WHO consultation on group B Streptococcus vaccine development: Report from a meeting held on 27-28 April 2016.

Globally, group B Streptococcus (GBS) remains a leading cause of sepsis and meningitis in infants in the first 90days of life. Intrapartum antibiotic prophylaxis (IAP) for women at increased risk of transmitting GBS to their newborns has been effective in reducing part, but not all, of the GBS disease burden in many high income countries (HICs). In low- and middle-income countries (LMICs), IAP use is low. Immunization of pregnant women with a GBS vaccine represents an alternative strategy to protecting newborns and young infants, through transplacental antibody transfer and potentially by reducing new vaginal colonization. This vaccination strategy was first suggested in the 1970s and several potential GBS vaccines have completed phase I/II clinical trials. During the 2015 WHO Product Development for Vaccines Advisory Committee meeting, GBS was identified as a high priority for the development of a vaccine for maternal immunization because of the major public health burden posed by GBS in LMICs, and the high technical feasibility for successful development. Following this meeting, the first WHO technical consultation on GBS vaccines was held on the 27th and 28th of April 2016, to consider development pathways for such vaccines, focused on their potential role in reducing newborn and young infant deaths and possibly stillbirths in LMICs. Discussion topics included: (1) pathophysiology of disease; (2) current gaps in the knowledge of global disease burden and serotype distribution; (3) vaccine candidates under development; (4) design considerations for phase III trials; and (5) pathways to licensure, policy recommendations and use. Efforts to address gaps identified in each of these areas are needed to establish the public health need for, the development and deployment of, efficacious GBS vaccines. In particular, more work is required to understand the global disease burden of GBS-associated stillbirths, and to develop quality-assured standardized antibody assays to identify correlates of protection.

Meeting report: WHO consultation on Respiratory Syncytial Virus (RSV) vaccine development, Geneva, 25-26 April 2016.

Respiratory syncytial virus (RSV) is a leading viral cause of respiratory morbidity and mortality in infants and young children worldwide. Low and middle income countries (LMICs) account for approximately 99% of the global mortality estimates in this population, with up to 200,000 RSV deaths per year. The vaccine product development pipeline is diverse with the most advanced clinical candidate currently in phase III efficacy testing in pregnant women. In addition, a long-acting RSV-neutralizing monoclonal antibody (mAb) to be administered at birth to prevent serious RSV-related respiratory disease is in late stage clinical development, as are additional conventional mAb for use in high-risk infants. Thus, there is a realistic possibility that an effective new intervention to prevent RSV disease will be available in the next 5-10year horizon. In anticipation of this outcome, the Strategic Advisory Group of Experts for Immunization (SAGE), WHO's vaccine policy recommendation body, reviewed the status of RSV vaccine and monoclonal antibody development in April 2016. Although substantial progress towards licensure has broadened the research agenda to consider intervention impact and cost effectiveness, significant gaps remain in the data that will be needed to inform and support a policy recommendation for implementation. These aspects were the focus of WHO's second consultation on RSV vaccines and single dosage extended half-life mAb for prophylaxis.

Toward Developing a Preventive MERS-CoV Vaccine-Report from a Workshop Organized by the Saudi Arabia Ministry of Health and the International Vaccine Institute, Riyadh, Saudi Arabia, November 14-15, 2015.

Middle East respiratory syndrome (MERS) remains a serious international public health threat. With the goal of accelerating the development of countermeasures against MERS coronavirus (MERS-CoV), funding agencies, nongovernmental organizations, and researchers across the world assembled in Riyadh, Saudi Arabia, on November 14-15, 2015, to discuss vaccine development challenges. The meeting was spearheaded by the Saudi Ministry of Health and co-organized by the International Vaccine Institute, South Korea. Accelerating the development of a preventive vaccine requires a better understanding of MERS epidemiology, transmission, and pathogenesis in humans and animals. A combination of rodent and nonhuman primate models should be considered in evaluating and developing preventive and therapeutic vaccine candidates. Dromedary camels should be considered for the development of veterinary vaccines. Several vaccine technology platforms targeting the MERS-CoV spike protein were discussed. Mechanisms to maximize investment, provide robust data, and affect public health are urgently needed.

