical testing and licensure are incompatible with the prompt deployment needed for an effective public health response. An alternative approach, proposed here, is to apply computational vaccine design tools and rapid production technologies that now make it possible to engineer vaccines for novel emerging pathogen and WMD biowarfare agent countermeasures in record time. These new tools have the potential to significantly reduce the time needed to design string-of-epitope vaccines for previously unknown pathogens. The design process—from genome to gene sequence, ready to insert in a DNA plasmid—can now be accomplished in less than 24 h. While these vaccines are by no means “standard,” the need for innovation in the vaccine design and production process is great. Should such vaccines be developed, their 60-d start-to-finish timeline would represent a 2-fold faster response than the current standard. PMID:23877094

Adjuvanted pandemic influenza vaccine: variation of emulsion components affects stability, antigen structure, and vaccine efficacy

PubMed Central

Fox, Christopher B.; Barnes V, Lucien; Evers, Tara; Chesko, James D.; Vedvick, Thomas S.; Coler, Rhea N.; Reed, Steven G.; Baldwin, Susan L.

2012-01-01

Please cite this paper as: Fox et al. (2012) Adjuvanted pandemic influenza vaccine: variation of emulsion components affects stability, antigen structure, and vaccine efficacy. Influenza and Other Respiratory Viruses DOI: 10.1111/irv.12031. Abstract Background  Adjuvant formulations are critical components of modern vaccines based on recombinant proteins, which are often poorly immunogenic without additional immune stimulants. Oil‐in‐water emulsions comprise an advanced class of vaccine adjuvants that are components of approved seasonal and pandemic influenza vaccines. However, few reports have been published that systematically evaluate the in vitro stability and in vivo adjuvant effects of different emulsion components. Objectives  To evaluate distinct classes of surfactants, oils, and excipients, for their effects on emulsion particle size stability, antigen structural interactions, and in vivo activity when formulated with a recombinant H5N1 antigen. Methods  Emulsions were manufactured by high pressure homogenization and characterized alone or in the presence of vaccine antigen by dynamic light scattering, zeta potential, viscosity, pH, hemolytic activity, electron microscopy, fluorescence spectroscopy, and SDS‐PAGE. In vivo vaccine activity in the murine model was characterized by measuring antibody titers, antibody‐secreting plasma cells, hemagglutination inhibition titers, and cytokine production. Results  We demonstrate that surfactant class and presence of additional excipients are not critical for biological activity, whereas oil structure is crucial. Moreover, we report that simplified two‐component emulsions appear more stable by particle size than more complex formulations.Finally, differences in antigen structural interactions with the various emulsions do not appear to correlate with in vivo activity. Conclusions  Oil‐in‐water emulsions can significantly enhance antibody and cellular immune responses to a pandemic influenza

Use of the mice passive protection test to evaluate the humoral response in goats vaccinated with Sterne 34F2 live spore vaccine.

PubMed

Phaswana, P H; Ndumnego, O C; Koehler, S M; Beyer, W; Crafford, J E; van Heerden, H

2017-09-07

The Sterne live spore vaccine (34F2) is the most widely used veterinary vaccine against anthrax in animals. Antibody responses to several antigens of Bacillus anthracis have been described with a large focus on those against protective antigen (PA). The focus of this study was to evaluate the protective humoral immune response induced by the live spore anthrax vaccine in goats. Boer goats vaccinated twice (week 0 and week 12) with the Sterne live spore vaccine and naive goats were used to monitor the anti-PA and toxin neutralizing antibodies at week 4 and week 17 (after the second vaccine dose) post vaccination. A/J mice were passively immunized with different dilutions of sera from immune and naive goats and then challenged with spores of B. anthracis strain 34F2 to determine the protective capacity of the goat sera. The goat anti-PA ELISA titres indicated significant sero-conversion at week 17 after the second doses of vaccine (p = 0.009). Mice receiving undiluted sera from goats given two doses of vaccine (twice immunized) showed the highest protection (86%) with only 20% of mice receiving 1:1000 diluted sera surviving lethal challenge. The in vitro toxin neutralization assay (TNA) titres correlated to protection of passively immunized A/J mice against lethal infection with the vaccine strain Sterne 34F2 spores using immune goat sera up to a 1:10 dilution (r s  ≥ 0.522, p = 0.046). This study suggests that the passive mouse protection model could be potentially used to evaluate the protective immune response in livestock animals vaccinated with the current live vaccine and new vaccines.

Methods for addressing "innocent bystanders" when evaluating safety of concomitant vaccines.

PubMed

Wang, Shirley V; Abdurrob, Abdurrahman; Spoendlin, Julia; Lewis, Edwin; Newcomer, Sophia R; Fireman, Bruce; Daley, Matthew F; Glanz, Jason M; Duffy, Jonathan; Weintraub, Eric S; Kulldorff, Martin

2018-04-01

The need to develop methods for studying the safety of childhood immunization schedules has been recognized by the Institute of Medicine and Department of Health and Human Services. The recommended childhood immunization schedule includes multiple vaccines in a visit. A key concern is safety of concomitant (same day) versus separate day vaccination. This paper addresses a methodological challenge for observational studies using a self-controlled design to investigate the safety of concomitant vaccination. We propose a process for distinguishing which of several concomitantly administered vaccines is responsible for increased risk of an adverse event while adjusting for confounding due to relationships between effect modifying risk factors and concomitant vaccine combinations. We illustrate the approach by re-examining the known increase in risk of seizure 7 to 10 days after measles-mumps-rubella (MMR) vaccination and evaluating potential independent or modifying effects of other vaccines. Initial analyses suggested that DTaP had both an independent and potentiating effect on seizure. After accounting for the relationship between age at vaccination and vaccine combination, there was little evidence for increased risk of seizure with same day administration of DTaP and MMR; incidence rate ratio, 95% confidence interval 1.2 (0.9-1.6), P value = θ.226. We have shown that when using a self-controlled design to investigate safety of concomitant vaccination, it can be critically important to adjust for time-invariant effect modifying risk factors, such as age at time of vaccination, which are structurally related to vaccination patterns due to recommended immunization schedules. Copyright © 2018 John Wiley & Sons, Ltd.

Vaccine stabilization: research, commercialization, and potential impact.

PubMed

Kristensen, Debra; Chen, Dexiang; Cummings, Ray

2011-09-22

All vaccines are susceptible to damage by elevated temperatures and many are also damaged by freezing. The distribution, storage, and use of vaccines therefore present challenges that could be reduced by enhanced thermostability, with resulting improvements in vaccine effectiveness. Formulation and processing technologies exist that can improve the stability of vaccines at temperature extremes, however, customization is required for individual vaccines and results are variable. Considerations affecting decisions about stabilization approaches include development cost, manufacturing cost, and the ease of use of the final product. Public sector agencies can incentivize vaccine developers to prioritize stabilization efforts through advocacy and by implementing policies that increase demand for thermostable vaccines. Copyright © 2011 Elsevier Ltd. All rights reserved.

Off-label use of vaccines.

PubMed

Neels, Pieter; Southern, James; Abramson, Jon; Duclos, Philippe; Hombach, Joachim; Marti, Melanie; Fitzgerald-Husek, Alanna; Fournier-Caruana, Jacqueline; Hanquet, Germaine

2017-04-25

This article reviews the off-label recommendations and use of vaccines, and focuses on the differences between the labelled instructions on how to use the vaccine as approved by the regulatory authorities (or "label" 1 ), and the recommendations for use issued by public health advisory bodies at national and international levels. Differences between public health recommendations and the product label regarding the vaccine use can lead to confusion at the level of vaccinators and vaccinees and possibly result in lower compliance with national vaccination schedules. In particular, in many countries, the label may contain regulatory restrictions and warnings against vaccination of specific population groups (e.g. pregnant women) due to a lack of evidence of safety from controlled trials at the time of initial licensure of the vaccine, while public health authorities may recommend the same vaccine for that group, based on additional post-marketing data and benefit risk analyses. We provide an overview of the different responsibilities between regulatory authorities and public health advisory bodies, and the rationale for off-label use 2 of vaccines, the challenges involved based on the impact of off-label use in real-life. We propose to reduce off-label use of vaccines by requiring the manufacturer to regularly adapt the label as much as possible to the public health needs as supported by new evidence. This would require manufacturers to collect and report post-marketing data, communicate them to all stakeholders and regulators to extrapolate existing evidence (when acceptable) to other groups or to other brands of a vaccine (class effect 3 ). Regulatory authorities have a key role to play by requesting additional post-marketing data, e.g. in specific target groups. When public health recommendations for vaccine use that are outside labelled indications are considered necessary, good communication between regulatory bodies, public health authorities, companies and

Evaluation of the efficacy of a new modified live porcine reproductive and respiratory syndrome virus (PRRSV) vaccine (Fostera PRRS) against heterologous PRRSV challenge.

PubMed

Park, Changhoon; Seo, Hwi Won; Han, Kiwon; Kang, Ikjae; Chae, Chanhee

2014-08-27

The objective of this study was to evaluate a new modified live porcine reproductive and respiratory syndrome virus (PRRSV) vaccine (Fostera PRRS, Zoetis, Florham, NJ, USA) that was based on a virulent US PRRSV isolate (P129) attenuated using CD163-expressing cell lines. Sixty-four PRRSV-seronegative 3-week-old pigs were randomly divided into the following four groups: vaccinated challenged (group 1), vaccinated unchallenged (group 2), unvaccinated challenged (group 3), and unvaccinated unchallenged (group 4). The pigs in groups 1 and 2 were immunized with a 2.0 mL dose of modified live PRRSV vaccine at 21 days of age, according to the manufacturer's recommendations. At 56 days of age (0 days post-challenge), the pigs in groups 1 and 3 were inoculated intranasally with 3 mL of tissue culture fluid containing 10(5) 50% tissue culture infective dose (TCID50)/mL of PRRSV (SNUVR090851 strain, fourth passage in MARC-145 cells). Vaccinated challenged pigs exhibited significantly lower (P<0.05) respiratory scores, viremia, macroscopic and microscopic lung lesion scores, and PRRSV-antigen with interstitial pneumonia than unvaccinated challenged pigs. The induction of PRRSV-specific IFN-γ-SCs by the new modified live PRRSV vaccine produced a protective immune response, leading to the reduction of PRRSV viremia. Although the new modified live PRRSV vaccine is not effective against heterologous PRRSV challenge, the new modified live PRRSV vaccine was able to reduce the levels of viremia and nasal shedding, and severity of PRRSV-induced lesions after challenging virus under experimental conditions. Copyright © 2014 Elsevier B.V. All rights reserved.

Vaccines against invasive Salmonella disease

PubMed Central

MacLennan, Calman A; Martin, Laura B; Micoli, Francesca

2014-01-01

Though primarily enteric pathogens, Salmonellae are responsible for a considerable yet under-appreciated global burden of invasive disease. In South and South-East Asia, this manifests as enteric fever caused by serovars Typhi and Paratyphi A. In sub-Saharan Africa, a similar disease burden results from invasive nontyphoidal Salmonellae, principally serovars Typhimurium and Enteritidis. The existing Ty21a live-attenuated and Vi capsular polysaccharide vaccines target S. Typhi and are not effective in young children where the burden of invasive Salmonella disease is highest. After years of lack of investment in new Salmonella vaccines, recent times have seen increased interest in the area led by emerging-market manufacturers, global health vaccine institutes and academic partners. New glycoconjugate vaccines against S. Typhi are becoming available with similar vaccines against other invasive serovars in development. With other new vaccines under investigation, including live-attenuated, protein-based and GMMA vaccines, now is an exciting time for the Salmonella vaccine field. PMID:24804797

Evaluating the promise of recombinant transmissible vaccines

PubMed Central

Basinski, Andrew J.; Varrelman, Tanner J.; Smithson, Mark W.; May, Ryan H.; Remien, Christopher H.; Nuismer, Scott L.

2018-01-01

Transmissible vaccines have the potential to revolutionize infectious disease control by reducing the vaccination effort required to protect a population against a disease. Recent efforts to develop transmissible vaccines focus on recombinant transmissible vaccine designs (RTVs) because they pose reduced risk if intra-host evolution causes the vaccine to revert to its vector form. However, the shared antigenicity of the vaccine and vector may confer vaccine-immunity to hosts infected with the vector, thwarting the ability of the vaccine to spread through the population. We build a mathematical model to test whether a RTV can facilitate disease management in instances where reversion is likely to introduce the vector into the population or when the vector organism is already established in the host population, and the vector and vaccine share perfect cross-immunity. Our results show that a RTV can autonomously eradicate a pathogen, or protect a population from pathogen invasion, when cross-immunity between vaccine and vector is absent. If cross-immunity between vaccine and vector exists, however, our results show that a RTV can substantially reduce the vaccination effort necessary to control or eradicate a pathogen only when continuously augmented with direct manual vaccination. These results demonstrate that estimating the extent of cross-immunity between vector and vaccine is a critical step in RTV design, and that herpesvirus vectors showing facile reinfection and weak cross-immunity are promising. PMID:29279283

Vaccine development and deployment: opportunities and challenges in India.

PubMed

Gupta, Sanjukta Sen; Nair, G Balakrish; Arora, Narendra Kumar; Ganguly, Nirmal Kumar

2013-04-18

The Indian economy is among the fastest growing economies in the world. The country forayed into manufacturing vaccines starting with a few public-sector manufacturers in the late 1960s but has emerged as the major supplier of basic Expanded Programme on Immunization vaccines to the United Nations Children's Fund (UNICEF) because of substantial private-sector investment in the area. The Indian vaccine industry is now able to produce new and more complex vaccines such as the meningitis, Haemophilus influenzae type b, and pneumococcal conjugate vaccines, rotavirus vaccine and influenza A (H1N1) vaccines. This has been possible because of an attractive investment environment, effective and innovative governmental support, international partnerships and the growing in-country technical work force. A large number of vaccines, including those mentioned, is available and administered in the private sector within the country, but India has been slow in introducing new vaccines in its publically funded programs. Growth in the economy and technological accomplishments are not reflected in a reduction in health inequalities, and India continues to contribute significantly to global child mortality figures. This paper reviews the development of the Indian vaccine industry, policy support for it and its current status. It also highlights opportunities and challenges for the introduction of new and underutilized vaccines at home. Copyright © 2012 Elsevier Ltd. All rights reserved.

Choosing between 7-, 10- and 13-valent pneumococcal conjugate vaccines in childhood: a review of economic evaluations (2006-2014).

PubMed

Wu, David Bin-Chia; Chaiyakunapruk, Nathorn; Chong, Huey-Yi; Beutels, Philippe

2015-03-30

Seven-valent pneumococcal conjugate vaccines (PCV7) have been used in children for more than a decade. Given the observed increase in disease caused by pneumococcal serotypes not covered by PCV7, an increasing number of countries are switching from 7-valent to 10- and 13-valent PCVs ("PCV10" and "PCV13"). Economic evaluations are important tools to inform decisions and price negotiations to make such a switch. This review aims to provide a critical assessment of economic evaluations involving PCV10 or PCV13, published since 2006. We searched Scopus, ISI Web of Science (SCI and SSCI) and Pubmed to retrieve, select and review relevant studies, which were archived between 1st January 2006 and 31st January 2014. The review protocol involved standard extraction of assumptions, methods, results and sponsorships from the original studies. Sixty-three economic evaluations on PCVs published since January 2006 were identified. About half of these evaluated PCV10 and/or PCV13, the subject of this review. At current prices, both PCV13 and PCV10 were likely judged preferable to PCV7. However, the combined uncertainty related to price differences, burden of disease, vaccine effectiveness, herd and serotype replacement effects determine the preference base for either PCV10 or PCV13. The pivotal assumptions and results of these analyses also depended on which manufacturer sponsored the study. A more thorough exploration of uncertainty should be made in future analyses on this subject, as we lack understanding to adequately model herd and serotype replacement effects to reliably predict the population impact of PCVs. The introduction of further improved PCVs in an environment of evolving antibiotic resistance and under the continuing influence of previous PCVs implies that the complexity and data requirements for relevant analyses will further increase. Decision makers using these analyses should not just rely on an analysis from a single manufacturer. Copyright © 2015 Elsevier

Framework for Optimal Global Vaccine Stockpile Design for Vaccine-Preventable Diseases: Application to Measles and Cholera Vaccines as Contrasting Examples.

PubMed

Thompson, Kimberly M; Duintjer Tebbens, Radboud J

2016-07-01

Managing the dynamics of vaccine supply and demand represents a significant challenge with very high stakes. Insufficient vaccine supplies can necessitate rationing, lead to preventable adverse health outcomes, delay the achievements of elimination or eradication goals, and/or pose reputation risks for public health authorities and/or manufacturers. This article explores the dynamics of global vaccine supply and demand to consider the opportunities to develop and maintain optimal global vaccine stockpiles for universal vaccines, characterized by large global demand (for which we use measles vaccines as an example), and nonuniversal (including new and niche) vaccines (for which we use oral cholera vaccine as an example). We contrast our approach with other vaccine stockpile optimization frameworks previously developed for the United States pediatric vaccine stockpile to address disruptions in supply and global emergency response vaccine stockpiles to provide on-demand vaccines for use in outbreaks. For measles vaccine, we explore the complexity that arises due to different formulations and presentations of vaccines, consideration of rubella, and the context of regional elimination goals. We conclude that global health policy leaders and stakeholders should procure and maintain appropriate global vaccine rotating stocks for measles and rubella vaccine now to support current regional elimination goals, and should probably also do so for other vaccines to help prevent and control endemic or epidemic diseases. This work suggests the need to better model global vaccine supplies to improve efficiency in the vaccine supply chain, ensure adequate supplies to support elimination and eradication initiatives, and support progress toward the goals of the Global Vaccine Action Plan. © 2014 Society for Risk Analysis.

[Evaluation of the National Vaccination Day in Bogota, D.C., 2001].

PubMed

Prieto Alvarado, Franklyn E; de la Hoz Restrepo, Fernando P

2003-01-01

A national immunization day-NID, aimed at improving vaccination coverage, was carried out in Colombia in November 2001. The main objective of the study was to measure the proportion of children under 2 years either completing their immunization schedule or advancing through it by receiving doses during the NID. Besides, we also evaluated the proportion of lost opportunities for vaccination during the NID and the impact of the media (TV, ratio, newspapers, etc.) in advertising the NID. In order to evaluate the impact of immunization a cross sectional survey was carried out in Bogotá in the waiting rows of the 30 randomly selected vaccination posts; 623 participants were systematically chosen. The outcomes were analyzed by age, socioeconomic level and type of health insurance-SSS. Only children holding a vaccination card were considered eligible for the study. Most people become aware about NID through TV, 81%, followed by radio advertisements, 22%. After attending NID the proportion of fully vaccinated children, according to PAHO scheme, raised from 46% to 66%, a 43% increase. This increase was even higher among children aged less than 6 months (140% increment). There were no differences in the increment by social stratum or affiliation to the SSS. Among the children studied we identified a 24% of loss opportunities for vaccination that did not differ by socioeconomic level or SSS groups. Our results suggest that, despite its high costs, NID might be useful to transiently overcome barriers for adequate access to health services.

Vaccine delivery management.

PubMed

Cheyne, J

1989-01-01

During the typical 12- to 18-month voyage of a vaccine from manufacturer to immunization site, many situations arise in which the cold chain may be interrupted. Extensive efforts have been made in the 1980s to ensure an uninterrupted cold chain through the use of improved equipment and better training of personnel. One important advance is the vaccine cold-chain monitor, which identifies weak spots in the cold chain and prevents the use of heat-damaged vaccine. Further improvements will require efforts by the recipient countries (e.g., better use of the private sector for transport and equipment management), by donor agencies (e.g., greater consideration of the operational and maintenance costs of the equipment selected and resolution of fuel shortages), and by industry (e.g., more appropriate packaging and pricing of vaccine, extension of the expiration period, and increased heat stability.

Vaccine development for allergen-specific immunotherapy based on recombinant allergens and synthetic allergen peptides: Lessons from the past and novel mechanisms of action for the future

PubMed Central

Valenta, Rudolf; Campana, Raffaela; Focke-Tejkl, Margit; Niederberger, Verena

2016-01-01

In the past, the development of more effective, safe, convenient, broadly applicable, and easy to manufacture vaccines for allergen-specific immunotherapy (AIT) has been limited by the poor quality of natural allergen extracts. Progress made in the field of molecular allergen characterization has now made it possible to produce defined vaccines for AIT and eventually for preventive allergy vaccination based on recombinant DNA technology and synthetic peptide chemistry. Here we review the characteristics of recombinant and synthetic allergy vaccines that have reached clinical evaluation and discuss how molecular vaccine approaches can make AIT more safe and effective and thus more convenient. Furthermore, we discuss how new technologies can facilitate the reproducible manufacturing of vaccines of pharmaceutical grade for inhalant, food, and venom allergens. Allergy vaccines in clinical trials based on recombinant allergens, recombinant allergen derivatives, and synthetic peptides allow us to target selectively different immune mechanisms, and certain of those show features that might make them applicable not only for therapeutic but also for prophylactic vaccination. PMID:26853127

Current Global Pricing For Human Papillomavirus Vaccines Brings The Greatest Economic Benefits To Rich Countries.

PubMed

Herlihy, Niamh; Hutubessy, Raymond; Jit, Mark

2016-02-01

Vaccinating females against human papillomavirus (HPV) prior to the debut of sexual activity is an effective way to prevent cervical cancer, yet vaccine uptake in low- and middle-income countries has been hindered by high vaccine prices. We created an economic model to estimate the distribution of the economic surplus-the sum of all health and economic benefits of a vaccine, minus the costs of development, production, and distribution-among different country income groups and manufacturers for a cohort of twelve-year-old females in 2012. We found that manufacturers may have received economic returns worth five times their original investment in HPV vaccine development. High-income countries gained the greatest economic surplus of any income category, realizing over five times more economic value per vaccinated female than low-income countries did. Subsidizing vaccine prices in low- and middle-income countries could both reduce financial barriers to vaccine adoption and still allow high-income countries to retain their economic surpluses and manufacturers to retain their profits. Project HOPE—The People-to-People Health Foundation, Inc.

Preventative Vaccines for Zika Virus Outbreak: Preliminary Evaluation.

PubMed

Kim, Eun; Erdos, Geza; Huang, Shaohua; Kenniston, Thomas; Falo, Louis D; Gambotto, Andrea

2016-11-01

Since it emerged in Brazil in May 2015, the mosquito-borne Zika virus (ZIKV) has raised global concern due to its association with a significant rise in the number of infants born with microcephaly and neurological disorders such as Guillain-Barré syndrome. We developed prototype subunit and adenoviral-based Zika vaccines encoding the extracellular portion of the ZIKV envelope gene (E) fused to the T4 fibritin foldon trimerization domain (Efl). The subunit vaccine was delivered intradermally through carboxymethyl cellulose microneedle array (MNA). The immunogenicity of these two vaccines, named Ad5.ZIKV-Efl and ZIKV-rEfl, was tested in C57BL/6 mice. Prime/boost immunization regimen was associated with induction of a ZIKV-specific antibody response, which provided neutralizing immunity. Moreover, protection was evaluated in seven-day-old pups after virulent ZIKV intraperitoneal challenge. Pups born to mice immunized with Ad5.ZIKV-Efl were all protected against lethal challenge infection without weight loss or neurological signs, while pups born to dams immunized with MNA-ZIKV-rEfl were partially protected (50%). No protection was seen in pups born to phosphate buffered saline-immunized mice. This study illustrates the preliminary efficacy of the E ZIKV antigen vaccination in controlling ZIKV infectivity, providing a promising candidate vaccine and antigen format for the prevention of Zika virus disease. Copyright © 2016 The Authors. Published by Elsevier B.V. All rights reserved.

