Plasmodium falciparum liver-stage antigens as mRNA-LNP vaccines induce robust B and follicular helper CD4 T cells for sustained protection

Malaria is an infectious disease caused by the protozoan parasite Plasmodium. In 2021, an estimated 241 million cases and 627,000 deaths were caused by Plasmodium falciparum (Pf), the deadliest of all Plasmodium spp. RTS,S, based on a recombinant Pf circumsporozoite protein (CSP), is the leading pre-erythrocytic vaccine but its efficacy and durability need to be improved. It is likely that immune response directed to a single target, the CSP, is the reason for this suboptimal vaccine efficacy. Combining Pf CSP with other pre-erythrocytic targets, e.g., Pf liver stage antigens (LS Ags), may improve vaccine efficacy by expanding the specificity repertoire as well as durability of functional immune attributes. mRNA-based vaccines have recently proven to be an effective platform against viral and other diseases. Recent preclinical data demonstrate that mRNA expressing Pf CSP confers some level of protective immunity; however, neither protective T cell reactivity nor durability of protection have been evaluated. Our approach will introduce a novel strategy based on a combination vaccine on an mRNA platform that expresses Pf CSP and Pf LS Ags. A sporozoite that escapes elimination by the CSP-specific immune response and starts developing into LS parasite, will be targeted by immune responses induced by LS Ags. Understanding immune responses induced by mRNA expressing a combination of pre-erythrocytic stage Ags that may serve as correlates of lasting protective immunity against malaria is critical to addressing the topic area – Infectious Diseases: Malaria; and strategic goal – Develop or optimize vaccine strategies, vaccine platforms, or compounds of any preventive type, to include active or passive immunoprophylaxis. These are Pf orthologues of protective P.berghei (Pb) and P.yoelii (Py) LS Ags. With the recent availability of a Pb transgenic parasite that expresses selected Pf LS Ags, the mouse model becomes an ideal host for a preclinical testing of combination vaccines containing the sine qua non CSP and Pf LS Ags for the induction of immune response and protection. Based on our initial results, Pf TBP induced follicular helper (fh) CD4+ Tfh cells and Ag-specific antibody (Ab) as early as day 4 post priming. In contrast, priming with Pf SHMT resulted in delayed and lower Ab titers and CD4+Tfh cells responses. The results showing Ag-specific temporal induction of Ab and CD4+ Tfh cells and suggesting divergent responses by each of the two Pf LS Ags are novel. It is hypothesized that B and CD4+Tfh cell responses to Pf TBP and possibly Pf CSP might be critical for the initiation of protective immune responses, whereas the indolent and delayed B and CD4+Tfh cell responses induced with Pf SHMT may suggest its involvement in protracted protective immunity by an ancillary mechanism involving CD8+T cells. Protective immunity is multifactorial involving cellular and molecular responses. Owing to the central importance of specialized CD4+Tfh cells in germinal center formation, B cell maturation, high affinity Ab production and effector CD8+T cells in elimination of the parasite by cytolytic mechanism, this project aims to identify the relationship among the different cellular and molecular components and durable protection induced by a combination Pf vaccine, mRNA-CSP-SHMT/TBP, in a mouse model exposed to Pb parasites transgenes for these immunogens. Understanding immune correlation patterns underpinning prolonged immunity may lead to better strategies for selecting malaria vaccine platforms for developing combination vaccines.

Immunology
Vaccines

Jan 2024 — Jan 2026

$284,000

United States