ABSTRACT
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
environmental exposures can 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 harmonized approach to interrogate immunological reactivities and
pathways across cohorts has been developed despite its public health importance and 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 if 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 and 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 P. falciparum, we will bring the research closer to mechanisms of tissue-specific responses and
to 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.