Inactivated polio vaccines from three different manufacturers have equivalent safety and immunogenicity when given as 1 or 2 additional doses after bivalent OPV: Results from a randomized controlled trial in Latin America.

PubMed

Lopez-Medina, Eduardo; Melgar, Mario; Gaensbauer, James T; Bandyopadhyay, Ananda S; Borate, Bhavesh R; Weldon, William C; Rüttimann, Ricardo; Ward, Joel; Clemens, Ralf; Asturias, Edwin J

2017-06-16

Since April 2016 inactivated poliovirus vaccine (IPV) has been the only routine source of polio type 2 protection worldwide. With IPV supply constraints, data on comparability of immunogenicity and safety will be important to optimally utilize available supplies from different manufacturers. In this multicenter phase IV study, 900 Latin American infants randomly assigned to six study groups received three doses of bOPV at 6, 10 and 14weeks and either one IPV dose at 14weeks (groups SP-1, GSK-1 and BBio-1) or two IPV doses at 14 and 36weeks (groups SP-2, GSK-2 and BBio-2) from three different manufacturers. Children were challenged with mOPV2 at either 18 (one IPV dose) or 40weeks (two IPV doses) and stools were collected weekly for 4weeks to assess viral shedding. Serum neutralizing antibodies were measured at various time points pre and post vaccination. Serious adverse events and important medical events (SAE and IME) were monitored for 6months after last study vaccine. At week 18, 4weeks after one dose of IPV, overall type 2 seroconversion rates were 80.4%, 80.4% and 73.3% for SP-1, GSK-1 and BBio-1 groups, respectively; and 92.6%, 96.8% and 88.0% in those who were seronegative before IPV administration. At 40weeks, 4weeks after a second IPV dose, type 2 seroconversion rates were ≥99% for any of the three manufacturers. There were no significant differences in fecal shedding index endpoint (SIE) after one or two IPV doses (SP: 2.3 [95% CI: 2.1-2.6]); GSK: 2.2 [1.7-2.5]; BBio 1.8 [1.5-2.3]. All vaccines appeared safe, with no vaccine-related SAE or IME. Current WHO prequalified IPV vaccines are safe and induce similar humoral and intestinal immunity after one or two doses. The parent study was registered with ClinicalTrials.gov, number NCT01831050. Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.

[Economic evaluation on different two-dose-vaccination-strategies related to Measles, Mumps and Rubella Combined Attenuated Live Vaccine].

PubMed

He, H Q; Zhang, B; Yan, R; Li, Q; Fu, J; Tang, X W; Zhou, Y; Deng, X; Xie, S Y

2016-08-10

To evaluate the economic effect of Measles, Mumps and Rubella Combined Attenuated Live Vaccine (MMR) under different two-dose vaccination programs. A hypothetical birth cohort of 750 000 infants over their lifetime, was followed up from birth through death in Zhejiang province. The current MMR vaccination strategie would include three different ones: 1) Childlern were vaccinated with Measles-Rubella Combined Attenuated Live Vaccine and MMR, respectively at the age of 8 months and 18 months. 2) Children receive MMR at 8 months and 18 months, 3) Strategy 1 plus an additional vaccination of MMR at 4 years of age. Incremental cost-effectiveness ratio (ICER), incremental cost-benefit ratio (ICBR) and incremental net benefit (INB) were applied to calculate the health economic difference for Strategy 2 and Strategy 3 as compared to Strategy 1. Univariate sensitivity analysis was used to assess the robustness of results with main parameters, including the rate of immunization coverage, effectiveness of the vaccines, incidence and burdens of the related diseases, cost of vaccines and the vaccination program itself. ICER, ICBR and INB for Strategy 2 and Strategy 3 appeared as 2 012.51∶1 RMB Yuan per case and 4 238.72∶1 RMB Yuan per case, 1∶3.14 and 1∶1.58, 21 277 800 RMB Yuan and 9 276 500 RMB Yuan, respectively. Only slight changes (<20%) were found under the univariate sensitivity analysis, with varied values on main parameters. Based on the current national immunization program, infants vaccinated with MMR at 8 months of age, generated more health economic effects than the Strategy 3.

Improving Global Access to New Vaccines: Intellectual Property, Technology Transfer, and Regulatory Pathways

PubMed Central

2014-01-01

The 2012 World Health Assembly Global Vaccine Action Plan called for global access to new vaccines within 5 years of licensure. Current approaches have proven insufficient to achieve sustainable vaccine pricing within such a timeline. Paralleling the successful strategy of generic competition to bring down drug prices, a clear consensus is emerging that market entry of multiple suppliers is a critical factor in expeditiously bringing down prices of new vaccines. In this context, key target objectives for improving access to new vaccines include overcoming intellectual property obstacles, streamlining regulatory pathways for biosimilar vaccines, and reducing market entry timelines for developing-country vaccine manufacturers by transfer of technology and know-how. I propose an intellectual property, technology, and know-how bank as a new approach to facilitate widespread access to new vaccines in low- and middle-income countries by efficient transfer of patented vaccine technologies to multiple developing-country vaccine manufacturers. PMID:25211753

Is a HIV vaccine a viable option and at what price? An economic evaluation of adding HIV vaccination into existing prevention programs in Thailand.

PubMed

Leelahavarong, Pattara; Teerawattananon, Yot; Werayingyong, Pitsaphun; Akaleephan, Chutima; Premsri, Nakorn; Namwat, Chawetsan; Peerapatanapokin, Wiwat; Tangcharoensathien, Viroj

2011-07-05

This study aims to determine the maximum price at which HIV vaccination is cost-effective in the Thai healthcare setting. It also aims to identify the relative importance of vaccine characteristics and risk behavior changes among vaccine recipients to determine how they affect this cost-effectiveness. A semi-Markov model was developed to estimate the costs and health outcomes of HIV prevention programs combined with HIV vaccination in comparison to the existing HIV prevention programs without vaccination. The estimation was based on a lifetime horizon period (99 years) and used the government perspective. The analysis focused on both the general population and specific high-risk population groups. The maximum price of cost-effective vaccination was defined by using threshold analysis; one-way and probabilistic sensitivity analyses were performed. The study employed an expected value of perfect information (EVPI) analysis to determine the relative importance of parameters and to prioritize future studies. The most expensive HIV vaccination which is cost-effective when given to the general population was 12,000 Thai baht (US$1 = 34 Thai baht in 2009). This vaccination came with 70% vaccine efficacy and lifetime protection as long as risk behavior was unchanged post-vaccination. The vaccine would be considered cost-ineffective at any price if it demonstrated low efficacy (30%) and if post-vaccination risk behavior increased by 10% or more, especially among the high-risk population groups. The incremental cost-effectiveness ratios were the most sensitive to change in post-vaccination risk behavior, followed by vaccine efficacy and duration of protection. The EVPI indicated the need to quantify vaccine efficacy, changed post-vaccination risk behavior, and the costs of vaccination programs. The approach used in this study differentiated it from other economic evaluations and can be applied for the economic evaluation of other health interventions not available in

Self-Assembly DNA Polyplex Vaccine inside Dissolving Microneedles for High-Potency Intradermal Vaccination.

PubMed

Liao, Jing-Fong; Lee, Jin-Ching; Lin, Chun-Kuang; Wei, Kuo-Chen; Chen, Pin-Yuan; Yang, Hung-Wei

2017-01-01

The strong immunogenicity induction is the powerful weapon to prevent the virus infections. This study demonstrated that one-step synthesis of DNA polyplex vaccine in microneedle (MN) patches can induce high immunogenicity through intradermal vaccination and increase the vaccine stability for storage outside the cold chain. More negative charged DNA vaccine was entrapped into the needle region of MNs followed by DNA polyplex formation with branched polyethylenimine (bPEI) pre-coated in the cavities of polydimethylsiloxane (PDMS) molds that can deliver more DNA vaccine to immune-cell rich epidermis with high transfection efficiency. Our data in this study support the safety and immunogenicity of the MN-based vaccine; the MN patch delivery system induced an immune response 3.5-fold as strong as seen with conventional intramuscular administration; the DNA polyplex formulation provided excellent vaccine stability at high temperature (could be stored at 45ºC for at least 4 months); the DNA vaccine is expected to be manufactured at low cost and not generate sharps waste. We think this study is significant to public health because there is a pressing need for an effective vaccination in developing countries.

Evaluating the Early Benefit of Quadrivalent HPV Vaccine on Genital Warts in Belgium: A Cohort Study.

PubMed

Dominiak-Felden, Geraldine; Gobbo, Corrado; Simondon, François

2015-01-01

Genital warts (GWs) are common, with about 5% to 10% of people having at least one episode in their lifetime. They develop about 2-3 months after infection with human papillomavirus (HPV) genotypes 6 and 11. The prophylactic quadrivalent HPV vaccine (qHPV), protects against HPV6/11 infections and diseases. In Belgium, HPV vaccines started to be reimbursed in 2007 and have been fully reimbursed since December 2008 for women 12 to 18 years old. This study aimed at evaluating the real-life benefit of qHPV vaccine introduction in Belgium on GWs by measuring both vaccine impact (VI) at a population level and the direct effect of the qHPV vaccine at an individual level (vaccine effectiveness (VE)), using data from a large sick-fund (MLOZ) reimbursement database. A first reimbursement for imiquimod (most common first-line GWs treatment in Belgium) was used as a surrogate for a first GWs episode; reimbursement of qHPV vaccine was used as surrogate for vaccination. VI was estimated by comparing the incidence of GWs before and after qHPV vaccine introduction in Belgium (ecologic evaluation). VE was assessed by comparing GWs incidences in vaccinated vs. unvaccinated women, among women eligible for HPV vaccination. VI was evaluated in 9,223,384 person-years. Overall, GWs incidence rates decreased significantly between the pre- and post-vaccination periods (-8.1% (95% CI: -15.3; -0.3) for men and women aged 18-59 years. This decrease was highest in women targeted by the HPV vaccination programme (-72.1% (95% CI: -77.9; -64.7) in women aged 16-22 years, with a 43% vaccine uptake in 2013). A significant decrease was also observed in men aged 16-22 years (-51.1%, 95%CI: -67.6; -26.2), suggesting herd-protection. VE was evaluated in 369,881 person-years. Age-adjusted VE for fully vaccinated women was 88.0% (95% CI: 79.4; 93.0). VE was higher when the first dose was given younger and remained high for over 4 years post-vaccination in all ages. High VI and VE of the qHPV vaccine were

Evaluating the Early Benefit of Quadrivalent HPV Vaccine on Genital Warts in Belgium: A Cohort Study

PubMed Central

Dominiak-Felden, Geraldine; Gobbo, Corrado; Simondon, François

2015-01-01

Genital warts (GWs) are common, with about 5% to 10% of people having at least one episode in their lifetime. They develop about 2–3 months after infection with human papillomavirus (HPV) genotypes 6 and 11. The prophylactic quadrivalent HPV vaccine (qHPV), protects against HPV6/11 infections and diseases. In Belgium, HPV vaccines started to be reimbursed in 2007 and have been fully reimbursed since December 2008 for women 12 to 18 years old. This study aimed at evaluating the real-life benefit of qHPV vaccine introduction in Belgium on GWs by measuring both vaccine impact (VI) at a population level and the direct effect of the qHPV vaccine at an individual level (vaccine effectiveness (VE)), using data from a large sick-fund (MLOZ) reimbursement database. A first reimbursement for imiquimod (most common first-line GWs treatment in Belgium) was used as a surrogate for a first GWs episode; reimbursement of qHPV vaccine was used as surrogate for vaccination. VI was estimated by comparing the incidence of GWs before and after qHPV vaccine introduction in Belgium (ecologic evaluation). VE was assessed by comparing GWs incidences in vaccinated vs. unvaccinated women, among women eligible for HPV vaccination. VI was evaluated in 9,223,384 person-years. Overall, GWs incidence rates decreased significantly between the pre- and post-vaccination periods (-8.1% (95% CI: -15.3; -0.3) for men and women aged 18–59 years. This decrease was highest in women targeted by the HPV vaccination programme (-72.1% (95% CI: -77.9; -64.7) in women aged 16–22 years, with a 43% vaccine uptake in 2013). A significant decrease was also observed in men aged 16-22 years (-51.1%, 95%CI: -67.6; -26.2), suggesting herd-protection. VE was evaluated in 369,881 person-years. Age-adjusted VE for fully vaccinated women was 88.0% (95% CI: 79.4; 93.0). VE was higher when the first dose was given younger and remained high for over 4 years post-vaccination in all ages. High VI and VE of the q

Evaluation of the first pharmacist-administered vaccinations in Western Australia: a mixed-methods study

PubMed Central

Hattingh, H Laetitia; Sim, T Fei; Parsons, R; Czarniak, P; Vickery, A; Ayadurai, S

2016-01-01

Objectives This study evaluated the uptake of Western Australian (WA) pharmacist vaccination services, the profiles of consumers being vaccinated and the facilitators and challenges experienced by pharmacy staff in the preparation, implementation and delivery of services. Design Mixed-methods methodology with both quantitative and qualitative data through surveys, pharmacy computer records and immuniser pharmacist interviews. Setting Community pharmacies in WA that provided pharmacist vaccination services between March and October 2015. Participants Immuniser pharmacists from 86 pharmacies completed baseline surveys and 78 completed exit surveys; computer records from 57 pharmacies; 25 immuniser pharmacists were interviewed. Main outcome measures Pharmacy and immuniser pharmacist profiles; pharmacist vaccination services provided and consumer profiles who accessed services. Results 15 621 influenza vaccinations were administered by immuniser pharmacists at 76 WA community pharmacies between March and October 2015. There were no major adverse events, and <1% of consumers experienced minor events which were appropriately managed. Between 12% and 17% of consumers were eligible to receive free influenza vaccinations under the National Immunisation Program but chose to have it at a pharmacy. A high percentage of vaccinations was delivered in rural and regional areas indicating that provision of pharmacist vaccination services facilitated access for rural and remote consumers. Immuniser pharmacists reported feeling confident in providing vaccination services and were of the opinion that services should be expanded to other vaccinations. Pharmacists also reported significant professional satisfaction in providing the service. All participating pharmacies intended to continue providing influenza vaccinations in 2016. Conclusions This initial evaluation of WA pharmacist vaccination services showed that vaccine delivery was safe. Convenience and accessibility were

Evaluation of direct and indirect additive manufacture of maxillofacial prostheses.

PubMed

Eggbeer, Dominic; Bibb, Richard; Evans, Peter; Ji, Lu

2012-09-01

The efficacy of computer-aided technologies in the design and manufacture of maxillofacial prostheses has not been fully proven. This paper presents research into the evaluation of direct and indirect additive manufacture of a maxillofacial prosthesis against conventional laboratory-based techniques. An implant/magnet-retained nasal prosthesis case from a UK maxillofacial unit was selected as a case study. A benchmark prosthesis was fabricated using conventional laboratory-based techniques for comparison against additive manufactured prostheses. For the computer-aided workflow, photogrammetry, computer-aided design and additive manufacture (AM) methods were evaluated in direct prosthesis body fabrication and indirect production using an additively manufactured mould. Qualitative analysis of position, shape, colour and edge quality was undertaken. Mechanical testing to ISO standards was also used to compare the silicone rubber used in the conventional prosthesis with the AM material. Critical evaluation has shown that utilising a computer-aided work-flow can produce a prosthesis body that is comparable to that produced using existing best practice. Technical limitations currently prevent the direct fabrication method demonstrated in this paper from being clinically viable. This research helps prosthesis providers understand the application of a computer-aided approach and guides technology developers and researchers to address the limitations identified.

Addressing a Yellow Fever Vaccine Shortage - United States, 2016-2017.

PubMed

Gershman, Mark D; Angelo, Kristina M; Ritchey, Julian; Greenberg, David P; Muhammad, Riyadh D; Brunette, Gary; Cetron, Martin S; Sotir, Mark J

2017-05-05

Recent manufacturing problems resulted in a shortage of the only U.S.-licensed yellow fever vaccine. This shortage is expected to lead to a complete depletion of yellow fever vaccine available for the immunization of U.S. travelers by mid-2017. CDC, the Food and Drug Administration (FDA), and Sanofi Pasteur are collaborating to ensure a continuous yellow fever vaccine supply in the United States. As part of this collaboration, Sanofi Pasteur submitted an expanded access investigational new drug (eIND) application to FDA in September 2016 to allow for the importation and use of an alternative yellow fever vaccine manufactured by Sanofi Pasteur France, with safety and efficacy comparable to the U.S.-licensed vaccine; the eIND was accepted by FDA in October 2016. The implementation of this eIND protocol included developing a systematic process for selecting a limited number of clinic sites to provide the vaccine. CDC and Sanofi Pasteur will continue to communicate with the public and other stakeholders, and CDC will provide a list of locations that will be administering the replacement vaccine at a later date.

Vaccination of children with a live-attenuated, intranasal influenza vaccine - analysis and evaluation through a Health Technology Assessment.

PubMed

Andersohn, Frank; Bornemann, Reinhard; Damm, Oliver; Frank, Martin; Mittendorf, Thomas; Theidel, Ulrike

2014-01-01

Influenza is a worldwide prevalent infectious disease of the respiratory tract annually causing high morbidity and mortality in Germany. Influenza is preventable by vaccination and this vaccination is so far recommended by the The German Standing Committee on Vaccination (STIKO) as a standard vaccination for people from the age of 60 onwards. Up to date a parenterally administered trivalent inactivated vaccine (TIV) has been in use almost exclusively. Since 2011 however a live-attenuated vaccine (LAIV) has been approved additionally. Consecutively, since 2013 the STIKO recommends LAIV (besides TIV) for children from 2 to 17 years of age, within the scope of vaccination by specified indications. LAIV should be preferred administered in children from 2 to 6 of age. The objective of this Health Technology Assessment (HTA) is to address various research issues regarding the vaccination of children with LAIV. The analysis was performed from a medical, epidemiological and health economic perspective, as well as from an ethical, social and legal point of view. An extensive systematic database research was performed to obtain relevant information. In addition a supplementary research by hand was done. Identified literature was screened in two passes by two independent reviewers using predefined inclusion and exclusion criteria. Included literature was evaluated in full-text using acknowledged standards. Studies were graded with the highest level of evidence (1++), if they met the criteria of European Medicines Agency (EMA)-Guidance: Points to consider on applications with 1. meta-analyses; 2. one pivotal study. For the medical section, the age of the study participants ranges from 6 months to 17 years. Regarding study efficacy, in children aged 6 months to ≤7 years, LAIV is superior to placebo as well as to a vac-cination with TIV (Relative Risk Reduction - RRR - of laboratory confirmed influenza infection approx. 80% and 50%, respectively). In children aged >7 to 17

Influenza vaccines: Evaluation of the safety profile

PubMed Central

Trombetta, Claudia Maria; Gianchecchi, Elena; Montomoli, Emanuele

2018-01-01

ABSTRACT The safety of vaccines is a critical factor in maintaining public trust in national vaccination programs. Vaccines are recommended for children, adults and elderly subjects and have to meet higher safety standards, since they are administered to healthy subjects, mainly healthy children. Although vaccines are strictly monitored before authorization, the possibility of adverse events and/or rare adverse events cannot be totally eliminated. Two main types of influenza vaccines are currently available: parenteral inactivated influenza vaccines and intranasal live attenuated vaccines. Both display a good safety profile in adults and children. However, they can cause adverse events and/or rare adverse events, some of which are more prevalent in children, while others with a higher prevalence in adults. The aim of this review is to provide an overview of influenza vaccine safety according to target groups, vaccine types and production methods. PMID:29297746

Fast tracking the vaccine licensure process to control an epidemic of serogroup B meningococcal disease in New Zealand.

PubMed

Lennon, Diana; Jackson, Catherine; Wong, Sharon; Horsfall, Maraekura; Stewart, Joanna; Reid, Stewart

2009-08-15

Epidemics of serogroup B meningococcal disease are rare. Strain-specific outer membrane vesicle vaccines, which are not marketed, are the only current tool for control. A correlate of protection is ill defined, but published data suggest that measured serum bactericidal antibody levels parallel efficacy. Even infants can mount a strain-specific antibody response to a strain-specific vaccine. New Zealand's epidemic (1991-2007; peak rate [in 2001], 17.4 cases per 100,000 persons) was dominated by a single strain. After a 5-year search (1996-2001) for a manufacturer for a strain-specific outer membrane vesicle vaccine, a fast-tracked research program (2002-2004) determined the safety and immunogenicity of vaccine in infants (2 age groups: 6-10 weeks and 6-8 months), children (age, 16-24 months), and school-aged children (age, 8-12 years) after an adult trial. The vaccine was reactogenic, compared with control vaccines (meningococcal C conjugate and routine infant vaccines), but retention was high. Three vaccine doses produced antibody levels (measured by serum bactericidal assay) that were considered to be adequate for public health intervention. However, in young infants, a fourth dose was required to achieve levels equivalent to those achieved by other age groups. Provisional licensure by New Zealand's MedSafe was based on serological criteria strengthened by bridged safety data from studies of the parent outer membrane vesicle vaccine, independent assessment of manufacturing quality, and a clear plan for safety monitoring and effectiveness evaluation after licensure.

Removal of gelatin from live vaccines and DTaP-an ultimate solution for vaccine-related gelatin allergy.

PubMed

Kuno-Sakai, Harumi; Kimura, Mikio

2003-12-01

From the early 1990s infants started to receive acellular pertussis vaccine combined with diphtheria and tetanus toxoids (DTaP) before live vaccines such as measles, rubella, and mumps vaccines, which contained gelatin as a stabilizer. Then, an increasing number of cases of anaphylactic/allergic reactions to those live vaccines were reported. Almost all these cases had a previous history of receiving three or four doses of DTaP containing gelatin.Anaphylactic/allergic reactions to live measles vaccine were analyzed using information obtained from the Reporting System, a retrospective study, as well as from the Monitoring System, a prospective study. Dramatic decreases in anaphylactic/allergic reactions to live measles vaccines were observed immediately after each manufacturer marketed gelatin-free or gelatin (hypo-allergic)-containing live measles vaccine, and since the end of 1998 reports on anaphylactic/allergic reactions to live measles vaccine have almost ceased.

Influenza vaccination guidelines and vaccine sales in southeast Asia: 2008-2011.

