Stakeholders’ perceptions of 10 years of the Global Action Plan for Influenza Vaccines (GAP) – Results from a survey

Ten years after the launch of the Global Action Plan for Influenza Vaccines (GAP), the World Health Organization (WHO) surveyed stakeholders to understand their perceptions of what the programme had achieved. This article provides a summary of the findings; the full report will be available on-line on the GAP website in November 2016 (http://www.who.int/influenza_vaccines_plan/en/). Seventy-seven responses were received from stakeholders including medical doctors, national influenza center officials, country immunization programme teams, surveillance and disease centers, policy-makers, researchers, vaccine manufacturers, and non-governmental organizations from 28 countries, representing all six WHO regions.Respondents cited GAP’s biggest successes as capacity building in developing countries; raising international awareness of global needs in the event of a pandemic; and collaborative alignment of influenza stakeholders. The most commonly reported challenges were the limited progress in development of a broadly protective or universal vaccine and the perceived absence of a major increase in seasonal demand. These findings aligned with the perception that less global progress had been made under the third GAP objective, focused on research and development of better vaccines, than on increasing seasonal vaccine use (objective 1) and pandemic vaccine production capacity (objective 2). Respondents explained what they saw as the major challenges to development of better vaccines, including to development of a universal influenza vaccine. The majority of respondents agreed that the goal chosen at the GAP II consultation is still relevant. Results highlighted the importance of promoting research and development of better vaccines, both for facilitating uptake of seasonal vaccines and for ensuring timely vaccine availability in the event of a pandemic. As the GAP concludes its mandate this year, these findings will contribute to discussions on the impact of programme closure and how to address the key issues facing influenza stakeholders thereafter.     

European Union vaccine research--an overview

Recent developments in vaccine research provide new momentum for an important area in health innovation. Particularly interesting are novel DNA vaccine approaches, many of which are already under clinical investigation. The Framework Programmes of the European Union play an important role in supporting collaborative efforts in vaccine research to develop new and better vaccines and bring them to the market. With a timely strategic reorientation towards a sustainable investment in innovation, the current seventh Framework Programme will help to bring large industry and small and medium-sized enterprises (SME) on board and foster partnership between stakeholders. As the first human DNA vaccines progresses through the development pipeline, more and more questions revolve around licensing and regulation and appropriate guidelines are being developed.     

The art of partnerships for vaccines

The Developing Countries Vaccine Manufacturers Network (DCVMN) convened vaccine manufacturing experts and leaders from local and global public health organizations for its 19th Annual General Meeting. Lectures and panel discussions centered on international cooperation for better access to vaccines, and partnerships in areas ranging from vaccine research and process development, to clinical studies, regulatory, supply chain and emergency preparedness and response.Global vaccine market trends and changes that will impact vaccine financing and procurement methods were discussed as well as capital sources, including funding, for the development of new or improved vaccines.DCVMN members presented their progress in developing novel Hexavalent, Meningitis, Pneumococcal Conjugate Vaccine, Shigella, Mumps, Rotavirus, Yellow Fever, Polio, Hepatitis E and Dengue vaccines, and a novel monoclonal antibody cocktail for post-bite prophylaxis against rabies infections.Access to and availability of vaccines is enhanced through sharing of best practices for vaccine quality control, reducing redundant testing and promoting development of harmonized common standards. Eligible stakeholders were encouraged to join the WHO-National Control Laboratory Network for Biologicals which serves as a platform for collaboration and technical exchange in this area.Increasing regulatory convergence at the regional and global levels through mechanisms such as joint dossier review and the WHO Collaborative Registration Procedure can help to accelerate vaccine access globally. Additionally, four proposals for streamlining procedures and alignment of dossiers were discussed.Successful partnerships between a broad range of stakeholders, including international organizations, manufacturers, academic research institutes and regulators have provided support for, and in some cases accelerated, vaccine innovation, clinical trials and registration, WHO prequalification, vaccine introduction and access. Strong partnerships, based on experience and trust, help leverage opportunities and are critically important to advancing the shared goal of providing quality vaccines for all people.     

