INTRODUCTION

Developing an effective HIV vaccine has proven to be a complex challenge and recent results of three late-stage trials showing nonefficacy [1–3] have highlighted the need to refocus vaccine development from traditional, empirical approaches towards rational vaccine design. The field finds itself in an era where discovery or experimental medicine vaccine trials (EMVTs) are important tools to test innovative scientific hypotheses and accelerate vaccine development in the HIV field. Experimental medicine vaccine trials have been defined as ‘clinical investigations of multiple immunogens undertaken to test or generate a scientific hypothesis that advances vaccine discovery and development rather than testing a specific product being designed to move into later-phase trials’ [4▪▪]. Data from these EMVTs would also iteratively inform vaccine design.

Despite the recent pipeline of late-stage trials, the field is several years away from additional efficacy testing and will need to address how to evaluate vaccine efficacy in the context of all other existing and soon to be available HIV prevention tools. A search of multiple clinical trial databases and vaccine pipelines presented at various conferences, showed that over 30 discovery medicine vaccine trials are either ongoing or planned in the next 2 years in various regions of the world. A few of these trials are in Africa. Though usually of short duration, they have tended towards complex vaccination and intense visit schedules, may deploy atypical sample collection procedures such as leukapheresis, ultrasound-guided fine needle lymph node aspirations (FNAs) or whole biopsies and large blood draws. They are often more likely to test investigational products in people for the first time. The trial endpoints for these trials usually involve complex immunological assessments, often with new assays and techniques and they can be resource intensive.

Given some of these issues, as well as the challenges engaging communities about the nature and purpose of these trials, one may ask why we need to conduct EMVTs in Africa. There is a critical need to ensure the relevance of vaccines under development for the African context. Populations in the various regions of the world can have different host parameters affecting immune responses to vaccines and this may be driven by genetic differences or environmental factors [5,6]. Epidemiological studies have also shown us that different regions of the world tend to have different virus strains circulating or dominating [7]. The emergence of drug-resistant strains may also differ in different parts of the world for several reasons [8,9]. We will need to understand the relevance of potential vaccines, their potential coverage, as well as the ability to generate desired immune responses in different regions.

Recent guidance on the ethical considerations of HIV prevention research highlights inclusive approaches to research in various areas [10]. An inclusive approach in the context of this discussion, emphasizes the need to remove the barriers and look at ways to enable the conduct of these complex early-stage trials in Africa and other regions of the world where the eventual vaccines will be deployed and will have the greatest impact. As a field, we must invest towards enabling four main areas in Africa: community and other stakeholder understanding of the purpose and value of these early, discovery stage trials; advanced clinical capacity to support nonconventional sampling methods (leukapheresis, FNAs and large blood draws) intense immune and adverse event monitoring; state-of-the art research capacities, including latest generation laboratory equipment and scientists to drive research questions and lead in immunological analyses with an understanding of local influences on vaccine responses and supportive regulatory and ethical review pathways providing rapid, rigorous and critical review of studies. 

Box 1:

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ENGAGING AFRICAN SCIENTISTS IN INNOVATIVE AND PROMISING VACCINE RESEARCH THROUGH THE ADVANCE PROGRAM

ADVANCE (Accelerating Development of Vaccines and New Technologies to combat the AIDS Epidemic) is a collaborative agreement between IAVI and USAID that focuses on preclinical and clinical vaccine R&D and enabling next generation vaccine evaluation in Africa through targeted and intensive capacity strengthening (Fig. 1). The program is built on the assertion that successful HIV prevention requires increased contribution to research efforts by those countries and regions hardest hit by the epidemic. In an important milestone for the field evaluating a leading germline targeting eOD-GT8 60mer mRNA vaccine, the experimental medicine vaccine trial IAVI G003 was conducted in Africa with local clinical investigators leading the trial in South Africa and Rwanda. Scientists at the Kenyan Medical Research Institute Wellcome Trust Research Programme (KWTRP) are leading the immunogenicity end point evaluation for the trial with four labs in Kenya and South Africa contributing to the endpoint analysis for the G003 trial. Working with scientists who have pioneered the germline targeting approach at the Scripps Research Institute and the IAVI Neutralizing Antibody Center (NAC) lab, cutting edge immunology analysis equipment has been set up, with scientific exchange and technology transfer activities focused on a regional group of senior and mid-early career scientists. A collaborative approach towards scientific exchange rather than the training of technologists has ensured that African scientists contribute to developing research questions and overseeing research activities related to G003 analysis within the region. The field cannot deny the paucity of studies contributing to HIV vaccine design and discovery led by and published by African scientists. Neither can we deny a long-held tradition of shipping samples outside of Africa for key immunological endpoint analysis. This may be explained by the lack of adequate technical capacity for antibody discovery and characterization, single-cell sorting, next generation sequencing (of antibodies and HIV envelope populations) and expertise in structural analysis of antibody-envelope interactions within the African region.

