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This article presented the World Health Organization’s (WHO) recommendations on the use of Rabies vaccines excerpted from the Rabies vaccines: WHO position paper – April 2018 published in the Weekly Epidemiological Record [1] This position paper replaces the 2010 WHO position paper on rabies vaccines [2] . It presents new evidence in the field of rabies and the use of rabies vaccines, focussing on programmatic feasibility, simplification of vaccination schedules and improved cost-effectiveness. The recommendations concern the 2 main immunization strategies, namely vaccination for post-exposure prophylaxis and vaccination for pre-exposure prophylaxis. In the context of post-exposure prophylaxis, recommendations are also provided on the use of rabies immunoglobulins. Footnotes to this paper provide a number of core references including references to grading tables that assess the quality of the scientific evidence, and to the evidence-to-recommendation tables. In accordance with its mandate to provide guidance to Member States on health policy matters, WHO issues a series of regularly updated position papers on vaccines and combinations of vaccines against diseases that have an international public health impact. These papers are concerned primarily with the use of vaccines in large-scale immunization programmes; they summarize essential background information on diseases and vaccines, and conclude with WHO’s current position on the use of vaccines in the global context. Recommendations on the use of cholera vaccines were discussed by the Strategic Advisory Group of Experts (SAGE) in October 2017; evidence presented at these meetings can be accessed at: http://www.who.int/immunization/sage/meetings/2017/october/presentations_background_docs/en/ . [ABSTRACT FROM AUTHOR]

This article presents the World Health Organization's (WHO) recommendations for pain mitigation at the time of vaccination from the WHO position paper on reducing pain at the time of vaccination: WHO position paper—September 2015, recently published in the Weekly Epidemiological Record [1] . This position paper summarizes the evidence and integrates information pertaining to the reduction of pain, distress and fear during immunization across all age groups. In accordance with its mandate to provide guidance to Member States on health policy matters, WHO issues a series of regularly updated position papers on vaccines and combinations of vaccines against diseases that have an international public health impact, and on vaccination-related policy questions particularly concerning the use of vaccines in large-scale immunization programmes. They summarize essential background information and conclude with the current WHO position. This position paper addresses a cross-cutting issue which is relevant for all injectable vaccines and reflects the recommendations of WHO's Strategic Advisory Group of Experts (SAGE) on immunization. These recommendations were discussed by SAGE at its April 2015 meeting. The evidence presented at the meetings can be accessed at http://www.who.int/immunization/sage/previous/en/index.html . [ABSTRACT FROM AUTHOR]

A high level of concern is placed on the storage, handling, transportation, and distribution of vaccines and other pharmaceutical products, particularly those that are time and temperature sensitive. While active and passive cooling equipment and monitoring devices are important, it is the various personnel responsible for executing and writing procedures, designing and operating systems, and investigating problems and helping prevent them who are paramount in establishing and maintaining a “cold chain” for time and temperature sensitive pharmaceutical products (TTSPPs). These professionals must possess the required competencies, knowledge, skills and abilities so they can effectively perform these activities with appropriate levels of expertise. These are complex tasks that require the development of higher cognitive skills that cannot be adequately addressed through professional development opportunities based on simple information delivery and content acquisition. This paper describes two unique learning solutions (one on a bus called the “wheels course” and the other online called “e-learning”) that have been developed by WHO Global Learning Opportunities (WHO/GLO) to provide participants with opportunities not just to learn about cold chain systems or vaccine management, but, rather, to develop high levels of expertise in their respective fields through experiential and authentic learning activities. In these interactive learning environments, participants have opportunities to address real-life situations in contexts similar to what they may face in their own work environments and develop solutions and critical thinking skills they can apply when they return to their jobs. This paper further delineates the managerial and operational vaccine management functions encompassed in these two unique learning environments. The paper also describes the alignment of the objectives addressed in the “wheels course” and the e-learning version with effective vaccine management (EVM) criteria as prescribed by WHO. The paper concludes with an example of a real world product developed by course graduates (specifically a decision tree that is now used by some national programmes). These types of products, valuable in their own right, often emerge when learning environments based on authentic learning principles are designed and implemented as they were by WHO/GLO. [ABSTRACT FROM AUTHOR]

Background Dengue fever is one of the most rapidly advancing viral vector-borne diseases worldwide and vaccine candidates are in the final stages of clinical trials, representing a decisive opportunity to control the disease. To decide whether and where to support the introduction of new vaccines it is crucial to assess costs imposed by the disease and cost-effectiveness of vaccine programmes. Objective To identify economic evidence about dengue fever immunization, by systematic review, to assist future policy decisions and investment. Methods The electronic search stage was conducted on PubMed/Medline, Embase, Web of Science, Global Health, NHS Economic Evaluation Database (NHS EED) and Latin American and Caribbean Health Sciences Literature (LILACS) databases. Searches were restricted to papers published between January 1970 and February 2016. Selected papers were quality assessed using three recognized checklists. Results Eleven relevant studies were identified and there is economic evidence of a satisfactory quality level, derived through modelling approaches, to conclude that dengue fever vaccines will be economically advantageous when compared to vector preventive strategies, despite uncertainties surrounding vaccine efficacy and costs per vaccine dose. Quality assessment based on checklists showed similar findings and although overall quality was considered satisfactory, there were relevant methodological issues not considered among studies reviewed. Conclusion Several uncertainties still remain about effectiveness of dengue fever vaccines; however, the reviewed economic evidence suggests that, when available, the vaccine can be economically advantageous at moderate prices. Future research needs to confirm findings from the economic models by using actual costs and effectiveness data. [ABSTRACT FROM AUTHOR]