The impact of globalization on vaccine development and availability

Globalization is likely to affect many aspects of public health, one of which is vaccine-preventable communicable diseases. Important forces include increased funding initiatives supporting immunization at the global level; regulatory harmonization; widespread intellectual property rights provisions through the World Trade Organization agreements; the emergence of developing-country manufacturers as major players in vaccine supply; and the appearance of new communicable disease threats, including those potentially linked to bioterrorism. All of these forces can affect, either positively and negatively, the development and availability of vaccines. Harnessing these will be a challenge for policymakers and immunization stakeholders.     

WHO/IVI global stakeholder consultation on group A Streptococcus vaccine development: Report from a meeting held on 12–13 December 2016

While progress towards a Group A Streptococcus (GAS) vaccine has been stalled by a combination of scientific, regulatory, and commercial barriers, the problem persists. The high and globally-distributed burden of disease attributable to GAS makes vaccination an imperative global public health goal. Advances across a range of scientific disciplines in understanding GAS diseases have made the goal a realistic one and focused attention on the need for coordinated global action. With a view to accelerating GAS vaccine development, the World Health Organization (WHO) and the International Vaccine Institute (IVI) convened a global stakeholder consultation on the 12th and 13th of December 2016, in Seoul, South Korea. Topics discussed included: (1) gaps in current knowledge of global GAS epidemiology, burden of disease, and molecular epidemiology; (2) contribution of pre-clinical models to candidate vaccine evaluation and new immunological assays to address GAS immunology knowledge gaps; (3) status and future of the GAS vaccine development pipeline; and (4) defining a pathway to licensure, policy recommendations and availability of a vaccine. The meeting determined to establish a GAS vaccine working group to coordinate preparation of a global vaccine values proposition, preferred product characteristics, and a technical research and development roadmap. A new global GAS vaccine consortium will drive strategic planning to anticipate requirements for licensure, prequalification, and policy recommendations.     

A global pandemic influenza vaccine action plan

In case of an influenza pandemic, the world will be in a situation where potential vaccine supply will fall short by several billion doses from global needs. The World Health Organization (WHO) convened in Geneva on May 2-3, 2006 a consultation of all stakeholders in influenza vaccines and immunization to identify practical solutions to fill this gap. The consultation resulted in a global action plan outlining promising specific strategies to increase influenza vaccine production and surge-capacity before and during an influenza pandemic. Although the timing and severity of the next influenza pandemic cannot be predicted, vaccines are considered the one of the most important medical interventions for reducing morbidity and mortality if and when such an event occurs. Despite this acknowledged role, current limitations on influenza vaccine manufacturing capacity mean that, should a pandemic virus emerge in the near future, vaccine supplies would fall short of the anticipated global demand by several billion doses. Concern about this situation was formally acknowledged in May 2005, when the World Health Assembly approved a resolution [1] on strengthening pandemic influenza preparedness and response. That resolution called on the World Health Organization (WHO) to seek solutions with international and national partners, including the private sector, to reduce the present global shortage of influenza vaccines. More specifically, the resolution asked WHO to look at strategies for economizing on the use of antigen and transferring production technologies from industrialized to developing countries. In response to this request, WHO convened a consultation from 2-3 May 2006 attended by representatives of the major stakeholders in the area of influenza vaccines and immunization. The consultation had two main objectives: (1) To prepare a global action plan with specific short-, medium-, and long-term activities designed to increase influenza vaccine production and surge-capacity, to identify key obstacles and driving forces, and to estimate funding needs.(2) To strengthen the engagement and collaboration of key partners and stakeholders.     

The Euvichol story – Development and licensure of a safe,effective and affordable oral cholera vaccine through global public private partnerships

Cholera, a diarrheal disease primarily affecting vulnerable populations in developing countries, is estimated to cause disease in more than 2.5 million people and kill almost 100,000 annually. An oral cholera vaccine (OCV) has been available globally since 2001; the demand for this vaccine from affected countries has however been very low, due to various factors including vaccine price and mode of administration. The low demand for the vaccine and limited commercial incentives to invest in research and development of vaccines for developing country markets has kept the global supply of OCVs down. Since 1999, the International Vaccine Institute has been committed to make safe, effective and affordable OCVs accessible. Through a variety of partnerships with collaborators in Sweden, Vietnam, India and South Korea, and with public and private funding, IVI facilitated development and production of two affordable and WHO-prequalified OCVs and together with other stakeholders accelerated the introduction of these vaccines for the global public-sector market.     

