International experts noted that for many of the diseases listed in the WHO R&D Blueprint, there is not only a need for a vaccine but also for developing a broader knowledge base of the disease itself. Basic and characterization research is needed, as well as epidemiological, entomological, and multidisciplinary studies; improved diagnostics; further elucidation of transmission routes; and social science research [24]. The knowledge built will be fundamental in the process of vaccine development.
To this purpose, CEPI has identified a set of research activities needed to accelerate vaccine development, and it is currently focusing on several enabling science projects related to the development of biological standards and assays, animal models, epidemiological studies, diagnostics, clinical trial capacity, and sustainable manufacturing. Although this list of research areas is not exhaustive, it represents a focused set of research activities and data collection priorities from a vaccine-development perspective.
Biological standards and assays
Development of biological standards and assays is important for evaluating vaccine-elicited immune responses and promoting standardization, transparency, and comparability among the vaccine candidates. There are currently no available international antibody standards for Lassa, MERS-CoV, or Nipah, and there is a wide variety of intermediate standards currently used by Lassa vaccine developers.
CEPI, in collaboration with international partners, is collecting serum from patients from endemic countries who recovered from the actual diseases for the development of reference antibody preparations and, ultimately, Expert Committee on Biological Standardization (ECBS)-endorsed International Reference Preparations (IRPs). It is the aim of CEPI to make biological standards available to all CEPI-funded vaccine developers as early as possible, and for this purpose CEPI has established a Working Group on Standards, Assays and Animal Models, which is co-chaired by the WHO. In addition to this overarching group of experts, pathogen-specific task forces have also been established to obtain advice on specific topics related to standards, assays, and animal models. The task forces are instrumental in describing major needs for each disease, providing technical advice, and fostering collaboration across projects. These disease-specific task forces engage scientists from various geographic regions and from multiple disciplines. Moreover, CEPI also seeks to make pathogen-specific antigens available to relevant CEPI-funded vaccine developers. When moving toward phase I/II and, potentially, phase III efficacy trials, access to common sets of reference standards will be crucial for the evaluation of the vaccine and the comparison of different vaccine candidates.
As an example, in the past year CEPI launched requests for proposals and signed several partnership agreements for the distribution of Lassa virus-specific antigens and the development of a Lassa antibody standard. In collaboration with the Viral Hemorrhagic Fever Consortium (VHFC), the Bernhard Nocht Institute for Tropical Medicine (BNITM), and the National Institute of Biological Standards and Control (NIBSC), CEPI is collecting serum from individuals who recovered from the disease in endemic countries (Sierra Leone, Liberia, Mali, and Nigeria) for the development of reference antibody preparation and, ultimately, an IRP available to all globally.
Animal models
Due to the nature of EIDs, obtaining human efficacy data may prove challenging for the vaccines in CEPI’s portfolio. Consequently, evidence of vaccine efficacy may need to rely, either in part or fully, on data from validated animal models acceptable to regulatory authorities. In 2002 the U.S. Food and Drug Administration (FDA) finalized the Animal Efficacy Rule (also known as the Animal Rule), which applies to the development and testing of drugs and biologicals to reduce or prevent serious and life-threatening conditions caused by exposure to lethal agents for which human efficacy trials are not feasible or ethical [28]. According to this rule, the FDA relies on animal studies to provide substantial evidence of product effectiveness akin to a traditional phase III clinical efficacy study. This route of licensure still requires human safety and immunogenicity, however. To rely on animal efficacy, much work needs to be done to build the foundation of data, such as natural history studies of one or more of the animal species selected, a reasonably well-understood mechanism for the toxicity of the pathogen, and pharmacokinetics and pharmacodynamics data sufficiently well understood to allow the selection of an effective dose in humans [29].
Therefore, CEPI is planning to support animal model development/refinement and natural history studies that can serve as a basis for qualification of the model by regulatory agencies. It is aligning with the National Centre for the Replacement, Refinement and Reduction of Animals in Research (NC3Rs) guidelines to accelerate the development of models and tools to avoid the use of animals where possible, reduce the number of animals used per experiment, minimize animal suffering, and improve welfare [30]. CEPI is currently mapping existing efforts and funding for such work and will explore collaborations and co-funding mechanisms as appropriate to avoid duplication of efforts in this space. The WHO has developed target product profiles (TPPs) for many of the priority pathogens, and CEPI uses the WHO TPPs as guiding documents to make many of its decisions regarding the feasibility and intended use of funded vaccines [31,32,33].
