From meningitis to COVID-19 vaccines: an overview of AVAREF´s contribution to research and development of priority vaccines from 2006 to 2022

¹Vaccine Preventable Diseases Program, World Health Organization Regional Office for Africa, Brazzaville, Congo, ²Regulation and Safety Unit, World Health Organization, Headquarters, Geneva, Switzerland

^&Corresponding author
Chinwe Iwu-Jaja, Vaccine Preventable Diseases Program, World Health Organization Regional Office for Africa, Brazzaville, Congo

Essay    

Introduction and objective

For several decades, Africa has lagged other regions of the world in research and development (R&D) and the introduction of health products into its health systems. The situation persists with clinical trials activity in Africa being about 2.2% of global clinical trials [1]. The consequences of this weak R&D, especially of vaccines, mean that Africa is always the last continent to introduce new vaccines already in use for several years in other parts of the world. As an example, all the vaccines made available to Africa during the COVID-19 pandemic were manufactured outside of the continent. Also, some new vaccines are designed for use in developed countries, and their costs are out of reach of African countries. At the time when the African Vaccine Regulatory Forum (AVAREF) was established in 2006, the only childhood vaccines in use in most African countries were against poliomyelitis, tuberculosis, diphtheria, whooping cough (pertussis), tetanus, and measles; often referred to as the six childhood killer diseases [2]. Other childhood vaccines available in high-income countries were unavailable in most of Africa.

Among the reasons for the non-involvement of Africa in R&D of vaccines are weak regulatory oversight of clinical development and registration of vaccines, inadequately resourced clinical trial sites, the unwillingness of developers and sponsors to bring clinical trials due to fewer experts, poor governance and lack of transparency, and prolonged timelines for evaluation of applications by both ethics committees (ECs) and national regulatory authorities (NRAs) [3]. Through its ethics and regulatory harmonization, AVAREF created a minimum capacity required for the regulation of clinical trials and attracted more clinical trials to the continent. Clinical trials on vaccines against meningococcal meningitis, diarrhea due to rotavirus, Hemophilus influenzae type b (Hib) disease, pneumococcal pneumonia, cholera, malaria, tuberculosis, and HIV have taken place [4-7]. Recently, the AVAREF platform has been supporting clinical trials for neglected tropical diseases such as Lassa Fever and Rift Valley Fever. The clinical trials in which AVAREF is involved also come with complex designs, such as adaptive designs for severe malaria, snakebite, and controlled human infection model (CHIM). These clinical trials were necessary for the generation of clinical data required for the prequalification and registration of these vaccines. Clinical trials were also meant for the development of vaccines for exclusive use in Africa, such as the meningococcal A conjugate vaccine, and the development of new vaccines against diseases for which there were no vaccines, such as malaria and HIV.

Therefore, AVAREF in building capacity for ethics and regulatory oversight of clinical trials on the continent provided the momentum for the rapid development of priority vaccines for the continent. How AVAREF addressed the gaps in R&D were through the development and optimization of harmonized submission and review templates and checklists as well as guidelines for review and approval processes for Clinical Trial Applications (CTAs), consistent with World Health Organization (WHO), International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use (ICH), and other international standards and guidelines. The Bill and Melinda Gates Foundation (BMGF), WHO, European Medicines Agency (EMA), United States Food and Drug Administration (USFDA), Health Canada, and other partners strengthened the capacities of ECs and NRAs through training, information sharing, and participation in working groups with AVAREF. Consequently, high-quality reviews and shorter timelines for clinical trials were achieved. These achievements were accompanied by improved transparency and clear submission requirements, and a common application process for clinical trials in different countries.

