Immunological profiles associated with distinct parasitemic states in volunteers undergoing malaria challenge in Gabon

Abstract

Controlled human malaria infection (CHMI) using cryopreserved non-attenuated Plasmodium falciparum sporozoites (PfSPZ) offers a unique opportunity to investigate naturally acquired immunity (NAI). By analyzing blood samples from 5 malaria-naïve European and 20 African adults with lifelong exposure to malaria, before, 5, and 11 days after direct venous inoculation (DVI) with SanariaR PfSPZ Challenge, we assessed the immunological patterns associated with control of microscopic and submicroscopic parasitemia. All (5/5) European individuals developed parasitemia as defined by thick blood smear (TBS), but 40% (8/20) of the African individuals controlled their parasitemia, and therefore remained thick blood smear-negative (TBS− Africans). In the TBS− Africans, we observed higher baseline frequencies of CD4+ T cells producing interferon-gamma (IFNγ) that significantly decreased 5 days after PfSPZ DVI. The TBS− Africans, which represent individuals with either very strong and rapid blood-stage immunity or with immunity to liver stages, were stratified into subjects with sub-microscopic parasitemia (TBS-PCR+) or those with possibly sterilizing immunity (TBS−PCR−). Higher frequencies of IFNγ+TNF+CD8+ γδ T cells at baseline, which later decreased within five days after PfSPZ DVI, were associated with those who remained TBS−PCR−. These findings suggest that naturally acquired immunity is characterized by different cell types that show varying strengths of malaria parasite control. While the high frequencies of antigen responsive IFNγ+CD4+ T cells in peripheral blood keep the blood-stage parasites to a sub-microscopic level, it is the IFNγ+TNF+CD8+ γδ T cells that are associated with either immunity to the liver-stage, or rapid elimination of blood-stage parasites.

γδ T‐cell–mediated immune responses to malaria

“…A recent study found out that PfSPZ vaccination-induced parasite control in malaria-exposed individuals was associated with IFN-γ-and TNF-co-producing γδ T cells together with IFN-γ-producing CD4 + T cells. 22 Although all sporozoite vaccination studies support the protective roles of γδ T cells, it is not clear whether their function in protection is purely as an effector or assist in inducing DCs or CD8 + T cells. Furthermore, better understanding of the biology and function of liver γδ T cells will be a valuable tool for developing PfSPZ-based vaccines for the induction of sterile immunity.…”

“…In malaria‐naïve individuals activated effector γδ T cells were maintained for 14 months without further exposure, 21 suggesting the formation of long‐lasting memory γδ T cells. A recent study found out that PfSPZ vaccination–induced parasite control in malaria‐exposed individuals was associated with IFN‐γ– and TNF‐co‐producing γδ T cells together with IFN‐γ–producing CD4 + T cells 22 . Although all sporozoite vaccination studies support the protective roles of γδ T cells, it is not clear whether their function in protection is purely as an effector or assist in inducing DCs or CD8 + T cells.…”