Lessons from the Meningitis Vaccine Project

Introduction

The Meningitis Vaccine Project (MVP), a Gates Foundation funded partnership between PATH and the World Health Organization (WHO), succeeded in developing, testing, licensing, and introducing a new and affordable Group A meningococcal conjugate vaccine in sub-Saharan Africa. Key partnerships with SynCoBioPartners, Amsterdam, the Serum Institute of India Ltd., Pune, India, and the Center for Biological Research (CBER) at the U.S. Food and Drug Administration, Bethesda allowed for the development of a novel and affordable Group A meningococcal conjugate vaccine. Rigorous clinical testing in India and Africa (Mali, Ghana, Senegal, and The Gambia) showed that the vaccine, called MenAfriVac, was safe, highly immunogenic, able to enhance immunologic memory, and antibody persistence in 1–29-year-olds. On the basis of these observations the Drugs Controller General of India granted an export license so that the PsA-TT conjugate vaccine could be used in Africa. WHO prequalification was granted in June 2010.

After the completion of further vaccine safety studies in Mali, Niger, and Burkina Faso, the new Group A meningococcal vaccine was introduced at public health scale in December 2010 in these countries. Over the next 7 years, over 260 million Africans between the ages of 1–29 years were immunized in national immunization campaigns that were led by WHO and UNICEF and funded by GAVI and country funds. The vaccine was well received with coverage rates above 90%. The public health impact on Group A meningococcal meningitis was immediate; vaccination campaigns rapidly engendered herd immunity, and Group A meningococcal disease disappeared. In 2015, a MenAfriVac pediatric (5 mcg) formulation was prequalified by WHO, and work is currently unfolding to introduce the 5 mcg MenAfriVac formulation into African Expanded Program on Immunization (EPI) schedules.

Many lessons were learned during the 16 years of the project's existence (2001–2017) and with the benefit of hindsight, we have chosen six elements that were critical in facilitating the achievement of the project's single goal, “The elimination of epidemic Group A meningococcal infections as a public health problem in Africa with the introduction of new meningococcal conjugate vaccines”: (a) country and African regional engagement during all phases of the project; (b) the evolution of the WHO/PATH partnership; (c) funding the introduction of MenAfriVac in meningitis belt countries; (d) regulatory challenges; (e) clinical trials in Africa and India; and (f) partnership realities. Interested readers are encouraged to refer to a 31-article festschrift that covers all aspects of the project, which was published as a Supplement to the November 2015 issue of Clinical Infectious Diseases (10).

Country and Regional African Engagement

Epidemic meningitis has been an important public health problem in sub-Saharan Africa for over a century (2). Almost all of the major meningococcal epidemics in Africa were due to Group A Neisseria meningitidis. The epidemics caused great havoc with major morbidity and mortality with disruptions in healthcare and attendant economic turmoil.

Dealing with meningitis epidemics resulted in the development of public health response plans that largely emphasized two areas: (a) ensuring that proper care was provided to affected populations largely through the adherence to WHO treatment schedules and (b) the provision of reactive vaccinations using meningococcal A/C polysaccharide vaccines. After the huge 1996 Group A meningococcal epidemic with over 188,000 reported cases, an Interagency Coordinating Group (ICG) was created with the secretariat located at WHO/HQ with the responsibility of facilitating meningitis response activities. In short, affected countries reported epidemics, and following a specific format could request vaccines from the ICG (11). Over time, the ICG served as an important locus for the acquisition and distribution of meningococcal vaccines that were needed to respond to epidemics. The ICG worked closely with vaccine manufacturers to ensure that vaccines were available.

Reactive vaccination campaigns are expensive, and they have to be done in the unenviable context of the chaos occasioned by the meningitis epidemic and the realities of competing public health demands. Too often, the reactive campaigns were done after the epidemics were over and the public health good, as differentiated from the political necessity of “doing something,” was, at best, unclear (1).