To overcome the above-mentioned challenges in the African continent, the WHO has also initiated a joint review model involving ECs and NRAs of multiple countries. The paper, therefore, highlights the successes of AVAREF in R&D, especially in vaccines, and identifies the model used to achieve results quickly. For the future, complexity in pathogen biology and disease pathogenesis, complexity in design for clinical trials, global health demands for shorter R&D timelines, and better use of resources demand that AVAREF adapts to the future. The emergence of the African Medicines Agency (AMA) and other regional regulatory harmonization networks also demands a reassessment and, hence, a repositioning of AVAREF´s role in R&D. Therefore, in addressing the challenges identified, the paper aims to explore how AVAREF can better support R&D of health products to meet local priority and global public health needs. The paper will argue for improvement in the AVAREF clinical trial application review model, address common implementation of outcomes of joint reviews, timelines, and use of digital platforms. Additionally, this essay reviews AVAREF´s contribution to vaccine R&D from 2006 to 2022, using four emblematic case studies (RTS,S malaria vaccine; MenAfriVac; childhood diarrhea and pneumonia vaccines; and Ebola/COVID-19 vaccines) to illustrate our impact, lessons learned, and future priorities. We first outline the historical challenges to vaccine R&D in Africa, then describe AVAREF´s model and its evolution, analyze each case study, and conclude with recommendations for sustaining and scaling this approach as AMA gets operationalized.

Catalyzing vaccine R&D for Africa´s neglected diseases

Among other reasons, published literature reveals that the feasibility of development, long-term manufacture, and profitability (economic viability) by manufacturers dictate which vaccines will be developed. Importantly, Africa contains the widest range of genetic variability around the globe, which is yet to be researched and fully integrated into clinical research and the resulting therapeutics. The emergence of the African Continental Free Trade Agreement and market (AfCTA), as well as the soon-to-be operationalized AMA, are noteworthy and potential game changers as we consider a renewed ecosystem for research. Often, vaccines against diseases which are only endemic in Africa and are responsible for epidemics such as Lassa fever, Ebola, and malaria appear non-profitable and are not high priority for R&D. AVAREF has played a critical role in advocating for vaccines against these neglected diseases of the African continent. Consequently, WHO ensured that AVAREF was represented in global R&D to promote the development of vaccines against diseases endemic in Africa. For example, AVAREF was involved in the development of a WHO R&D Blueprint and prioritization of diseases for R&D [8,9]. A series of case studies was used to showcase the success of AVAREF in the R&D of priority vaccines. These case studies address R&D of: i) the first malaria vaccine (RTS,S); ii) conjugate meningitis A vaccine (MenAfriVac) iii) vaccines against childhood diarrhoea and pneumonia (Rotavirus vaccine and pneumococcal conjugate vaccine); iv) epidemic and pandemic vaccines (Ebola and COVID-19 vaccines). Under each case study, a brief background and the importance of the vaccines are provided. The objectives and challenges of R&D are explained. The role of AVAREF in addressing these challenges, resulting in the successful development of these vaccines and subsequent impact, is presented. Finally, all the AVAREF activities that contributed to the R&D of each of these vaccines are chronicled in Table 1.

Case study 1 - RTS,S malaria vaccine

The first case study described focuses on the only antiprotozoal vaccine to be developed, prequalified, successfully piloted, and rolled out after regulatory registration in Africa. The first challenge to its development was how to provide ethics and regulatory approvals of a CTA and oversight for a large Phase III study involving over 15,000 infants and children within eleven sites and seven countries in Africa [11]. AVAREF developed a common submission requirement for the CTA and organized a joint review of the CTA, bringing together NRAs and ECs of the seven countries, the developers of the vaccine GSK Bio and their investigators, as well as PATH. This joint review of a multisite, multicountry clinical trial application by ECs and NRAs was facilitated by WHO and supported by its partners. This simplified the review and approval process for a rather complex product clinically evaluated in different countries. The joint review was a success, and within one year, the trial had begun in all seven countries, a process that could have taken several years and involved different submissions to different countries with multiple reviews [12]. The process could also have resulted in different outcomes with different timelines and could have affected the initiation of the clinical trials in the seven different countries.