Adolescents and young adults are at a high risk of developing human papillomavirus (HPV) infections, which can be prevented with the use of vaccines. Moreover, a combined immunization strategy for administration of HPV vaccines with other routine vaccines may lead to better compliance. We aim to comprehensively evaluate immunogenicity and safety in the case of concomitantly administered HPV vaccine in individuals aged 9–25 years. Relevant studies, published up to December 27, 2018, were identified through searches of Medline/PubMed, EMBASE, Web of Knowledge. The pooled relative risk (RR) of immunogenicity and safety information pertaining to the concomitant administration of HPV vaccines with other routine vaccines in healthy participants aged 9–25 years were evaluated. A total of 13 papers (11,657 participants) were included in this meta -analysis. The analyses showed that, between the concomitant and nonconcomitant administration groups, the seroconversion rate for the specific antibodies against all HPV types (type 16-, 18-, 6-, 11-, 31-, 33-, 45-, 52-, and 58) were the same (the pooled RR = 1.00, 95% confidence interval (CI) of 1.00–1.00); for the bivalent HPV (2vHPV) vaccine, the risks of local adverse events showed no significant difference (the pooled RR = 1.00, 95%CI: 0.97–1.04), and the risks of systemic adverse events were almost similar (the pooled RR = 1.10, 95% CI: 1.03–1.18); for the non-bivalent HPV (4vHPV and 9vHPV) vaccines, the risks of local adverse events were slightly higher in the concomitant administration groups (the pooled RR = 1.31, 95%CI: 1.17–1.47), and the risks of systemic adverse events were higher in the concomitant administration groups (the pooled RR = 2.09, 95% CI: 1.69–2.59). We believe that the concomitant administration of other vaccines along with HPV vaccine is acceptable and there is no interference with the immune response to HPV vaccine. Concomitant vaccine administration has the potential to minimize the number of vaccination visits, leading to increased compliance, hence more effective disease prevention. [ABSTRACT FROM AUTHOR]

The development of human rabies vaccines has evolved dramatically from the first crude nerve tissue vaccine produced then administered in the presence of Louis Pasteur in 1885. New cell culture technology has enabled highly potent and well-tolerated rabies vaccines to be produced that have reduced the volume and number of doses required to save human lives after exposure. However, these highly potent vaccines are still unaffordable to many patients living at risk of exposure on a daily basis. The cost of post-exposure prophylaxis (PEP) is not only related to the direct cost of rabies biologicals and equipment but is also associated with indirect costs that patients incur as a result of travel, loss of work time (income loss), and accommodation over the period of time that a PEP regimen requires to be completed. This paper summarizes the particular criteria that the SAGE Working Group and WHO personnel reviewed as part of the evaluation process for recommending the new one-week intradermal vaccination regimen (2-2-2-0-0) for rabies post-exposure prophylaxis. These criteria included: Cost-effectiveness; evaluation of number of doses; seroconversion after vaccination; efficacy; safety; and patient follow-up. [ABSTRACT FROM AUTHOR]

Butantan Institute is a public Brazilian biomedical research-manufacturer center affiliated to the São Paulo State Secretary of Health. Currently, Butantan is one of the main public producers of vaccines, antivenoms, and antitoxins in Latin America. The partnership between Butantan and the National Institutes of Health (NIH) of the United Sates has been one of the longest and most successful partnerships in the development and manufacturing of new vaccines. Recently, Butantan Institute has developed and manufactured a lyophilized tetravalent live attenuated dengue vaccine with the four dengue viruses attenuated and licensed from the Laboratory of Infectious Diseases at The National Institutes of Allergy and Infectious Diseases (LID/NIAID/NIH). The objective of this paper is to describe the clinical evaluation strategies of a live attenuated tetravalent dengue vaccine (Butantan-DV) developed and manufactured by Butantan Institute. These clinical strategies will be used to evaluate the Butantan-DV Phase III trial to support the Butantan-DV licensure for protection against any symptomatic dengue caused by any serotype in people aged 2 to 59 years. [ABSTRACT FROM AUTHOR]

Papua New Guinea's difficult and varied topography, poor transport infrastructure, changing dynamics of population and economy in recent times and understaffed and poorly financed health service present major challenges for successful delivery of vaccination and other preventative health interventions to both the rural majority and urban populations, thereby posing risks for vaccine preventable disease outbreaks in the country. The country has struggled to meet the vaccination coverage targets required for the eradication of poliomyelitis and elimination of measles. Escalation of inter and intra country migration resulting from major industrial developments, particularly in extraction industries, has substantially increased the risk of infectious disease importation. This case study documents the evolution of immunisation programmes since the introduction of supplementary immunisation activities (SIAs). Single antigen SIAs have advantages and disadvantages. In situations in which the delivery of preventative health interventions is difficult, it is likely that the cost benefit is greater for multiple than for single intervention. The lessons learned from the conduct of single antigen SIAs can be effectively used for programmes delivering multiple SIA antigens, routine immunisations, and other health interventions. This paper describes a successful and cost effective multiple intervention programme in Papua New Guinea. The review of the last SIA in Papua New Guinea showed relatively high coverage of all the interventions and demonstrated the operational feasibility of delivering multiple interventions in resource constrained settings. Studies in other developing countries such as Lesotho and Ethiopia have also successfully integrated health interventions with SIA. In settings such as Papua New Guinea there is a strong case for integrating supplementary immunisation activity with routine immunisation and other health interventions through a comprehensive outreach programme. [ABSTRACT FROM AUTHOR]

Abstract: The U.S. has experienced many major interruptions of its pediatric vaccine production in the past decade. The Centers for Disease Control and Prevention (CDC) copes with these shortages by building a national stockpile of pediatric vaccines, which it makes accessible to the public in the event of a shortage. The management of this stockpile is difficult due to limited production capacity and long and unpredictable production interruptions. In this paper, we address policies for managing the stockpile. We provide sufficient conditions for the optimal policy to be a modified state-dependent base-stock policy, with the base-stock level decreasing in the pipeline inventory. Since the optimal policy is in general difficult to evaluate, we derive bounds on the optimal decision in each period. We develop an efficient policy that performs on average within 1% of optimality in simulations. We show that stocking the same supply of vaccine of every type can be over-conservative in some cases, and inadequate in others by large factors. We also quantify the substantial reduction in inventory level that can be achieved when there are multiple suppliers in the market. [Copyright &y& Elsevier]

Abstract: As Europe''s population ages, disease morbidity and treatment costs in the adult population are likely to rise substantially, making this a pertinent time to review and revise preventive strategies such as vaccination. Vaccine uptake remains a problem for adults and there is a lack of coordinated programmes for vaccination of adults. Countries in Western Europe have begun to identify the need to increase adult vaccination, but the situation in Central European countries remains poorly identified and inadequately described. This paper summarises the evidence to support the development of an adult vaccination calendar in the Central European Vaccination Awareness Group (CEVAG) member countries (Bulgaria, Croatia, the Czech Republic, Estonia, Hungary, Latvia, Lithuania, Romania, Slovakia, Slovenia and Turkey). CEVAG recommends the introduction of an adult vaccination calendar, which should include vaccination against diseases that represent a large burden in adults in terms of mortality and morbidity. This calendar could be modified to meet the priorities of individual countries. [Copyright &y& Elsevier]