FIGURE 1:

The ADVANCE clinical research network and established capacity. ADVANCE, Accelerating Development of Vaccines and New Technologies to combat the AIDS Epidemic.

In 2019, the ADVANCE program began working with several partner clinical research centres (CRCs) to establish platforms and assays for high dimensional and high throughput assessment of B-cell responses to allow local researchers to address critical knowledge gaps within natural HIV infection studies such as discovery of broadly neutralizing antibodies against specificities that do not map to any of the known epitopes and characterizing bnAbs that bind to undefined epitope regions such as the fusion peptide, gp120-gp41 interface and silent face regions. The knowledge will contribute to refining current immunogen and bnAb strategies. These same platforms are being leveraged to conduct endpoint immunogenicity analysis for EMVTs such as IAVI G003. Nearly four new experimental medicine trials are planned in the next 2–3 years in the ADVANCE network. An important determinant being the local investigators who will co-lead in the conceptualization of the key research questions and clinical trial designs. Sample analysis pipelines must be carefully planned to support multiple iterative trials, often with a range of exploratory endpoints to support deep immunological investigation. Projections in various product pipelines, including the germline targeting space, indicate that the amount and complexity of the work that will need to take place globally and in Africa will grow significantly. Although trial implementation sites may be more readily deployable, the clinical sample analysis pipelines will need to expand significantly and global efforts towards a vaccine will be accelerated by positioning African scientists to contribute to this and future efforts in innovative vaccine science.

Similar efforts have been made to contribute to development of vaccines aiming to induce effective cytotoxic T-cell responses against HIV. Virus surveillance activities are ongoing under ADVANCE to identify and sequence currently circulating variants of HIV to continuously inform immunogen design. In carrying out trials of the conserved mosaic vaccines in collaboration with the University of Oxford, scientists within the ADVANCE network have been able to demonstrate the immunogenicity and safety of these constructs. During these trials, four labs in the ADVANCE CRC network developed proficiency in analysis of fresh PBMC ELISpot samples and have developed capacity to carry out a new functional T-cell-based virus inhibition assay. This luciferase-based viral inhibition assay to measure the in-vitro ability of CD8+ T cells to directly inhibit the replication of HIV-1 isolates in autologous CD4+ T cells has been reported in the assessment of diverse panels of transmitted/founder HIV-1 infectious molecular clones [11,12]. The capacity developed through this program will allow for assessment of other T-cell immunogens within this network in the future.

For African researchers to fully engage and meaningfully contribute to HIV vaccine development approaches, a concerted effort not only for financial support but also for improving research ecosystems and pace at which research is performed will be a major determining factor. Current delays in access to resources and bureaucracies may suffocate the progress made in scientific and technological advances on the continent. For a true shift where African scientists contribute to the HIV vaccine development process, concerted efforts by African governments, funders, research institutions, ethical review boards and national regulatory authorities to create and support an enabling research environment will be necessary.

Ultimately, innovative science is a global activity that cannot just be done in a single geography but needs global collaboration in addition to empowerment of local researchers.

ENGAGING LOCAL COMMUNITIES AND STAKEHOLDERS TO ACCELERATE PROGRESS AND INCLUDE RELEVANT POPULATIONS IN RESEARCH

There is widely held consensus on the need to engage relevant and local stakeholders in the clinical trial research process to improve the implementation and outcomes of research [13]. Stakeholders have been defined as ‘any individual or group who can have an impact on or is affected by a clinical trial’ [14]. These can be trial participants, members of local communities where trials are conducted, civil society groups, policy makers or other governmental organizations. Strategic and meaningful stakeholder engagement fosters trials that more effectively address stakeholders’ needs and perspectives, support successful trial implementation and participant welfare. Stakeholder engagement is particularly important in EMVTs, which require careful consideration of the differences in previous messaging around efficacy trials and talking to communities who have become highly sensitized to vaccines and surrounding debates in this post-COVID pandemic era. The scientific discourse around HIV vaccine trials has shifted tremendously in the past few years and we need to be able to convey complex scientific concepts related to current vaccine approaches and manage expectations about timelines towards a vaccine that can be deployed, whilst highlighting why support for HIV vaccine research must not wane. Engagement with various stakeholders must move in parallel with EMVTs performed on the continent. This will allow communities to contextualize the relevance of EMVTs to overall goal of an effective HIV vaccine.