Malaria transmission is highly seasonal across different countries [13-15], and as such, accumulating sufficient cases to meet the endpoint is often dependent on the period of initiation of any studies. Built into the joint review model and facilitated by WHO and PATH, the developer met annually with the seven countries at each of the annual AVAREF meetings. This was to provide updates on the progress of the clinical trials across the eleven sites, enabling the African regulators to monitor progress while contributing scientific advice to the investigators. This is unique to the joint review of RTS,S, and was important for building consensus around the development of the vaccine. After the clinical trials, the AVAREF platform was used in 2017 and 2018 in the authorization (in 2019) of the pilot studies in Kenya, Ghana, and Malawi, where additional data was required following the need for confirmation (validation) of some safety signals identified during the clinical trials. The AVAREF platform was used in the final registration of the RTS,S in 9 countries with 7 observers in 2023.

Case study 2 - MenAfriVac (conjugate meningitis A vaccine)

In the second case study, a conjugate meningococcal meningitis vaccine was required for exclusive use in the meningitis belt countries across Africa. The call for this vaccine was made by African leaders, who recognized the public health impact of epidemics of meningitis in their countries. WHO, working with PATH and the African countries, endorsed a plan for the vaccine to be manufactured in India, clinically tested in Africa, licensed, prequalified by WHO, and rolled out to end the epidemics of meningitis due to Neisseria meningitidis. The challenge was how to organize ethics and regulatory reviews of a common CTA, ensure joint inspections of clinical trial sites, and involve African regulators in the prequalification process, and eventual regulatory registration across the continent to meet its rollout plan. In this case, AVAREF organized a joint GCP inspection of the clinical trial sites in three countries to ensure compliance with approved protocols and the generation of consistent data applicable to the populations in the different countries. Additionally, AVAREF organized the participation of regulators from Niger, Chad, and Burkina Faso in the prequalification process. AVAREF, through the WHO expedited review procedure, ensured that large numbers of countries came together to register the vaccines, thereby ensuring their smooth rollout. Good Clinical Practice (GCP) inspections are an important means of auditing clinical trials after ethics and regulatory approvals. WHO recognized this and therefore made it one of AVAREF´s strategic priorities [12]. By applying the joint GCP inspections of the clinical trial sites for the conjugate meningitis A vaccine, AVAREF ensured the success of its development.

Case study 3 - childhood vaccines for rotavirus and pneumococcal disease

In the third case, the need to generate local data in support of the registration and introduction of childhood vaccines against Rotavirus diarrhea and pneumococcal pneumonia became necessary. The challenge was how to facilitate the engagement of the sponsors of clinical trials by all the regulators of the continent and to ensure a common registration pathway for the vaccines after prequalification. AVAREF immediately provided solutions to these challenges. Thus, AVAREF engaged investigators who were conducting clinical trials of these vaccines, ensuring that they presented data for discussion by the regulators in closed-door sessions of their annual meetings. The regulators provided invaluable scientific and regulatory advice to the developers. Subsequently, when these vaccines were prequalified by WHO, AVAREF used the WHO expedited review procedure to ensure registration of these vaccines before their roll out into childhood immunization programs [6].