Abstract: Efficacy studies of investigational HIV vaccines require enrollment of individuals at ‘high risk’ for HIV. This paper examines participation in HIV vaccine trials among women at ‘high risk’ for HIV acquisition. In-depth interviews were conducted with 17 African-American women who use crack cocaine and/or exchange sex for money/drugs to elicit attitudes toward medical research and motivators and deterrents to HIV vaccine trial participation. Interviews were digitally recorded and transcribed; data were coded and compiled into themes. Most women expressed favorable attitudes toward medical research in general. Motivators for trial participation included compensation; personal benefits including information, social services, and the possibility that the trial vaccine could prevent HIV; and altruism. Deterrents included: dislike of needles; distrust; concern about future consequences of participating. In addition, contingencies, care-giving responsibilities, and convenience issues constituted barriers which could impede participation. Respondents described varied, complex perspectives, and individual cases illustrate how these themes played out as women contemplated trial participation. Understanding factors which influence vaccine research participation among women at ‘high risk’ can aid sites to tailor recruitment procedures to local contexts. Concerns about future reactions can be addressed through sustained community education. Convenience barriers can be ameliorated by providing rides to study visits when necessary, and/or conducting study visits in accessible neighborhood locations. Women in this sample thought carefully about enrolling in HIV vaccine trials given the structural constraints within which they lived. Further research is needed regarding structural factors which influence personal agency and individuals’ thinking about research participation. [Copyright &y& Elsevier]

Abstract: Mass vaccination campaigns during which new vaccines may be administered to many millions of people in a short period of time call for timely and accurate post-licensure surveillance to monitor vaccine safety. To address the need for timely H1N1 influenza vaccine safety information during the 2009–2010 H1N1 influenza pandemic, the Vaccine Safety Datalink (VSD) project assessed the feasibility and potential mechanisms for utilizing data from state and local immunization registries to capture vaccinations that would not otherwise be captured by the data systems of the participating VSD managed care organizations (MCOs). Three of the eight VSD sites were able to capture H1N1 immunization data electronically from the state and local registries, and one site was able to capture the immunizations through a paper-based system; however, the remaining four sites encountered various obstacles that prevented capture of such data. Additional work will be required at these sites to overcome the barriers, which included privacy and confidentiality laws, time constraints brought on by the pandemic, as well as data quality concerns. [Copyright &y& Elsevier]

Abstract: Western equine encephalitis virus (WEEV) is a mosquito-borne RNA virus which causes lethal infection in humans and equines. There are no commercial vaccines or anti-WEEV drugs available for humans. We used replication-defective, human adenovirus serotype-5 (HAd5) as a delivery vector for developing WEEV vaccine. Our previous study found delivery of both E1 and E2 envelope proteins of WEEV by HAd5 vector offers complete protection against lethal challenge of WEEV. In this paper, we constructed a HAd5-vectored E1 vaccine, Ad5-E1. Mice given single-dose vaccination of Ad5-E1 were completely protected against both homologous and heterologous WEEV strains. The protection was rapid, which was achieved as early as day 7 after vaccination. In addition, Ad5-E1 induced a strong WEEV-specific T cell response. Our data suggest E1 is a potential target for developing single-dose, fast-acting, HAd5-vectored vaccine for WEEV. [ABSTRACT FROM AUTHOR]

Abstract: Eradication of a disease promises significant health and financial benefits. Preserving those benefits, hopefully in perpetuity, requires preparing for the possibility that the causal agent could re-emerge (unintentionally or intentionally). In the case of a vaccine-preventable disease, creation and planning for the use of a vaccine stockpile becomes a primary concern. Doing so requires consideration of the dynamics at different levels, including the stockpile supply chain and transmission of the causal agent. This paper develops a mathematical framework for determining the optimal management of a vaccine stockpile over time. We apply the framework to the polio vaccine stockpile for the post-eradication era and present examples of solutions to one possible framing of the optimization problem. We use the framework to discuss issues relevant to the development and use of the polio vaccine stockpile, including capacity constraints, production and filling delays, risks associated with the stockpile, dynamics and uncertainty of vaccine needs, issues of funding, location, and serotype dependent behavior, and the implications of likely changes over time that might occur. This framework serves as a helpful context for discussions and analyses related to the process of designing and maintaining a stockpile for an eradicated disease. [Copyright &y& Elsevier]

Abstract: Hepatitis B is a serious public health problem. Worldwide three different levels of hepatitis B endemicity (high, intermediate and low) can be distinguished. Areas with different levels of endemicity require tailored vaccination strategies to fit the needs for individuals at risk and/or countries, depending on the infection risk per age group, vaccination rate, duration of protection after vaccination, cost effectiveness of vaccination strategies and ease of implementation in the national immunization schedules.This opinion paper evaluates these factors and proposes a combination of infant risk group and universal adolescent vaccination for low endemic countries thus targeting the different groups at risk. A universal infant vaccination schedule starting with a newborn vaccination within 24h after birth is more appropriate in intermediate- and high-endemic regions. [Copyright &y& Elsevier]

Abstract: Conjugate vaccines exist that offer protection against disease caused by Haemophilus influenzae type b (Hib), and selected serogroups/serotypes of Neisseria meningitidis and Streptococcus pneumoniae. These vaccines are not only able to prevent serious disease, but they also provide protection against asymptomatic carriage. The resulting herd immunity effects have been striking, and have played an important role in the public health success of conjugate vaccination programmes. The aim of this paper is to review the state of the current evidence on conjugate vaccines and to identify important areas for further study, in order to inform the debate regarding the best use of these vaccines. [Copyright &y& Elsevier]

Summary: The paper explores the low uptake of livestock vaccination among poor farming communities in Bolivia utilising core elements of the original innovation diffusion theory. Contrary to the recent literature, we found that vaccination behaviour was strongly linked to social and cultural, rather than economic, drivers. While membership in a group increased uptake, the ‘hot’ and ‘cold’ distinctions which dictate health versus illness within Andean cosmology also played a role, with vaccination viewed as a means of addressing underlying imbalances. We concluded that uptake of livestock vaccination was unlikely to improve without knowledge transfer that acknowledges local epistemologies for livestock disease. [Copyright &y& Elsevier]