PubMed

Gupta, Vinay; Dawood, Fatimah S; Muangchana, Charung; Lan, Phan Trong; Xeuatvongsa, Anonh; Sovann, Ly; Olveda, Remigio; Cutter, Jeffery; Oo, Khin Yi; Ratih, Theresia Sandra Diah; Kheong, Chong Chee; Kapella, Bryan K; Kitsutani, Paul; Corwin, Andrew; Olsen, Sonja J

2012-01-01

Southeast Asia is a region with great potential for the emergence of a pandemic influenza virus. Global efforts to improve influenza surveillance in this region have documented the burden and seasonality of influenza viruses and have informed influenza prevention strategies, but little information exists about influenza vaccination guidelines and vaccine sales. To ascertain the existence of influenza vaccine guidelines and define the scope of vaccine sales, we sent a standard three-page questionnaire to the ten member nations of the Association of Southeast Asian Nations. We also surveyed three multinational manufacturers who supply influenza vaccines in the region. Vaccine sales in the private sector were <1000 per 100,000 population in the 10 countries. Five countries reported purchasing vaccine for use in the public sector. In 2011, Thailand had the highest combined reported rate of vaccine sales (10,333 per 100,000). In the 10 countries combined, the rate of private sector sales during 2010-2011 (after the A(H1N1)2009pdm pandemic) exceeded 2008 pre-pandemic levels. Five countries (Indonesia, Malaysia, Singapore, Thailand and Vietnam) had guidelines for influenza vaccination but only two were consistent with global guidelines. Four recommended vaccination for health care workers, four for elderly persons, three for young children, three for persons with underlying disease, and two for pregnant women. The rate of vaccine sales in Southeast Asia remains low, but there was a positive impact in sales after the A(H1N1)2009pdm pandemic. Low adherence to global vaccine guidelines suggests that more work is needed in the policy arena.

Economic evaluation of pneumococcal conjugate vaccination in The Gambia.

PubMed

Kim, Sun-Young; Lee, Gene; Goldie, Sue J

2010-09-03

Gambia is the second GAVI support-eligible country to introduce the 7-valent pneumococcal conjugate vaccine (PCV7), but a country-specific cost-effectiveness analysis of the vaccine is not available. Our objective was to assess the potential impact of PCVs of different valences in The Gambia. We synthesized the best available epidemiological and cost data using a state-transition model to simulate the natural histories of various pneumococcal diseases. For the base-case, we estimated incremental cost (in 2005 US dollars) per disability-adjusted life year (DALY) averted under routine vaccination using PCV9 compared to no vaccination. We extended the base-case results for PCV9 to estimate the cost-effectiveness of PCV7, PCV10, and PCV13, each compared to no vaccination. To explore parameter uncertainty, we performed both deterministic and probabilistic sensitivity analyses. We also explored the impact of vaccine efficacy waning, herd immunity, and serotype replacement, as a part of the uncertainty analyses, by assuming alternative scenarios and extrapolating empirical results from different settings. Assuming 90% coverage, a program using a 9-valent PCV (PCV9) would prevent approximately 630 hospitalizations, 40 deaths, and 1000 DALYs, over the first 5 years of life of a birth cohort. Under base-case assumptions ($3.5 per vaccine), compared to no intervention, a PCV9 vaccination program would cost $670 per DALY averted in The Gambia. The corresponding values for PCV7, PCV10, and PCV13 were $910, $670, and $570 per DALY averted, respectively. Sensitivity analyses that explored the implications of the uncertain key parameters showed that model outcomes were most sensitive to vaccine price per dose, discount rate, case-fatality rate of primary endpoint pneumonia, and vaccine efficacy against primary endpoint pneumonia. Based on the information available now, infant PCV vaccination would be expected to reduce pneumococcal diseases caused by S. pneumoniae in The Gambia

Methods for Health Economic Evaluation of Vaccines and Immunization Decision Frameworks: A Consensus Framework from a European Vaccine Economics Community.

PubMed

Ultsch, Bernhard; Damm, Oliver; Beutels, Philippe; Bilcke, Joke; Brüggenjürgen, Bernd; Gerber-Grote, Andreas; Greiner, Wolfgang; Hanquet, Germaine; Hutubessy, Raymond; Jit, Mark; Knol, Mirjam; von Kries, Rüdiger; Kuhlmann, Alexander; Levy-Bruhl, Daniel; Perleth, Matthias; Postma, Maarten; Salo, Heini; Siebert, Uwe; Wasem, Jürgen; Wichmann, Ole

2016-03-01

Incremental cost-effectiveness and cost-utility analyses [health economic evaluations (HEEs)] of vaccines are routinely considered in decision making on immunization in various industrialized countries. While guidelines advocating more standardization of such HEEs (mainly for curative drugs) exist, several immunization-specific aspects (e.g. indirect effects or discounting approach) are still a subject of debate within the scientific community. The objective of this study was to develop a consensus framework for HEEs of vaccines to support the development of national guidelines in Europe. A systematic literature review was conducted to identify prevailing issues related to HEEs of vaccines. Furthermore, European experts in the field of health economics and immunization decision making were nominated and asked to select relevant aspects for discussion. Based on this, a workshop was held with these experts. Aspects on 'mathematical modelling', 'health economics' and 'decision making' were debated in group-work sessions (GWS) to formulate recommendations and/or--if applicable--to state 'pros' and 'contras'. A total of 13 different aspects were identified for modelling and HEE: model selection, time horizon of models, natural disease history, measures of vaccine-induced protection, duration of vaccine-induced protection, indirect effects apart from herd protection, target population, model calibration and validation, handling uncertainty, discounting, health-related quality of life, cost components, and perspectives. For decision making, there were four aspects regarding the purpose and the integration of HEEs of vaccines in decision making as well as the variation of parameters within uncertainty analyses and the reporting of results from HEEs. For each aspect, background information and an expert consensus were formulated. There was consensus that when HEEs are used to prioritize healthcare funding, this should be done in a consistent way across all interventions

Lessons from pandemic influenza A(H1N1): the research-based vaccine industry's perspective.

PubMed

Abelin, Atika; Colegate, Tony; Gardner, Stephen; Hehme, Norbert; Palache, Abraham

2011-02-01

As A(H1N1) influenza enters the post-pandemic phase, health authorities around the world are reviewing the response to the pandemic. To ensure this process enhances future preparations, it is essential that perspectives are included from all relevant stakeholders, including vaccine manufacturers. This paper outlines the contribution of R&D-based influenza vaccine producers to the pandemic response, and explores lessons that can be learned to improve future preparedness. The emergence of 2009 A(H1N1) influenza led to unprecedented collaboration between global health authorities, scientists and manufacturers, resulting in the most comprehensive pandemic response ever undertaken, with a number of vaccines approved for use three months after the pandemic declaration. This response was only possible because of the extensive preparations undertaken during the last decade. During this period, manufacturers greatly increased influenza vaccine production capacity, and estimates suggest a further doubling of capacity by 2014. Producers also introduced cell-culture technology, while adjuvant and whole virion technologies significantly reduced pandemic vaccine antigen content. This substantially increased pandemic vaccine production capacity, which in July 2009 WHO estimated reached 4.9 billion doses per annum. Manufacturers also worked with health authorities to establish risk management plans for robust vaccine surveillance during the pandemic. Individual producers pledged significant donations of vaccine doses and tiered-pricing approaches for developing country supply. Based on the pandemic experience, a number of improvements would strengthen future preparedness. Technical improvements to rapidly select optimal vaccine viruses, and processes to speed up vaccine standardization, could accelerate and extend vaccine availability. Establishing vaccine supply agreements beforehand would avoid the need for complex discussions during a period of intense time pressure. Enhancing

AF03-adjuvanted and non-adjuvanted pandemic influenza A (H1N1) 2009 vaccines induce strong antibody responses in seasonal influenza vaccine-primed and unprimed mice.

PubMed

Caillet, Catherine; Piras, Fabienne; Bernard, Marie-Clotilde; de Montfort, Aymeric; Boudet, Florence; Vogel, Frederick R; Hoffenbach, Agnès; Moste, Catherine; Kusters, Inca

2010-04-19

Pandemic influenza vaccines have been manufactured using the A/California/07/2009 (H1N1) strain as recommended by the World Health Organization. We evaluated in mice the immunogenicity of pandemic (H1N1) 2009 vaccine and the impact of prior vaccination against seasonal trivalent influenza vaccines (TIV) on antibody responses against pandemic (H1N1) 2009. In naïve mice, a single dose of unadjuvanted H1N1 vaccine (3 microg of HA) was shown to elicit hemagglutination inhibition (HI) antibody titers >40, a titer associated with protection in humans against seasonal influenza. A second vaccine dose of pandemic (H1N1) 2009 vaccine strongly increased these titers, which were consistently higher in mice previously primed with TIV than in naïve mice. At a low immunization dose (0.3 microg of HA), the AF03-adjuvanted vaccine elicited higher HI antibody titers than the corresponding unadjuvanted vaccines in both naïve and TIV-primed animals, suggesting a potential for antigen dose-sparing. These results are in accordance with the use in humans of a split-virion inactivated pandemic (H1N1) 2009 vaccine formulated with or without AF03 adjuvant to protect children and young adults against influenza A (H1N1) 2009 infection. Copyright 2010 Elsevier Ltd. All rights reserved.

Consensus document on the approach to children with allergic reactions after vaccination or allergy to vaccine components.

PubMed

Echeverría-Zudaire, Luis A; Ortigosa-del Castillo, Luis; Alonso-Lebrero, Elena; Álvarez-García, Francisco J; Cortés-Álvarez, Nuria; García-Sánchez, Nuria; Martorell-Aragonés, Antonio

2015-01-01

Vaccinations are one of the main public health tools for the control of vaccine-preventable diseases. If a child is identified as having had an allergic reaction to a vaccine, subsequent immunisations will probably be suspended - with the risks such a decision implies. The incidence of severe allergic reactions is very low, ranging between 0.5 and 1 cases/100,000 doses. Rather than the vaccine antigens as such, the causes of allergic reactions to vaccines are often residual protein components of the manufacturing process such as gelatine or egg, and less commonly yeasts or latex. Most vaccine reactions are mild and circumscribed to the injection site; although in some cases severe anaphylactic reactions can be observed. If an immediate-type allergic reaction is suspected at vaccination, or if a child with allergy to some of the vaccine components is scheduled for vaccination, a correct diagnosis of the possible allergic process must be made. The usual vaccine components must be known in order to determine whether vaccination can be safely performed. Copyright © 2015 SEICAP. Published by Elsevier Espana. All rights reserved.

Advancing a multivalent ‘Pan-anthelmintic’ vaccine against soil-transmitted nematode infections

PubMed Central

Zhan, Bin; Beaumier, Coreen M; Briggs, Neima; Jones, Kathryn M; Keegan, Brian P; Bottazzi, Maria Elena; Hotez, Peter J

2014-01-01

Ascaris lumbricoides The Sabin Vaccine Institute Product Development Partnership is developing a Pan-anthelmintic vaccine that simultaneously targets the major soil-transmitted nematode infections, in other words, ascariasis, trichuriasis and hookworm infection. The approach builds off the current bivalent Human Hookworm Vaccine now in clinical development and would ultimately add both a larval Ascaris lumbricoides antigen and an adult-stage Trichuris trichiura antigen from the parasite stichosome. Each selected antigen would partially reproduce the protective immunity afforded by UV-attenuated Ascaris eggs and Trichuris stichosome extracts, respectively. Final antigen selection will apply a ranking system that includes the evaluation of expression yields and solubility, feasibility of process development and the absence of circulating antigen-specific IgE among populations living in helminth-endemic regions. Here we describe a five year roadmap for the antigen discovery, feasibility and antigen selection, which will ultimately lead to the scale-up expression, process development, manufacture, good laboratory practices toxicology and preclinical evaluation, ultimately leading to Phase 1 clinical testing. PMID:24392641

Likelihood-based methods for evaluating principal surrogacy in augmented vaccine trials.

PubMed

Liu, Wei; Zhang, Bo; Zhang, Hui; Zhang, Zhiwei

2017-04-01

There is growing interest in assessing immune biomarkers, which are quick to measure and potentially predictive of long-term efficacy, as surrogate endpoints in randomized, placebo-controlled vaccine trials. This can be done under a principal stratification approach, with principal strata defined using a subject's potential immune responses to vaccine and placebo (the latter may be assumed to be zero). In this context, principal surrogacy refers to the extent to which vaccine efficacy varies across principal strata. Because a placebo recipient's potential immune response to vaccine is unobserved in a standard vaccine trial, augmented vaccine trials have been proposed to produce the information needed to evaluate principal surrogacy. This article reviews existing methods based on an estimated likelihood and a pseudo-score (PS) and proposes two new methods based on a semiparametric likelihood (SL) and a pseudo-likelihood (PL), for analyzing augmented vaccine trials. Unlike the PS method, the SL method does not require a model for missingness, which can be advantageous when immune response data are missing by happenstance. The SL method is shown to be asymptotically efficient, and it performs similarly to the PS and PL methods in simulation experiments. The PL method appears to have a computational advantage over the PS and SL methods.

A quantitative risk assessment of exposure to adventitious agents in a cell culture-derived subunit influenza vaccine.

PubMed

Gregersen, Jens-Peter

2008-06-19

A risk-assessment model has demonstrated the ability of a new cell culture-based vaccine manufacturing process to reduce the level of any adventitious agent to a million-fold below infectious levels. The cell culture-derived subunit influenza vaccine (OPTAFLU), Novartis Vaccines and Diagnostics) is produced using Madin-Darby canine kidney (MDCK) cells to propagate seasonal viral strains, as an alternative to embryonated chicken-eggs. As only a limited range of mammalian viruses can grow in MDCK cells, similar to embryonated eggs, MDCK cells can act as an effective filter for a wide range of adventitious agents that might be introduced during vaccine production. However, the introduction of an alternative cell substrate (for example, MDCK cells) into a vaccine manufacturing process requires thorough investigations to assess the potential for adventitious agent risk in the final product, in the unlikely event that contamination should occur. The risk assessment takes into account the entire manufacturing process, from initial influenza virus isolation, through to blending of the trivalent subunit vaccine and worst-case residual titres for the final vaccine formulation have been calculated for >20 viruses or virus families. Maximum residual titres for all viruses tested were in the range of 10(-6) to 10(-16) infectious units per vaccine dose. Thus, the new cell culture-based vaccine manufacturing process can reduce any adventitious agent to a level that is unable to cause infection.

Evaluation of Temporal Association Between Vaccinations and Retinal Hemorrhage in Children.

PubMed

Binenbaum, Gil; Christian, Cindy W; Guttmann, Katy; Huang, Jiayan; Ying, Gui-Shuang; Forbes, Brian J

2015-11-01

Vaccinations have been proposed as a cause of retinal hemorrhage in children, primarily as part of a defense strategy in high-stakes abusive head trauma cases. If vaccination injections cause retinal hemorrhage, this consideration would affect the evaluation of children for suspected child abuse. To describe the prevalence and causes of retinal hemorrhage among infants and young children in an outpatient ophthalmology clinic and to test the hypothesis that, if vaccination injections cause retinal hemorrhage, then retinal hemorrhage would be seen frequently and be temporally associated with immunization. Retrospective cohort study between June 1, 2009, and August 30, 2012, at The Children's Hospital of Philadelphia pediatric ophthalmology clinics among 5177 children 1 to 23 months old undergoing a dilated fundus examination as an outpatient for any reason. Children with intraocular surgery or active retinal neovascularization were excluded from the study. The prevalence and causes of retinal hemorrhage, as well as the temporal association between vaccination injection within 7, 14, or 21 days preceding examination and retinal hemorrhage. Among 7675 outpatient fundus examinations, 9 of 5177 children had retinal hemorrhage for a prevalence of 0.17% (95% CI, 0.09%-0.33%). All 9 had abusive head trauma diagnosable with nonocular findings. Among a subset of 2210 children who had complete immunization records and underwent 3425 fundoscopic examinations, 163 children had an eye examination within 7 days of vaccination, 323 within 14 days, and 494 within 21 days. No children had retinal hemorrhage within 7 days of vaccination, 1 child had hemorrhage within 14 days, and no additional child had hemorrhage within 21 days. There was no temporal association between vaccination injection and retinal hemorrhage in the prior 7 days (P > .99), 14 days (P = .33), or 21 days (P = .46). Retinal hemorrhage was rare among outpatients younger than 2 years. Considering both

Guidelines for evaluating the efficacy and safety of live anticoccidial vaccines, and obtaining approval for their use in chickens and turkeys.

PubMed

Chapman, H D; Roberts, B; Shirley, M W; Williams, R B

2005-08-01

These guidelines are intended to aid those engaged in poultry research in the design, implementation and interpretation of laboratory, floor-pen and field studies for the assessment of the efficacy and safety of live anticoccidial vaccines for immunization of chickens and turkeys against Eimeria species. In addition to efficacy and safety requirements, manufacture, quality control and licensing considerations are discussed. The guidelines do not address subunit vaccines comprising non-viable material, but many of the principles described will be relevant to such vaccines if they are developed in the future. Guidelines are available in some countries for avian vaccines of bacterial or viral origin but specific standards for anticoccidial vaccines in poultry have not, as far as we know, been produced. Information is provided on general requirements of registration authorities (based upon regulations applicable in the European Union and the USA) for obtaining marketing authorizations for vaccines. These guidelines may assist poultry specialists in providing specific information for administrators involved in the decision-making process leading to registration of new vaccines, and are intended to facilitate the worldwide adoption of consistent, standard procedures.

Evaluation of the first pharmacist-administered vaccinations in Western Australia: a mixed-methods study.

PubMed

Hattingh, H Laetitia; Sim, T Fei; Parsons, R; Czarniak, P; Vickery, A; Ayadurai, S

2016-09-20

This study evaluated the uptake of Western Australian (WA) pharmacist vaccination services, the profiles of consumers being vaccinated and the facilitators and challenges experienced by pharmacy staff in the preparation, implementation and delivery of services. Mixed-methods methodology with both quantitative and qualitative data through surveys, pharmacy computer records and immuniser pharmacist interviews. Community pharmacies in WA that provided pharmacist vaccination services between March and October 2015. Immuniser pharmacists from 86 pharmacies completed baseline surveys and 78 completed exit surveys; computer records from 57 pharmacies; 25 immuniser pharmacists were interviewed. Pharmacy and immuniser pharmacist profiles; pharmacist vaccination services provided and consumer profiles who accessed services. 15 621 influenza vaccinations were administered by immuniser pharmacists at 76 WA community pharmacies between March and October 2015. There were no major adverse events, and <1% of consumers experienced minor events which were appropriately managed. Between 12% and 17% of consumers were eligible to receive free influenza vaccinations under the National Immunisation Program but chose to have it at a pharmacy. A high percentage of vaccinations was delivered in rural and regional areas indicating that provision of pharmacist vaccination services facilitated access for rural and remote consumers. Immuniser pharmacists reported feeling confident in providing vaccination services and were of the opinion that services should be expanded to other vaccinations. Pharmacists also reported significant professional satisfaction in providing the service. All participating pharmacies intended to continue providing influenza vaccinations in 2016. This initial evaluation of WA pharmacist vaccination services showed that vaccine delivery was safe. Convenience and accessibility were important aspects in usage of services. There is scope to expand pharmacist vaccination

Correlation of genetic variability with safety of mumps vaccine Urabe AM9 strain.

PubMed

Amexis, G; Fineschi, N; Chumakov, K

2001-08-15

The Urabe AM9 strain of mumps vaccine live is known for its genetic instability and some vaccines derived from this strain were withdrawn from the market due to an excessive number of vaccine-associated parotitis and meningitis cases. To identify the molecular basis of this instability, we determined complete nucleotide sequences of several stocks of the Urabe strain used for vaccine production by different manufacturers and of two clinical isolates from cases of vaccine-associated meningitis. In contrast to previously published studies relating the Lys335 --> Glu mutation in the viral HN gene with neurovirulence of mumps virus, we could not confirm any association of this mutation with the safety of mumps vaccine. Each of the three vaccine stocks studied had its own characteristic profile of mutations that was identified by cDNA sequencing and quantitated by mutant analysis by PCR and restriction enzyme cleavage. Determination of the mutational profile of mumps vaccine lots could allow vaccine manufacturers to characterize seed viruses and monitor the consistency of vaccine production to prevent emergence of virulent revertants.

Factors associated with the pricing of childhood vaccines in the U.S. public sector.

PubMed

Chen, Weiwei; Messonnier, Mark; Zhou, Fangjun

2018-02-01

Vaccine purchase cost has grown substantially over the last few decades. A closer look at vaccine prices reveals that not all vaccines shared the same increasing pattern. Various factors, such as vaccine attributes, competition, and supply shortages, could relate to price changes. In this study, we examined whether a variety of factors influenced the prices of noninfluenza childhood vaccines purchased in the public sector from 1996 to 2014. The association differed among price-capped vaccines and combination vaccines. There was an increasing time trend in real prices for non-price-capped vaccines, which was mostly offset by the effect of market longevity. The effect of competition in lowering prices was more pronounced among non-price-capped vaccines when manufacturer and vaccine component fixed effects were excluded. Supply shortage, manufacturer name change, and number of vaccine doses in series showed no effect. The results may help policy makers better understand price behaviors and make more informed decisions in vaccine planning and financing. Copyright © 2017 John Wiley & Sons, Ltd.

Impact of changing the measles vaccine vial size on Niger's vaccine supply chain: a computational model

PubMed Central

2011-01-01

Background Many countries, such as Niger, are considering changing their vaccine vial size presentation and may want to evaluate the subsequent impact on their supply chains, the series of steps required to get vaccines from their manufacturers to patients. The measles vaccine is particularly important in Niger, a country prone to measles outbreaks. Methods We developed a detailed discrete event simulation model of the vaccine supply chain representing every vaccine, storage location, refrigerator, freezer, and transport device (e.g., cold trucks, 4 × 4 trucks, and vaccine carriers) in the Niger Expanded Programme on Immunization (EPI). Experiments simulated the impact of replacing the 10-dose measles vial size with 5-dose, 2-dose and 1-dose vial sizes. Results Switching from the 10-dose to the 5-dose, 2-dose and 1-dose vial sizes decreased the average availability of EPI vaccines for arriving patients from 83% to 82%, 81% and 78%, respectively for a 100% target population size. The switches also changed transport vehicle's utilization from a mean of 58% (range: 4-164%) to means of 59% (range: 4-164%), 62% (range: 4-175%), and 67% (range: 5-192%), respectively, between the regional and district stores, and from a mean of 160% (range: 83-300%) to means of 161% (range: 82-322%), 175% (range: 78-344%), and 198% (range: 88-402%), respectively, between the district to integrated health centres (IHC). The switch also changed district level storage utilization from a mean of 65% to means of 64%, 66% and 68% (range for all scenarios: 3-100%). Finally, accounting for vaccine administration, wastage, and disposal, replacing the 10-dose vial with the 5 or 1-dose vials would increase the cost per immunized patient from $0.47US to $0.71US and $1.26US, respectively. Conclusions The switch from the 10-dose measles vaccines to smaller vial sizes could overwhelm the capacities of many storage facilities and transport vehicles as well as increase the cost per vaccinated child. PMID

HPV Vaccination's Second Act: Promotion, Competition, and Compulsion

PubMed Central

2010-01-01

Developments regarding human papillomavirus (HPV) vaccines will transform HPV vaccination in the United States while simultaneously raising several new policy and ethical concerns. Policymakers, vaccine manufacturers, and the public health community must now respond to the presence of competing vaccines that are similar but distinct, particularly with respect to genital wart prevention and the benefits of vaccinating males. This work arises in the shadow of the contentious introduction of the HPV vaccine Gardasil (Merck & Co, Inc, Whitehouse Station, NJ) in 2006, particularly the opposition to efforts in many states to require the vaccine for school attendance. I review the current status of HPV vaccine policy in the United States and examine issues of public health ethics and policy central to ongoing and future HPV vaccination programs. PMID:20724671

Malaria vaccines: past, present and future.

