The kinetics and dynamics of functional immune responses to Plasmodium falciparum strains

Malaria caused by Plasmodium falciparum remains a leading cause of death primarily in children under the age of five in Sub-Saharan Africa. Despite being treatable with chemotherapy, the global spread of drug resistance, along with the lack of natural sterilizing immunity and a vaccine with only modest efficacy has made the goal of malaria elimination an ever more distant goal. Identification of highly conserved antigen targets that prove to be true correlates of immune protection would create transformational tools in malaria research. To do this, there is need for a better understanding of the mechanisms underlying the development of immunity to malaria. With defined immune correlates of protection not yet broadly established in malaria, it is essential to move beyond antibody-antigen recognition and towards a better understanding of antibody-mediated mechanisms of functional immune responses. The blood-stage of malaria represents an attractive target as it is responsible for both clinical disease severity and onward transmission and previous studies have demonstrated that antibodies against P. falciparum antigens play a critical role in controlling blood-stage infection. Extensive consideration for the development of the next malaria vaccine needs to understand the extent of genetic diversity on protective functional immune responses. To evaluate the objectives, the project will use serum samples collected longitudinally following a genomically well-characterized malaria infection and P. falciparum parasite isolates from these day 0 infections from a Senegalese cohort. The central hypothesis is that functional immune responses against P. falciparum are developed through changes in antibody composition over the course of infection, with broadly functionally protective responses dependent on the degree of parasite genomic and genetic relatedness. Senegal is an ideal setting for understanding the determinants of highly functional immune responses to key merozoite antigens, as transmission is low, and multiple individuals in the population are exposed to genomically identical strains and have monogenomic infections. Understanding determinants of highly functional immune responses and the ability to generate strain-transcending immune responses will ultimately help to define immune correlates of protection in malaria and aid in vaccine development.

NIH Project details

Vaccines (Immune Correlates)

Jul 2024 — Jun 2027

$48,974

Senegal
United States