Summary: Previous work in pigs, has demonstrated that full protection against foot-and-mouth disease (FMD) can be achieved following vaccination with chimeric foot-and-mouth disease virus (FMDV) vaccines, in which the VP1 G–H loop had been substituted with that from another serotype. If proven to be effective in other economically important species such as cattle, such vaccine constructs could be trialed as potential marker vaccines. Here, we determine if G–H loop chimera FMDV vaccines can: (i) protect cattle from virus challenge and (ii) induce an antibody response that would enable the identification of infection, regardless of vaccination status. Inactivated, oil adjuvanated, chimeric vaccine constructs, based on the backbone sequence of the A12119 serotype virus, fully protected cattle from challenge 21 days post-vaccination. Differentiation assays developed for use in this study were able to identify sub-clinical infection, which in one vaccinated animal, persisted beyond day 32 post-challenge. This paper emphasises the importance of epitopes outside of the VP1 G–H loop for protective immunity in cattle, and demonstrates that chimeric FMDV vaccines could prove to be useful marker vaccines for the future. [Copyright &y& Elsevier]

Summary: Vaccinia virus (VACV) has been used as the vaccine to protect against smallpox, and recombinant VACVs have been used to develop vaccine candidates against numerous cancers and infectious diseases. Although relatively safe for use in humans, the strains of VACV that were used as smallpox vaccines led to several complications including, progressive infection in immune compromised individuals, eczema vaccinatum in individuals with a history of atopic dermatitis, and encephalitis and perimyocarditis in apparently healthy individuals. The work described in this paper focuses on attenuated strains of VACV that may have the potential for use as vaccine vectors with reduced pathogenicity. We have generated several VACV mutants in a WR background with specific mutations in the E3L gene that were at least a 1000-fold less pathogenic compared to wtVACV upon intra-nasal infection of mice. Many of these mutant viruses replicated to high titers in the nasal mucosa of mice following intra-nasal administration. Despite replication to high titers in the nose, there was little spread to other organs in infected animals. Intra-nasal vaccination with doses as low as 100–1000pfu (plaque forming units) of these replicating VACV constructs were sufficient to protect the host from challenge with large doses of wtVACV. Similar constructs in a Copenhagen and a NYCBH background were highly attenuated, yet effective as vaccines in the mouse model. These recombinant VACV constructs may be promising vector candidates for use in vaccination strategies against smallpox and other pathogens. [Copyright &y& Elsevier]

Abstract: Despite the demonstration of effectiveness and public health impact of Hib conjugate vaccines, the majority of infants from poorest countries do not yet have access to this safe and effective preventive intervention. This paper provides a descriptive analysis of the main characteristics of countries that have included Hib vaccine in their national immunization programmes before 2006. It highlights the importance of regularly analyzing the process of decision-making involved in implementation of public health interventions, in order to learn from cumulative experience and expedite the introduction of future interventions. [Copyright &y& Elsevier]

Abstract: This paper evaluates the incremental health and programmatic cost impacts of new vaccine products, as compared to the standard vaccine products in multi-dose vials in Cambodia, Ghana, and Bangladesh. The authors use a cost-effectiveness model to estimate the impacts of introducing four thermostable vaccines with single-dose presentations: measles, yellow fever, bacille Calmette-Guérin, and diphtheria–tetanus–pertussis–hepatitis B. The effectiveness of all of the vaccines increases with the thermostable formats. The incremental costs associated with the introduction of thermostable vaccines increases for three out of four vaccines. Single-dose presentations of thermostable vaccines are potentially cost-effective interventions to reduce childhood deaths and disability in low-resource settings in Asia and Africa. [Copyright &y& Elsevier]

Abstract: Physicochemical and immunochemical techniques can be used to assess the quality of diphtheria toxoid vaccines. In a previous paper [Metz B, Jiskoot W, Hennink WE, Crommelin DJA, Kersten GFA. Physicochemical and immunochemical techniques predict the quality of diphtheria toxoid vaccines. Vaccine 2003;22(2):156–67], techniques were introduced which indicated toxoid quality with respect to safety and potency: SDS-PAGE, primary amino group determination, fluorescence/denaturation, circular dichroism and biosensor analyses. These analyses were performed with experimental toxoids from one toxin batch. In the present study, the quality of regular vaccine batches of different manufacturers, the properties of real-time aged products and a number of experimental toxoids were investigated, using the above-mentioned analytical techniques. We had the unique opportunity to analyse toxoids that were up to 40 years old. The real-time aged diphtheria toxoids showed hardly any structural differences as compared to the recently prepared products in both the analytical chemical techniques and the conventional potency and safety tests. The analytical assays discriminated between regular diphtheria toxoids and experimental toxoids prepared by methylation, acetylation or glutaraldehyde treatment. The analytical data showed a clear correlation with potency and safety of these toxoids. Based on the results, we refined the described physicochemical and immunochemical criteria that a standard diphtheria toxoid has to meet. We recommend further validation of these techniques for quality control of diphtheria toxoid vaccine because of their high precision and easy performance as compared to conventional in vivo procedures. [Copyright &y& Elsevier]

Abstract: Failure to remove cattle diseased with Mycobacterium bovis has immense financial implications for disease control, animal health and agricultural trade as well as the zoonotic risk to human health. Current disease control strategies based on DTH skin testing fail to detect all diseased cattle and additional measures are urgently needed to improve detection of disease and to prevent naïve animals becoming exposed to infection. Experimental models of bovine TB traditionally based on intra-nasal instillation, intra-tracheal inoculation or placed in-contact with infected cattle, have been further developed using aerosolised bacteria delivered to the respiratory tract, allowing field-like bovine TB to be recreated under controlled, experimental conditions. Experimental infection models have already been used to improve diagnostic tests. Specificity of DTH skin testing can be improved under experimental conditions, using recombinant ESAT-6, while laboratory assays such as IFN-γ release have benefited from the use of defined proteins to improve assay specificity. In combination, antigen cocktails may also improve test sensitivity. There is a concerted international effort to evaluate vaccines for use in cattle populations and to define vaccination strategies which will eliminate disease from infected herds. DNA, protein and genetically modified vaccines inoculated in a single dose, given as prime-boost or injected concurrently, will elicit significant protection against challenge with M. bovis under controlled conditions. However, vaccines and vaccination strategies require evaluation under field conditions. Furthermore, complementary strategies are under development to differentiate immune responses that follow vaccination from those following disease. This paper describes those recent advances which may lead to the introduction of improved disease control strategies. [Copyright &y& Elsevier]