PubMed

von Seidlein, Lorenz; Bejon, Philip

2013-12-01

The currently available malaria control tools have allowed malaria elimination in many regions but there remain many regions where malaria control has made little progress. A safe and protective malaria vaccine would be a huge asset for malaria control. Despite the many challenges, efforts continue to design and evaluate malaria vaccine candidates. These candidates target different stages in the life cycle of Plasmodia. The most advanced vaccine candidates target the pre-erythrocytic stages in the life cycle of the parasite and include RTS,S/AS01, which has progressed through clinical development to the stage that it may be licensed in 2015. Attenuated whole-parasite vaccine candidates are highly protective, but there are challenges to manufacture and to administration. Cellular immunity is targeted by the prime-boost approach. Priming vectors trigger only modest responses but these are focused on the recombinant antigen. Boosting vectors trigger strong but broad non-specific responses. The heterologous sequence produces strong immunological responses to the recombinant antigen. Candidates that target the blood stages of the parasite have to result in an immune response that is more effective than the response to an infection to abort or control the infection of merozoites and hence disease. Finally, the sexual stages of the parasite offer another target for vaccine development, which would prevent the transmission of malaria. Today it seems unlikely that any candidate targeting a single antigen will provide complete protection against an organism of the complexity of Plasmodium. A systematic search for vaccine targets and combinations of antigens may be a more promising approach.

Low uptake of influenza vaccine among university students: evaluating predictors beyond cost and safety concerns.

PubMed

Bednarczyk, Robert A; Chu, Samantha L; Sickler, Heather; Shaw, Jana; Nadeau, Jessica A; McNutt, Louise-Anne

2015-03-30

Annual influenza vaccine coverage for young adults (including college students) remains low, despite a 2011 US recommendation for annual immunization of all people 6 months and older. College students are at high risk for influenza morbidity given close living and social spaces and extended travel during semester breaks when influenza circulation typically increases. We evaluated influenza vaccine uptake following an on-campus vaccine campaign at a large, public New York State university. Consecutive students visiting the University Health Center were recruited for a self-administered, anonymous, written survey. Students were asked about recent influenza vaccination, barriers to influenza vaccination, and willingness to get vaccinated to protect other vulnerable individuals they may encounter. Frequencies and proportions were evaluated. Of 653 students approached, 600 completed surveys (92% response proportion); respondents were primarily female (61%) and non-Hispanic white (59%). Influenza vaccine coverage was low (28%). Compared to coverage among non-Hispanic white students (30%), coverage was similar among Hispanic (30%) and other race/ethnicity students (28%) and lowest among non-Hispanic black students (17%). Among the unvaccinated, the most commonly selected vaccination barriers were "Too lazy to get the vaccine" (32%) and "Don't need the vaccine because I'm healthy" (29%); 6% of unvaccinated students cited cost as a barrier. After being informed that influenza vaccination of young, healthy people can protect other vulnerable individuals (e.g., infants, elderly), 71% of unvaccinated students indicated this would increase their willingness to get vaccinated. Influenza vaccine uptake among college students is very low. While making vaccine easily obtained may increase vaccine uptake, college students need to be motivated to get vaccinated. Typically healthy students may not perceive a need for influenza vaccine. Education about vaccinating healthy individuals

Randomised field trial to evaluate serological response after foot-and-mouth disease vaccination in Turkey.

PubMed

Knight-Jones, T J D; Bulut, A N; Gubbins, S; Stärk, K D C; Pfeiffer, D U; Sumption, K J; Paton, D J

2015-02-04

Despite years of biannual mass vaccination of cattle, foot-and-mouth disease (FMD) remains uncontrolled in Anatolian Turkey. To evaluate protection after mass vaccination we measured post-vaccination antibodies in a cohort of cattle (serotypes O, A and Asia-1). To obtain results reflecting typical field protection, participants were randomly sampled from across Central and Western Turkey after routine vaccination. Giving two-doses one month apart is recommended when cattle are first vaccinated against FMD. However, due to cost and logistics, this is not routinely performed in Turkey, and elsewhere. Nested within the cohort, we conducted a randomised trial comparing post-vaccination antibodies after a single-dose versus a two-dose primary vaccination course. Four to five months after vaccination, only a third of single-vaccinated cattle had antibody levels above a threshold associated with protection. A third never reached this threshold, even at peak response one month after vaccination. It was not until animals had received three vaccine doses in their lifetime, vaccinating every six months, that most (64% to 86% depending on serotype) maintained antibody levels above this threshold. By this time cattle would be >20 months old with almost half the population below this age. Consequently, many vaccinated animals will be unprotected for much of the year. Compared to a single-dose, a primary vaccination course of two-doses greatly improved the level and duration of immunity. We concluded that the FMD vaccination programme in Anatolian Turkey did not produce the high levels of immunity required. Higher potency vaccines are now used throughout Turkey, with a two-dose primary course in certain areas. Monitoring post-vaccination serology is an important component of evaluation for FMD vaccination programmes. However, consideration must be given to which antigens are present in the test, the vaccine and the field virus. Differences between these antigens affect the

Cost effectiveness evaluation of a rotavirus vaccination program in Argentina.

PubMed

Martí, Sebastián García; Alcaraz, Andrea; Valanzasca, Pilar; McMullen, Mercedes; Standaert, Baudouin; Garay, Ulises; Lepetic, Alejandro; Gomez, Jorge

2015-10-13

Rotavirus diarrhea is one of the most important vaccine-preventable causes of severe diarrhea in children worldwide. There are two live-attenuated virus vaccines licensed, Rotarix (RV1) a monovalent vaccine by GlaxoSmithKline and a pentavalent vaccine, RotaTeq(RV5), by Merck & Co., with similar results. This study aim was to evaluate the cost-effectiveness of the utilization of RV1 compared with RV5 in Argentina. A deterministic Markov model based on the lifetime follow up of a static cohort was used. Quality Adjusted Life Years (QALYs) as a measure of results, the perspective of the health care system and a 5% discount rate for health benefits and costs has been used. A review of the literature to obtain epidemiologic and resources utilization of rotavirus diarrhea was performed. The sources used to estimate epidemiologic parameters were the National Health Surveillance System, the national mortality statistics and national database of hospital discharges records. Costs were obtained from different health subsectors and are expressed in local currency. Both vaccination alternatives were less costly and more effective than the strategy without vaccination (total costs $ 69,700,645 and 2575 total QALYs lost). When comparing RV1 vs. RV5, RV1 was less expensive ($ 60,174,508 vs. $ 67,545,991 total costs) and more effective (1105 vs. 1213 total QALYs lost) than RV5, RV1 being therefore a dominating strategy. Probabilistic sensitivity analysis showed results to be robust with a 100% probability of being cost-effective at a WTP threshold of 1 GDP per capita when comparing the RV1 vs. no vaccination. Both RV1 and RV5 schedules dominate the no vaccination strategy and RV5 was dominated by RV1. This information is a valuable input regarding the incorporation of this kind of vaccines into the national vaccination programs. Copyright © 2015 Elsevier Ltd. All rights reserved.

Minimum estimated incidence in Japan of anaphylaxis to live virus vaccines including gelatin.

PubMed

Sakaguchi, M; Nakayama, T; Fujita, H; Toda, M; Inouye, S

2000-10-15

We have previously found that most occurrences of anaphylaxis to live virus vaccines are caused by gelatin present in the vaccines as a stabilizer. After we published the evidence for the role of gelatin in anaphylaxis, vaccine manufacturers in Japan began to eliminate gelatin from live virus vaccines. In the present study, we tried to estimate its incidence before the gelatin elimination was started. Physicians and vaccine manufacturers submitted serum samples from children with anaphylaxis to measles, mumps, rubella or varicella vaccine to National Institute of Infectious Diseases (NIID) for 3 years from April 1994 to March 1997. Specific IgE to gelatin was assayed at NIID or two manufacturers by the CAP and ELISA methods. There were 44 children with life-threatening severe anaphylaxis (airway obstruction or anaphylactic shock) during the 3-year period, 41 of whom had anti-gelatin IgE. There were 64 children with mild anaphylaxis (without airway obstruction); 62 had anti-gelatin IgE. There were 100 children with only systemic cutaneous signs; 81 had anti-gelatin IgE. The estimates for the incidence of the severe anaphylaxis in 1994-1996 are: 6.84, 7.31, 4. 36, and 10.3 cases per million doses of gelatin-containing measles, rubella, mumps, and varicella vaccines, respectively.

Manufacturing Methods for Liposome Adjuvants.

PubMed

Perrie, Yvonne; Kastner, Elisabeth; Khadke, Swapnil; Roces, Carla B; Stone, Peter

2017-01-01

A wide range of studies have shown that liposomes can act as suitable adjuvants for a range of vaccine antigens. Properties such as their amphiphilic character and biphasic nature allow them to incorporate antigens within the lipid bilayer, on the surface, or encapsulated within the inner core. However, appropriate methods for the manufacture of liposomes are limited and this has resulted in issues with cost, supply, and wider scale application of these systems. Within this chapter we explore manufacturing processes that can be used for the production of liposomal adjuvants, and we outline new manufacturing methods can that offer fast, scalable, and cost-effective production of liposomal adjuvants.

Evaluation of Training Programs in Russian Manufacturing Companies

ERIC Educational Resources Information Center

Kucherov, Dmitry; Manokhina, Daria

2017-01-01

Purpose: This study aims to examine the features of training evaluation process in Russian manufacturing companies. On the basis of three assumptions regarding the differences in group of employees involved in training, duration and costs of a training program, the authors tried to find out the peculiarities of training evaluation tools and levels…

Process Evaluation of an Intervention to Increase Provision of Adolescent Vaccines at School Health Centers

ERIC Educational Resources Information Center

Golden, Shelley D.; Moracco, Kathryn E.; Feld, Ashley L.; Turner, Kea L.; DeFrank, Jessica T.; Brewer, Noel T.

2014-01-01

Background: Vaccination programs in school health centers (SHCs) may improve adolescent vaccine coverage. We conducted a process evaluation of an intervention to increase SHC-located vaccination to better understand the feasibility and challenges of such interventions. Method: Four SHCs participated in an intervention to increase provision of…

An allergen-free antirabies vaccine

PubMed Central

Svet-Moldavskij, G. JA.; Andjaparidze, O. G.; Unanov, S. S.; Karakajumc̆an, M. K.; Svet-Moldavskaja, I. A.; Muc̆nik, L. S.; Hieninson, M. A.; Ravkina, L. I.; Mtvarelidze, A. A.; Volkova, O. F.; Kriegshaber, M. R.; Kalinkina, A. G.; S̆alita, T. V.; Klimovickaja, V. I.; Bondaletova, I. N.; Rojheĺ, V. M.; Kiseleva, I. S.; Levc̆enko, E. N.; Marennikova, S. S.; Leonidova, S. L.

1965-01-01

Studies on the development of encephalitogenic activity in the cerebral tissue of various animals (rabbits, rats, mice and sheep) showed that the brains of albino rats did not become encephalitogenic until after the 18th day of life, which is later than in any of the other animals studied. On the basis of this finding, a method was developed for the preparation of an entirely allergen-free, non-encephalitogenic antirabies vaccine using the brains of suckling rats. The phenolized vaccine, both in liquid and in lyophilized form, consistently gave high antigenic titres when tested in animals and produced a good increase in virus-neutralizing antibodies in man. It also showed a low thromboplastic activity. More than 1500 litres of this vaccine have since been manufactured on an industrial scale and more than 9500 persons vaccinated. General reactions have been far less frequent than with the conventional Fermi vaccine and no neuroparalytic accidents or shock reactions have been reported. Vaccination with the allergen-free vaccine has proceeded smoothly even in persons considered to be especially at risk owing to previous vaccination with antirabies vaccine or a history of trauma or disease of the central nervous system. PMID:20604207

Quantifying benefits and risks of vaccinating Australian children aged six months to four years with trivalent inactivated seasonal influenza vaccine in 2010.

PubMed

Kelly, H; Carcione, D; Dowse, G; Effler, P

2010-09-16

Australian and New Zealand health authorities identified seasonal trivalent inactivated influenza vaccines manufactured by CSL Biotherapies as the probable cause of increased febrile convulsions in children under five within 24 hours of vaccination and recommended against their use in this age group. We quantified the benefit-risk profile of the CSL vaccines using the number needed to vaccinate and suggest they might have caused two to three hospital admissions due to febrile convulsions for every hospital admission due to influenza prevented.

Universal influenza vaccines: Shifting to better vaccines.

PubMed

Berlanda Scorza, Francesco; Tsvetnitsky, Vadim; Donnelly, John J

2016-06-03

Influenza virus causes acute upper and lower respiratory infections and is the most likely, among known pathogens, to cause a large epidemic in humans. Influenza virus mutates rapidly, enabling it to evade natural and vaccine-induced immunity. Furthermore, influenza viruses can cross from animals to humans, generating novel, potentially pandemic strains. Currently available influenza vaccines induce a strain specific response and may be ineffective against new influenza viruses. The difficulty in predicting circulating strains has frequently resulted in mismatch between the annual vaccine and circulating viruses. Low-resource countries remain mostly unprotected against seasonal influenza and are particularly vulnerable to future pandemics, in part, because investments in vaccine manufacturing and stockpiling are concentrated in high-resource countries. Antibodies that target conserved sites in the hemagglutinin stalk have been isolated from humans and shown to confer protection in animal models, suggesting that broadly protective immunity may be possible. Several innovative influenza vaccine candidates are currently in preclinical or early clinical development. New technologies include adjuvants, synthetic peptides, virus-like particles (VLPs), DNA vectors, messenger RNA, viral vectors, and attenuated or inactivated influenza viruses. Other approaches target the conserved exposed epitope of the surface exposed membrane matrix protein M2e. Well-conserved influenza proteins, such as nucleoprotein and matrix protein, are mainly targeted for developing strong cross-protective T cell responses. With multiple vaccine candidates moving along the testing and development pipeline, the field is steadily moving toward a product that is more potent, durable, and broadly protective than previously licensed vaccines. Copyright © 2016 World Health Organization. Published by Elsevier Ltd.. All rights reserved.

Safety, immunogenicity and protective efficacy in mice of a new cell-cultured Lister smallpox vaccine candidate.

PubMed

Ferrier-Rembert, Audrey; Drillien, Robert; Meignier, Bernard; Garin, Daniel; Crance, Jean-Marc

2007-11-28

It is now difficult to manufacture the first-generation smallpox vaccine, as the process could not comply with current safety and manufacturing regulations. In this study, a candidate non-clonal second-generation smallpox vaccine developed by Sanofi-Pasteur from the Lister strain has been assessed using a cowpox virus challenge in mice. We have observed similar safety, immunogenicity and protection (from disease and death) after a short or long interval following vaccination, as well as similar virus clearance post-challenge, with the second-generation smallpox vaccine candidate as compared to the traditional vaccine used as a benchmark.

Trust in Vaccines: Why It Takes More than Good Faith.

PubMed

Begg, Norman

2013-08-12

This Vaccines issue on "Confidence in Vaccines" provides sound evidence through multiple perspectives of life-saving impacts when vaccination programs are effectively implemented in a population. Yet there remain challenges to achieving this impact, including scientific, medical, manufacturing, policy-related and logistical issues. Additionally, socio-cultural, religious and political agendas can come into play, taking public health hostage and sometimes allowing the circulation of myths regarding vaccination. All of these challenges play a role in public confidence in vaccines and vaccination. What we trust, we embrace. What we do not trust, we do not embrace.

Overview of measles and mumps vaccine: origin, present, and future of vaccine production.

PubMed

Betáková, T; Svetlíková, D; Gocník, M

2013-01-01

Measles and mumps are common viral childhood diseases that can cause serious complications. Vaccination remains the most efficient way to control the spread of these viruses. The manufacturing capability for viral vaccines produced in embryonated hen eggs and conventional/classical cell substrates, such as chicken embryo fibroblast or primary dog kidney cell substrates, is no longer sufficient. This limitation can be overcome by utilizing other recognized cell substrates such as Madin Darby Canine Kidney (MDCK), Chinese Hamster Ovary (CHO), Vero (monkey origin) cells, MRC-5 (human diploid) or as an alternative, introducing new cell substrates of human or avian origin. A very important factor in vaccine production is the safety and immunogenicity of the final vaccine, where the proper choice of cell substrate used for virus propagation is made. All substrates used in vaccine production must be fully characterized to avoid the contamination of hidden unknown pathogens which is difficult to achieve in primary cell substrates.

Evaluation of Advanced Polymers for Additive Manufacturing

DOE Office of Scientific and Technical Information (OSTI.GOV)

Rios, Orlando; Carter, William G.; Kutchko, Cindy

The goal of this Manufacturing Demonstration Facility (MDF) technical collaboration project between Oak Ridge National Laboratory (ORNL) and PPG Industries, Inc. (PPG) was to evaluate the feasibility of using conventional coatings chemistry and technology to build up material layer-by-layer. The PPG-ORNL study successfully demonstrated that polymeric coatings formulations may overcome many limitations of common thermoplastics used in additive manufacturing (AM), allow lightweight nozzle design for material deposition, and increase build rate. The materials effort focused on layer-by-layer deposition of coatings with each layer fusing together. The combination of materials and deposition results in an additively manufactured build that has sufficientmore » mechanical properties to bear the load of additional layers, yet is capable of bonding across the z-layers to improve build direction strength. The formulation properties were tuned to enable a novel, high-throughput deposition method that is highly scalable, compatible with high loading of reinforcing fillers, and inherently low-cost.« less

Reducing routine vaccination dropout rates: evaluating two interventions in three Kenyan districts, 2014.

PubMed

Haji, Adam; Lowther, S; Ngan'ga, Z; Gura, Z; Tabu, C; Sandhu, H; Arvelo, Wences

2016-02-16

Globally, vaccine preventable diseases are responsible for nearly 20% of deaths annually among children <5 years old. Worldwide, many children dropout from the vaccination program, are vaccinated late, or incompletely vaccinated. We evaluated the impact of text messaging and sticker reminders to reduce dropouts from the vaccination program. The evaluation was conducted in three selected districts in Kenya: Machakos, Langata and Njoro. Three health facilities were selected in each district, and randomly allocated to send text messages or provide stickers reminding parents to bring their children for second and third dose of pentavalent vaccine, or to the control group (routine reminder) with next appointment date indicated on the well-child booklet. Children aged <12 months presenting for their first dose of pentavalent vaccine were enrolled. A dropout was defined as not returning for vaccination ≥ 2 weeks after scheduled date for third dose of pentavalent vaccine. We calculated dropout rate as a percentage of the difference between first and third pentavalent dose. We enrolled 1,116 children; 372 in each intervention and 372 controls between February and October 2014. Median age was 45 days old (range: 31-99 days), and 574 (51%) were male. There were 136 (12%) dropouts. Thirteen (4%) children dropped out among those who received text messages, 60 (16%) among who received sticker reminders, and 63 (17%) among the controls. Having a caregiver with below secondary education [Odds Ratio (OR) 1.8, 95% Confidence Interval (CI) 1.1-3.2], and residing >5 km from health facility (OR 1.6, CI 1.0-2.7) were associated with higher odds of dropping out. Those who received text messages were less likely to drop out compared to controls (OR 0.2, CI 0.04-0.8). There was no statistical difference between those who received stickers and controls (OR 0.9, CI 0.5-1.6). Text message reminders can reduce vaccination dropout rates in Kenya. We recommend the extended implementation of

Lessons learned from a review of the development of selected vaccines. National Vaccine Advisory Committee.

PubMed

Peter, G; des Vignes-Kendrick, M; Eickhoff, T C; Fine, A; Galvin, V; Levine, M M; Maldonado, Y A; Marcuse, E K; Monath, T P; Osborn, J E; Plotkin, S; Poland, G A; Quinlisk, M P; Smith, D R; Sokol, M; Soland, D B; Whitley-Williams, P N; Williamson, D E; Breiman, R F

1999-10-01

Although the vaccine research and development network in the United States remains vibrant, its continued success requires maintaining harmonious interaction among its many components. Changing one component is likely to affect the system overall. An examination of case studies of the development of selected vaccines would allow an examination of the network as a whole. This article presents conclusions drawn from the case study review undertaken. Successful development of vaccines is a time-intensive process requiring years of commitment from a network of scientists and a continuum of regulatory and manufacturing entities. We undertook this work to shed light on how well the vaccine development system in the United States performs. The National Vaccine Advisory Committee examined the research and development pathways of several vaccines that reached licensure expeditiously (hepatitis B vaccine, Haemophilus influenzae type b conjugate vaccines); some that became licensed only after considerable delay (oral typhoid Ty21a vaccine, varicella vaccine); some that are at the point of imminent or recent licensure (reassortant Rhesus rotavirus vaccine, which was licensed by the Food and Drug Administration on August 30, 1998) or near submission for licensure (intranasal cold adapted influenza vaccine); and one for which clinical development is slow because of hurdles that must be overcome (respiratory syncytial virus vaccines). Some common themes emerged from the reviews of these vaccine "case histories": the expediting influence of a strong scientific base and rationale; the need for firm quantitation of disease burden and clear identification of target populations; the critical role played by individuals or teams who act as "champions" to overcome the inevitable obstacles; availability of relevant animal models, high-quality reagents and standardized assays to measure immune response; the absolute requirement for well designed, meticulously executed clinical trials of

Mind the gaps: what's missing from current economic evaluations of universal HPV vaccination?

