Understanding and overcoming Plasmodium-specific immune evasion mechanisms

Infection with Plasmodium parasites leads to over 240 million cases of malaria and 700 thousand deaths annually, the majority of which are children under the age of five. Vector control has reduced transmission of Plasmodium, though a protective vaccine is required to reduce disease burden further. Currently deployed vaccines focus on the liver stage circumsporozoite protein (CSP) and offer moderate protection in Plasmodium- naïve individuals. However, vaccine efficacy and durability severely decline in individuals who have previously been infected with Plasmodium. Understanding how Plasmodium infection influences the pre-vaccine CSP- specific memory B cell pool is essential to identify why our current vaccinations are ineffective in endemic areas. Previous research has demonstrated that antibody responses towards two domains of CSP, the immunodominant repeat region (RR) and the non-dominant C terminus (CT), may be protective against infection. In contrast, other data suggest that the highly repetitive sequence of the RR may instead be a mechanism of immune evasion. The high avidity of this region may drive short-lived humoral responses or concentrate responses to the RR rather than perhaps more functional regions of CSP. Unique tetramers were generated that allows isolation and tracking of RR and CT-specific B cell responses during infection and/or immunization. In a murine model, it was found that Plasmodium infection preferentially expands B cells specific to the RR at the expense of CT-specific B cells. In contrast, vaccination alone expands B cell populations specific to both domains. The hypothesis is that Plasmodium infection induces a predominantly RR-specific pre-vaccine memory B cell pool that, due the high avidity of the region, will differentiate into short-lived plasmablasts upon a subsequent vaccination rather than reseeding memory pools. Understanding how to induce a larger breadth of B cell responses or induce longer lived RR-specific cells is important to improve vaccine efficacy in individuals previously infected with Plasmodium.

NIH Project details

Vaccines (Immune Correlates)

Jun 2024 — May 2026

$76,756

United States