Abstract: Western equine encephalitis virus (WEEV) is an important pathogen for both humans and equines. The virus is also listed as a bioterrorism agent due to its ability for aerosol transmission with high mortality. No commercial vaccines or antiviral drugs are available for the prevention and treatment of WEEV infection in humans. In this paper, we constructed a recombinant WEEV vaccine, designated as Ad5-WEEV, using a replication defective, human adenovirus serotype 5 (HAd5) as a delivery vector. Ad5-WEEV contains the E3-E2-6K-E1 structural protein gene of the 71V-1658 strain of WEEV and the E1 and E2 proteins were synthesized in cells inoculated with Ad5-WEEV. After intramuscular immunization of mice with two doses of Ad5-WEEV, neutralizing antibodies against WEEV were generated and the mice were completely protected from a lethal dose challenge of 71V-1658. In addition, we showed that passive transfer of serum from the Ad5-WEEV-immunized mice could partially control WEEV infection. These results demonstrate that HAd5 vectors are promising for WEEV vaccine development. [Copyright &y& Elsevier]

Abstract: Oral tolerance has been applied successfully as a potential therapeutic strategy for preventing and treating autoimmune diseases including type 1 diabetes. In this paper we constructed an edible vaccine consisting of a fusion protein composed of cholera toxin B subunit (CTB) and insulin B chain (InsB) that was produced in silkworm larvae. The silkworm larvae produced this fusion protein at levels of up to 0.97mg/ml of hemolymph as the pentameric CTB–InsB form, which retained the GM1-ganglioside binding affinity and the native antigenicity of CTB. Non-obese diabetic mice fed hemolymph containing microgram quantities of the CTB–InsB fusion protein showed a prominent reduction in pancreatic islet inflammation and a delay in the development of diabetic symptoms. This study demonstrates that silkworm-produced CTB–InsB fusion protein can be used as an ideal oral protein vaccine for induction of immunological tolerance against autoimmune diabetes. [Copyright &y& Elsevier]

Abstract: Twice a year, the World Health Organization recommends the composition of the influenza vaccine depending on the strains which circulate several months before the beginning of the epidemic. Therefore, it is important to assess the field vaccine effectiveness (FVE) yearly. Thanks to data on vaccine coverage and data on influenza like illness cases collected by the French Sentinel Network, we are able to estimate the FVE few weeks after the beginning of the yearly influenza epidemic. In this paper, we have analysed the estimates obtained for the last 10 epidemic seasons for people over and under 65. Making the assumption that the vaccine coverage is stable from 1 year to another, we are able to assess the level of the FVE few weeks after the beginning of the epidemic and we should detect a lack of effectiveness of the vaccine. [Copyright &y& Elsevier]

Abstract: This paper reviews the current status of research and development of vaccines against meningococcal disease due to Neisseria meningitidis, a major cause of severe meningitis and septicemia with epidemic potential. While five serogroups (A, B, C, Y, and W135) are responsible for most of the disease, Group A remains unique in its ability to cause large scale epidemics mainly in Africa but also in Asia. The majority of cases in Europe and America are due to Groups B and C. The successful experience with Hib and pneumococcal conjugate vaccines has paved the way for the development of polysaccharide conjugate vaccines for the prevention of meningococcal disease. Widespread vaccination with Group C conjugate vaccines now in use in several European countries indicates that these vaccines are immunogenic, induce immunological memory, reduce colonization and provide herd immunity to the general population. A monovalent group A conjugate vaccine being developed at an affordable price, offers hope for the elimination of large epidemics in African countries. Multivalent (A, C, Y, W) conjugate vaccines are being developed, and one has already been licensed. However, effective global prevention of meningococcal disease will not be achievable without the development of a vaccine against Group B meningitis, for which outer membrane protein vaccines are under development. [Copyright &y& Elsevier]

Abstract: A challenge in epidermal DNA vaccination is the efficient and targeted delivery of polynucleotides to immunologically sensitive Langerhans cells. This paper investigates this particular challenge for physical delivery approaches. The skin immunology and material properties are examined in the context of the physical cell targeting requirements of the viable epidermis. Selected current physical cell targeting technologies engineered to meet these needs are examined: needle and syringe; diffusion patches; liquid jet injectors; microneedle arrays/patches; and biolistic particle injection. The operating methods and relative performance of these approaches are discussed, with a comment on potential future developments and technologies. [Copyright &y& Elsevier]

Abstract: The use of gene guns in ballistically delivering DNA vaccine coated gold micro-particles to skin can potentially damage targeted cells, therefore influencing transfection efficiencies. In this paper, we assess cell death in the viable epidermis by non-invasive near infrared two-photon microscopy following micro-particle bombardment of murine skin. We show that the ballistic delivery of micro-particles to the viable epidermis can result in localised cell death. Furthermore, experimental results show the degree of cell death is dependant on the number of micro-particles delivered per unit of tissue surface area. Micro-particles densities of 0.16±0.27 (mean±S.D.), 1.35±0.285 and 2.72±0.47 per 1000μm2 resulted in percent deaths of 3.96±5.22, 45.91±10.89, 90.52±12.28, respectively. These results suggest that optimization of transfection by genes administered with gene guns is − among other effects − a compromise of micro-particle payload and cell death. [Copyright &y& Elsevier]

Abstract: HIV-1 specific cellular immune responses play a significant part in controlling HIV-1 viral replication and are an important component of an HIV-1 vaccine induced immune response. We reported earlier that recombinant DNA vaccine delivered intramuscularly, and recombinant Listeria monocytogenes, delivered orally induced CD8+ and CD4+ T cell immune responses in rhesus macaques and that this vaccine protocol showed partial protection against an SIV239 challenge. In this paper, we have analyzed the SIV antigen-specific immune responses at the time of challenge and during the subsequent infection course. We find that the immune status of the animals, as measured by the frequency of antigen-specific IFN-gamma secreting peripheral blood mononuclear cells, at the time of challenge correlates more strongly with viral loads at set point than peak viral loads. The correlation between the immune response and viral load was strongest early, as viral set-point was just being established and disintegrates overtime. This study demonstrates the cellular immune response to SIV at the time of challenge of a nonhuman primate is able to impact on viral set-point following SIV239 challenge. Further, this study demonstrates that as virus replicates the T cell immune response to SIV antigens induced by the vaccine is modulated by antigen encountered by immune cells during viral replication. [Copyright &y& Elsevier]