PubMed

Marsh, Kevin; Chapman, Ruth; Baggaley, Rebecca F; Largeron, Nathalie; Bresse, Xavier

2014-06-24

Since the original licensing of human papilloma virus (HPV) vaccination for women, evidence is accumulating of its effectiveness in preventing HPV-related conditions in men, and universal vaccination (vaccinating men and women) is now recommended in some countries. Several models of the cost-effectiveness of universal HPV vaccination have been published, but results have been mixed. This article assesses the extent to which economic studies have captured the range of values associated with universal HPV vaccination, and how this influences estimates of its cost-effectiveness. Eight published economic evaluations of universal HPV vaccination were reviewed to identify which of the values associated with universal HPV vaccination were included in each analysis. Studies of the cost-effectiveness of universal HPV vaccination capture only a fraction of the values generated. Most studies focused on impacts on health and health system cost, and only captured these partially. A range of values is excluded from most studies, including impacts on productivity, patient time and costs, carers and family costs, and broader social values such as the right to access treatment. Further, those studies that attempted to capture these values only did so partially. Decisions to invest in universal HPV vaccination need to be based on a complete assessment of the value that it generates. This is not provided by existing economic evaluations. Further work is required to understand this value. First, research is required to understand how HPV-related health outcomes impact on society including, for instance, their impact on productivity. Second, consideration should be given to alternative approaches to capture this broader set of values in a manner useful to decisions-makers, such as multi-criteria decision analysis. Copyright © 2014 Elsevier Ltd. All rights reserved.

Evaluation of smallpox vaccines using variola neutralization.

PubMed

Damon, Inger K; Davidson, Whitni B; Hughes, Christine M; Olson, Victoria A; Smith, Scott K; Holman, Robert C; Frey, Sharon E; Newman, Frances; Belshe, Robert B; Yan, Lihan; Karem, Kevin

2009-08-01

The search for a 'third'-generation smallpox vaccine has resulted in the development and characterization of several vaccine candidates. A significant barrier to acceptance is the absence of challenge models showing induction of correlates of protective immunity against variola virus. In this light, virus neutralization provides one of few experimental methods to show specific 'in vitro' activity of vaccines against variola virus. Here, we provide characterization of the ability of a modified vaccinia virus Ankara vaccine to induce variola virus-neutralizing antibodies, and we provide comparison with the neutralization elicited by standard Dryvax vaccination.

Identification and characterization of avian retroviruses in chicken embryo-derived yellow fever vaccines: investigation of transmission to vaccine recipients.

PubMed

Hussain, Althaf I; Johnson, Jeffrey A; Da Silva Freire, Marcos; Heneine, Walid

2003-01-01

All currently licensed yellow fever (YF) vaccines are propagated in chicken embryos. Recent studies of chick cell-derived measles and mumps vaccines show evidence of two types of retrovirus particles, the endogenous avian retrovirus (EAV) and the endogenous avian leukosis virus (ALV-E), which originate from the chicken embryonic fibroblast substrates. In this study, we investigated substrate-derived avian retrovirus contamination in YF vaccines currently produced by three manufacturers (YF-vax [Connaught Laboratories], Stamaril [Aventis], and YF-FIOCRUZ [FIOCRUZ-Bio-Manguinhos]). Testing for reverse transcriptase (RT) activity was not possible because of assay inhibition. However, Western blot analysis of virus pellets with anti-ALV RT antiserum detected three distinct RT proteins in all vaccines, indicating that more than one source is responsible for the RTs present in the vaccines. PCR analysis of both chicken substrate DNA and particle-associated RNA from the YF vaccines showed no evidence of the long terminal repeat sequences of exogenous ALV subgroups A to D in any of the vaccines. In contrast, both ALV-E and EAV particle-associated RNA were detected at equivalent titers in each vaccine by RT-PCR. Quantitative real-time RT-PCR revealed 61,600, 348,000, and 1,665,000 ALV-E RNA copies per dose of Stamaril, YF-FIOCRUZ, and YF-vax vaccines, respectively. ev locus-specific PCR testing of the vaccine-associated chicken substrate DNA was positive both for the nondefective ev-12 locus in two vaccines and for the defective ev-1 locus in all three vaccines. Both intact and ev-1 pol sequences were also identified in the particle-associated RNA. To investigate the risks of transmission, serum samples from 43 YF vaccine recipients were studied. None of the samples were seropositive by an ALV-E-based Western blot assay or had detectable EAV or ALV-E RNA sequences by RT-PCR. YF vaccines produced by the three manufacturers all have particles containing EAV genomes and

Better vaccines for healthier life. Part I. Conference report of the DCVMN International 14th Annual General Meeting Hanoi, Vietnam.

PubMed

Pagliusi, Sonia; Rustan, Rahman; Huang, Weidan; Nguyen, Thuvan

2014-11-12

The Developing Countries Vaccine Manufacturers' Network (DCVMN) brought together nearly 220 senior representatives of governmental and non-governmental global health organizations, as well as corporate executives of emerging vaccine manufacturers, from 26 countries for a two-day tailored lectures, Q&A sessions, CEOs panel discussion and networking opportunities, followed by a vaccine-technology symposium and visit to manufacturing facilities in Hanoi, Vietnam. Participants included representatives of 38 vaccine manufacturers, as well as international partners and collaborating research institutions, with 39% female participants. The Vice-Minister of Health to Vietnam commended the speakers and participants to this Annual General Meeting, devoted to achieve our common goal of protecting people against infectious diseases with better vaccines, for a healthier life. He reminded the audience that the first vaccine produced in Vietnam was oral polio vaccine (OPV) in the early 1960s and contributed to polio eradication in Vietnam, in 2000. Through its manufacturing resources, Vietnam eliminated neonatal tetanus in 2005, and has controlled measles and hepatitis B spread. The Ministry of Health hopes that by sharing experiences, delegates at this conference will foster international cooperation and partnerships among organizations. CEOs elaborated on challenges and opportunities for emerging countries. Copyright © 2014. Published by Elsevier Ltd.. All rights reserved.

Development, theoretical framework, and evaluation of a parent and teacher-delivered intervention on adolescent vaccination.

PubMed

Gargano, Lisa M; Herbert, Natasha L; Painter, Julia E; Sales, Jessica M; Vogt, Tara M; Morfaw, Christopher; Jones, LaDawna M; Murray, Dennis; DiClemente, Ralph J; Hughes, James M

2014-07-01

The Advisory Committee on Immunization Practices recommended immunization schedule for adolescents includes three vaccines (tetanus, diphtheria, and acellular pertussis [Tdap]; human papillomavirus [HPV] vaccine; and meningococcal conjugate vaccine [MCV4]) and an annual influenza vaccination. Given the increasing number of recommended vaccines for adolescents and health and economic costs associated with nonvaccination, it is imperative that effective strategies for increasing vaccination rates among adolescents are developed. This article describes the development, theoretical framework, and initial first-year evaluation of an intervention designed to promote vaccine acceptance among a middle and high school-based sample of adolescents and their parents in eastern Georgia. Adolescents, parents, and teachers were active participants in the development of the intervention. The intervention, which consisted of a brochure for parents and a teacher-delivered curriculum for adolescents, was guided by constructs from the health belief model and theory of reasoned action. Evaluation results indicated that our intervention development methods were successful in creating a brochure that met cultural relevance and the literacy needs of parents. We also demonstrated an increase in student knowledge of and positive attitudes toward vaccines. To our knowledge, this study is the first to extensively engage middle and high school students, parents, and teachers in the design and implementation of key theory-based educational components of a school-based, teacher-delivered adolescent vaccination intervention. © 2014 Society for Public Health Education.

[Economic evaluation of routine vaccination of 15 month old children against chicken-pox-zoster].

PubMed

Forcén, T; Garuz, R; Cabasés, J; Ruiz de Ocenda, M; Martínez, J A; Izko, J

2000-01-01

An economic, cost-effectiveness evaluation was carried out that compared a hypothetical program of routine mass vaccination against the chicken-pox-zoster virus in children aged 15 months in the Foral Community of Navarra against the present strategy of vaccination that is restricted to the high risk population. Decision trees based on Markov models were used to calculate the costs of the health care of cases of infection and the costs of the effects of the vaccination program. The efficacy of the vaccination is 90-95%, and the scenario produces an immunogenicity of at least ten years, with a coverage of 90%. Account was taken of both the direct costs of health care and the indirect costs, with 1995 Pesetas taken as a constant, due to the loss in productivity of a family member, and a social view point was adopted for evaluating the study The index of cost-effectiveness reflects the additional cost or saving for each case of avoided infection brought about by vaccinating the children in comparison with vaccinating only those persons belonging to the high risk population sectors. The cost per avoided case is situated between 3,500 Ptas and 4,000 Ptas. For each Peseta invested in the vaccination program there would be a reimbursement of 0.45 Pesetas. The routine vaccination program produces an incremental cost. Only in the case of a reduction in the price of the vaccine by more than 50% would the cost-effectiveness index offer a net social profit.

The Effectiveness of Influenza Vaccination in Different Groups.

PubMed

Domínguez, Angela; Godoy, Pere; Torner, Nuria

2016-06-01

Annual administration of the seasonal influenza vaccine, especially to persons known to be at elevated risk for developing serious complications, is the focus of current efforts to reduce the impact of influenza. The main factors influencing estimated inactivated influenza vaccine efficacy and effectiveness, the results obtained in different population groups, current vaccination strategies and the possible advantages of new vaccines are discussed. The available evidence suggests that influenza vaccines are less effective in the elderly than in young adults, but vaccination is encouraged by public health institutions due to higher mortality and complications. There is no consensus on universal vaccination of children yet economic studies suggest that yearly paediatric vaccination is cost saving. The benefits of herd immunity generated by paediatric vaccination require further study. Newer vaccines should be more and more-broadly protective, stable, easy to manufacture and administer and highly immunogenic across all population groups.

Vaccine purchasing groups in the United States: An overview of their policies and practices.

PubMed

Cowan, Anne E; Clark, Sarah J; Gordon, Jennifer L; Bok, Karin; Shen, Angela K

2016-09-30

Vaccine purchasing groups (VPGs) may help reduce the upfront cost of vaccines. The objective of this study was to describe key business practices of VPGs in the United States. Semi-structured, qualitative telephone interviews were conducted with representatives from 11 VPGs, based on a sampling frame of 53 VPGs. Interviews were transcribed and summarized by topic. Characteristics of the 11 VPGs interviewed reflect the broader VPG population: 64% national vs 36% regional; 8% charge a membership fee; membership ranging from 40 to over 300,000 sites. VPGs establish agreements with vaccine manufacturers, typically with either GlaxoSmithKline or Merck and Sanofi Pasteur; 1 VPG reported a single-product (Trumenba) agreement with Pfizer. VPG agreements specify "product loyalty" benchmarks (proportion of that manufacturer's product line) that the VPG and its members must meet to receive discounted vaccine pricing. The amount of discount is considered proprietary. Practices may actively participate with only one VPG; the member discount is automatically applied by the manufacturer at the time of ordering. Vaccine manufacturers monitor sales data to ensure compliance with product loyalty terms; practices that do not meet benchmarks may be removed from the VPG. VPGs are paid administration fees by the manufacturers. VPGs use these fees to cover their operating expenses and often rebate a portion of these fees back to their members. All 11 VPGs offer additional services to members, ranging from immunization-focused education and technical assistance to discounts on a broad range of medical and business supplies. VPGs can facilitate access to reduced purchase prices for most vaccines routinely recommended in the United States. Data on the magnitude of the price reductions were not publicly available. VPG members must balance loyalty-based price reductions against considerations of having a wider choice of vaccine products. Copyright © 2016 Elsevier Ltd. All rights reserved.

Vaccines, our shared responsibility.

PubMed

Pagliusi, Sonia; Jain, Rishabh; Suri, Rajinder Kumar

2015-05-05

The Developing Countries Vaccine Manufacturers' Network (DCVMN) held its fifteenth annual meeting from October 27-29, 2014, New Delhi, India. The DCVMN, together with the co-organizing institution Panacea Biotec, welcomed over 240 delegates representing high-profile governmental and nongovernmental global health organizations from 36 countries. Over the three-day meeting, attendees exchanged information about their efforts to achieve their shared goal of preventing death and disability from known and emerging infectious diseases. Special praise was extended to all stakeholders involved in the success of polio eradication in South East Asia and highlighted challenges in vaccine supply for measles-rubella immunization over the coming decades. Innovative vaccines and vaccine delivery technologies indicated creative solutions for achieving global immunization goals. Discussions were focused on three major themes including regulatory challenges for developing countries that may be overcome with better communication; global collaborations and partnerships for leveraging investments and enable uninterrupted supply of affordable and suitable vaccines; and leading innovation in vaccines difficult to develop, such as dengue, Chikungunya, typhoid-conjugated and EV71, and needle-free technologies that may speed up vaccine delivery. Moving further into the Decade of Vaccines, participants renewed their commitment to shared responsibility toward a world free of vaccine-preventable diseases. Copyright © 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.

Evaluation of smallpox vaccines using variola neutralization

PubMed Central

Damon, Inger K.; Davidson, Whitni B.; Hughes, Christine M.; Olson, Victoria A.; Smith, Scott K.; Holman, Robert C.; Frey, Sharon E.; Newman, Frances; Belshe, Robert B.; Yan, Lihan; Karem, Kevin

2009-01-01

The search for a ‘third’-generation smallpox vaccine has resulted in the development and characterization of several vaccine candidates. A significant barrier to acceptance is the absence of challenge models showing induction of correlates of protective immunity against variola virus. In this light, virus neutralization provides one of few experimental methods to show specific ‘in vitro’ activity of vaccines against variola virus. Here, we provide characterization of the ability of a modified vaccinia virus Ankara vaccine to induce variola virus-neutralizing antibodies, and we provide comparison with the neutralization elicited by standard Dryvax vaccination. PMID:19339477

WASTE REDUCTION TECHNOLOGY EVALUATIONS AT THREE PRINTED WIRE BOARD MANUFACTURERS

EPA Science Inventory

Technologies at three printed wire board (PWB) manufacturers were evaluated for waste reduction, and costs were compared to existing operations. rom 1989 to 1993, these evaluations were conducted under US EPA's Waste Reduction Innovative Technology Evaluation (WRITE) Program, in ...

77 FR 42319 - Vaccines and Related Biological Products Advisory Committee; Notice of Meeting

Federal Register 2010, 2011, 2012, 2013, 2014

2012-07-18

...] Vaccines and Related Biological Products Advisory Committee; Notice of Meeting AGENCY: Food and Drug...: Vaccines and Related Biological Products Advisory Committee. General Function of the Committee: To provide... consideration of the appropriateness of cell lines derived from human tumors for vaccine manufacture. FDA...

A DNA vaccine against yellow fever virus: development and evaluation.

PubMed

Maciel, Milton; Cruz, Fábia da Silva Pereira; Cordeiro, Marli Tenório; da Motta, Márcia Archer; Cassemiro, Klécia Marília Soares de Melo; Maia, Rita de Cássia Carvalho; de Figueiredo, Regina Célia Bressan Queiroz; Galler, Ricardo; Freire, Marcos da Silva; August, Joseph Thomas; Marques, Ernesto T A; Dhalia, Rafael

2015-04-01

Attenuated yellow fever (YF) virus 17D/17DD vaccines are the only available protection from YF infection, which remains a significant source of morbidity and mortality in the tropical areas of the world. The attenuated YF virus vaccine, which is used worldwide, generates both long-lasting neutralizing antibodies and strong T-cell responses. However, on rare occasions, this vaccine has toxic side effects that can be fatal. This study presents the design of two non-viral DNA-based antigen formulations and the characterization of their expression and immunological properties. The two antigen formulations consist of DNA encoding the full-length envelope protein (p/YFE) or the full-length envelope protein fused to the lysosomal-associated membrane protein signal, LAMP-1 (pL/YFE), aimed at diverting antigen processing/presentation through the major histocompatibility complex II precursor compartments. The immune responses triggered by these formulations were evaluated in H2b and H2d backgrounds, corresponding to the C57Bl/6 and BALB/c mice strains, respectively. Both DNA constructs were able to induce very strong T-cell responses of similar magnitude against almost all epitopes that are also generated by the YF 17DD vaccine. The pL/YFE formulation performed best overall. In addition to the T-cell response, it was also able to stimulate high titers of anti-YF neutralizing antibodies comparable to the levels elicited by the 17DD vaccine. More importantly, the pL/YFE vaccine conferred 100% protection against the YF virus in intracerebrally challenged mice. These results indicate that pL/YFE DNA is an excellent vaccine candidate and should be considered for further developmental studies.

A DNA Vaccine against Yellow Fever Virus: Development and Evaluation

PubMed Central

Maciel, Milton; Cruz, Fábia da Silva Pereira; Cordeiro, Marli Tenório; da Motta, Márcia Archer; Cassemiro, Klécia Marília Soares de Melo; Maia, Rita de Cássia Carvalho; de Figueiredo, Regina Célia Bressan Queiroz; Galler, Ricardo; Freire, Marcos da Silva; August, Joseph Thomas; Marques, Ernesto T. A.; Dhalia, Rafael

2015-01-01

Attenuated yellow fever (YF) virus 17D/17DD vaccines are the only available protection from YF infection, which remains a significant source of morbidity and mortality in the tropical areas of the world. The attenuated YF virus vaccine, which is used worldwide, generates both long-lasting neutralizing antibodies and strong T-cell responses. However, on rare occasions, this vaccine has toxic side effects that can be fatal. This study presents the design of two non-viral DNA-based antigen formulations and the characterization of their expression and immunological properties. The two antigen formulations consist of DNA encoding the full-length envelope protein (p/YFE) or the full-length envelope protein fused to the lysosomal-associated membrane protein signal, LAMP-1 (pL/YFE), aimed at diverting antigen processing/presentation through the major histocompatibility complex II precursor compartments. The immune responses triggered by these formulations were evaluated in H2b and H2d backgrounds, corresponding to the C57Bl/6 and BALB/c mice strains, respectively. Both DNA constructs were able to induce very strong T-cell responses of similar magnitude against almost all epitopes that are also generated by the YF 17DD vaccine. The pL/YFE formulation performed best overall. In addition to the T-cell response, it was also able to stimulate high titers of anti-YF neutralizing antibodies comparable to the levels elicited by the 17DD vaccine. More importantly, the pL/YFE vaccine conferred 100% protection against the YF virus in intracerebrally challenged mice. These results indicate that pL/YFE DNA is an excellent vaccine candidate and should be considered for further developmental studies. PMID:25875109

Developing an Inactivated Rotavirus Vaccine and Evaluating the Immunogenicity Against a Commercially Available Attenuated Rotavirus Vaccine Using a Mice Animal Model.

PubMed

Hashim, Ayaa S M; Aboshanab, Khaled M A; El-Sayed, Aly F M

2016-12-01

There is a high demand for public immunization against Rotavirus (RV), especially in Africa. In Africa, the attenuated RV vaccination is contraindicated in patients with immune diseases and nutrition deficiency. Therefore, the inactivated RV vaccine (IRVV) could be an alternative. In this study, we aimed to develop a pentavalent-IRVV using the most circulating RV strains in Egypt and evaluate it against the commercially available Rotarix ® vaccine. Trial-IRVV was developed with 5% sucrose, 2% polysorbate-80, and adsorbed on Alum to potentiate the vaccine immune response. Then, it was injected subcutaneously into mice groups at 0-, 21-, and 35-time intervals. In parallel, Rotarix was administered twice on 0 and 28 th day. The success of the pentavalent-IRVV/monovalent-Rotarix vaccine immunity rested on achieving immunoglobulin G (IgG) exceeding 1:6,400 that implies less susceptibility to RV infection (RVI). IRVV stimulating IgG >1:6,400 could be an alternative vaccination approach to reach a reasonable protective immunization level against RVI. In addition, Alum adjuvant incorporation effectively provoked a triple elevation of the immunization pattern.

Functional evaluation of malaria Pfs25 DNA vaccine by in vivo electroporation in olive baboons.

PubMed

Kumar, Rajesh; Nyakundi, Ruth; Kariuki, Thomas; Ozwara, Hastings; Nyamongo, Onkoba; Mlambo, Godfree; Ellefsen, Barry; Hannaman, Drew; Kumar, Nirbhay

2013-06-28

Plasmodium falciparum Pfs25 antigen, expressed on the surface of zygotes and ookinetes, is one of the leading targets for the development of a malaria transmission-blocking vaccine (TBV). Our laboratory has been evaluating DNA plasmid based Pfs25 vaccine in mice and non-human primates. Previously, we established that in vivo electroporation (EP) delivery is an effective method to improve the immunogenicity of DNA vaccine encoding Pfs25 in mice. In order to optimize the in vivo EP procedure and test for its efficacy in more clinically relevant larger animal models, we employed in vivo EP to evaluate the immune response and protective efficacy of Pfs25 encoding DNA vaccine in nonhuman primates (olive baboons, Papio anubis). The results showed that at a dose of 2.5mg DNA vaccine, antibody responses were significantly enhanced with EP as compared to without EP resulting in effective transmission blocking efficiency. Similar immunogenicity enhancing effect of EP was also observed with lower doses (0.5mg and 1mg) of DNA plasmids. Further, final boosting with a single dose of recombinant Pfs25 protein resulted in dramatically enhanced antibody titers and significantly increased functional transmission blocking efficiency. Our study suggests priming with DNA vaccine via EP along with protein boost regimen as an effective method to elicit potent immunogenicity of malaria DNA vaccines in nonhuman primates and provides the basis for further evaluation in human volunteers. Copyright © 2013 Elsevier Ltd. All rights reserved.

Evaluation of human papilloma virus (HPV) vaccination strategies and vaccination coverage in adolescent girls worldwide.

PubMed

Owsianka, Barbara; Gańczak, Maria

2015-01-01

An analysis of HPV vaccination strategies and vaccination coverage in adolescent girls worldwide for the last eight years with regard to potential improvement of vaccination coverage rates in Poland. Literature search, covering the period 2006-2014, was performed using Medline. Comparative analysis of HPV vaccination strategies and coverage between Poland and other countries worldwide was conducted. In the last eight years, a number of countries introduced HPV vaccination for adolescent girls to their national immunization programmes. Vaccination strategies differ, consequently affecting vaccination coverage, ranging from several percent to more than 90%. Usually, there are also disparities at national level. The highest HPV vaccination coverage rates are observed in countries where vaccines are administered in school settings and funded from the national budget. Poland is one of the eight EU countries where HPV vaccination has not been introduced to mandatory immunization programme and where paid vaccination is only provided in primary health care settings. HPV vaccination coverage in adolescent girls is estimated at 7.5-10%. Disparities in HPV vaccination coverage rates in adolescent girls worldwide may be due to different strategies of vaccination implementation between countries. Having compared to other countries, the low HPV vaccination coverage in Polish adolescent girls may result from the lack of funding at national level and the fact that vaccines are administered in a primary health care setting. A multidimensional approach, involving the engagement of primary health care and school personnel as well as financial assistance of government at national and local level and the implementation of media campaigns, particularly in regions with high incidence of cervical cancer, could result in an increase of HPV vaccination coverage rates in Poland.

The impact of deposition site on vaccination efficiency of a live bacterial poultry vaccine.

