Innate immune activation restricts priming and protective efficacy of the radiation-attenuated PfSPZ malaria vaccine
Leetah Senkpeil, Jyoti Bhardwaj, Morgan R. Little, Prasida Holla, Aditi Upadhye, Elizabeth M. Fusco, Phillip A. Swanson II, 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
Leetah Senkpeil, Jyoti Bhardwaj, Morgan R. Little, Prasida Holla, Aditi Upadhye, Elizabeth M. Fusco, Phillip A. Swanson II, 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
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Research Article Infectious disease Vaccines

Innate immune activation restricts priming and protective efficacy of the radiation-attenuated PfSPZ malaria vaccine

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.

Authors

Leetah Senkpeil, Jyoti Bhardwaj, Morgan R. Little, Prasida Holla, Aditi Upadhye, Elizabeth M. Fusco, Phillip A. Swanson II, 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

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Figure 8

Stimulation of innate immunity reduces liver parasite burden but dampens RAS-induced CD8+ T cell responses.

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Stimulation of innate immunity reduces liver parasite burden but dampens...
(A) GSEA using baseline transcriptomes between infants with detectable (red) versus without detectable (blue) PfSPZ-specific CD8+ T cell responses. Only BTMs with Benjamini-Hochberg–adjusted P < 0.05 are shown. (B) Study design for mouse experiments to determine the effect of innate stimuli on P. yoelii (Py) liver stage infection. (C) Liver parasite burden quantification. Each symbol represents a single mouse. Data (median) are representative of 2 independent experiments. Significance determined by Kruskal-Wallis test. (D) Kaplan-Meier plot of time to first parasitemia after injection of 1,000 Py 17XNL sporozoites in mice pretreated with LPS or saline for 24 hours. Significance determined by log-rank test. (E) C57BL/6 mice were treated with the indicated innate stimuli or control 24 hours before injection of ~1 × 104 Py 17XNL RAS. RAS-induced CD8+ T cell responses were enumerated in peripheral blood on the indicated days. (F) Representative flow cytometry plots identifying RAS-induced CD8+ T cell (CD8loCD11ahi). Shown are the percentages of all circulating CD8+ T cells that are CD8loCD11ahi. (G) Percent of circulating CD8+ T cells that are CD8loCD11ahi on the indicated day after RAS injection. Data (mean ± SEM) are cumulative results (n = 8 mice/treatment) from 2 independent experiments. Significance determined by Kruskal-Wallis test. (H) Ratio of circulating CD8+ T cells that are CD8loCD11ahi at day 7 after RAS injection over preinfection baseline in 2 experiments independent of those in G. Shown are global P values for 1-way ANOVA. *P < 0.05 when compared pairwise to saline control by t test.