Vaccines against Ebola virus

We have just witnessed the largest and most devastating outbreak of Ebola virus disease, which highlighted the urgent need for development of an efficacious vaccine that could be used to curtail future outbreaks. Prior to 2014, there had been limited impetus worldwide to develop a vaccine since the virus was first discovered in 1976. Though too many lives were lost during this outbreak, it resulted in the significantly accelerated clinical development of a number of candidate vaccines through an extraordinary collaborative global effort coordinated by the World Health Organisation (WHO) and involving a number of companies, trial centres, funders, global stakeholders and agencies. We have acquired substantial safety and immunogenicity data on a number of vaccines in Caucasian and African populations. The rapid pace of events led to the initiation of the landmark efficacy trial testing the rVSV-vectored vaccine, which showed high level efficacy in an outbreak setting when deployed using an innovative ring vaccination strategy. Though the Public Health Emergency of International Concern (PHEIC) declared by the WHO has now been lifted, the global scientific community faces numerous challenges ahead to ensure that there is a licensed, deployable vaccine available for use in future outbreaks for at least the Zaire and Sudan strains of Ebola virus. There remain several unanswered questions on the durability of protection, mechanistic immunological correlates and preferred deployment strategies. This review outlines a brief history of the development of Ebola vaccines, the significant progress made since the scale of the outbreak became apparent, some lessons learnt and how they could shape future development of vaccines and the management of similar outbreaks.     

Meeting Report: WHO Workshop on modelling global mortality and aetiology estimates of enteric pathogens in children under five. Cape Town, 28–29th November 2018

Investment in vaccine product development should be guided by up-to-date and transparent global burden of disease estimates, which are also fundamental to policy recommendation and vaccine introduction decisions. For low- and middle-income countries (LMICs), vaccine prioritization is primarily driven by the number of deaths caused by different pathogens. Enteric diseases are known to be a major cause of death in LMICs. The two main modelling groups providing mortality estimates for enteric diseases are the Institute for Health Metrics and Evaluation (IHME) at the University of Washington, Seattle and the Maternal Child Epidemiology Estimation (MCEE) group, led by Johns Hopkins Bloomberg School of Public Health. Whilst previous global diarrhoea mortality estimates for under five-year-olds from these two groups were closely aligned, more recent estimates for 2016 have diverged, particularly with respect to numbers of deaths attributable to different enteric pathogens. This has impacted prioritization and investment decisions for vaccines in the development pipeline.The mission of the Product Development for Vaccines Advisory Committee (PDVAC) at the World Health Organisation (WHO) is to accelerate product development of vaccines and technologies that are urgently needed and ensure they are appropriately targeted for use in LMICs. At their 2018 meeting, PDVAC recommended the formation of an independent working group of subject matter experts to explore the reasons for the difference between the IHME and MCEE estimates, and to assess the respective strengths and limitations of the estimation approaches adopted, including a review of the data on which the estimates are based.Here, we report on the proceedings and recommendations from a consultation with the working group of experts, the IHME and MCEE modelling groups, and other key stakeholders. We briefly review the methodological approaches of both groups and provide a series of proposals for investigating the drivers for the differences in enteric disease burden estimates.     

The expanding vaccine development pipeline, 1995–2008

Successful launches of recently licensed vaccines contrast with pharmaceutical industry concerns about unfavorable market conditions, making the status and future of vaccine development uncertain. We assessed trends in private-sector vaccine research and development for the period 1995–2008, using a global pharmaceutical database to identify prophylactic vaccines in preclinical, Phase I, Phase II, or Phase III stages of development. We counted companies that research and/or manufacture vaccines (“vaccine originators”) and their vaccine products in each year. The global number of vaccine originators doubled (to 136), as did the number of prophylactic vaccine products in development (to 354); the majority of this growth was in preclinical and early phase clinical research. Because rapid growth in earlier research phases has not yet led to growth in Phase III, it is not yet clear whether recent industry expansion will translate to an increase in the number of available vaccines in the near future.     