The sole goal of the MVP was to eliminate Group A meningococcal epidemics from the meningitis belt by developing, testing, licensing, and introducing affordable Group A meningococcal conjugate vaccines that could establish herd immunity. For the project to succeed, it was necessary to have the strong and unambiguous support of African Ministers of Health, the regional WHO office (WHO/AFRO), public health leaders as well as in-country partners such as Medecins Sans Frontieres.

Two MVP Africa-specific experiences are cited as concrete examples of the importance of African know-how and support that led to the development of successful strategies.

The WHO/PATH Partnership

WHO has a global mandate to improve immunization services. For over 40 years through its Expanded Program on Immunization, WHO has provided effective leadership at the international, regional, and country levels in the development, introduction, and evaluation of EPI vaccines. In addition, WHO has played a key role in the public health response to African meningitis outbreaks and as noted previously, it serves as the secretariat for the meningitis ICG that helps manage and distribute global meningococcal vaccine supplies when epidemics occur.

The MVP/PATH office was located in Ferney, France, near the WHO/HQ offices in Geneva, Switzerland. The PATH/WHO proximity greatly facilitated the development of a close working relationship between PATH and WHO/HQ. The MVP Project Management Committee was made up of two senior leaders from WHO and PATH and functioned as the “MVP Board.” The Management Committee met twice yearly when they reviewed and approved work plans and budgets. The arrangement ensured that both PATH and WHO were fully vested in MVP strategies and plans.

Nonetheless, it is worth noting that initially, and not surprisingly, there were important tensions between WHO and PATH relating to the project and partner responsibilities, which continued through 2002, and were resolved once a formal Memorandum of Understanding (MOU) between PATH and WHO was negotiated and signed in June 2003. The MOU clearly identified the leadership role of WHO for meningitis surveillance and vaccine introduction in Africa, while PATH took the lead in terms of vaccine development. The MOU specified that all MVP activities and decisions were collaborative, and despite the occasional misunderstanding, the WHO/PATH partnership matured such that trust across both institutions became a defining trait of the project (4).

Funding the Vaccine Introduction

The PsA-TT (MenAfriVac) vaccine development costs at the time of Indian licensure (December 2009) were about $U.S. 100 million and fully supported by Gates Foundation grants and capital investments by Serum Institute. The vaccine introduction strategy was based on comprehensively immunizing 1–29-year-olds (about 70% of African meningitis belt country populations) in vaccination programs done largely in the fourth quarter of successive years. With good coverage (defined as better than 90%), it was expected that herd immunity could be achieved with the resultant disappearance of Group A meningococcal infections (6).

The project envisioned giving from 250 to 300 million doses of MenAfriVac from 2000 to 2017. Even at a vaccine price of $U.S. 0.50 per dose the scope of the proposed vaccine intervention meant that there were major financial hurdles to surmount. An Investment Case requesting support for vaccine introduction was submitted to GAVI in 2008, and a revised Investment Case was approved later that year. Countries were expected to pay one half of the local immunization costs (vaccinators, cold chain, logistics), while GAVI agreed to fund vaccine purchases, the second half of the vaccine administration costs plus supporting disease surveillance, and communication costs. The GAVI commitment stood at about $U.S. 1.20 per vaccine, which meant that if 300 million Africans were to be immunized, about $U.S. 360 million dollars needed to be pledged by GAVI from 2010 to 2017.

The first countries to use the new PsA-TT vaccine were Burkina Faso, Mali, and Niger, countries that had historically suffered greatly from epidemic Group A meningococcal meningitis. Of the three countries, only Burkina Faso was capable of mounting a full national campaign in 2010. The Burkina Faso vaccination campaign proved to be an unqualified success. From December 6 to 15, 2010, more than 95% of 1–29-year-old Burkinabes (10.8 million persons) received the vaccine. The 2011 Burkina Faso surveillance data documented the disappearance of Group A meningococcal disease and carriage studies showed that the organism had disappeared, data consistent with the postvaccination establishment of herd immunity (5).

