Awarded Amount$4,692,924DiseaseMalariaInterventionVaccineDevelopment StagePreclinical DevelopmentCollaboration PartnersEhime University , University of Copenhagen (UCPH) , Institut national de la santé et de la recherche médicale , Groupe de Recherche Action en Santé (GRAS) , Noguchi Memorial Institute for Medical Research , Institut de recherche pour le développement , European Vaccine Initiative (EVI)
Introduction and Background of the Project
Placental Malaria (PM) constitutes a major health problem causing an estimated 10,000 maternal and 200,000 infant deaths, annually. An effective vaccine would be an attractive tool to control PM on its own, or to complement the existing yet imperfect tools. This project will expand an existing collaboration and build on previously conducted pre-clinical and first-in-human (phase Ia/b) clinical studies in Europe and Africa. The two PM vaccine candidates PAMVAC and PRIMVAC consist of recombinant proteins encompassing the placental binding region of VAR2CSA, using similar but complementary approaches.
The two vaccine candidates have been assessed head-to-head in non-human primate immunogenicity studies and both have undergone independent phase I clinical trials using harmonized procedures. The clinical trial results demonstrated that both adjuvanted vaccine candidates are safe and well-tolerated and induce good homologous immune responses. Clinical trial data and animal immunization results show lasting immune responses. However, VAR2CSA is a diverse antigen, and it is therefore essential to optimize the cross-reactivity against different VAR2CSA variants and to further evaluate the longevity of the immune response, prior to embarking on costly, large scale phase II clinical trials
2. Project objective
This project will advance and accelerate the development of a PM vaccine by establishing a global portfolio of vaccine candidates that will be evaluated according to the following objectives:
1. Objective 1: to assess the longevity of the immune response induced by PRIMVAC through an extended follow up of PRIMVAC vaccinated women in Burkina Faso
2. Objective 2: to assess the capacity of adjuvanted PRIMVAC to boost naturally acquired VAR2CSA specific immune responses
3. Objective 3: to assess the potential of a capsid-like particle (CLP) based vaccine formulation to increase vaccine induced immune responses
4. Objective 4: to evaluate cross-reactivity of the immune responses induced by VAR2CSA antigens
Generated data will inform the next steps of PM vaccine development, will allow a decision on the formulation for further development and the preparation of a larger phase II immunogenicity study.
3. Project design
Recombinant soluble proteins are often thought to induce an immune response of insufficient strength and breadth to confer full protection. However, we have observed that our vaccine candidates, especially PRIMVAC, produced a lasting immune response. We propose therefore to further characterize the longevity of the PRIMVAC-induced immune response in women in malaria-endemic areas, as well as the capacity of the vaccine to boost and broaden a natural acquired immune response.
We will also undertake an in-depth analysis of the cross-reactivity against the different haplotypes by the immune response elicited by the PM vaccine candidates.
Additionally, we propose to undertake the pre-clinical development of PAMVAC-CLP. PAMVAC-CLP is an improved version of PAMVAC, where a capsid-like particle (CLP) has been added as backbone, thereby potentially improving immunogenicity, cross-reactivity and longevity of the induced immune response. Taken together, PRIMVAC and PAMVAC-CLP, together with additional PRIMVAC variants in early pre-clinical evaluation constitute a promising portfolio of PM vaccine candidates.
How can your partnership (project) address global health challenges?
Currently, treatment and prevention of PM relies on the use of long-lasting insecticidal nets (LLINs) and sulfadoxine-pyrimethamine (SP)-based Intermittent Preventive Treatment (IPTp) strategies; tools suffering from drug- and insecticide-resistance of parasites and mosquitoes. PM is also often sub-clinical, with sub-microscopic parasitaemia, and pregnant women are often unaware of the infection and do not seek treatment. At the time of the first antenatal visit when usually receiving the first SP dose, many pregnant women and their fetuses have thus already suffered negative effects of PM. A malaria vaccine that completely prevents blood-stage infection would potentially be an excellent tool to protect against PM. However, RTS,S/AS01 (and other vaccine candidates in current development) only confer partial protection waning over some months as antibody levels rapidly decline after vaccination. It is therefore difficult to envisage how these vaccines could control PM. Vaccines specific against PM are attractive because they could lead to reduction in disease-incidence and severity, protecting the mother and unborn already early on in pregnancy. A PM vaccine could be included in the Expanded Program on Immunization for adolescent girls (e.g. together with rubella or HPV vaccination campaigns), which would provide an easy and cost-efficient roll out.
What sort of innovation are you bringing in your project?
In addition to the recombinant soluble protein approach for PRIMVAC that has shown to induce lasting antibody responses, we will further advance a PM vaccine candidate that is based on capsid-like particle (CLP) approach that was recently invented by the University of Copenhagen. We will also use the CLP platform to assess if an optimized PM vaccine can be designed that increases the cross-reactivity against different VAR2CSA variants. We will evaluate if the strength and breadth of the immune response will be increased using this novel formulation, but also with adjuvanted PRIMVAC in pre-exposed women. To investigate how vaccination will induce cross-reactive antibodies against any types of variants in the field, expression of genetic variants of the target VAR2CSA vaccine antigens will be conducted using Ehime’s innovative wheat germ cell-free protein expression system (WGCFS). Additionally, we will further evaluate the longevity of the vaccine immune response, an information that is crucial for the further development of PM vaccines.
Role and Responsibility of Each Partner
The project partners have long-standing partner histories building on previous and on-going collaborations. In this project, the European Vaccine Initiative (EVI) will be responsible for overall coordination and management, oversee clinical trial activities, lead in protocol development to ensure harmonization of clinical activities and will support dossier preparation for ethical/regulatory submissions, and data management. Ehime University (Ehime) will produce a variety of genetic variants of VAR2CSA to investigate the level of cross-reactive antibodies induced by vaccination. University of Copenhagen (UCPH) has the proprietary knowledge of the CLP platform and will be responsible for vaccine manufacture and development of the CLP-PM formulation for pharmaco-toxicology studies and up to EU phase I clinical trials. Inserm is inventor of the PRIMVAC vaccine, will provide the PRIMVAC vaccine candidate and will further perform the functional immunological characterization and statistical analyses for the PRIMVAC studies. The Groupe de Recherche en Santé (GRAS) in Burkina Faso will conduct the phase Ib follow-up study of the PRIMVAC-vaccinated women and will perform the phase Ib booster study. The Noguchi Memorial Institute for Medical Research in Ghana/ Institut de recherche pour le développement will be involved in the preclinical characterization of the vaccine candidates with the aim to increase cross-reactivity of the vaccines, and the immunological characterization of human samples.
Others (including references if necessary)
Mordmüller B et al. Clin Infect Dis. 2019 Oct 15;69(9):1509-1516.
Sirima SB et al. Lancet Infect Dis. 2020 May;20(5):585-597.
Clinical development of placental malaria vaccine candidates