Abstract: In this paper, we describe the development of VCUSM2, a live metabolic auxotroph of Vibrio cholerae O139. Auxotrophy was achieved by mutating a house keeping gene, hemA, that encodes for glutamyl-tRNA reductase, an important enzyme in the C5 pathway for δ-aminolevulenic acid (ALA) biosynthesis, which renders this strain dependent on exogenous ALA for survival. Experiments using the infant mouse and adult rabbit models show that VCUSM2 is a good colonizer of the small intestine and elicits greater than a four-fold rise in vibriocidal antibodies in vaccinated rabbits. Rabbits vaccinated with VCUSM2 were fully protected against subsequent challenge with 1×1011 CFU of the virulent wild type (WT) strain. Experiments using ligated ileal loops of rabbits show that VCUSM2 is 2.5-fold less toxic at the dose of 1×106 CFU compared to the WT strain. Shedding of VCUSM2 in rabbits were found to occur for no longer than 4 days and its maximum survival rate in environmental waters is 8 days compared to the greater than 20 days for the WT strain. VCUSM2 is thus a potential vaccine candidate against infection by V. cholerae O139. [Copyright &y& Elsevier]

Abstract: In recent years, several factors have led to pediatric vaccine manufacturers experiencing vaccine production interruptions that resulted in vaccine supply shortages. One unfortunate consequence of such events is that not all children in the United States could be vaccinated on time, as set forth by the Recommended Childhood Immunization Schedule, and hence, created the potential for epidemic outbreaks of several childhood diseases. The Centers for Disease Control and Prevention (CDC) have responded to such events by releasing vaccine supplies from the national pediatric vaccine stockpiles, which were designed to mitigate the impact of vaccine production interruptions. This paper analyzes the CDC-proposed vaccine stockpile levels using a stochastic inventory model. The results from this analysis examine the adequacy of the proposed pediatric vaccine stockpile levels, as well as provide insights into what the appropriate pediatric vaccine stockpile levels should be to achieve prespecified vaccination coverage rates. Given that the average pediatric vaccine production interruption has lasted more than 1 year, the model is used to compute appropriate pediatric vaccine stockpile levels sufficient to absorb the effect of such vaccine production interruptions. The level of funding needed to create such pediatric vaccine stockpile levels is also reported. [Copyright &y& Elsevier]

Abstract: Previous work, in sheep vaccinated with emergency foot-and-mouth disease (FMD) vaccine, indicated the benefit of increasing the antigen payload in inhibiting local virus replication and consequently persistence following an indirect aerosol challenge with a virus homologous to the vaccine strain. The work presented here investigates this possibility further using cattle and a more severe semi-heterologous direct contact challenge. The quantitative dynamics of virus replication and excretion in both vaccinated and non-vaccinated cattle following challenge are examined. Two experiments were carried out each involving 20 vaccinated and 5 non-vaccinated cattle. An O1 Manisa vaccine (18 PD50) was used for the first, previously reported experiment [Cox SJ, Voyce C, Parida S, Reid SM, Hamblin PA, Paton DJ, et al. Protection against direct contact challenge following emergency FMD vaccination of cattle and the effect on virus excretion from the oropharynx. Vaccine 2005;23:1106–13]. The same vaccine was used for the second experiment described in this paper except the antigen payload was increased 10-fold per bovine dose, resulting in significantly higher FMD virus neutralising antibody titres prior to challenge. Twenty-one days post-vaccination the cattle received a 5-day direct contact challenge with FMD virus from five further non-vaccinated cattle infected 24h earlier with O UKG 34/2001. All vaccinated cattle regardless of antigen payload were protected against clinical disease. Sub-clinical oropharyngeal infection was detected in animals from both experiments but the level of virus replication shortly after direct contact challenge was significantly reduced in vaccinated animals. Cattle immunised with the 10-fold antigen payload cleared the virus more readily and consequently at 28 days post-challenge fewer animals were persistently infected compared to the single strength vaccine. Following a severe challenge, the results from both experiments show that use of emergency vaccine can prevent or decrease local virus replication and thereby dramatically reduce the amount of virus released into the environment, particularly during the early post-exposure period. Additionally, increasing the antigen payload of the vaccine may reduce sub-clinical infection, leading to fewer persistently infected virus carrier animals. [Copyright &y& Elsevier]

Abstract: Hepatitis B virus infection is a serious problem globally, and particularly in the Western Pacific Region where the population suffers disproportionately from the infection and its sequelae. By 2001, every immunization programme in the Region had included hepatitis B vaccine in their schedule. However, many challenges remain if every one of the 26 million children born in the 37 countries and areas of the Region each year is to be protected against hepatitis B infection. In 2003, the Regional Committee of the World Health Organization''s Western Pacific Region resolved to improve hepatitis B control by making it one of two new pillars for strengthening the Expanded Programme on Immunization. The Committee endorsed the strategies of the Regional Plan to improve hepatitis B control through immunization, reducing chronic HBV infection (chronic carriage rate) to less than 1%, and aiming for coverage of at least 80% of the birth cohort in every district with three doses of hepatitis B vaccine by 2005. To help guide this process, an assessment was made of the progress to date, and is reported in this paper. Coverage data used in this evaluation were not independently verified, and could over-estimate progress made in some countries. Whilst there has indeed been great progress in the Region, a number of national programmes still lack the ability to reach all children with immunization services. Other major issues that need to be addressed are the challenges of delivering a timely birth dose, and for certain countries, the affordability of the vaccine over the short- and long-term. [Copyright &y& Elsevier]

Abstract: The European Commission (EC) has strong commitments and recognises the need to continue to ensure that HIV/AIDS research efforts receive global attention. The EC is facing this challenge in a global context and has made substantial investments together with European Developing Countries Clinical Trial Partnership (EDCTP) to formulate a program for the accomplishment of a scientific strategic plan promoting the European/African HIV vaccine development approach. The EC and EDCTP has convened a number of meetings by experts in basic and clinical virology, immunology, epidemiology, as well as industrial and regulatory representatives. The remit of the committee of experts was to define (1) objective criteria for selection of HIV candidates; (2) to determine criteria for selection of sites for clinical trials in Europe and Africa. The resulting consensus paper will guide the EC and EDCTP in developing HIV vaccine strategy and recommendations. [Copyright &y& Elsevier]