Successful vaccination of immune suppressed recipients using Listeria vector HIV-1 vaccines in helminth infected mice

Vaccines for HIV, malaria and TB remain high priorities, especially for sub-Saharan populations. The question is: will vaccines currently in development for these diseases function in populations that have a high prevalence of helminth infection? Infection with helminth parasites causes immune suppression and a CD4+ Th2 skewing of the immune system, thereby impairing Th1-type vaccine efficacy. In this study, we conduct HIV vaccine trials in mice with and without chronic helminth infection to mimic the human vaccine recipient populations in Sub-Saharan Africa and other helminth parasite endemic regions of the world, as there is large overlap in global prevalence for HIV and helminth infection. Here, we demonstrate that Listeria monocytogenes functions as a vaccine vector to drive robust and functional HIV-specific cellular immune responses, irrespective of chronic helminth infection. This observation represents a significant advance in the field of vaccine research and underscores the concept that vaccines in the developmental pipeline should be effective in the target populations.     

Using social network analysis to examine the decision-making process on new vaccine introduction in Nigeria

The decision-making process to introduce new vaccines into national immunization programmes is often complex, involving many stakeholders who provide technical information, mobilize finance, implement programmes and garner political support. Stakeholders may have different levels of interest, knowledge and motivations to introduce new vaccines. Lack of consensus on the priority, public health value or feasibility of adding a new vaccine can delay policy decisions. Efforts to support country-level decision-making have largely focused on establishing global policies and equipping policy makers with the information to support decision-making on new vaccine introduction (NVI). Less attention has been given to understanding the interactions of policy actors and how the distribution of influence affects the policy process and decision-making. Social network analysis (SNA) is a social science technique concerned with explaining social phenomena using the structural and relational features of the network of actors involved. This approach can be used to identify how information is exchanged and who is included or excluded from the process. For this SNA of vaccine decision-making in Nigeria, we interviewed federal and state-level government officials, officers of bilateral and multilateral partner organizations, and other stakeholders such as health providers and the media. Using data culled from those interviews, we performed an SNA in order to map formal and informal relationships and the distribution of influence among vaccine decision-makers, as well as to explore linkages and pathways to stakeholders who can influence critical decisions in the policy process. Our findings indicate a relatively robust engagement of key stakeholders in Nigeria. We hypothesized that economic stakeholders and implementers would be important to ensure sustainable financing and strengthen programme implementation, but some economic and implementation stakeholders did not appear centrally on the map; this may suggest a need to strengthen the decision-making processes by engaging these stakeholders more centrally and earlier.     

Maternal immunization against Group B streptococcus: World Health Organization research and development technological roadmap and preferred product characteristics

Group B streptococcus, found in the vagina or lower gastrointestinal tract of about 10–40% of women of reproductive age, is a leading cause of early life invasive bacterial disease, potentially amenable to prevention through maternal immunization during pregnancy. Following a consultation process with global stakeholders, the World Health Organization is herein proposing priority research and development pathways and preferred product characteristics for GBS vaccines, with the aim to facilitate and accelerate vaccine licensure, policy recommendation for wide scale use and implementation.     

Next generation dengue vaccines: a review of candidates in preclinical development

Dengue represents a major public health problem of growing global importance. In the absence of specific dengue therapeutics, strategies for disease control have increasingly focused on the development of dengue vaccines. While a licensed dengue vaccine is not yet available, several vaccine candidates are currently being evaluated in clinical trials and are described in detail in accompanying articles. In addition, there are a large variety of candidates in preclinical development, which are based on diverse technologies, ensuring a continued influx of innovation into the development pipeline. Potentially, some of the current preclinical candidates may become next generation dengue vaccines with superior product profiles. This review provides an overview of the various technological approaches to dengue vaccine development and specifically focuses on candidates in preclinical development.     

Evidence-to-policy gap on hepatitis A vaccine adoption in 6 countries: Literature vs. policymakers’ beliefs

Background

National vaccine adoption decisions may be better understood by linking multiple data sources. When examining countries’ decisions to adopt the hepatitis A vaccine, applying multiple research methods can facilitate assessments of gaps between evidence and policy. We conducted a literature review on hepatitis A and stakeholder interviews about decisions to adopt the vaccine in six countries (Chile, India, South Korea, Mexico, Russia, and Taiwan).

Methods

A systematic literature review was conducted across five literature databases. The review identified and abstracted 340 articles, supplemented by internet search. In addition, we interviewed 62 experts and opinion leaders on hepatitis A and/or vaccines. Data from the two sources were analyzed to identify gaps around epidemiologic data, economic data, and barriers/facilitators of hepatitis A vaccine adoption.