PubMed

Evans, J D; Leigh, S A; Purswell, J L; Collier, S D; Kim, E J; Boykin, D L; Branton, S L

2015-08-01

Vaccines are utilized within the poultry industry to minimize disease-associated losses and spray vaccination is a commonly utilized means for the mass application of poultry vaccines. During this process, vaccine-laden particles are deposited upon target areas (e.g., eyes, nares, and oral cavity) resulting in the direct internalization of the vaccine. However, particles are also deposited on nontarget areas such as the exterior of the subject and its surrounding environment. To better determine the fate of particles deposited upon nontarget areas and the impact of deposition site on the efficiency of vaccine application, a live bacterial poultry vaccine (AviPro(®) MG F) was applied via spray using a spray cabinet with a slotted partition allowing for head-only, body-only, and whole-bird spray application. At 11 wk age, Hy-Line(®) W-36 pullets (n = 280) were allocated equally among 7 treatments including: nonvaccinated controls, pullets spray-vaccinated at the manufacturer's recommended dose (1X) in a site-specific manner (head-only, body-only, and whole-bird), pullets spray-vaccinated at 5X the recommended level (body-only), pullets vaccinated by manual eye-drop application (1X), and pullets eye-drop vaccinated at a level approximating that achieved during the spray vaccination process (1/700X). At 6 to 7 wk postvaccination, vaccination efficiency was assessed via serological-based assays [serum plate agglutination (SPA) and ELISA] and the detection of vaccine-derived in vivo populations. Results indicate an additive contribution of the vaccine deposited on the body to the overall vaccination efficiency of this live bacterial live poultry vaccine. © 2015 Poultry Science Association Inc.

Evaluation of measles-rubella vaccination for mothers in early puerperal phase.

PubMed

Hisano, Michi; Kato, Tatsuo; Inoue, Eisuke; Sago, Haruhiko; Yamaguchi, Koushi

2016-02-24

The postpartum period is an ideal opportunity to vaccinate mothers with inadequate immunity to vaccine-preventable diseases including measles and rubella. A prospective study of measles-rubella (MR) vaccination in the early puerperal phase was conducted in 171 mothers, who had insufficient antibody titers when screened for immunity to measles (≤ 1:4 on the neutralization test [NT]) or rubella (≤ 1:16 on the hemagglutination inhibition [HI] test) during pregnancy. To evaluate the efficacy of MR vaccination in the postpartum period, we determined their post-vaccination antibody titers and immune responses to vaccination, and investigated the association between these and their prolactin (PRL) levels and Th1/Th2 ratios at the time of vaccination. We also examined the passage of viral RNA and antigen into breast milk. Of the 169 participants who completed the study schedule, 117 and 101 had low antibody titers against measles and rubella, respectively. In the measles-seronegative group, the antibody-positive rate was 87% on the NT assay, and the NT geometric mean antibody titer was 11.4 (95% confidence interval [CI], 10.0-13.0). In the rubella-seronegative group, the antibody-positive rate was 88% on the HI test assay, and the HI geometric mean antibody titer was 64.0 (95% CI, 53.9-76.0). There was no association between the post-vaccination antibody titers and the PRL levels or Th1/Th2 ratios at the time of vaccination. In the rubella-seronegative group, subjects with higher Th1/Th2 ratios showed higher rates of responsiveness than those with lower ratios (P=0.045). Although measles virus RNA was isolated from the breast milk of two vaccinated mothers, breastfeeding was not associated with clinical disease in any infants. MR vaccination in the early puerperal phase is considered an effective way to prevent the diseases, regardless of the mother's immunological status and hormonal milieu. Copyright © 2016 Elsevier Ltd. All rights reserved.

Safety of vaccines that have been kept outside of recommended temperatures: Reports to the Vaccine Adverse Event Reporting System (VAERS), 2008-2012.

PubMed

Hibbs, Beth F; Miller, Elaine; Shi, Jing; Smith, Kamesha; Lewis, Paige; Shimabukuro, Tom T

2018-01-25

Vaccines should be stored and handled according to manufacturer specifications. Inadequate cold chain management can affect potency; but, limited data exist on adverse events (AE) following administration of vaccines kept outside of recommended temperatures. To describe reports to the Vaccine Adverse Event Reporting System (VAERS) involving vaccines inappropriately stored outside of recommended temperatures and/or exposed to temperatures outside of manufacturer specifications for inappropriate amounts of time. We searched the VAERS database (analytic period 2008-2012) for reports describing vaccines kept outside of recommended temperatures. We analyzed reports by vaccine type, length outside of recommended temperature and type of temperature excursion, AE following receipt of potentially compromised vaccine, and reasons for cold chain breakdown. We identified 476 reports of vaccines kept outside of recommended temperatures; 77% described cluster incidents involving multiple patients. The most commonly reported vaccines were quadrivalent human papillomavirus (n = 146, 30%), 23-valent pneumococcal polysaccharide (n = 51, 11%), and measles, mumps, and rubella (n = 45, 9%). Length of time vaccines were kept outside of recommended temperatures ranged from 15 mins to 6 months (median 51 h). Most (n = 458, 96%) reports involved patients who were administered potentially compromised vaccines; AE were reported in 32 (7%), with local reactions (n = 21) most frequent. Two reports described multiple patients contracting diseases they were vaccinated against, indicating possible influenza vaccine failure. Lack of vigilance, inadequate training, and equipment failure were reasons cited for cold chain management breakdowns. Our review does not indicate any substantial direct health risk from administration of vaccines kept outside of recommended temperatures. However, there are potential costs and risks, including vaccine wastage, possible decreased

Influenza Vaccination Guidelines and Vaccine Sales in Southeast Asia: 2008–2011

PubMed Central

Gupta, Vinay; Dawood, Fatimah S.; Muangchana, Charung; Lan, Phan Trong; Xeuatvongsa, Anonh; Sovann, Ly; Olveda, Remigio; Cutter, Jeffery; Oo, Khin Yi; Ratih, Theresia Sandra Diah; Kheong, Chong Chee; Kapella, Bryan K.; Kitsutani, Paul; Corwin, Andrew; Olsen, Sonja J.

2012-01-01

Background Southeast Asia is a region with great potential for the emergence of a pandemic influenza virus. Global efforts to improve influenza surveillance in this region have documented the burden and seasonality of influenza viruses and have informed influenza prevention strategies, but little information exists about influenza vaccination guidelines and vaccine sales. Methods To ascertain the existence of influenza vaccine guidelines and define the scope of vaccine sales, we sent a standard three-page questionnaire to the ten member nations of the Association of Southeast Asian Nations. We also surveyed three multinational manufacturers who supply influenza vaccines in the region. Results Vaccine sales in the private sector were <1000 per 100,000 population in the 10 countries. Five countries reported purchasing vaccine for use in the public sector. In 2011, Thailand had the highest combined reported rate of vaccine sales (10,333 per 100,000). In the 10 countries combined, the rate of private sector sales during 2010–2011 (after the A(H1N1)2009pdm pandemic) exceeded 2008 pre-pandemic levels. Five countries (Indonesia, Malaysia, Singapore, Thailand and Vietnam) had guidelines for influenza vaccination but only two were consistent with global guidelines. Four recommended vaccination for health care workers, four for elderly persons, three for young children, three for persons with underlying disease, and two for pregnant women. Conclusions The rate of vaccine sales in Southeast Asia remains low, but there was a positive impact in sales after the A(H1N1)2009pdm pandemic. Low adherence to global vaccine guidelines suggests that more work is needed in the policy arena. PMID:23285200

Synergizing vaccinations with therapeutics for measles eradication.

PubMed

Plemper, Richard K; Hammond, Anthea L

2014-02-01

The measles virus is a major human pathogen responsible for approximately 150,000 deaths annually. The disease is vaccine preventable and eradication of the virus is considered feasible, in principle. However, a herd immunity exceeding 95% is required to prevent sporadic viral outbreaks in a population. Declining disease prevalence, combined with public anxiety over the vaccination's safety, has led to increased vaccine refusal, especially in Europe. This has led to the resurgence of measles in some areas. This article discusses whether synergizing effective measles therapeutics with the measles vaccination could contribute to finally eradicating measles. The authors identify key elements in a desirable drug profile and review current disease management strategies and the state of experimental inhibitor candidates. The authors also evaluate the risk associated with viral escape from inhibition, and consider the potential of measles therapeutics in the management of persistent central nervous system (CNS) viral infection. Finally, the authors contemplate the possible impact of therapeutics in controlling the threat imposed by closely related zoonotic pathogens of the same genus as measles. Efficacious therapeutics used for post-exposure prophylaxis of high-risk social contacts of confirmed index cases may aid measles eradication by closing herd immunity gaps; this is due to vaccine refusal or failure in populations with overall good vaccination coverage. The envisioned primarily prophylactic application of measles therapeutics to a predominantly pediatric and/or adolescent population, dictates the drug profile. It also has to be safe and efficacious, orally available, shelf-stable at ambient temperature and amenable to cost-effective manufacturing.

[Evaluation of immunogenicity and safety of 2 immunizations with allantoic intranasal live influenza vaccine Ultragrivac].

PubMed

Shishkina, L N; Mazurkova, N A; Ternovoĭ, V A; Bulychev, L E; Tumanov, Iu V; Skarnovich, M O; Kabanov, A S; Ryndiuk, N N; Kuzubov, V I; Mironov, A N; Stavskiĭ, E A; Drozdov, I G

2011-01-01

Evaluate reactogenicity, safety and immunogenicity in phase 2 clinical trials of 2 immunization schedules with Ultragrivac--an allantoic intranasal life influenza vaccine based on A/17/ duck/Potsdam/86/92 [17/H5] reassortant strain. 4 groups of volunteers participated in the study: group 1--40 individuals were vaccinated twice with a 10 day interval; group 2--40 individuals were vaccinated twice with a 21 day interval; group 3 (control)--10 individuals received placebo twice with a 10 day interval; group 4 (control)--10 individuals received placebo twice with a 21 day interval. Local (secretory IgA), cellular and humoral immune response were evaluated. Humoral immunity was evaluated by the intensity of increase of geometric mean antibody titers against 2 influenza virus strains A/17/duck/Potsdam/86/92 [17/H5] and A/chicken/Suzdalka/Nov-1 1/2005 (H5N1), and by the level of significant (4 times or more) antibody seroconversions after the vaccination. After the use of Ultragrivac the level of secretory IgA in the nasal cavity of vaccinated volunteers in the groups with revaccination intervals of 10 and 21 days increased significantly. The second immunization with 10 or 21 day intervals significantly increased postvaccinal humoral immune response. Humoral immune response induction after 2 vaccinations with 10 day interval was no less effective than with 21 day interval. Ultragrivac allantoic intranasal live influenza vaccine is areactogenic, harmless for vaccinated individuals, safe for those around, and has immunogenic properties against not only homologous virus A(H5N2), but also against influenza strain A(H5N1).

Evaluation of the Protection Provided by Hepatitis B Vaccination in India.

PubMed

Puliyel, Jacob; Naik, Pathik; Puliyel, Ashish; Agarwal, Kishore; Lal, Vandana; Kansal, Nimmi; Nandan, Devki; Tripathi, Vikas; Tyagi, Prashant; Singh, Saroj K; Srivastava, Rajeev; Sharma, Utkarsh; Sreenivas, V

2018-07-01

In India, Hepatitis B vaccination is recommended at 6 wk except for hospital-deliveries. The authors examined protection afforded by the birth dose. A case-control study was done. HBsAg and HBcAb were tested in 2671 children, 1 to 5 y and HBsAb was evaluated in a subset of 1413 children. Vaccination history was recorded. Cases were HBsAg carriers. In another analysis, children who got infected (HBsAg and/or HBcAb positive) were considered as cases. Exposed were the unvaccinated. In another analysis, exposed were those vaccinated without the birth dose. The odds ratio (OR) for HBsAg positivity with birth vaccination was 0.35 (95% CI 0.19-0.66); while with vaccination at 6 wk was 0.29 (95%CI 0.14-0.61), both compared to unvaccinated. Birth vaccination has no added protection when compared to the unvaccinated. Unvaccinated children in index study had HBsAg positivity of 4.38%. The number needed to treat (NNT) to prevent one case of HBsAg positivity was 32.6 (95% CI, 20.9 to 73.6). The odds of getting HBV infection was 0.42 (CI 0.25-0.68) with birth dose and 0.49 (CI 0.30-0.82) without the birth dose compared to the unvaccinated. Protective antibody (HBsAb) was present in about 70% of the vaccinated. In the unimmunised, in the first 2 y HBsAb protection was present in 40%. The odds ratio (OR) for HBsAb in the fully vaccinated between 4 and 5 y was 1.4 (95%CI 0.9-2.18) compared to the unvaccinated. The present study lends support to the pragmatic approach of the Government to vaccinate babies born at home starting at 6 wk.

Written reminders increase vaccine coverage in Danish children - evaluation of a nationwide intervention using The Danish Vaccination Register, 2014 to 2015.

PubMed

Suppli, Camilla Hiul; Rasmussen, Mette; Valentiner-Branth, Palle; Mølbak, Kåre; Krause, Tyra Grove

2017-04-27

We evaluated a national intervention of sending written reminders to parents of children lacking childhood vaccinations, using the Danish Vaccination Register (DDV). The intervention cohort included the full birth cohort of 124,189 children born in Denmark who reached the age of 2 and 6.5 years from 15 May 2014 to 14 May 2015. The reference cohort comprised 124,427 children who reached the age of 2 and 6.5 years from 15 May 2013 to 14 May 2014. Vaccination coverage was higher in the intervention cohort at 2.5 and 7 years of age. The differences were most pronounced for the second dose of the measles-mumps-rubella vaccine (MMR2) and the diphtheria-tetanus-pertussis-polio vaccine DTaP-IPV4 among the 7-year-olds, with 5.0 percentage points (95% confidence interval (CI): 4.5-5.4) and 6.4 percentage points (95% CI: 6.0-6.9), respectively. Among the 2.5 and 7-year-olds, the proportion of vaccinations in the preceding 6 months was 46% and three times higher, respectively, in the intervention cohort than the reference cohort. This study indicates a marked effect of personalised written reminders, highest for the vaccines given later in the schedule in the older cohort. In addition, the reminders increased awareness about correct registration of vaccinations in DDV. This article is copyright of The Authors, 2017.

Written reminders increase vaccine coverage in Danish children - evaluation of a nationwide intervention using The Danish Vaccination Register, 2014 to 2015

PubMed Central

Suppli, Camilla Hiul; Rasmussen, Mette; Valentiner-Branth, Palle; Mølbak, Kåre; Krause, Tyra Grove

2017-01-01

We evaluated a national intervention of sending written reminders to parents of children lacking childhood vaccinations, using the Danish Vaccination Register (DDV). The intervention cohort included the full birth cohort of 124,189 children born in Denmark who reached the age of 2 and 6.5 years from 15 May 2014 to 14 May 2015. The reference cohort comprised 124,427 children who reached the age of 2 and 6.5 years from 15 May 2013 to 14 May 2014. Vaccination coverage was higher in the intervention cohort at 2.5 and 7 years of age. The differences were most pronounced for the second dose of the measles-mumps-rubella vaccine (MMR2) and the diphtheria-tetanus-pertussis-polio vaccine DTaP-IPV4 among the 7-year-olds, with 5.0 percentage points (95% confidence interval (CI): 4.5–5.4) and 6.4 percentage points (95% CI: 6.0–6.9), respectively. Among the 2.5 and 7-year-olds, the proportion of vaccinations in the preceding 6 months was 46% and three times higher, respectively, in the intervention cohort than the reference cohort. This study indicates a marked effect of personalised written reminders, highest for the vaccines given later in the schedule in the older cohort. In addition, the reminders increased awareness about correct registration of vaccinations in DDV. PMID:28488995

Seasonal influenza vaccination delivery through community pharmacists in England: evaluation of the London pilot

PubMed Central

Atkins, Katherine; van Hoek, Albert Jan; Watson, Conall; Baguelin, Marc; Choga, Lethiwe; Patel, Anika; Raj, Thara; Jit, Mark; Griffiths, Ulla

2016-01-01

Objective To evaluate the effectiveness and cost of the pan-London pharmacy initiative, a programme that allows administration of seasonal influenza vaccination to eligible patients at pharmacies. Design We analysed 2013–2015 data on vaccination uptake in pharmacies via the Sonar reporting system, and the total vaccination uptake via 2011–2015 ImmForm general practitioner (GP) reporting system data. We conducted an online survey of London pharmacists who participate in the programme to assess time use data, vaccine choice, investment costs and opinions about the programme. We conducted an online survey of London GPs to assess vaccine choice of vaccine and opinions about the pharmacy vaccine delivery programme. Setting All London boroughs. Participants London-based GPs, and pharmacies that currently offer seasonal flu vaccination. Interventions Not applicable. Main outcome measures Comparison of annual vaccine uptake in London across risk groups from years before pharmacy vaccination introduction to after pharmacy vaccination introduction. Completeness of vaccine uptake reporting data. Cost to the National Health Service (NHS) of flu vaccine delivery at pharmacies with that at GPs. Cost to pharmacists of flu delivery. Opinions of pharmacists and GPs regarding the flu vaccine pharmacy initiative. Results No significant change in the uptake of seasonal vaccination in any of the risk groups as a result of the pharmacy initiative. While on average a pharmacy-administered flu vaccine dose costs the NHS up to £2.35 less than a dose administered at a GP, a comparison of the 2 recording systems suggests there is substantial loss of data. Conclusions Flu vaccine delivery through pharmacies shows potential for improving convenience for vaccine recipients. However, there is no evidence that vaccination uptake increases and the use of 2 separate recording systems leads to time-consuming data entry and missing vaccine record data. PMID:26883237

Matrix and Backstage: Cellular Substrates for Viral Vaccines

PubMed Central

Jordan, Ingo; Sandig, Volker

2014-01-01

Vaccines are complex products that are manufactured in highly dynamic processes. Cellular substrates are one critical component that can have an enormous impact on reactogenicity of the final preparation, level of attenuation of a live virus, yield of infectious units or antigens, and cost per vaccine dose. Such parameters contribute to feasibility and affordability of vaccine programs both in industrialized countries and developing regions. This review summarizes the diversity of cellular substrates for propagation of viral vaccines from primary tissue explants and embryonated chicken eggs to designed continuous cell lines of human and avian origin. PMID:24732259

Vaccine production training to develop the workforce of foreign institutions supported by the BARDA influenza vaccine capacity building program.

PubMed

Tarbet, E Bart; Dorward, James T; Day, Craig W; Rashid, Kamal A

2013-03-15

In the event of an influenza pandemic, vaccination will be the best method to limit virus spread. However, lack of vaccine biomanufacturing capacity means there will not be enough vaccine for the world's population. The U.S. Department of Health and Human Services, Biomedical Advanced Research and Development Authority (BARDA) provides support to the World Health Organization to enhance global vaccine production capacity in developing countries. However, developing a trained workforce in some of those countries is necessary. Biomanufacturing is labor-intensive, requiring unique skills not found in traditional academic programs. Employees must understand the scientific basis of biotechnology, operate specialized equipment, and work in an environment regulated by good manufacturing practices (cGMP). Therefore, BARDA supported development of vaccine biomanufacturing training at Utah State University. The training consisted of a three-week industry-focused course for participants from institutions supported by the BARDA and WHO influenza vaccine production capacity building program. The curriculum was divided into six components: (1) biosafety, (2) cell culture and growth of cells in bioreactors, (3) virus assays and inactivation, (4) scale-up strategies, (5) downstream processing, and (6) egg- and cell-based vaccine production and cGMP. Lectures were combined with laboratory exercises to provide a balance of theory and hands-on training. The initial course included sixteen participants from seven countries including: Egypt, Romania, Russia, Serbia, South Korea, Thailand, and Vietnam. The participant's job responsibilities included: Production, Quality Control, Quality Assurance, and Research; and their education ranged from bachelors to doctoral level. Internal course evaluations utilized descriptive methods including surveys, observation of laboratory activities, and interviews with participants. Generally, participants had appropriate academic backgrounds, but

Are vaccine strain, type or administration protocol risk factors for canine parvovirus vaccine failure?

PubMed

Altman, K D; Kelman, M; Ward, M P

2017-10-01

Canine parvovirus (CPV) is a highly contagious and worldwide cause of serious and often fatal disease in dogs, despite the widespread availability of vaccines. Which vaccine-related factors are associated with vaccination failure is largely unknown, and there are no reports from Australia. In this study - the first national population-level CPV study of its kind ever conducted - we analysed data on 594 cases of apparent CPV vaccination failure reported from an Australian national surveillance system to determine whether vaccine strain, type or administration protocol are risk factors for vaccination failures. The strain of CPV used in vaccine manufacture was not significantly associated with vaccination failure in clinical practice. The vaccine type (killed versus attenuated vaccine) for puppies diagnosed with CPV was associated with a lower mean age at time of vaccination (P=0.0495). The age at administration of the last CPV vaccination a puppy received prior to presenting with disease was a significant (P=0.0334) risk factor for vaccination failure, irrespective of whether the vaccine was marketed for a 10-week or 12-week or greater vaccination finish protocol. There was also a strong negative correlation between age at last vaccination prior to disease and vaccination failure (P<0.0001): the later a puppy received this last vaccination, the lower the risk of vaccination failure. This supports the hypothesis that the use of final vaccination in puppies at less than 16 weeks of age predisposes to vaccination failure and warrants a final age for vaccination recommendation to be at least 16 weeks for all canine parvovirus vaccines, especially in outbreak situations. The large number of cases identified in this study confirms that CPV vaccination failure is occurring in Australia. Veterinarians should consider CPV as a differential diagnosis in cases with appropriate clinical presentation, regardless of the reported vaccination status of the dog. Copyright © 2017

COVER (cover of vaccination evaluated rapidly): description of the England and Wales scheme.

PubMed

Begg, N T; Gill, O N; White, J M

1989-03-01

The COVER scheme, a method for the rapid evaluation of vaccine coverage in England and Wales, is described. The primary aim of the scheme is to improve cover by providing health district vaccination programme coordinators with relevant timely information. Quarterly data were obtained from, analysed and promptly fed back to, 126 health districts on cohorts of children who had recently attained the target ages for receiving the selected sentinel vaccines; 18 months for third diphtheria and third pertussis and 2 years for measles. Although the data suggested that vaccination cover is improving, national performance still falls well short of 90%, the 1990 target set by the World Health Organisation for countries in Europe.

Transmission blocking malaria vaccines: Assays and candidates in clinical development.

PubMed

Sauerwein, R W; Bousema, T

2015-12-22

Stimulated by recent advances in malaria control and increased funding, the elimination of malaria is now considered to be an attainable goal for an increasing number of malaria-endemic regions. This has boosted the interest in transmission-reducing interventions including vaccines that target sexual, sporogenic, and/or mosquito-stage antigens to interrupt malaria transmission (SSM-VIMT). SSM-VIMT aim to prevent human malaria infection in vaccinated communities by inhibiting parasite development within the mosquito after a blood meal taken from a gametocyte carrier. Only a handful of target antigens are in clinical development and progress has been slow over the years. Major stumbling blocks include (i) the expression of appropriately folded target proteins and their downstream purification, (ii) insufficient induction of sustained functional blocking antibody titers by candidate vaccines in humans, and (iii) validation of a number of (bio)-assays as correlate for blocking activity in the field. Here we discuss clinical manufacturing and testing of current SSM-VIMT candidates and the latest bio-assay development for clinical evaluation. New testing strategies are discussed that may accelerate the evaluation and application of SSM-VIMT. Copyright © 2015. Published by Elsevier Ltd.