The global roadmap for advancing development of vaccines against sexually transmitted infections: Update and next steps.

In 2014, the World Health Organization, the US National Institutes of Health, and global technical partners published a comprehensive roadmap for development of new vaccines against sexually transmitted infections (STIs). Since its publication, progress has been made in several roadmap activities: obtaining better epidemiologic data to establish the public health rationale for STI vaccines, modeling the theoretical impact of future vaccines, advancing basic science research, defining preferred product characteristics for first-generation vaccines, and encouraging investment in STI vaccine development. This article reviews these overarching roadmap activities, provides updates on research and development of individual vaccines against herpes simplex virus, Chlamydia trachomatis, Neisseria gonorrhoeae, and Treponema pallidum, and discusses important next steps to advance the global roadmap for STI vaccine development.

Report from the World Health Organization's Product Development for Vaccines Advisory Committee (PDVAC) meeting, Geneva, 7-9th Sep 2015.

There are more vaccines in development, against a greater number of pathogens, than ever before. A challenge with this exceptional level of activity and investment is how to select and resource the most promising approaches to have the most significant impact on public health. The WHO Product Development for Vaccines Advisory Committee (PDVAC) was established in 2014 to provide strategic advice and recommendations to WHO for vaccines in clinical development that could have a significant impact on public health in low and middle income countries. On 7-9th September 2015, PDVAC was convened for the second time, when the committee reviewed vaccine developments in 24 disease areas. This report summarises the key recommendations from that consultation.

WHO consultation on Respiratory Syncytial Virus Vaccine Development Report from a World Health Organization Meeting held on 23-24 March 2015.

Respiratory syncytial virus (RSV) is a globally prevalent cause of lower respiratory infection in neonates and infants. Despite its disease burden, a safe and effective RSV vaccine has remained elusive. In recent years, improved understanding of RSV biology and innovations in immunogen design has resulted in the advancement of multiple vaccine candidates into the clinical development pipeline. Given the growing number of vaccines in clinical trials, the rapid pace at which they are being tested, and the likelihood that an RSV vaccine will reach the commercial market in the next 5-10 years, consensus and guidance on clinical development pathways and licensure routes are needed now, before large-scale efficacy trials commence. In pursuit of this aim, the World Health Organization convened the first RSV vaccine consultation in 15 years on the 23rd and 24th of March, 2015 in Geneva, Switzerland. The meeting's primary objective was to provide guidance on clinical endpoints and development pathways for vaccine trials with a focus on considerations of low- and middle-income countries. Meeting participants reached consensus on candidate case definitions for RSV disease, considerations for clinical efficacy endpoints, and the clinical development pathway for active and passive immunization trials in maternal and pediatric populations. The strategic focus of this meeting was on the development of high quality, safe and efficacious RSV preventive interventions for global use and included: (1) maternal/passive immunization to prevent RSV disease in infants less than 6 months; (2) pediatric immunization to prevent RSV disease in infants and young children once protection afforded by maternal immunization wanes.

Design, recruitment, and microbiological considerations in human challenge studies.

Since the 18th century a wealth of knowledge regarding infectious disease pathogenesis, prevention, and treatment has been accumulated from findings of infection challenges in human beings. Partly because of improvements to ethical and regulatory guidance, human challenge studies-involving the deliberate exposure of participants to infectious substances-have had a resurgence in popularity in the past few years, in particular for the assessment of vaccines. To provide an overview of the potential use of challenge models, we present historical reports and contemporary views from experts in this type of research. A range of challenge models and practical approaches to generate important data exist and are used to expedite vaccine and therapeutic development and to support public health modelling and interventions. Although human challenge studies provide a unique opportunity to address complex research questions, participant and investigator safety is paramount. To increase the collaborative effort and future success of this area of research, we recommend the development of consensus frameworks and sharing of best practices between investigators. Furthermore, standardisation of challenge procedures and regulatory guidance will help with the feasibility for using challenge models in clinical testing of new disease intervention strategies.

Malaria vaccine research and development: the role of the WHO MALVAC committee.

