Clinical development of Rift Valley fever vaccines in endemic regions

Project Information

RIFTVAX

Grant agreement ID: 101081290

DOI

10.3030/101081290

EC signature date 14 July 2022

Start date 1 August 2022

End date 31 July 2026

Funded under

• Health

Total cost

€ 50 000 000,00

EU contribution

€ 35 000 000,00

Coordinated by

COALITION FOR EPIDEMIC PREPAREDNESS INNOVATIONS
Norway

Periodic Reporting for period 2 - RIFTVAX (Clinical development of Rift Valley fever vaccines in endemic regions)

Reporting period: 2024-02-01 to 2025-07-31

Summary of the context and overall objectives of the project

Rift Valley fever is a is a viral haemorrhagic disease caused by a virus of the same name. It is part of the Phenuivirus family.

It most commonly affects domesticated animals however people can be infected. Symptoms range from mild disease to a severe haemorrhagic form that can have up to 50 percent fatality. As climate change accelerates, there is a high likelihood that RVF outbreaks may occur outside of endemic regions, including in Europe.

In recognition of its epidemic potential, Rift Valley fever is listed on the WHO’s R+D Blueprint, as well as by the World Organization for Animal Health (WOAH). Under this project and building on earlier work including a Phase I trial of a vaccine candidate, CEPI is working with applicants to advance the development of vaccines against RVF with a focus on endemic regions and underpinned by the principle of equitable access.

The project has the following specific objectives:

a) Phase I/II clinical testing of the most advanced RVFV candidates, including identification of correlates of protection and their validation, which can facilitate future regulatory approval;
b) Identify potential pathways to licensure either through a pivotal clinical trial or via a pre-clinical route;
c) Produce clinical trial material suitable for the conduct of Phase I/II trials;
d) Develop human vaccines for RVFV which could be used to exemplify and develop a viable One Health approach;
e) Identify supporting technologies and/or innovations which could be useful in the development of other vaccines against the WHO R&D Blueprint pathogens.

Work performed from the beginning of the project to the end of the period covered by the report and main results achieved so far

Stichting Wageningen:
The LARISSA 2 CMC partner, Batavia Biosciences successfully received the full transfer of the hRVFV-4s vaccine manufacturing process and associated analytical assays from IDT Biologika.
Engineering run material was successfully produced and released.
Correlates of Protection research: Successful passive antibody studies utilising hRVFV-4s–induced human antibodies, yielded valuable data on the minimal protective titre required for efficacy.
A Phase IIa clinical trial design, spanning two countries and incorporating defined endpoints, has been advanced and captured in a protocol that is now in its final draft.
Regulatory engagement activities have been initiated
Published and unpublished RVF data repositories for humans and animals were merged, updated, and quality-controlled


University of California, Davis:
Successful production of GMP batch of DDvax manufactured
Completed site Study assessment and tour of facilities at Ifakara Health Institute Clinical Trial Facility
Phase I Study Procedures and Protocols progressed
Initial enrolment of 1,503 participants in Epidemiology Study completed
Tanzania Medicines and Medical Devices Authority (TMDA): Completed pre-submission meeting with successful outcomes that addressed key Phase I preparatory inquiries related to CMC formulation/process, Phase I study protocol, and GMO status of vaccine candidate.
Technology transfer of key assay to study site: Dedicated staff and laboratorians identified and trained at IHI study site to complete core laboratory assays specific to RVF immune and vaccine assessment.
Assay testing, training, and refresher training near complete and ongoing with site laboratory staff at IHI Clinical Trial Facility in Bagamoyo, Tanzania.

Progress beyond the state of the art and expected potential impact (including the socio-economic impact and the wider societal implications of the project so far)

LARISSA 2

o LARISSA I Phase 1 completion and data: First CSR Feb 2024 – this report contains the clinical results for the first 6 months of follow-up of participants vaccinated during the Phase I trial. Further CSR, containing clinical results for the 2-year follow up will be due Dec 2025 – note for next RP. This was pivotal in demonstrating the safety and immunogenicity of a CEPI and EC funded, next generation live attenuated RVF vaccine candidate in humans, thereby paving the way for continued evaluation and development in RVF-endemic countries

o Project successfully completed passive antibody studies in mice and marmosets, utilizing hRVFV-4s–induced human antibodies form the Phase 1 clinical trial. Animals were protected against viremia and disease. To our knowledge this is the first time this has been conducted using human vaccine trial sera in an NHP model and significantly advances the field in terms of understanding the minimal protective titer required for efficacy i.e. correlates of protection.

o During this period, the LARISSA 2 team has conducted a simulation exercise using the Phase 1 regulatory submissions with AVAREF. This is a novel regulatory capability strenthening exercise which will contribute to future AVAREF capability and benefit LARISSA 2 clinical trial protocol submission and review.

UC Davis

o The DD Vax group has generated a One Health Vaccination Strategies (OHVS) manuscript for RVF. This is an epidemiological and modelling activty which considers optimal human and veterinary vaccine usage scenarios to best control RVF outbreaks and proposes a OHVS framework for Rift Valley fever. This will be a valuable tool for catalysing one health approaches to control of RVF and which CEPI intends to use as a foundation for development of an OHVS strategy

o DD Vax epidemiology activities have demonstrated ~4% RVF IgM seroprevalence around the Bagamoyo Phase 1 trial site for RVF. Indicates previously undiscovered/ unobserved RVF transmission in Northern Tanzania at the Ifakara Bagamoyo site & has potentially positive implications for trial deisgn and also regional RVF control (unpublished data)
o Epidemiology Knowledge Attitudes and Practice Survey: Cross-sectional fieldwork completed October 2024; manuscript in preparation. Advances our understanding of social science aspects related to RVF vaccination and result will be applied to vaccine communication planning and community engagement strategies which should contribute to success of vaccine trials.

o Staff and laboratorians identified and trained at IHI study site to complete core laboratory assays specific to RVF immune and vaccine assessment. E.g. RVF IgG ELISA, RVFV RT-qPCR, targeted innate immunity bioassays (EliSpot), and t-cell flow cytometry).

CfP launch press release