Evaluating investments in typhoid vaccines in two slums in Kolkata, India.

PubMed

Cook, Joseph; Sur, Dipika; Clemens, John; Whittington, Dale

2009-12-01

New-generation vaccines against typhoid fever have the potential to reduce the burden of disease in areas where the disease is endemic. The case for public expenditure on typhoid Vi polysaccharide vaccines for two low-income, high-incidence slums (Narkeldanga and Tiljala) in Kolkata, India, was examined. Three measures of the economic benefits of the vaccines were used: private and public cost-of-illness (COI) avoided; avoided COI plus mortality risk-reduction benefits; and willingness-to-pay (WTP) derived from stated preference (contingent valuation) studies conducted in Tiljala in 2004. Benefits and costs were examined from a social perspective. The study represents a unique opportunity to evaluate typhoid-vaccine programmes using a wealth of new site-specific epidemiological and economic data. Three typhoid-vaccination strategies (targeting only enrolled school children, targeting all children, and targeting adults and children) would most likely pass a social cost-benefit test, unless benefits are restricted to include only avoided COI. All three strategies would be considered 'very cost-effective' using the standard comparisons of cost per disability-adjusted life-year avoided with per-capita gross domestic product. However, at an average total cost per immunized person of approximately US$ 1.1, a typhoid-vaccination programme would absorb a sixth of existing public-sector spending on health (on a per-capita basis) in India. Because there appears to be significant private economic demand for typhoid vaccines, the Government could design a financially-sustainable programme with user-fees. The results show that a programme where adults pay a higher fee to subsidize vaccines for children (who have higher incidence) would avoid more cases than a uniform user-fee and still achieve revenue-neutrality.

Microneedle-based vaccines

PubMed Central

Prausnitz, Mark R.; Mikszta, John A.; Cormier, Michel; Andrianov, Alexander K.

2010-01-01

The threat of pandemic influenza and other public health needs motivates development of better vaccine delivery systems. To address this need, microneedles have been developed as micron-scale needles fabricated using low-cost manufacturing methods that administer vaccine into the skin using a simple device that may be suitable for self-administration. Delivery using solid or hollow microneedles can be accomplished by (i) piercing the skin and then applying a vaccine formulation or patch onto the permeabilized skin, (ii) coating or encapsulating vaccine onto or within microneedles for rapid, or delayed, dissolution and release in the skin and (iii) injection into the skin using a modified syringe or pump. Extensive clinical experience with smallpox, TB and other vaccines has shown that vaccine delivery into the skin using conventional intradermal injection is generally safe and effective and often elicits the same immune responses at lower doses compared to intramuscular injection. Animal experiments using microneedles have shown similar benefits. Microneedles have been used to deliver whole, inactivated virus; trivalent split antigen vaccines; and DNA plasmid encoding the influenza hemagglutinin to rodents and found strong antibody responses. In addition, ChimeriVax™-JE against yellow fever was administered to non-human primates and generated protective levels of neutralizing antibodies more than seven times greater than subcutaneous delivery; DNA plasmid encoding hepatitis B surface antigen was administered to mice and generated antibody and T cell responses at least as strong as hypodermic injections; recombinant Protective Antigen of Baccilus anthracis was administered to rabbits and provided complete protection from lethal aerosol anthrax spore challenge at a lower dose than intramuscular injection; and DNA plasmid encoding four vaccinia virus genes administered to mice in combination with electroporation generated neutralizing antibodies that apparently

Assessing the economic benefits of vaccines based on the health investment life course framework: a review of a broader approach to evaluate malaria vaccination.

PubMed

Constenla, Dagna

2015-03-24

Economic evaluations have routinely understated the net benefits of vaccination by not including the full range of economic benefits that accrue over the lifetime of a vaccinated person. Broader approaches for evaluating benefits of vaccination can be used to more accurately calculate the value of vaccination. This paper reflects on the methodology of one such approach - the health investment life course approach - that looks at the impact of vaccine investment on lifetime returns. The role of this approach on vaccine decision-making will be assessed using the malaria health investment life course model example. We describe a framework that measures the impact of a health policy decision on government accounts over many generations. The methodological issues emerging from this approach are illustrated with an example from a recently completed health investment life course analysis of malaria vaccination in Ghana. Beyond the results, various conceptual and practical challenges of applying this framework to Ghana are discussed in this paper. The current framework seeks to understand how disease and available technologies can impact a range of economic parameters such as labour force participation, education, healthcare consumption, productivity, wages or economic growth, and taxation following their introduction. The framework is unique amongst previous economic models in malaria because it considers future tax revenue for governments. The framework is complementary to cost-effectiveness and budget impact analysis. The intent of this paper is to stimulate discussion on how existing and new methodology can add to knowledge regarding the benefits from investing in new and underutilized vaccines. Copyright © 2015 Elsevier Ltd. All rights reserved.

Evaluating human papillomavirus vaccination programs in Canada: should provincial healthcare pay for voluntary adult vaccination?

PubMed

Llamazares, Marco; Smith, Robert J

2008-04-10

Recently, provincial health programs in Canada and elsewhere have begun rolling out vaccination against human papillomavirus for girls aged 9-13. While vaccination is voluntary, the cost of vaccination is waived, to encourage parents to have their daughters vaccinated. Adult women who are eligible for the vaccine may still receive it, but at a cost of approximately CAN$400. Given the high efficacy and immunogenicity of the vaccine, the possibility of eradicating targeted types of the virus may be feasible, assuming the vaccination programs are undertaken strategically. We develop a mathematical model to describe the epidemiology of vaccination against human papillomavirus, accounting for a widespread childhood vaccination program that may be supplemented by voluntary adult vaccination. A stability analysis is performed to determine the stability of the disease-free equilibrium. The critical vaccine efficacy and immunogenicity thresholds are derived, and the minimum level of adult vaccination required for eradication of targeted types is determined. We demonstrate that eradication of targeted types is indeed feasible, although the burden of coverage for a childhood-only vaccination program may be high. However, if a small, but non-negligible, proportion of eligible adults can be vaccinated, then the possibility of eradication of targeted types becomes much more favourable. We provide a threshold for eradication in general communities and illustrate the results with numerical simulations. We also investigate the effects of suboptimal efficacy and immunogenicity and show that there is a critical efficacy below which eradication of targeted types is not possible. If eradication is possible, then there is a critical immunogenicity such that even 100% childhood vaccination will not eradicate the targeted types of the virus and must be supplemented with voluntary adult vaccination. However, the level of adult vaccination coverage required is modest and may be achieved

Systematic review of economic evaluations of vaccination programs in mainland China: Are they sufficient to inform decision making?

PubMed

Pan, Xiong-Fei; Griffiths, Ulla K; Pennington, Mark; Yu, Hongjie; Jit, Mark

2015-11-17

The purpose of the study was to systematically review economic evaluations of vaccine programs conducted in mainland China. We searched for economic evaluations of vaccination in China published prior to August 3, 2015 in eight English-language and three Chinese-language databases. Each article was appraised against the 19-item Consensus on Health Economic Criteria list (CHEC-list). We found 23 papers evaluating vaccines against hepatitis B (8 articles), Streptococcus pneumoniae (5 articles), human papillomavirus (3 articles), Japanese encephalitis (2 articles), rotavirus (2 articles), hepatitis A (1 article), Enterovirus 71 (1 article) and influenza (1 article). Studies conformed to a mean of 12 (range: 6-18) items in the CHEC-list criteria. Five of six Chinese-language articles conformed to fewer than half of the 19 criteria items. The main criteria that studies failed to conform to included: inappropriate measurement (20 articles) and valuation (18 articles) of treatment and/or vaccination costs, no discussion about distributional implications (18 articles), missing major health outcomes (14 articles), no discussion about generalizability to other contexts (14 articles), and inadequate sensitivity analysis (13 articles). In addition, ten studies did not include major cost components of vaccination programs, and nine did not report outcomes in terms of life years even in cases where QALYs or DALYs were calculated. Only 13 studies adopted a societal perspective for analysis. All studies concluded that the appraised vaccination programs were cost-effective except for one evaluation of universal 7-valent pneumococcal conjugate vaccine (PCV-7) in children. However, three of the five studies on PCV-7 showed poor overall quality, and the number of studies on vaccines other than hepatitis B vaccine and PCV-7 was limited. In conclusion, major methodological flaws and reporting problems exist in current economic evaluations of vaccination programs in China. Local

Utilizing dynamic light scattering as a process analytical technology for protein folding and aggregation monitoring in vaccine manufacturing.

PubMed

Yu, Zhou; Reid, Jennifer C; Yang, Yan-Ping

2013-12-01

Protein aggregation is a common challenge in the manufacturing of biological products. It is possible to minimize the extent of aggregation through timely measurement and in-depth characterization of aggregation. In this study, we demonstrated the use of dynamic light scattering (DLS) to monitor inclusion body (IB) solubilization, protein refolding, and aggregation near the production line of a recombinant protein-based vaccine candidate. Our results were in good agreement with those measured by size-exclusion chromatography. DLS was also used to characterize the mechanism of aggregation. As DLS is a quick, nonperturbing technology, it can potentially be used as an at-line process analytical technology to ensure complete IB solubilization and aggregate-free refolding. © 2013 Wiley Periodicals, Inc. and the American Pharmacists Association.

Vaccines for preventing influenza in healthy adults.

PubMed

Demicheli, V; Rivetti, D; Deeks, J J; Jefferson, T O

2001-01-01

Three different types of influenza vaccines are currently produced world wide. None is traditionally targeted to healthy adults. Despite the publication of a large number of clinical trials, there is still substantial uncertainty about the clinical effectiveness of influenza vaccines and this has negative impact on the vaccines acceptance and uptake. To identify, retrieve and assess all studies evaluating the effects of vaccines on influenza in healthy adults. To assess the effectiveness of vaccines in preventing cases of influenza in healthy adults. To estimate the frequency of adverse effects associated with influenza vaccination in healthy adults. MEDLINE was searched using the strategy of the Cochrane Acute Respiratory Infections Group. The bibliography of retrieved articles, the Cochrane Controlled Trials Register (CCTR), and EMBASE (1990 to 1997) were also searched. Handsearch of the journal Vaccine from its first issue to the end of 1997 (Jefferson and Jefferson, 1996; Jefferson, 1998). We wrote to vaccine manufacturers and first or corresponding authors of studies in the review. Any randomised or quasi-randomised studies comparing influenza vaccines in humans with placebo, control vaccines or no intervention, or comparing types, doses or schedules of influenza vaccine. Live, attenuated or killed vaccines or fractions thereof administered by any route, irrespective of antigenic configuration were considered. Only studies assessing protection from exposure to naturally occurring influenza in healthy individuals aged 14 to 60 (irrespective of influenza immune status) were considered. Both clinically defined cases and serologically confirmed cases of influenza were considered as outcomes according to the authors' definitions. Time off work, complication and hospitalisation rates were considered, together with adverse effects. Vaccine schedules were analysed including one component matching the recommended vaccine (WHO or government recommendations) for the year

Traditional and New Influenza Vaccines

PubMed Central

Wong, Sook-San

2013-01-01

SUMMARY The challenges in successful vaccination against influenza using conventional approaches lie in their variable efficacy in different age populations, the antigenic variability of the circulating virus, and the production and manufacturing limitations to ensure safe, timely, and adequate supply of vaccine. The conventional influenza vaccine platform is based on stimulating immunity against the major neutralizing antibody target, hemagglutinin (HA), by virus attenuation or inactivation. Improvements to this conventional system have focused primarily on improving production and immunogenicity. Cell culture, reverse genetics, and baculovirus expression technology allow for safe and scalable production, while adjuvants, dose variation, and alternate routes of delivery aim to improve vaccine immunogenicity. Fundamentally different approaches that are currently under development hope to signal new generations of influenza vaccines. Such approaches target nonvariable regions of antigenic proteins, with the idea of stimulating cross-protective antibodies and thus creating a “universal” influenza vaccine. While such approaches have obvious benefits, there are many hurdles yet to clear. Here, we discuss the process and challenges of the current influenza vaccine platform as well as new approaches that are being investigated based on the same antigenic target and newer technologies based on different antigenic targets. PMID:23824369

Antibody Immunity Induced by H7N9 Avian Influenza Vaccines: Evaluation Criteria, Affecting Factors, and Implications for Rational Vaccine Design

PubMed Central

Hu, Zenglei; Jiao, Xinan; Liu, Xiufan

2017-01-01

Severe H7N9 avian influenza virus (AIV) infections in humans have public health authorities around the world on high alert for the potential development of a human influenza pandemic. Currently, the newly-emerged highly pathogenic avian influenza A (H7N9) virus poses a dual challenge for public health and poultry industry. Numerous H7N9 vaccine candidates have been generated using various platforms. Immunization trials in animals and humans showed that H7N9 vaccines are apparently poorly immunogenic because they induced low hemagglutination inhibition and virus neutralizing antibody titers. However, H7N9 vaccines elicit comparable levels of total hemagglutinin (HA)-reactive IgG antibody as the seasonal influenza vaccines, suggesting H7N9 vaccines are as immunogenic as their seasonal counterparts. A large fraction of overall IgG antibody is non-neutralizing antibody and they target unrecognized epitopes outside of the traditional antigenic sites in HA. Further, the Treg epitope identified in H7 HA may at least partially contribute to regulation of antibody immunity. Here, we review the latest advances for the development of H7N9 vaccines and discuss the influence of serological criteria on evaluation of immunogenicity of H7N9 vaccines. Next, we discuss factors affecting antibody immunity induced by H7N9 vaccines, including the change in antigenic epitopes in HA and the presence of the Treg epitope. Last, we present our perspectives for the unique features of antibody immunity of H7N9 vaccines and propose some future directions to improve or modify antibody response induced by H7N9 vaccines. This perspective would provide critical implications for rational design of H7N9 vaccines for human and veterinary use. PMID:29018438

DNA vaccine-generated duck polyclonal antibodies as a postexposure prophylactic to prevent hantavirus pulmonary syndrome (HPS).

PubMed

Brocato, Rebecca; Josleyn, Matthew; Ballantyne, John; Vial, Pablo; Hooper, Jay W

2012-01-01

Andes virus (ANDV) is the predominant cause of hantavirus pulmonary syndrome (HPS) in South America and the only hantavirus known to be transmitted person-to-person. There are no vaccines, prophylactics, or therapeutics to prevent or treat this highly pathogenic disease (case-fatality 35-40%). Infection of Syrian hamsters with ANDV results in a disease that closely mimics human HPS in incubation time, symptoms of respiratory distress, and disease pathology. Here, we evaluated the feasibility of two postexposure prophylaxis strategies in the ANDV/hamster lethal disease model. First, we evaluated a natural product, human polyclonal antibody, obtained as fresh frozen plasma (FFP) from a HPS survivor. Second, we used DNA vaccine technology to manufacture a polyclonal immunoglobulin-based product that could be purified from the eggs of vaccinated ducks (Anas platyrhynchos). The natural "despeciation" of the duck IgY (i.e., Fc removed) results in an immunoglobulin predicted to be minimally reactogenic in humans. Administration of ≥ 5,000 neutralizing antibody units (NAU)/kg of FFP-protected hamsters from lethal disease when given up to 8 days after intranasal ANDV challenge. IgY/IgYΔFc antibodies purified from the eggs of DNA-vaccinated ducks effectively neutralized ANDV in vitro as measured by plaque reduction neutralization tests (PRNT). Administration of 12,000 NAU/kg of duck egg-derived IgY/IgYΔFc protected hamsters when administered up to 8 days after intranasal challenge and 5 days after intramuscular challenge. These experiments demonstrate that convalescent FFP shows promise as a postexposure HPS prophylactic. Moreover, these data demonstrate the feasibility of using DNA vaccine technology coupled with the duck/egg system to manufacture a product that could supplement or replace FFP. The DNA vaccine-duck/egg system can be scaled as needed and obviates the necessity of using limited blood products obtained from a small number of HPS survivors. This is the

Challenges and successes for the grantees and the Technical Advisory Group of WHO's influenza vaccine technology transfer initiative.

PubMed

Grohmann, Gary; Francis, Donald P; Sokhey, Jaspal; Robertson, James

2016-10-26

One of the aims of the WHO Global Action Plan for Influenza Vaccines (GAP) was to transfer influenza vaccine production technology to interested manufacturers and governments in developing countries, to enable greater influenza vaccine manufacturing capacity against any pandemic threat or pandemic. For this objective, the GAP was supported by an independent Technical Advisory Group (TAG) to assist WHO to select vaccine manufacturing proposals for funding and to provide programmatic support for successful grantees. While there were many challenges, for both the TAG and grantees, there were also notable successes with an additional capacity of 338-600 million pandemic vaccine doses being made possible by the programme between 2007 and 2015, and a potential capacity of more than 600 million by 2016/17 with up to one billion doses expected by 2018/19. Seasonal vaccine production was also developed in 4 countries with another 4-5 countries expected to be producing seasonal vaccine by 2018/19. The relatively small WHO investments - in time and funding - made in these companies to develop their own influenza vaccine production facilities have had quite dramatic results. Copyright © 2016 Elsevier Ltd. All rights reserved.

Current status of Zika vaccine development: Zika vaccines advance into clinical evaluation.

PubMed

Barrett, Alan D T

2018-01-01

Zika virus (ZIKV), a mosquito-borne flavivirus, was first identified in the 1940s in Uganda in Africa and emerged in the Americas in Brazil in May 2015. In the 30 months since ZIKV emerged as a major public health problem, spectacular progress has been made with vaccine development cumulating with the publication of three reports of phase 1 clinical trials in the 4th quarter of 2017. Clinical trials involving candidate DNA and purified inactivated virus vaccines showed all were safe and well-tolerated in the small number of volunteers and all induced neutralizing antibodies, although these varied by vaccine candidate and dosing regimen. These results suggest that a Zika vaccine can be developed and that phase 2 clinical trials are warranted. However, it is difficult to compare the results from the different phase 1 studies or with neutralizing antibodies induced by licensed flavivirus vaccines (Japanese encephalitis, tick-borne encephalitis, and yellow fever) as neutralizing antibody assays vary and, unfortunately, there are no standards for Zika virus neutralizing antibodies. In addition to clinical studies, substantial progress continues to be made in nonclinical development, particularly in terms of the ability of candidate vaccines to protect reproductive tissues, and the potential use of monoclonal antibodies for passive prophylaxis.

Evaluation of Additive Manufacturing for Stainless Steel Components

DOE Office of Scientific and Technical Information (OSTI.GOV)

Peter, William H.; Lou, Xiaoyuan; List, III, Frederick Alyious

This collaboration between Oak Ridge National Laboratory and General Electric Company aimed to evaluate the mechanical properties, microstructure, and porosity of the additively manufactured 316L stainless steel by ORNL’s Renishaw AM250 machine for nuclear application. The program also evaluated the stress corrosion cracking and corrosion fatigue crack growth rate of the same material in high temperature water environments. Results show the properties of this material to be similar to the properties of 316L stainless steel fabricated additively with equipment from other manufacturers with slightly higher porosity. The stress corrosion crack growth rate is similar to that for wrought 316L stainlessmore » steel for an oxygenated high temperature water environment and slightly higher for a hydrogenated high temperature water environment. Optimized heat treatment of this material is expected to improve performance in high temperature water environments.« less

The history of vaccines and immunization: familiar patterns, new challenges.

PubMed

Stern, Alexandra Minna; Markel, Howard

2005-01-01

Human beings have benefited from vaccines for more than two centuries. Yet the pathway to effective vaccines has been neither neat nor direct. This paper explores the history of vaccines and immunization, beginning with Edward Jenner's creation of the world's first vaccine for smallpox in the 1790s. We then demonstrate that many of the issues salient in Jenner's era-such as the need for secure funding mechanisms, streamlined manufacturing and safety concerns, and deep-seated public fears of inoculating agents-have frequently reappeared and have often dominated vaccine policies. We suggest that historical awareness can help inform viable long-term solutions to contemporary problems with vaccine research, production, and supply.

Timing and delay in children vaccination; evaluation of expanded program of immunization in outskirt of Iranian cities.

PubMed

Rejali, Mehri; Mohammadbeigi, Abolfazl; Mokhtari, Mohsen; Zahraei, Seyed Mohsen; Eshrati, Babak

2015-01-01

Most studies evaluated the vaccine coverage, but the time of vaccination is important as coverage. This study was conducted to evaluate the Expanded Program of Immunization (EPI) in outskirt of Iranian cities regarding to incidence of delay vaccination among children less than 4 years. This cross sectional descriptive study was conducted among children 24-47 months old, living in the suburbs of five metropolises of Iran. Totally, 3610 eligible children selected with proportioned cluster sampling method and data of vaccination card extracted after interview with child parents. Delayed incidence rate reported and predictive factors assessed by Chi square test and Multivariate logistic regression. Overall, 56.6% to 93.2% vaccines were administered out of time. Delayed vaccination incidence with more than one-week delay varies from 5.5% to 74.9% for polio at birth and MMR2 at 18 month, respectively. Mother's educational level and birth order were the most important predictors of delayed vaccination. Incidence of delayed vaccination was enlarged by increasing birth order and decreased in lower educated mothers. Incidence rate of delayed vaccination is more than expectation. Regarding to high coverage vaccines in Iran, heath officers and health policy makers should attempt for on-time vaccination beside of high immunization coverage especially in slum areas with more concentrated immigrants due to low literature and crowded families.

Evaluation of the Mycobacterium tuberculosis SO2 vaccine using a natural tuberculosis infection model in goats.

PubMed

Bezos, J; Casal, C; Álvarez, J; Roy, A; Romero, B; Rodríguez-Bertos, A; Bárcena, C; Díez, A; Juste, R; Gortázar, C; Puentes, E; Aguiló, N; Martín, C; de Juan, L; Domínguez, L

2017-05-01

The development of new vaccines against animal tuberculosis (TB) is a priority for improving the control and eradication of this disease, particularly in those species not subjected to compulsory eradication programmes. In this study, the protection conferred by the Mycobacterium tuberculosis SO 2 experimental vaccine was evaluated using a natural infection model in goats. Twenty-six goats were distributed in three groups: (1) 10 goats served as a control group; (2) six goats were subcutaneously vaccinated with BCG; and (3) 10 goats were subcutaneously vaccinated with SO 2 . Four months after vaccination, all groups were merged with goats infected with Mycobacterium bovis or Mycobacterium caprae, and tested over a 40 week period using a tuberculin intradermal test and an interferon-γ assay for mycobacterial reactivity. The severity of lesions was determined at post-mortem examination and the bacterial load in tissues were evaluated by culture. The two vaccinated groups had significantly lower lesion and bacterial culture scores than the control group (P<0.05); at the end of the study, the SO 2 vaccinated goats had the lowest lesion and culture scores. These results suggest that the SO 2 vaccine provides some protection against TB infection acquired from natural exposure. Copyright © 2017 Elsevier Ltd. All rights reserved.

mRNA vaccines — a new era in vaccinology

PubMed Central

Pardi, Norbert; Hogan, Michael J.; Porter, Frederick W.; Weissman, Drew

2018-01-01

mRNA vaccines represent a promising alternative to conventional vaccine approaches because of their high potency, capacity for rapid development and potential for low-cost manufacture and safe administration. However, their application has until recently been restricted by the instability and inefficient in vivo delivery of mRNA. Recent technological advances have now largely overcome these issues, and multiple mRNA vaccine platforms against infectious diseases and several types of cancer have demonstrated encouraging results in both animal models and humans. This Review provides a detailed overview of mRNA vaccines and considers future directions and challenges in advancing this promising vaccine platform to widespread therapeutic use. PMID:29326426

Implications of the licensure of a partially efficacious malaria vaccine on evaluating second-generation vaccines.