Abstract: The assignment of infectious potency to test articles of adenovirus has been conducted mainly using classical end-point dilution methods, which rely on virus induced cytopathology to reveal the presence of infectious virus. These assays suffer the disadvantages of labor intensity, duration, throughput restriction and variability. In the course of our development of an Ad5 based HIV vaccine for clinical evaluation, we sought a facile method for the assignment of potency to the numerous test articles generated during the development of bioprocesses for bulk manufacture, downstream purification and formulation. In this paper we describe a quantitative PCR based potency assay (QPA) which uses QPCR to quantitate adenovirus genomes replicated 24h after the inoculation of a test article on 293 cell monolayers, and then relates that mass to potency by interpolation to a standard curve of replicated adenovirus genomes constructed with a reference adenovirus standard to which infectious potency has been previously assigned in the classical end-point dilution assay. The QPA assay for adenovirus is simple and rapid, with a throughput capacity adequate to the potency assay demands of bioprocess development, and with a precision expressed as a root variability of 16.8% R.S.D., allowing for close discriminations of the products of alternative process configurations. The adenovirus QPA principle can be applied to the quantitation of infectious potency of both RNA and DNA viruses and we report briefly on the development of QPA assays for measles and mumps. QPA assays owing to their simplicity and easy automation, rapidity, capacity and precision hold promise to become widely practiced methods for the quantitation of the potency of live virus vaccines and other recombinant virus vectors. [Copyright &y& Elsevier]

Abstract: The foundation for any vaccine immunogenicity trial is the identification of appropriate correlates for protection and the measurement of these quantities with well-designed bioassays. An important requirement for developing bioassay protocols is the standardization of each procedure, so it is performed in a uniform manner within a facility and, in the case of multicenter trials, across laboratories. It is also crucial to recognize that the selection and use of techniques used to quantify assay endpoints (e.g., antibody concentration) will affect their accuracy and precision and these methods must also be defined and uniformly applied within and across laboratories. This paper discusses a number of methodological issues related to bioassay design and analysis that would ultimately lead to highly accurate assay endpoint determinations with minimum variance that would be comparable across laboratories. Guidelines are presented for the development of bioassay and data analysis protocols. Strengthening vaccine immunogenicity trial protocols will ensure that these quantities are estimated with the greatest degree of reliability and facilitate the subsequent evaluation of new vaccine formulations. Following these guidelines will give other researchers as well as regulatory authorities more confidence in evaluating and comparing the differences in immunogenicity levels elicited by new and developing vaccines. [Copyright &y& Elsevier]

Abstract: Background:: During February 2003 a number of Australian sailors were returned home from their deployment to the Persian Gulf after refusing anthrax vaccination. This paper examines the media coverage of this episode as a case study in how controversies about vaccine safety escalate. Methods:: Frame analysis of articles from major Australian newspapers (n = 83) and transcripts of radio and television news and current affairs programs (n = 22) to identify the main supportive and oppositional themes used in reportage and media debate. Findings:: Initially, the major news frames were supportive of the vaccine refusing soldiers, and conveyed a sense of distrust of the government’s actions. These initial themes were rapidly re-framed and new dominant discourses appeared. First, sailors went from brave whistleblowers to being portrayed as deserters and cowards. Second, proponents shifted from their portrayal as faceless regulators to personal risk takers embodied in a well-respected Major General having the vaccine. Third, the voluntary nature of the vaccine was emphasised, thus dousing the flames of implied coercion. Conclusion:: Marked shifts in the representation of vaccine opponents and proponents possibly contributed to the rapid diminishment of media interest in the story. [Copyright &y& Elsevier]

Enterovirus 71 (EV71) is an enterovirus that could lead to severe neurological disorders and fatalities. The inactivated vaccine is an appropriate EV71 vaccine format for meeting current needs. Large-scale preparation of the inactivated EV71vaccine depends on a scalable cell culture system for industrial mass production. In this paper, Vero cells were found to produce higher titers of EV71 than did MRC-5 and WI-38 cells. High-density microcarrier Vero cell cultures were established using 5g/L Cytodex 1 microcarriers and found to promote the release of EV71s from infected Vero cells. For the large-scale production of the inactivated vaccine antigen, the extracellular virus titers produced in the 2L bioreactor were found to be 10 times lower than the spinner flask culture but improved by 30-folds using glucose/glutamine feedings during infection. A serum-free Vero cell microcarrier culture was also established in the bioreactor, yielding a high-titer of 5.8 × 107 TCID50/mL for EV71 production. The immunogenicity of the inactivated virions produced in serum-free culture elicited a slightly higher level of neutralizing antibody response in immunized mice. These results constitute valuable information on the development of a large-scale microcarrier cell culture process for producing inactivated EV71 vaccine. [Copyright &y& Elsevier]

The prevalence rate of hepatitis B virus (HBV) infection in Pacific Island countries is amongst the highest in the world. Hepatitis B immunisation has been incorporated into national programmes at various times, often with erratic supply and coverage, until a regionally co-ordinated programme, which commenced in 1995 ensured adequate supply. The effectiveness of these programmes was recently evaluated in four countries, Vanuatu and Fiji in Melanesia, Tonga in Polynesia and Kiribati in Micronesia. That evaluation established that the programmes had a substantial beneficial impact in preventing chronic hepatitis B infection [Vaccine 18 (2000) 3059]. Several studies of hepatitis B vaccination programmes in endemic countries have identified the potential significance of surface gene mutants as a cause for failure of immunisation. In the study outlined in this paper, we screened infected children and their mothers for the emergence and prevalence of these variants in specimens collected from the four country evaluation. Although the opportunity for the emergence of HBV vaccine escape mutants in these populations was high due to the presence of a considerable amount of the virus in the population and the selection pressure from vaccine use, there were no “a” determinant vaccine escape mutants found. This suggests that vaccine escape variants are not an important cause for failure to prevent HBV transmission in this setting. Other HBsAg variants were detected, but their functional significance remains to be determined. The failure to provide satisfactory protection during such immunisation programmes reflects the need for achieving and sustaining high vaccine coverage, improving the timeliness of doses as well as improving ‘cold-chain’ support, rather than the selection of vaccine-escape mutants of HBV. [Copyright &y& Elsevier]

