Innate immune activation restricts priming and protective efficacy of the radiation-attenuated PfSPZ malaria vaccine
Year: 2024
Type: article
Abstract: A systems analysis was conducted to determine the potential molecular mechanisms underlying differential immunogenicity and protective efficacy results of a clinical trial of the radiation-attenuated whole-sporozoite PfSPZ vaccine in African infants. Innate immune activation and myeloid signatures at prevaccination baseline correlated with protection from P. falciparum parasitemia in placebo controls. These same signatures were associated with susceptibility to parasitemia among infants who received the highest and most protective PfSPZ vaccine dose. Machine learning identified spliceosome, proteosome, and resting DC signatures as prevaccination features predictive of protection after highest-dose PfSPZ vaccination, whereas baseline circumsporozoite protein-specific (CSP-specific) IgG predicted nonprotection. Prevaccination innate inflammatory and myeloid signatures were associated with higher sporozoite-specific IgG Ab response but undetectable PfSPZ-specific CD8+ T cell responses after vaccination. Consistent with these human data, innate stimulation in vivo conferred protection against infection by sporozoite injection in malaria-naive mice while diminishing the CD8+ T cell response to radiation-attenuated sporozoites. These data suggest a dichotomous role of innate stimulation for malaria protection and induction of protective immunity by whole-sporozoite malaria vaccines. The uncoupling of vaccine-induced protective immunity achieved by Abs from more protective CD8+ T cell responses suggests that PfSPZ vaccine efficacy in malaria-endemic settings may be constrained by opposing antigen presentation pathways.
Source: JCI Insight
Authors: Leetah Senkpeil, Jyoti Bhardwaj, Morgan R. Little, Prasida Holla, Aditi Upadhye, Elizabeth M. Fusco, Phillip A. Swanson, Ryan E. Wiegand, Michael D. Macklin, Kevin Bi, Barbara J. Flynn, Ayako Yamamoto, Erik L. Gaskin, D. Noah Sather, Adrian L. Oblak, Edward Simpson, Hongyu Gao, W. Nicholas Haining, Kathleen B. Yates, Xiaowen Liu, Tooba Murshedkar, Thomas L. Richie, B. Kim Lee Sim, Kephas Otieno, Simon Kariuki, Xiaoling Xuei, Yunlong Liu, Rafael B. Polidoro, Stephen L. Hoffman, Martina Oneko, Laura C. Steinhardt, Nathan W. Schmidt, Robert A. Seder, Tuan M. Tran
Institutions: Indiana University Indianapolis, Indiana University School of Medicine, Indiana University – Purdue University Indianapolis, National Institutes of Health, National Institute of Allergy and Infectious Diseases, Vaccine Research Center, Centers for Disease Control and Prevention, Center for Global Health, Division of Parasitic Diseases and Malaria, Broad Institute, Seattle Children's Research Institute, Dana-Farber Cancer Institute, Tulane University, Sanaria, Kenya Medical Research Institute
Language: English
Topic: Malaria Research and Control
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $4,100
Awards: Universal Attenuated Sporozoite Vaccine and Challenge System, Defining clinical and sterile immunity to Plasmodium falciparum infection using systems biology approaches, G2653436921, Plasmodium Falciparum Whole Sporozoite Malaria Vaccine, G3349051739, G4940684865, G5357766052, G7321284031, G7395631274, Investigating gene regulatory networks in immune cells of children who differ in susceptibility to malaria infection using single-cell approaches, G8952826573, G9000025480, G9000304140, Immunology and Infectious Diseases Training Program, Evaluating the role of P53 pathways in malaria, Hematopoietic stem and progenitor cell regulation for enhanced clinical efficacy, Indiana University Melvin and Bren Simon Comprehensive Cancer Center Support Grant
OpenAlex ID: W4396509574