Once the success of the new vaccine was demonstrated in Burkina Faso, other African countries pushed to be vaccinated as soon as possible, and new GAVI funds to support the vaccination campaigns were made available. Much of this work was facilitated by a broad collaboration between country Ministries of Health working with WHO/AFRO, WHO/HQ, UNICEF, MVP/Ouagadougou, and bilateral international agencies. Detailed introduction plans were formulated and harmonized with Serum Institute's ability to produce and ship vaccine so that no stock outs occurred. Over the next 6 years, African vaccination campaigns with PsA-TT proceeded virtually flawlessly in 16 countries. The success of the combined effort is testimony to the effectiveness of the partnership that existed between countries, international organizations, and the Serum Institute of India.

Working with multiple international agencies required time, tact, patience, and constant attention. Nonetheless, the time spent by MVP staff at innumerable meetings and conferences proved to be useful in ensuring that the successful results of the vaccination campaigns and the satisfaction of participating countries were brought to the attention of partners and funding agencies.

Regulatory Challenges

Licensing a new vaccine in the country of origin and obtaining WHO prequalification are complex tasks. Compliance with international and Indian national requirements as well as ethical regulations for preclinical (i.e., ICH-GCP, EU/WHO guidelines, EU Pharmacopea) and clinical vaccine development (ICH-GCP, Declaration of Helsinki, WHO/EU guidelines) were followed. The PsA-TT conjugate vaccine was to be the first new vaccine to be globally qualified and produced outside of the major Pharma companies in Europe and the United States and to be used at such a large scale. MVP deemed that the highest recognized regulatory standards were adhered to. Both the DCGI and the WHO prequalification groups were regularly briefed on the progress of the PsA-TT vaccine development and both provided critical review on the regulatory and development strategies.

WHO routinely audits vaccine-related activities of National Regulatory Agencies (NRA). In 2007, the India Minister of Health was notified that the DCGI was being decertified as a WHO-qualified NRA. This took MVP by surprise and meant that all formal DCGI regulatory advice on the PsA-TT vaccine development would cease and could not begin until the DCGI was recertified by WHO.

Over the next 6 months, an extensive plan of corrective activities was developed between the DCGI and WHO. An important component of the planned corrective activities was a training collaboration between Health Canada, the Government of Canada's regulatory authority, and the DCGI. Discussions among WHO, Health Canada, and the DCGI resulted in a decision to use the licensure of the PsA-TT vaccine as a case study and a training opportunity.

The DCGI underwent a WHO reevaluation in 2008, and WHO decertification on DCGI was lifted later that year. In April 2009, a full dossier was submitted to the DCGI from the Serum Institute of India requesting export license for the new PsA-TT conjugate vaccine. In December 2009, DCGI was granted an export license for the new PsA-TT conjugate vaccine. WHO prequalification was obtained in June 2010.

The linked activities between WHO's prequalification group in Geneva and the DCGI proved to be a model on how to improve country regulatory activities. This task was viewed by Indian officials as important. Serious work by all participating agencies led to the DCGI's success in becoming recertified by WHO, which proved to be a critical step in the regulatory strategy for the new vaccine.

African Trials

The clinical strategy for the testing and licensure of the PsA-TT conjugate vaccine included eight clinical trials that were done in Africa and India. The clinical development team was based in the PATH/Ferney-Voltaire office with liaison at WHO/HQ and SIIPL. With the goal of complying with existing regulations and guidelines for the clinical development of new vaccines, the MVP clinical team built an efficiently tailored quality system, which was comprehensive and cost/effective. Capacity building was a major element of MVP clinical work, and study sites in India and Africa were initiated to ICP-GCP trials. Clinical Research Organizations (CROs) were based in Dakar and Mumbai.