A hazard assessment of Venezuelan equine encephalitis (VEE) virus sub-types and vaccine candidates was performed according to standard risk assessment procedures. Data from published literature demonstrates a considerable degree of safety of V3526 when compared to TC-83 vaccine, the protective measure that has been used to protect laboratory workers for over four decades. V3526 is a new recombinant vaccine candidate that is a vastly different product with a diminished hazard to public health and the general environment. A weight-of-evidence (WOE)-based scheme was employed to assign weights for relevance, quality, and adequacy of evidence in published literature on medical pathology, epidemiology, pre-clinical investigational studies, and environmental studies. The results of this assessment indicated that V3526 has a low adverse impact on public health and the general environment. Although there are currently no human infectivity or pathogenicity data for V3526, existing evidence from published experimental animal studies reveals a diminished hazard for environmental transmission and distribution. Recently, the US Centers for Disease Control and Prevention (CDC) excluded V3526 from select agent requirements set forth under the Health and Human Services (HHS) regulations in Title 42 C.F.R. Part 73 and the US Department Agriculture (USDA) regulations set forth in Title 7 C.F.R. Part 331 and Title 9 C.F.R. Part 121. This paper summarizes the background, rationale, and hazard analysis used for assessing the environmental hazard of the VEE vaccine candidate strain V3526. [Copyright &y& Elsevier]

Health inequities are the unjust differences in health among different social groups. Unfortunately, inequities are the norm, both in terms of health status and access to, and use of, health services. Childhood immunizations reduce the incidence of vaccine-preventable diseases and represent a cost-effective way to foster health equity. This paper reflects a 2015 review of data from surveys conducted in developing countries from 2005 to 2011 that show significant inequities in immunization coverage and discusses several initiatives currently underway (including Gavi, the Vaccine Alliance) that are directed at increasing childhood immunizations or reducing or abolishing overall health inequities. These initiatives have already had a significant impact on disease burden and childhood mortality and give rise to optimism that health disparities may further be reduced and health equity achieved as a result of investments made in immunization. [ABSTRACT FROM AUTHOR]

Abstract: Recombinant hepatitis B vaccine has been used widely in the world since 1991. The side effects of hepatitis B vaccine are seen rarely. In this paper, we present clinical and laboratory progress of an infant who gets severe thrombocytopenia after the second dosage hepatitis B vaccine. Our case is different from other cases because our patient is very young, the number of platelet is the lowest in the literature, and intravenous immunoglobulin (IVIG) are used in the treatment. Although it is a severe thrombocytopenia, the patient has recovered without any bleeding. [Copyright &y& Elsevier]

Abstract: Therapeutic vaccination for the treatment of allergy has been used for nearly a century but it is only recently that the mechanisms whereby benefits can be achieved have begun to be identified [Bousquet J, Lockey FR, Malling HJ. Allergy immunotherapy: therapeutic vaccines for allergic diseases. WHO Position Paper. Allergy 1998;53:1–42.]. The induction of blocking antibodies was originally thought to lead to amelioration of allergic symptoms. There is now evidence that a switch from a Th2(IgE/inflammatory) response to a Th1 biased allergen specific response is part of the answer [Durham SR, Till SJ, Immunologic changes associated with allergen immunotherapy. J Allergy Clin Immunol, 1998;102:157–64.]. Specific anergy induced by raised IL10 and TGFβ and the induction of regulatory T cells may also be important [Akdis CA, Blaser K, Allergen-specific immunotherapy. Allergy 2000;55:522–30.]. A new adjuvant complex, l-tyrosine-MPL can accelerate these processes. [Copyright &y& Elsevier]

Abstract: Advocacy, social mobilisation and communication are key components of the successful introduction of new vaccines into childhood immunisation schedules. The development of many new vaccines and the innovation of finance mechanisms, means more efficacious vaccines are becoming available to children in developing countries. At the same time, communication technology is developing at a rapid rate, and with the dramatic decrease in vaccine-preventable diseases over the past few decades, the public have become increasingly exposed to confusing and conflicting information about the need for vaccination. The science of vaccines has become more complex, making effective, clear and consistent communication for healthcare workers and caregivers critical to the uptake of and adherence to life-saving vaccination. The introduction of two new vaccines, the 7-valent pneumococcal conjugate vaccine and the rotavirus vaccine together with the new pentavalent vaccine, which includes inactivated polio vaccine and replaced the former combination vaccine with four antigens, into the South African Expanded Programme on Immunisation over a short period of time, has been met with a number of challenges, some of which led to a lowering of confidence in the Department of Health to deliver on its promises. Had consistent advocacy, social mobilisation and communication efforts not been in place, efforts to make an impact on the burden of disease may not have been as successful. This paper focuses on the lessons learned about effective advocacy with decision makers, social mobilisation, communication with parents and caregivers, and training healthcare workers regarding the introduction of the new vaccines. [Copyright &y& Elsevier]

Abstract: This paper discusses the controversy between top-down, disease-focused, vertical programs, on the one hand, and activities that have been horizontally integrated into health services, on the other, using as a reference the public health initiatives developed in Mexico in the context of a recent comprehensive health care reform. The main message is that it is possible to achieve a synthesis between vertical and horizontal strategies, and also between public health and personal health care programs. Public health and personal care are the two sides of the health system coin, and both are central to a comprehensive concept of health security. Investments in epidemiological surveillance and response clearly contribute to the control of threats facing nation-states, such as pandemics and biological warfare. At the same time, investments in the protection of individuals from threats that endanger their health would also make our world a safer place. [Copyright &y& Elsevier]

Abstract: In the last two decades, computer-based models of cervical cancer screening have been used to evaluate the cost-effectiveness of different secondary prevention policies. Analyses in countries with existing screening programs have focused on identifying the optimal screening interval, ages for starting and stopping screening, and consideration of enhancements to conventional cytology, such as human papillomavirus (HPV)-DNA testing as a triage for equivocal results or as a primary screening test for women over the age of 30. Analyses in resource-poor settings with infrequent or no screening have focused on strategies that enhance the linkage between screening and treatment, consider noncytologic alternatives such as HPV-DNA testing, and target women between the ages of 35 and 45 for screening one, two, or three times per lifetime. Despite differences in methods and assumptions, this paper identifies the qualitative themes that are consistent among studies, and highlights important methodological challenges and high-priority areas for further work. [Copyright &y& Elsevier]