Repeat Controlled Human Plasmodium falciparum Infections Delay Bloodstream Patency and Reduce Symptoms

Authors

Patricia Ferrer
Andrea A Berry
Allison N Bucsan
Surendra K Prajapati
Karthik Krishnan
Michelle C Barbeau
David M Rickert
Sandra Mendoza Guerrero
Miho Usui
Yonas Abebe
Asha Patil
Sumana Chakravarty
Peter F Billingsley
Faith Pa'ahana-Brown
Kathy Strauss
Biraj Shrestha
Effie Nomicos
Gregory A Deye
B Kim Lee Sim
Stephen L Hoffman
Kim C Williamson
Kirsten E Lyke

Publication Date

6-18-2024

Journal

Nature Communications

Abstract

Resistance to clinical malaria takes years to develop even in hyperendemic regions and sterilizing immunity has rarely been observed. To evaluate the maturation of the host response against controlled repeat exposures to P. falciparum (Pf) NF54 strain-infected mosquitoes, we systematically monitored malaria-naïve participants through an initial exposure to uninfected mosquitoes and 4 subsequent homologous exposures to Pf-infected mosquitoes over 21 months (n = 8 males) (ClinicalTrials.gov# NCT03014258). The primary outcome was to determine whether protective immunity against parasite infection develops following repeat CHMI and the secondary outcomes were to track the clinical signs and symptoms of malaria and anti-Pf antibody development following repeat CHMI. After two exposures, time to blood stage patency increases significantly and the number of reported symptoms decreases indicating the development of clinical tolerance. The time to patency correlates positively with both anti-Pf circumsporozoite protein (CSP) IgG and CD8 + CD69+ effector memory T cell levels consistent with partial pre-erythrocytic immunity. IFNγ levels decrease significantly during the participants' second exposure to high blood stage parasitemia and could contribute to the decrease in symptoms. In contrast, CD4-CD8 + T cells expressing CXCR5 and the inhibitory receptor, PD-1, increase significantly after subsequent Pf exposures, possibly dampening the memory response and interfering with the generation of robust sterilizing immunity.

Keywords

Humans, Malaria, Falciparum, Plasmodium falciparum, Male, Protozoan Proteins, Animals, Adult, Antibodies, Protozoan, Interferon-gamma, Female, Immunoglobulin G, Young Adult, CD8-Positive T-Lymphocytes, Mosquito Vectors, Anopheles

Comments

Supplementary Materials

Data Availability Statement

PMID: 38890271