The WHO Malaria Vaccine Advisory Committee (MALVAC) provides advice to WHO on strategic priorities, activities and technical issues related to global efforts to develop vaccines against malaria. MALVAC convened a series of meetings to obtain expert, impartial consensus views on the priorities and best practice for vaccine-related research and development strategies. The technical areas covered during these consultations included: guidance on clinical trial design for candidate sporozoite and asexual blood stage vaccines; measures of efficacy of malaria vaccines in Phase IIb and Phase III trials; standardization of immunoassays; the challenges of developing assays and designing trials for interventions against malaria transmission; modelling impact of anti-malarial interventions; whole organism malaria vaccines, and Plasmodium vivax vaccine-related research and evaluation. These informed discussions and opinions are summarized here to provide guidance on harmonization of strategies to help ensure high standards of practice and comparability between centres and the outcome of vaccine trials.

Malaria vaccine R&D in the Decade of Vaccines: breakthroughs, challenges and opportunities.

While recent progress has been made in reducing malaria mortality with other interventions, vaccines are still urgently needed to further reduce the incidence of clinical disease, including during pregnancy, and to provide "herd protection" by blocking parasite transmission. The most clinically advanced candidate, RTS,S, is presently undergoing Phase 3 evaluation in young African children across 13 clinical sites in eight African countries. In the 12-month period following vaccination, RTS,S conferred approximately 50% protection from clinical Plasmodium falciparum disease in children aged 5-17 months, and approximately 30% protection in children aged 6-12 weeks when administered in conjunction with Expanded Program for Immunization (EPI) vaccines. The development of more highly efficacious vaccines to prevent clinical disease caused by both P. falciparum and Plasmodium vivax, as well as vaccines to support elimination efforts by inducing immunity that blocks malaria parasite transmission, are priorities. Some key barriers to malaria vaccine development include: a paucity of well-characterized target immunogens and an absence of clear correlates of protection to enable vaccine development targeting all stages of the P. falciparum and P. vivax lifecycles; a limited number of safe and effective delivery systems, including adjuvants, that induce potent, long-lived protective immunity, be it by antibody, CD4+, and/or CD8+ T cell responses; and, for vaccines designed to provide "herd protection" by targeting sexual stage and/or mosquito antigens, the lack of a clear clinical and regulatory pathway to licensure using non-traditional endpoints. Recommendations to overcome these, and other key challenges, are suggested in this document.

A systematic review of safety data reporting in clinical trials of vaccines against malaria, tuberculosis, and human immunodeficiency virus.

INTRODUCTION: Malaria, tuberculosis (TB) and human immunodeficiency virus (HIV) are diseases with devastating effects on global public health, especially in the developing world. Clinical trials of candidate vaccines for these diseases are being conducted at an accelerating rate, and require accurate and consistent methods for safety data collection and reporting. We performed a systematic review of publications describing the safety results from clinical trials of malaria, TB and HIV vaccines, to ascertain the nature and consistency of safety data collection and reporting. METHODS: The target for the review was pre-licensure trials for malaria, TB and HIV vaccines published in English from 2000 to 2009. Search strategies were customized for each of the databases utilized (MEDLINE, EMBASE, the Cochrane Database of Systematic Reviews and the Database of Reviews and Effects). Data extracted included age of trial participants, vaccine platform, route and method of vaccine administration, duration of participant follow-up, reporting of laboratory abnormalities, and the type, case definitions, severity, reporting methods and internal reporting consistency of adverse events. RESULTS: Of 2278 publications screened, 124 were eligible for inclusion (malaria: 66, TB: 9, HIV: 49). Safety data reporting was found to be highly variable among publications and often incomplete: overall, 269 overlapping terms were used to describe specific adverse events. 17% of publications did not mention fever. Descriptions of severity or degree of relatedness to immunization of adverse events were frequently omitted. 26% (32/124) of publications failed to report data on serious adverse events. CONCLUSIONS: The review demonstrated lack of standardized safety data reporting in trials for vaccines against malaria, TB and HIV. Standardization of safety data collection and reporting should be encouraged to improve data quality and comparability. LIMITATIONS: The search strategy missed studies published in languages other than English and excluded studies reporting on vaccine trials for diseases besides malaria, TB and HIV.