A sound ethical platform was a key element at all the African and Indian trial sites. MVP paid close attention to the quality of community involvement and the consensus that characterized the African and Indian trials. MVP took great care in ensuring that all participants, particularly at the village level, were aware of the trials and participated actively in decisions relating to informed consent and the conduct of the clinical trials. Community consent was obtained in addition to the required individual consent. The administrative demands that were required at MVP to maintain proper documentation with multiple ethical panels at the national, regional, and local levels consumed a great deal of time but were viewed as essential for the successful completion of the clinical goals of the project (3).

Work on the MVP clinical trials helped strengthen clinical trial capabilities at a number of African and Indian sites. Follow-on studies at these sites that yielded important information on other vaccines were very reassuring to MVP staff that their site work had led to the sites being viewed by other vaccine developers as good loci for testing other needed vaccines (7).

Partnership Realities

Successful partnerships were a hallmark of MVP work. They were over 30 partnerships that were part of the MenAfriVac development and licensure activities. Each of the partners had their own goals, be they financial, political, aspirational, philanthropic, or humanistic. An important task was a clear understanding of what individual partners wished to receive out of a partnership with MVP. We soon learned that respecting partner interests was key to ensuring that partners wanted to continue working with MVP. With some partners, financial issues were not as important as getting the project's goals done. Other partners emphasized financials. Each partner was different, but as the project matured, it became clearer that a highly immunogenic and safe vaccine was being made and that there was increasing likelihood that the vaccine would be introduced, general attitudes did move from a purely partner perspective to what was happening to the project.

Ensuring that MVP's goal of eliminating Group A meningococcal meningitis in sub-Saharan Africa was brought up at all partner meetings along with a summary of the most recent Group A epidemics in Africa (usually by Dr. Mamoudou Djingarey) maintained a sense of urgency. What became obvious over time was that groups became more interested in the entire effort. Transparency about problems and challenges also helped. The quality and the depth of the MVP partnerships were probably best sensed at two meetings.

Among the many partner meetings that took place as the project matured, two international meetings stand out. The most important international Neisseria meeting is the biennial International Pathogenic Neisseria Conference. The 2008 meeting in Rotterdam (September 7–12) was a particularly important meeting for MVP. The project was at that time well on its way and now had sound information on the safety and immunogenicity of its new vaccine PsA-TT. During a 2 h session, an international audience was briefed on the epidemiology of meningococcal meningitis in Africa, the clinical results of the new PsA-TT vaccine, and the projected public health impact that could follow introduction of the vaccine in Africa. An evening session allowed for extensive interchanges with conference attendees on the details of the vaccine development and meningitis in sub-Saharan Africa. Many of MVP partners attended the Rotterdam meeting, which allowed for broad dissemination of the results of 7 years of work.

From February 10 to 12, 2010, an MVP Scientific Workshop took place in Pune, India. The meeting was funded by MVP with a generous grant from the Merieux Foundation. During the 3-day meeting, all aspects of the project (vaccine development, epidemiology, clinical trial results, regulatory issues) were presented in detail at a time when the DCGI export license had been granted (December 2009) and the WHO prequalification dossier had been submitted to WHO/Geneva. For many of the participants, the Pune meeting was their first visit to India and the meeting allowed all participants to tour Serum Institute facilities and freely interact with Serum Institute scientists and administrative staff. The collegiality, energy, and enthusiasm expressed by all participants presaged the success that the vaccine was to have after its introduction in Africa.

Conclusion

MVP's efforts have resulted in the addition of a potent, safe, and affordable new Group A meningococcal conjugate vaccine for Africa. The vaccine has successfully eliminated African Group A epidemics, but the work will not be finished until stable and comprehensive use of PsA-TT conjugate vaccine in African childhood immunization programs is achieved to ensure that newborn cohorts are protected against Group A N. meningitidis. Unless this is done, Group A meningococcal disease will return to Africa (4,8).