Case study 4 - vaccines for Ebola and COVID‑19

The final case study has summed up the involvement of AVAREF in the rapid clinical evaluations of vaccines against epidemics of Ebola and the COVID-19 pandemic. Clinical trials during epidemics and in pandemics pose special challenges to ethics committees and regulators. These challenges include how to accelerate the trials and generate sufficient data for product licensure and use while ensuring safety in subjects. Additionally, the availability of limited data for product evaluation, coupled with global health pressure and public expectations to provide effective vaccines and therapeutics, further puts a burden on regulators. As an additional challenge, during the Ebola epidemic of 2014/2015 and the COVID-19 pandemic, restrictions were placed on travel, making it difficult to carry out in-person submission of CTAs and the reviews of these applications by ECs and NRAs. Furthermore, the limited knowledge about these diseases and the unavailability of experts placed another burden on the regulators. To accelerate product development within the Ebola epidemic and the COVID-19 pandemic, AVAREF developed and approved the expedited review and the emergency reviews of CTAs with shorter timelines of 30 days and 10 days, respectively. To address the next challenges, AVAREF organized regular online capacity-building webinars and invited clinical trial investigators to share new knowledge and information about COVID-19 vaccine candidates and preliminary safety and efficacy results with the regulators. To overcome travel restrictions, AVAREF promoted online CTA submissions and reviews. The AVAREF joint review was transformed from a series of physical meetings into an online process. During the Ebola epidemic, AVAREF overcame travel restrictions by organizing a joint review at the WHO headquarters in Geneva [16] and facilitated a review in Europe of another Ebola vaccine candidate by the regulators of Guinea [17]. Finally, AVAREF was also involved in the emergency use listing process implemented by the WHO for COVID-19 vaccines. Thus, facilitating shorter timelines for the regulatory approvals of COVID-19 vaccines and their rollout. These vaccines were rapidly approved by African countries before their introduction, contributing to the end of the pandemic [18,19].

Advances in regulatory maturity levels

This current publication has demonstrated that AVAREF has played an important role in accelerating the R&D of medicines, including vaccines, on the continent. This major achievement of AVAREF has come from the capacity of the NRAs and ECs, consistently built from 2006 to date. Thus, over the years, the continent has seen an increase in maturity levels (MLs) of its NRAs, and the emergence of strong ethics and regulatory systems has resulted in the clinical development, prequalification, and registration of important vaccines now in use on the continent. Before the establishment of AVAREF in 2006, the African continent contributed very little to the R&D and the introduction of priority medicines and vaccines [10]. The introduction of any vaccines into a country requires regulatory approvals, which are guaranteed in most developed countries. In low- and medium-income countries (LMICs), and especially in Africa, the lack of adequate capacity to carry out this important regulatory oversight function and to oversee post-marketing surveillance remained a challenge before the establishment of AVAREF. Most of the vaccines in current use in Africa were introduced following the establishment of AVAREF and with close involvement of the regulators, ensuring an accelerated registration and introduction of vaccines. PCV, Rotavirus vaccine, MenAfriVac, Hib, IPV, in addition to vaccines against Ebola and cholera, were all developed, prequalified, and licensed with the involvement of AVAREF.

Through the work of AVAREF, the maturity levels for African countries with ML-3 for the clinical trial component have risen, and currently, the African continent has eight NRAs assessed at ML-3, namely South Africa, Tanzania, Ghana, Nigeria, Egypt, Zimbabwe, and recently, Senegal and Rwanda. Basically, attaining ML-3 for clinical trials paves the way for ML-3 for all regulatory functions, as was observed in Zimbabwe. R&D comprises early basic and laboratory (non-clinical) research, applied research, and epidemiological studies to establish disease burdens and justify product development. Once this is established, a decision is made in favor of clinical studies in human subjects to establish the safety and efficacy of the product and to generate data for regulatory approval of the product and its use. In Africa and other LMICs, where UN agencies and their partners are involved in the procurement and supply of health products, WHO prequalification is mandatory before the UN agencies procure the vaccine for use in target countries and the introduction of the product. Through the work of AVAREF, African countries with mature regulatory systems require regulatory approval in their countries before the authorization of the use of prequalified vaccines via UNICEF. African countries need regulatory capacities sufficient to meet their role along the innovation life cycle, namely in clinical trial application assessment, good manufacturing practices, product registration, and post-registration monitoring and assessment. Countries with weak regulatory and ethics systems tend to rely solely on prequalification for the use of priority public health products without further regulatory decisions. With the operationalization of AMA, as well as the integration of reliance mechanisms, modelled by AVAREF and WHO-listed authorities, this practice of sole reliance on prequalification would soon be a thing of the past.

What made AVAREF so successful in contributing to R&D?