PubMed

Fowkes, Freya J I; Simpson, Julie A; Beeson, James G

2013-10-30

Malaria is a leading cause of morbidity and mortality, with approximately 225 million clinical episodes and >1.2 million deaths annually attributed to malaria. Development of a highly efficacious malaria vaccine will offer unparalleled possibilities for disease prevention and remains a key priority for long-term malaria control and elimination. The Malaria Vaccine Technology Roadmap's goal is to 'develop and license a first-generation malaria vaccine that has protective efficacy of more than 50%'. To date, malaria vaccine candidates have only been shown to be partially efficacious (approximately 30% to 60%). However, licensure of a partially effective vaccine will create a number of challenges for the development and progression of new, potentially more efficacious, malaria vaccines in the future. In this opinion piece we discuss the methodological, logistical and ethical issues that may impact on the feasibility and implementation of superiority, non-inferiority and equivalence trials to assess second generation malaria vaccines in the advent of the licensure of a partially efficacious malaria vaccine. Selecting which new malaria vaccines go forward, and defining appropriate methodology for assessment in logistically challenging clinical trials, is crucial. It is imperative that the scientific community considers all the issues and starts planning how second-generation malaria vaccines will advance in the advent of licensure of a partially effective vaccine.

Immunisation of chickens with live Salmonella vaccines - Role of booster vaccination.

PubMed

Methner, U

2018-05-17

It is accepted that booster vaccinations of chickens with live Salmonella vaccines are essential part of vaccinations schemes to induce an effective adaptive immune response. As manufacturer of registered live Salmonella vaccines recommend different times of booster the question raises whether the duration between the first and second immunisation might influence the protective effect against Salmonella exposure. Chickens were immunised with a live Salmonella Enteritidis vaccine on day 1 of age followed by a booster vaccination at different intervals (day 28, 35 or 42 of age) to study the effects on the colonisation and invasion of the Salmonella vaccine strain, the humoral immune response and the efficacy against infection with Salmonella Enteritidis on day 56 of age. Immunisation of all groups resulted in a very effective adaptive immune response and a high degree of protection against severe Salmonella exposure, however, the time of booster had only an unverifiable influence on either the colonisation of the vaccine strain, the development of the humoral immune response or the colonisation of the Salmonella challenge strain. Therefore, the first oral immunisation of the chicks on day 1 of age seems to be of special importance and prerequisite for the development of the effective immune response. A booster immunisation should be carried out, however, the time of booster may vary between week 3 and week 7 of age of the chickens without adversely impact on the efficacy of the adaptive immune response or the protective effects. Copyright © 2018 Elsevier Ltd. All rights reserved.

Vaccines for Pandemic Influenza

PubMed Central

Luke, Catherine J.

2006-01-01

Recent outbreaks of highly pathogenic avian influenza in Asia and associated human infections have led to a heightened level of awareness and preparation for a possible influenza pandemic. Vaccination is the best option by which spread of a pandemic virus could be prevented and severity of disease reduced. Production of live attenuated and inactivated vaccine seed viruses against avian influenza viruses, which have the potential to cause pandemics, and their testing in preclinical studies and clinical trials will establish the principles and ensure manufacturing experience that will be critical in the event of the emergence of such a virus into the human population. Studies of such vaccines will also add to our understanding of the biology of avian influenza viruses and their behavior in mammalian hosts. PMID:16494720

The Meningitis Vaccine Project.

PubMed

LaForce, F Marc; Konde, Kader; Viviani, Simonetta; Préziosi, Marie-Pierre

2007-09-03

Epidemic meningococcal meningitis is an important public health problem in sub-Saharan Africa. Current control measures rely on reactive immunizations with polysaccharide (PS) vaccines that do not induce herd immunity and are of limited effectiveness in those under 2 years of age. Conversely, polysaccharide conjugate vaccines are effective in infants and have consistently shown an important effect on decreasing carriage, two characteristics that facilitate disease control. In 2001 the Meningitis Vaccine Project (MVP) was created as a partnership between PATH and the World Health Organization (WHO) with the goal of eliminating meningococcal epidemics in Africa through the development, licensure, introduction, and widespread use of conjugate meningococcal vaccines. Since group A Neisseria meningitidis (N. meningitidis) is the dominant pathogen causing epidemic meningitis in Africa MVP is developing an affordable (US$ 0.40 per dose) meningococcal A (Men A) conjugate vaccine through an innovative international partnership that saw transfer of a conjugation and fermentation technology to a developing country vaccine manufacturer. A Phase 1 study of the vaccine in India has shown that the product is safe and immunogenic. Phase 2 studies have begun in Africa, and a large demonstration study of the conjugate vaccine is envisioned for 2008-2009. After extensive consultations with African public health officials a vaccine introduction plan has been developed that includes introduction of the Men A conjugate vaccine into standard Expanded Programme on Immunization (EPI) schedules but also emphasizes mass vaccination of 1-29 years old to induce herd immunity, a strategy that has been shown to be highly effective when the meningococcal C (Men C) conjugate vaccine was introduced in several European countries. The MVP model is a clear example of the usefulness of a "push mechanism" to finance the development of a needed vaccine for the developing world.

Development of a metabolically active, non-replicating sporozoite vaccine to prevent Plasmodium falciparum malaria.

PubMed

Hoffman, Stephen L; Billingsley, Peter F; James, Eric; Richman, Adam; Loyevsky, Mark; Li, Tao; Chakravarty, Sumana; Gunasekera, Anusha; Chattopadhyay, Rana; Li, Minglin; Stafford, Richard; Ahumada, Adriana; Epstein, Judith E; Sedegah, Martha; Reyes, Sharina; Richie, Thomas L; Lyke, Kirsten E; Edelman, Robert; Laurens, Matthew B; Plowe, Christopher V; Sim, B Kim Lee

2010-01-01

Immunization of volunteers by the bite of mosquitoes carrying radiation-attenuated Plasmodium falciparum sporozoites protects greater than 90% of such volunteers against malaria, if adequate numbers of immunizing biting sessions and sporozoite-infected mosquitoes are used. Nonetheless, until recently it was considered impossible to develop, license and commercialize a live, whole parasite P. falciparum sporozoite (PfSPZ) vaccine. In 2003 Sanaria scientists reappraised the potential impact of a metabolically active, non-replicating PfSPZ vaccine, and outlined the challenges to producing such a vaccine. Six years later, significant progress has been made in overcoming these challenges. This progress has enabled the manufacture and release of multiple clinical lots of a 1(st) generation metabolically active, non-replicating PfSPZ vaccine, the Sanaria PfSPZ Vaccine, submission of a successful Investigational New Drug application to the US Food and Drug Administration, and initiation of safety, immunogenicity and protective efficacy studies in volunteers in MD, US. Efforts are now focused on how best to achieve submission of a successful Biologics License Application and introduce the vaccine to the primary target population of African children in the shortest possible period of time. This will require implementation of a systematic, efficient clinical development plan. Short term challenges include optimizing the (1) efficiency and scale up of the manufacturing process and quality control assays, (2) dosage regimen and method of administration, (3) potency of the vaccine, and (4) logistics of delivering the vaccine to those who need it most, and finalizing the methods for vaccine stabilization and attenuation. A medium term goal is to design and build a facility for manufacturing highly potent and stable vaccine for pivotal Phase 3 studies and commercial launch.

Characterization of a Cynomolgus Macaque Model of Pneumonic Plague for Evaluation of Vaccine Efficacy.

PubMed

Fellows, Patricia; Price, Jessica; Martin, Shannon; Metcalfe, Karen; Krile, Robert; Barnewall, Roy; Hart, Mary Kate; Lockman, Hank

2015-09-01

The efficacy of a recombinant plague vaccine (rF1V) was evaluated in cynomolgus macaques (CMs) to establish the relationship among vaccine doses, antibody titers, and survival following an aerosol challenge with a lethal dose of Yersinia pestis strain Colorado 92. CMs were vaccinated with a range of rF1V doses on a three-dose schedule (days 0, 56, and 121) to provide a range of survival outcomes. The humoral immune response following vaccination was evaluated with anti-rF1, anti-rV, and anti-rF1V bridge enzyme-linked immunosorbent assays (ELISAs). Animals were challenged via aerosol exposure on day 149. Vaccine doses and antibody responses were each significantly associated with the probability of CM survival (P < 0.0001). Vaccination also decreased signs of pneumonic plague in a dose-dependent manner. There were statistically significant correlations between the vaccine dose and the time to onset of fever (P < 0.0001), the time from onset of fever to death (P < 0.0001), the time to onset of elevated respiratory rate (P = 0.0003), and the time to onset of decreased activity (P = 0.0251) postinfection in animals exhibiting these clinical signs. Delays in the onset of these clinical signs of disease were associated with larger doses of rF1V. Immunization with ≥ 12 μg of rF1V resulted in 100% CM survival. Since both the vaccine dose and anti-rF1V antibody titers correlate with survival, rF1V bridge ELISA titers can be used as a correlate of protection. Copyright © 2015, American Society for Microbiology. All Rights Reserved.

Evaluation of the immunogenicity of an experimental subunit vaccine that allows differentiation between infected and vaccinated animals against bluetongue virus serotype 8 in cattle.

PubMed

Anderson, Jenna; Hägglund, Sara; Bréard, Emmanuel; Comtet, Loic; Lövgren Bengtsson, Karin; Pringle, John; Zientara, Stéphan; Valarcher, Jean Francois

2013-08-01

Bluetongue virus (BTV), the causative agent of bluetongue in ruminants, is an emerging virus in northern Europe. The 2006 outbreak of BTV serotype 8 (BTV-8) in Europe was marked by an unusual teratogenic effect and a high frequency of clinical signs in cattle. Conventional control strategies targeting small ruminants were therefore extended to include cattle. Since cattle were not routinely vaccinated before 2006, the immune responses to BTV have not been studied extensively in this species. With the aims of developing a subunit vaccine against BTV-8 for differentiation between infected and vaccinated animals based on viral protein 7 (VP7) antibody detection and of improving the current understanding of the immunogenicity of BTV proteins in cattle, the immune responses induced by recombinant VP2 (BTV-8) and nonstructural protein 1 (NS1) and NS2 (BTV-2) were studied. Cows were immunized twice (with a 3-week interval) with the experimental vaccine, a commercial inactivated vaccine, or a placebo. The two vaccines induced similar neutralizing antibody responses to BTV-8. Furthermore, the antibody responses detected against VP2, NS1, and NS2 were strongest in the animals immunized with the experimental vaccine, and for the first time, a serotype cross-reactive antibody response to NS2 was shown in cattle vaccinated with the commercial vaccine. The two vaccines evoked measurable T cell responses against NS1, thereby supporting a bovine cross-reactive T cell response. Finally, VP7 seroconversion was observed after vaccination with the commercial vaccine, as in natural infections, but not after vaccination with the experimental vaccine, indicating that the experimental vaccine may allow the differentiation of vaccinated animals from infected animals regardless of BTV serotype. The experimental vaccine will be further evaluated during a virulent challenge in a high-containment facility.

Evaluation of the Immunogenicity of an Experimental Subunit Vaccine That Allows Differentiation between Infected and Vaccinated Animals against Bluetongue Virus Serotype 8 in Cattle

PubMed Central

Hägglund, Sara; Bréard, Emmanuel; Comtet, Loic; Lövgren Bengtsson, Karin; Pringle, John; Zientara, Stéphan

2013-01-01

Bluetongue virus (BTV), the causative agent of bluetongue in ruminants, is an emerging virus in northern Europe. The 2006 outbreak of BTV serotype 8 (BTV-8) in Europe was marked by an unusual teratogenic effect and a high frequency of clinical signs in cattle. Conventional control strategies targeting small ruminants were therefore extended to include cattle. Since cattle were not routinely vaccinated before 2006, the immune responses to BTV have not been studied extensively in this species. With the aims of developing a subunit vaccine against BTV-8 for differentiation between infected and vaccinated animals based on viral protein 7 (VP7) antibody detection and of improving the current understanding of the immunogenicity of BTV proteins in cattle, the immune responses induced by recombinant VP2 (BTV-8) and nonstructural protein 1 (NS1) and NS2 (BTV-2) were studied. Cows were immunized twice (with a 3-week interval) with the experimental vaccine, a commercial inactivated vaccine, or a placebo. The two vaccines induced similar neutralizing antibody responses to BTV-8. Furthermore, the antibody responses detected against VP2, NS1, and NS2 were strongest in the animals immunized with the experimental vaccine, and for the first time, a serotype cross-reactive antibody response to NS2 was shown in cattle vaccinated with the commercial vaccine. The two vaccines evoked measurable T cell responses against NS1, thereby supporting a bovine cross-reactive T cell response. Finally, VP7 seroconversion was observed after vaccination with the commercial vaccine, as in natural infections, but not after vaccination with the experimental vaccine, indicating that the experimental vaccine may allow the differentiation of vaccinated animals from infected animals regardless of BTV serotype. The experimental vaccine will be further evaluated during a virulent challenge in a high-containment facility. PMID:23720365

The golden jubilee of vaccination against poliomyelitis.

PubMed

John, T Jacob

2004-01-01

Inactivated poliovirus vaccine (IPV), developed in the USA by Jonas Salk in the early 1950s, was field tested in 1954, and found to be safe and effective. The year 2004 marks the golden jubilee of this breakthrough. From 1955 IPV was used extensively in the US and polio incidence declined by more than 95 per cent. However, in 1962, when oral poliovirus vaccine (OPV) became available, the national policy was shifted to its exclusive use, for reasons other than science and economics. The World Health Organisation (WHO) also adopted the policy of the exclusive use of OPV in developing countries. Thus IPV fell into disrepute in much of the world, while Northern European countries continued to use it. New research led to improving its potency, reducing its manufacturing costs and combining it with the diphtheria-tetanus-pertussis (DTP) vaccine to simplify its administration and reduce programmatic costs. All countries that chose to persist with IPV eliminated poliovirus circulation without OPV-induced polio or the risk of live vaccine viruses reverting to wild-like nature. IPV is highly immunogenic, confers mucosal immunity and exerts herd protective effect, all qualities of a good vaccine. It can be used in harmony with the extendend programme on immunization (EPI) schedule of infant immunisation with DTP, thus reducing programmatic costs. During the last ten years IPV has once again regained its popularity and some 25 industrialised countries use it exclusively. The demand is increasing from other countries and the supply has not caught up, leaving market forces to dictate the sale price of IPV. Anticipating such a turn of events India had launched its own IPV manufacturing programme in 1987, but the project was closed in 1992. Today it is not clear if we can complete the job of global polio eradication without IPV, on account of the genetic instability of OPV and the consequent tendency of vaccine viruses to revert to wild-like properties. The option to use IPV is

Seasonal influenza vaccination delivery through community pharmacists in England: evaluation of the London pilot.

PubMed

Atkins, Katherine; van Hoek, Albert Jan; Watson, Conall; Baguelin, Marc; Choga, Lethiwe; Patel, Anika; Raj, Thara; Jit, Mark; Griffiths, Ulla

2016-02-16

To evaluate the effectiveness and cost of the pan-London pharmacy initiative, a programme that allows administration of seasonal influenza vaccination to eligible patients at pharmacies. We analysed 2013-2015 data on vaccination uptake in pharmacies via the Sonar reporting system, and the total vaccination uptake via 2011-2015 ImmForm general practitioner (GP) reporting system data. We conducted an online survey of London pharmacists who participate in the programme to assess time use data, vaccine choice, investment costs and opinions about the programme. We conducted an online survey of London GPs to assess vaccine choice of vaccine and opinions about the pharmacy vaccine delivery programme. All London boroughs. London-based GPs, and pharmacies that currently offer seasonal flu vaccination. Not applicable. Comparison of annual vaccine uptake in London across risk groups from years before pharmacy vaccination introduction to after pharmacy vaccination introduction. Completeness of vaccine uptake reporting data. Cost to the National Health Service (NHS) of flu vaccine delivery at pharmacies with that at GPs. Cost to pharmacists of flu delivery. Opinions of pharmacists and GPs regarding the flu vaccine pharmacy initiative. No significant change in the uptake of seasonal vaccination in any of the risk groups as a result of the pharmacy initiative. While on average a pharmacy-administered flu vaccine dose costs the NHS up to £2.35 less than a dose administered at a GP, a comparison of the 2 recording systems suggests there is substantial loss of data. Flu vaccine delivery through pharmacies shows potential for improving convenience for vaccine recipients. However, there is no evidence that vaccination uptake increases and the use of 2 separate recording systems leads to time-consuming data entry and missing vaccine record data. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/

Can dendritic cells improve whole cancer cell vaccines based on immunogenically killed cancer cells?

PubMed Central

Cicchelero, Laetitia; Denies, Sofie; Devriendt, Bert; de Rooster, Hilde; Sanders, Niek N

2015-01-01

Immunogenic cell death (ICD) offers interesting opportunities in cancer cell (CC) vaccine manufacture, as it increases the immunogenicity of the dead CC. Furthermore, fusion of CCs with dendritic cells (DCs) is considered a superior method for generating whole CC vaccines. Therefore, in this work, we determined in naive mice whether immunogenically killed CCs per se (CC vaccine) elicit an antitumoral immune response different from the response observed when immunogenically killed CCs are associated with DCs through fusion (fusion vaccine) or through co-incubation (co-incubation vaccine). After tumor inoculation, the type of immune response in the prophylactically vaccinated mice differed between the groups. In more detail, fusion vaccines elicited a humoral anticancer response, whereas the co-incubation and CC vaccine mainly induced a cellular response. Despite these differences, all three approaches offered a prophylactic protection against tumor development in the murine mammary carcinoma model. In summary, it can be concluded that whole CC vaccines based on immunogenically killed CCs may not necessarily require association with DCs to elicit a protective anticancer immune response. If this finding can be endorsed in other cancer models, the manufacture of CC vaccines would greatly benefit from this new insight, as production of DC-based vaccines is laborious, time-consuming and expensive. PMID:26587315

Implications for registry-based vaccine effectiveness studies from an evaluation of an immunization registry: a cross-sectional study.

PubMed

Mahon, Barbara E; Shea, Kimberly M; Dougherty, Nancy N; Loughlin, Anita M

2008-05-14

Population-based electronic immunization registries create the possibility of using registry data to conduct vaccine effectiveness studies which could have methodological advantages over traditional observational studies. For study validity, the base population would have to be clearly defined and the immunization status of members of the population accurately recorded in the registry. We evaluated a city-wide immunization registry, focusing on its potential as a tool to study pertussis vaccine effectiveness, especially in adolescents. We conducted two evaluations - one in sites that were active registry participants and one in sites that had implemented an electronic medical record with plans for future direct data transfer to the registry - of the ability to match patients' medical records to registry records and the accuracy of immunization records in the registry. For each site, records from current pediatric patients were chosen randomly. Data regarding pertussis-related immunizations, clinic usage, and demographic and identifying information were recorded; for 11-17-year-old subjects, information on MMR, hepatitis B, and varicella immunizations was also collected. Records were then matched, when possible, to registry records. For records with a registry match, immunization data were compared. Among 350 subjects from sites that were current registry users, 307 (87.7%) matched a registry record. Discrepancies in pertussis-related data were common for up-to-date status (22.6%), number of immunizations (34.7%), dates (10.2%), and formulation (34.4%). Among 442 subjects from sites that planned direct electronic transfer of immunization data to the registry, 393 (88.9%) would have matched a registry record; discrepancies occurred frequently in number of immunizations (11.9%), formulation (29.1%), manufacturer (94.4%), and lot number (95.1%.) Inability to match and immunization discrepancies were both more common in subjects who were older at their first visit to

Implications of the licensure of a partially efficacious malaria vaccine on evaluating second-generation vaccines

PubMed Central

2013-01-01

Background Malaria is a leading cause of morbidity and mortality, with approximately 225 million clinical episodes and >1.2 million deaths annually attributed to malaria. Development of a highly efficacious malaria vaccine will offer unparalleled possibilities for disease prevention and remains a key priority for long-term malaria control and elimination. Discussion The Malaria Vaccine Technology Roadmap’s goal is to 'develop and license a first-generation malaria vaccine that has protective efficacy of more than 50%’. To date, malaria vaccine candidates have only been shown to be partially efficacious (approximately 30% to 60%). However, licensure of a partially effective vaccine will create a number of challenges for the development and progression of new, potentially more efficacious, malaria vaccines in the future. In this opinion piece we discuss the methodological, logistical and ethical issues that may impact on the feasibility and implementation of superiority, non-inferiority and equivalence trials to assess second generation malaria vaccines in the advent of the licensure of a partially efficacious malaria vaccine. Conclusions Selecting which new malaria vaccines go forward, and defining appropriate methodology for assessment in logistically challenging clinical trials, is crucial. It is imperative that the scientific community considers all the issues and starts planning how second-generation malaria vaccines will advance in the advent of licensure of a partially effective vaccine. PMID:24228861

Field evaluation of a canine parvovirus vaccination program, using feline origin modified live virus vaccine.

PubMed

Gordon, J C; Rogers, W A

1982-06-15

Antibody titers measured by hemagglutination inhibition testing were determined in previously vaccinated dogs at the time of booster vaccination and 2 weeks later. All vaccines consisted of modified live panleukopenia virus. The booster injection was administered approximately 6 months after the initial parvovirus vaccination series was given. Fecal and serum specimens were collected immediately before and 2 weeks after administration of the booster vaccine for hemagglutination and hemagglutination inhibition testing, respectively. All dogs were privately owned and were from the Columbus, Ohio, area but were from environments with various exposure potentials to canine parvovirus. Results of hemagglutination (HA) testing on feces were negative in all dogs before and after booster vaccination. Therefore, these vaccinations did not interfere with interpretation of HA testing of feces. Results of serum hemagglutination inhibition (HI) testing indicated that 50% of the dogs had serum titers less than 1:80 prior to vaccination and that, of these dogs, 65.2% still had serum titers less than 1:80 2 weeks after the booster vaccination. Only 10.9% of all dogs had a marked increase in serum HI titer after the booster vaccination, indicating that overall serologic response to vaccination was poor. High HI titers (greater than or equal to 1:640) were associated with exposure to other dogs and cats in the neighborhood or to dogs suspected of having had parvovirus infection.