EMVTs have the potential to accelerate the development of promising candidates by providing human data at an earlier stage. They answer important scientific questions in people, usually addressing questions that cannot be addressed in animal models and inform how we design actual vaccine products for development, though the products tested in these trials are usually not on a committed pathway to licensure. It will be increasingly important to explain the role of EMVTs in the overall pathway to HIV vaccine development as well as the nature and goals of the science. The field is noting how various complex concepts will need to be relayed in relatively easy to understand ways that are accurate and balanced [4▪▪]. A significant amount of work has been conducted in the past decade with an important body of evidence developed around vaccine research literacy. The evolving vaccine science and other important sociological and technological factors that contributed to misinformation or disinformation around COVID vaccines require that we continue to learn and refine scientific literacy approaches to enable effective stakeholder engagement and partnership. One approach taken in the ADVANCE program is to embed sociobehavioural research in EMVTs to explore participant understanding of study goals and acceptance of atypical sampling methods. Other related SBR studies are exploring experiential learning-based interventions in strengthening vaccine science literacy and conveying the increasing complexity in current vaccine approaches, outcomes and trial designs. These examples are but a small part of the broader work that is needed to effectively partner with communities around important discovery vaccine trials.

There also needs to be consensus on the communities/populations that need to be included in the early-stage trials. For example, when and where does it make sense to involve infants, children, adolescents and persons living with HIV (PLWH) in trials for development of HIV prevention products. Traditionally, adolescents, children and infants have either been excluded entirely from development programs for biomedical prevention products against HIV or only included following demonstration of efficacy in adults. As the epidemic has evolved, adolescent girls and young women in sub-Saharan Africa continue to be identified as a priority population that is disproportionally affected by new HIV infections. Inclusion of adolescent populations in EMVTs to characterize immune responses and to inform rational vaccine design could ensure that future products are able to address the medical need in this population.

For infants, there is evidence that immune responses in early life may be better suited for the development of neutralizing antibody responses against HIV [15–18,19▪,20]. The field has an opportunity to review the justification for inclusion of HIV-exposed and uninfected infants in early development programs for promising immunogens against HIV and a need to engage communities on the rationale and approach to be taken. As the medical need for new products to prevent the postnatal transmission of HIV is especially pressing in sub-Saharan Africa, it is important to work with affected communities to design relevant product development programs.

PLWH may contribute to the development of new prevention products against the virus. The opportunity to demonstrate the in-vivo efficacy of candidate vaccines using analytical treatment interruption trials, could aid in the design of vaccination regimens and accelerate the clinical development of these products. Similarly, for approaches aiming to elicit broadly neutralizing antibody responses, trials in PLWH could be used to test booster immunogens within germline targeting programs. Meaningful engagement of this population on the role they could play in the development of these products could benefit the HIV prevention, treatment and cure research fields and is essential to enable continual conduct of these trials for advancement of promising candidates.

CONCLUSION

EMVTs will enable exploration of important scientific hypotheses and advance HIV vaccine discovery and development. We need to conduct more of these trials in multiple regions of the world, including Africa, to ensure the global relevance of vaccines under development. African scientists and communities can contribute to accelerating efforts in HIV vaccine development through EMVTs and the ADVANCE program shows that it is possible to enable select clinical and lab capacity and refine approaches to research literacy to support effective community and stakeholder engagement. New ways of thinking around incorporating relevant populations in early-stage vaccine development are also needed.

Acknowledgements

IAVI's work is made possible by the generous support of many donors. The full list of IAVI donors is available atwww.iavi.org. The ADVANCE program (cooperative agreement – AID-OAA-A-16-00032) and this publication are made possible by the support of the American People through PEPFAR and USAID. The contents of this manuscript are the sole responsibility of IAVI and do not necessarily reflect the views of PEPFAR, USAID or the United States Government.

We also acknowledge the Director General, KEMRI.

Financial support and sponsorship

None.

Conflicts of interest

The authors are investigators on the ADVANCE cooperative agreement.

REFERENCES AND RECOMMENDED READING

Papers of particular interest, published within the annual period of review, have been highlighted as:

▪ of special interest

▪▪ of outstanding interest

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