Diagnostics
Diagnostic tests can serve multiple functions, including epidemiological surveillance, diagnosis in efficacy trials, case detection, and outbreak response. CEPI focuses on supporting the development of diagnostic tests to prepare for phase IIb/III clinical trials and identify cases of disease. Its efforts are in mapping the needs around the development of diagnostic tools, without which CEPI vaccine candidates cannot be advanced.
CEPI has limited funding for diagnostics-related activities; therefore, the diagnostic work is mainly accomplished through establishing partnerships and collaboration with potential product development partners. The Foundation for Innovative New Diagnostics (FIND) and CEPI have developed a partnership framework called CEPI.dx to address diagnostic needs for priority pathogens, and CEPI recently funded FIND with a total of US$1 million to support the evaluation of serological assays (IgG, IgM ELISA), clinical trial site development, and laboratory capacity strengthening in Lassa-affected countries. CEPI has also actively supported FIND’s application for the mobilization of a total of €4.2 million from the Federal Ministry for Education and Research (BMBF) of the German government. This funding has been used to support clinical evaluation of the Altona RealStar Lassa Virus RT-PCR Kit 2.0 (Altona Diagnostics, Hamburg, Germany), strengthening outbreak surveillance, research capacity, and activities related to biobanking in Lassa-affected countries.
Epidemiological studies
Epidemiological studies are essential to understand the incidence and prevalence of EIDs, as well as their clinical characteristics and risk factors. These data are also essential to assess the feasibility of clinical field efficacy trials of promising vaccine candidates. Some CEPI-funded vaccine candidates have already entered testing in phase I clinical trials. If these initial trials are successful and vaccine candidates are deemed safe to proceed to the next stages of testing, further vaccine phase IIa trials in affected countries, and potentially phase IIb trials, will be conducted. To ensure the feasibility of efficacy trials and to support trial design, quality epidemiological data is needed. Epidemiological research can also help strengthen site and investigator capacity to conduct clinical trials. Therefore, CEPI is providing grants for epidemiological studies that aim to collect data that can contribute to vaccine development in support of trial design, appropriate end points, and site capacity.
To accelerate Lassa vaccine development, CEPI promoted an open call for research groups/consortia across Nigeria, Benin, Sierra Leone, Guinea, and Liberia to develop a core study protocol for a major multinational epidemiological study. This epidemiological study will be supported by an effort to develop and validate diagnostic assays in collaboration with FIND. Moreover, clinical trial site development and the establishment of one fully accredited clinical trial site and two to three sites in Nigeria, meeting Good Clinical Laboratory Practice (GCLP) standards for reliable diagnosis of Lassa fever cases, will be carried out to support future trials of vaccines. This will allow expanded sample collection and archiving to accelerate the research and development and regulatory approvals for new diagnostics and vaccines [23, 24].
Building clinical trial capacity and exploring regulatory pathways
In addition, CEPI will provide support with respect to the clinical development of vaccine candidates, as well as in exploring regulatory pathways. The aim is to conduct clinical trials in affected endemic countries as early in the development as possible. CEPI will support the identification of clinical trial sites covering target populations and will engage in capacity building. It cooperates with the Brighton Collaboration, an international network of pharmacovigilance experts, to, among other activities, develop case definitions for potential adverse events of special interest (AESIs), including, for example, sensorineural hearing loss for the safety evaluation of Lassa vaccine candidates [34]. Moreover, the Brighton Collaboration will provide expertise in program-specific (upon request) and cross-program pharmacovigilance, for example by establishing a metadata safety monitoring board (meta-DSMB).
As CEPI’s priority pathogens mainly result in outbreaks, it is essential to explore the feasibility of field efficacy trials (phase IIb or III). CEPI will provide support in scenario planning, clinical trial design, capacity building, and so on for advanced-stage clinical trials to prove the vaccine candidate’s efficacy against infection, disease, or both. These advanced-stage clinical trials will have to be placed in an overall clinical development plan that is aligned and supported by the relevant regulatory authorities, as well as the WHO prequalification group. In this context, CEPI will also explore alternative regulatory pathways in case vaccine efficacy cannot be demonstrated in field trials, for instance when there is rapid decline of the infectious disease outbreak or no ongoing outbreak.
Sustainable manufacturing
After the generation of an investigational stockpile for the candidate vaccines, a sustainable supply of vaccine will be critical. Cost and time efficiency during manufacturing for future stockpiles, outbreak response, and routine use of new vaccines in endemic regions will be of great importance. Since many of the vaccines CEPI is developing will not find commercial markets to sustain them, CEPI is exploring different approaches to provide for the long-term manufacturing of any successful vaccine candidates and is considering establishing advanced manufacturing partnerships with a limited number of public and private-sector manufacturing organizations. Ongoing efforts to understand potential epidemic scenarios and to model supply chain and stockpile requirements will contribute to this effort.