Elsevier

Vaccine

Volume 38, Issue 26, 27 May 2020, Pages 4135-4141
Vaccine

Conference report
Meeting report: WHO consultation on accelerating Lassa fever vaccine development in endemic countries, Dakar, 10–11 September 2019

https://doi.org/10.1016/j.vaccine.2020.01.017Get rights and content

Abstract

At the time of writing in 2019, there have been 754 confirmed cases of Lassa fever in Nigeria, 21% of whom have died. Lassa is on the priority pathogen list for WHO’s R&D Blueprint for Action to Prevent Epidemics. In September 2019, WHO convened 67 scientists, regulators, ethicists, public health officials, funders and vaccine developers to discuss the end-to-end clinical development plan for Lassa fever vaccines. The substantial increases in vaccine trial capacity in Africa were reviewed, together with lessons learned from the evaluation of vaccines against HIV, TB, malaria, and Ebola in Africa. Participants agreed on a pathway for Lassa vaccine trial progression, as outlined in WHO’s Lassa fever R&D roadmap and the WHO Lassa fever Target Product Profile. Two Phase 1 trials of Lassa vaccines have already started, and it was agreed that continuing interactions between high income and African regulatory and ethics authorities and WHO will be important in progression towards Phase 2b/3 efficacy trials in Lassa fever endemic areas. There was agreement that, for diseases whose burden is mainly in Africa, it should be the norm that African regulatory authorities are consulted on trial design/progression before first-in-human Phase 1 trials. Phase 2b-3 vaccine trial capacity needs to be in place in high Lassa fever burden areas where efficacy trials will take place. Licensure of one or more Lassa fever vaccines suitable for West African populations is a realistic goal in the next 5 years, with CEPI and WHO aligned on the pathway forward for vaccine development.

Introduction

Lassa fever virus (LASV) is a pathogen on the World Health Organization (WHO) research and development (R&D) blueprint priority diseases list. Since 2016, WHO has conducted a series of activities aimed at accelerating the clinical development of Lassa fever (LF) medical countermeasures while identifying critical knowledge gaps that must be addressed ahead of conducting relevant clinical trials. These efforts have included the development of a Lassa R&D roadmap that identified key research priorities in LASV vaccine development [1]. The unprecedented recent large LF outbreaks in Nigeria have further highlighted the need for LASV vaccines [2], [3]. WHO published a Target Product Profile (TPP) for LASV vaccines in 2017, focusing on preventive use [4], and held expert consultations on the design of Phase 3 trials for both vaccines and therapeutics in 2018 [5]. WHO supports the public health goal of facilitating the clinical development of LASV vaccines to prevent disease and death in the endemic region of West Africa. In preparation for vaccine trials, however, there is also a need to better characterize LF disease burden and epidemiology (see Fig. 1).

The LASV vaccine pipeline is one of the more robust among the WHO R&D blueprint priority pathogens and several vaccine candidates have shown protection in animal models, with further development of some candidates being supported by the Coalition for Epidemic Preparedness Innovations (CEPI). Candidates include those based on recombinant measles virus, vesicular stomatitis virus, Mopiea- Lassa virus reassortants expressing Lassa virus antigens, and DNA platforms. The DNA and recombinant measles virus candidates have already commenced safety studies in human volunteers [6], [7].

While WHO has generic guidance on the clinical evaluation of vaccines [8], there are no specific guidelines for Phase 1–2 trials of LASV vaccines in LF endemic areas. This was the focus of the workshop in Dakar, with the following objectives:

  • (1)

    to review the status of current LASV vaccine candidates.

  • (2)

    to identify the knowledge gaps in the epidemiology of LF which are critical for the evaluation of vaccines.

  • (3)

    to assess the support required for infrastructure and capacity development to facilitate the conduct of LASV vaccine trials in West Africa.

  • (4)

    To ensure the appropriate involvement of African regulatory authorities and ethics committees in the design and monitoring of trials.

Section snippets

Overview of the LASV vaccination strategies

In the WHO LASV vaccine TPP, two scenarios for vaccine use are considered. The first is a preventive approach in which vaccines are administered in advance of an outbreak of LF to persons or communities at high risk, including defined communities in endemic areas as well as health care workers (HCWs) and laboratory personnel at high risk of exposure to LASV. Vaccines for this purpose will need to generate long lasting immunity, so that vaccinated individuals are protected over at least several

Update on laboratory diagnosis of Lassa fever

A necessary requirement for LASV vaccine evaluation will be a standardized definition of suspected clinical disease due to LF, and a confirmatory diagnostic test. The development of commercially available diagnostic assays which quantify viremia, and which detect genetically diverse LF strains in a timely manner is a priority. Polymerase chain reaction (PCR) has emerged as the mainstay of diagnosis of acute cases, but many countries rely on in-house (non-validated) tests. Going forward,

Safety considerations for first in human and Phase 1 trials and Phase 2 trials

Safety is a key endpoint across all stages of clinical development, and any vaccine considered for public health use must have a clear favorable benefit-risk ratio. Approaches to evaluating vaccine safety are reasonably well-established. For LASV vaccines, a safety and reactogenicity profile at least comparable to WHO-recommended routine vaccines is expected. Some patients with LF develop sensorineural hearing loss. This is believed to be immunologically mediated [15], and thus could

Regulatory perspectives

Licensing a LASV vaccine by relevant regulatory agencies is dependent on demonstration of quality, safety and efficacy through clinical and non-clinical studies. Randomized controlled trials (RCTs), that are placebo-controlled and double-blind provide the highest quality evidence of efficacy against clinical disease. Vaccines can also be licensed through demonstration of protection through validated immune correlates of protection in human or animal studies [16]. However, this is unlikely to be

Conclusion

During the workshop, considerable consensus was reached on vaccine trial progression for Lassa fever vaccines, as outlined above. Intense preparatory work is now underway to generate key epidemiological data. Research sites mapping, and selection are ongoing, while capacity development needs that can be addressed in the short term have been identified. The meeting highlighted a strategic shift that needs to occur in all medical product clinical trial authorization processes for diseases for

CRediT authorship contribution statement

Vasee Moorthy: Conceptualization, Funding acquisition, Methodology, Project administration, Resources, Supervision, Writing - review & editing. Kolawole Salami: Conceptualization, Methodology, Project administration, Resources, Validation, Writing - original draft, Writing - review & editing. Pierre-Stéphane Gsell: Methodology, Project administration, Resources, Writing - review & editing. Adebola Olayinka: Methodology, Project administration, Resources, Writing - review & editing. Diadie Maiga:

Declaration of Competing Interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Acknowledgements

We are grateful to Veronique Bruniquel and Chaima Essid, both of WHO, for their tireless logistic support towards the actualization of the meeting objectives.

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