Results

Epidemiologic data gaps were found in Chile and Russia, where stakeholders believed data to be more solid than the literature documented. Economic data on hepatitis A was found to be weak across all countries despite stakeholders’ agreement on its importance. Barriers and facilitators of vaccine adoption such as political will, prioritization among vaccines, and global or local recommendations were discussed more by stakeholders than the literature. Stakeholders in India and Mexico were not concerned with the lack of data, despite growing recognition in the literature of the epidemiological transition and threat of outbreaks.

Conclusions

Triangulation of results from two methods captured a richer story behind vaccine adoption decisions for hepatitis A. The discrepancy between policymakers’ beliefs and existing data suggest a decline in priority of hepatitis A or weak investment in data collection. Filling the confirmed data gaps in seroprevalence or economic data is important to help guide policy decisions. Greater communication of the risk of hepatitis A and the benefits of the vaccine may help countries undergoing the epidemiologic transition.     

Current barriers,challenges and opportunities for the development of effective STI vaccines: Point of view of vaccine producers,biotech companies and funding agencies

Several barriers limit the development of vaccines against sexually transmitted diseases (STIs). Critical scientific information is missing that makes the feasibility and the likelihood of success of vaccines against genital herpes, chlamydia, gonorrhea and trichomonas uncertain: the immunity induced by natural infection is absent or imperfect which seriously limits the capacity to define the types of immune responses that an effective vaccine must induce. Reliable animal models are lacking and a number of crucial clinical questions are still unanswered about the goal of these vaccines and definition of endpoints for clinical trials. In the absence of a clear recognition of the need for vaccines against these diseases, there is no motivation for public or private research and industry to invest in the development of vaccines against STIs. The STI burden should be evaluated not only in terms of mortality and morbidity, but also in terms of economic and psycho-social impact. A global public–private consortium could mobilize the joint efforts of all stakeholders involved in the research, development and implementation of STI vaccines of the public and private sectors; ensure that sufficient resources are applied to R&D of vaccines against these STIs; and provide the pull–push forces that are necessary to overcome the barriers to develop safe and effective vaccines against these diseases.     

Vaccines: Shaping global health

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.     

WHO initiative to increase global and equitable access to influenza vaccine in the event of a pandemic: supporting developing country production capacity through technology transfer

Should a highly pathogenic avian influenza virus, such as the H5N1 virus type currently circulating in birds, become transmissible among humans, an effective vaccine, rapidly available in vast quantities, would be the best tool to prevent high case-fatalities and the breakdown of health and social services. The number of vaccine doses that could be produced on demand has risen sharply over the last few years; however, it is still alarmingly short of the 13 billion doses that would be needed if two doses were required to protect fully the world's population. Most developing countries would be last in the queue to benefit from a pandemic vaccine. The World Health Organization, together with governments, the pharmaceutical industry and other stakeholders, has been implementing the global pandemic influenza action plan to increase vaccine supply since 2006. Building capacity in developing countries to manufacture influenza vaccine is an integral part of this plan, as well as research and development into more efficacious technologies, e.g. those that allow significant dose-sparing. To this end, the influenza vaccine technology transfer initiative was launched in 2007 and, to date, vaccine manufacturers in 11 developing countries have received grants to acquire the capacity to produce inactivated or live attenuated influenza vaccine for their populations. In addition, a centralized 'hub' has been established to facilitate training in the new technologies for scientists and regulators in the countries. This supplement of Vaccine is devoted to showcasing the interim results of the WHO initiative and the impressive progress made by the developing country manufacturers.     

Being global in public health practice and research: complementary competencies are needed

Different sets of competencies in public health, global health and research have recently emerged, including the Core Competencies for Public Health in Canada (CCPHC). Within this context, we believe it is important to articulate competencies for globalhealth practitioners-educators and researchers that are in addition to those outlined in the CCPHC. In global health, we require knowledge and skills regarding: north-south power dynamics, linkages between local and global health problems, and the roles of international organizations. We must be able to work responsibly in low-resource settings, foster self-determination in a world rife with power differentials, and engage in dialogue with stakeholders globally. Skills in cross-cultural communication and the ability to critically self-reflect on one's own social location within the global context are essential. Those in global health must be committed to improving health equity through global systems changes and be willing to be mentored and to mentor others across borders. We call for dialogue on these competencies and for development of ways to assess both their demonstration in academic settings and their performance in global health practice and research.