BASEMALVAC

Duración

01/01/2022 - 31/12/2027

Coordinador

Maria Yazdanbakhsh (LUMC)

Financiadores

National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), USA

An effective vaccine would complement other public health measures and is likely essential for putting an end to the high burden of malaria worldwide. Unfortunately, most malaria vaccines that entered late-stage clinical development have shown moderate efficacy in low- and middle-income countries. Through a number of studies, vaccine efficacy was shown to vary from 20% to 100% when used in different countries and populations. Better understanding of factors that influence this variation is urgently needed. Even within a country, significant differences in vaccine efficacy in rural and urban areas are present. This implies that exposure to environmental factors plays a major role besides genetic determinants.

How, and to what extent, can environmental exposures influence immune profiles and in turn affect responses to vaccines? This question will be addressed in the current proposal. Technological advances in “omics” platforms have improved our ability to examine the immune system in a more unbiased manner. Such platforms, involving transcriptomics, are being increasingly applied to understand vaccine responses, with promising results.

However, for malaria vaccines, no harmonised approach to interrogate immunological reactivities and pathways across cohorts has been developed, despite its public health importance and the availability of cohorts assessed for a clinically relevant outcome (prevention of infection or disease). Even less has been done regarding integrated “omics”, comparing populations living in different geographical locations and their response to vaccines. Moreover, there are very little data that link environmental exposures to in-depth changes in the immune system, and when available, the studies often address one environmental factor at a time.

We propose to address this and not only assess correlations in malaria vaccine cohorts, but also to address the mechanisms underlying vaccine (hypo)responsiveness. We will build on available knowledge of immunological processes that can affect malaria vaccine responses, and use samples from the cohorts where high-dimensional cytometry, RNASeq and antibody interrogations will help to refine and enrich the questions regarding malaria vaccine (hypo)responsiveness. In addition, by using human primary hepatocytes infected with Plasmodium falciparum, we will bring the research closer to mechanisms of tissue-specific responses and extrapolate pre-erythrocytic immunity to malaria in the liver. This is of particular importance for pre-erythrocytic vaccines, where tissue-resident responses can play an important role.

By generating data on the same individuals, data integration approaches for high-dimensional mediation analysis will be used to pinpoint the specific immunological pathways and mechanisms that result in malaria vaccine (hypo)responsiveness. This information can be used to improve malaria vaccine efficacy and also to identify individuals who will not benefit from the vaccine regimens used so far. It can direct, in an evidence-based manner, alterations to the vaccination dose, intervals and adjuvants.

Total Funding

2.230.000 €