Since 2006, AVAREF has demonstrated its value in R&D, resulting in the licensure and prequalification of important vaccines against diseases on the continent. How was it achieved, and what was the impact? We have enumerated and explained below the reasons why AVAREF has been so successful in making substantial contributions to research and development on the African continent since its inception in 2006. 1) WHO as convener: As a neutral broker with presence in nearly all its 194 member states, a pool of experts, and engagement with global public health partners and stakeholders, WHO remains the lead convener in response to epidemics and pandemics [20]. Through the establishment of AVAREF and the hosting of its secretariat, WHO also brought the additional need for regulatory support for R&D in emergencies to find solutions for these diseases. 2) Strong relationships, solidarity, and engagement of all stakeholders: Over the years, WHO has established sustained partnerships with global public health partners. WHO has also led in the response to health emergencies and threats. This effort includes the eradication of Smallpox, significant reductions in the burdens of poliomyelitis, measles, and other childhood illnesses. Several of the AVAREF partners have been with the forum since its inception in 2006, with a large majority of over 10 years of steady support and still supporting. 3) Extreme flexibility, which allowed countries to modify their policies and to adapt the AVAREF processes and timelines quickly. The ethics committees and regulators developed and implemented their own norms and guidelines, allowing for acceptance of decisions and outcomes of joint activities [21]. 4) Capacity building alongside implementation helped to accelerate the R&D process without delaying reviews due to a lack of expertise. Through joint activities, the continental network shared resources, including the limited expertise, often accepting the advice of African experts irrespective of where they come from. This is exemplified by the establishment of the AVAREF Technical Coordinating Committee (TCC) and Steering Committee (SC), experts nominated by the different regional economic communities [22]. 5) Common timelines and standardized templates ensured that all trial sites used a common clinical trial application and review process. Timelines for specific stages of clinical trial processing were endorsed by all participating countries. AVAREF, through TCC, developed timelines for the processing of applications of products against specific health priorities based on the WHO classification of the target diseases. Thus, timelines were set for priority endemic diseases of the continent, epidemics, and pandemics [21]. 6) Digitalization encouraged online submissions by sponsors and principal investigators and application processing by ECs and NRAs. The restrictions placed on travel during the Ebola epidemic and the COVID-19 pandemic resulted in the use of online reviews of CTAs and product dossiers. This shift to digitization helped the ECs and NRAs to process applications without delays. Several countries have an online application submission and review process. 7) The strong partnership and collaboration with the Bill and Melinda Gates Foundation enabled AVAREF to respond to global health challenges through R&D. A significant difference was made by the technical support and repurposing of grants to WHO to address the Ebola epidemic and the COVID-19 pandemic by the BMGF, without which AVAREF could not have made a difference in R&D.

Conclusion     

The role of AVAREF in regulatory and ethics capacity building, and hence in R&D, has been demonstrated with these case studies. The impact of the years of capacity building in Africa by AVAREF and others is increasingly being observed that in the last 12 months, as at when this paper was written, three member states have attained ML-3 status is an indication of that. As such, we expect that in the near future, we will have more member states increase their respective capacities. It is important to recognize that the contribution of regulatory and ethics capacity building to R&D is limited and probably not the main driver for innovation. As such, it is important that an ecosystem approach is employed, so that all actors in the ecosystem, such as researchers, clinical trialists, laboratories, etc., are supported to ensure a viable and thriving ecosystem. Hence, the need for AVAREF to continue its collaborations and partnerships with others within the ecosystem for sustainability.

Competing interests     

The authors declare no competing interests.

Authors' contributions     

Bartholomew Dicky Akanmori conceptualized the study and wrote the first draft. All authors provided critical inputs to subsequent versions. Chinwe Iwu-Jaja prepared the manuscript for submission and managed the submission process. All authors have read and approved the final version of this manuscript.

Table     

Table 1: priority vaccines developed over the period 2006 to 2022 with AVAREF involvement

References