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 9

Innate immune activation modulates monocyte phagocytic capacity of sporozoites independent of CSP-specific antibodies.

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Innate immune activation modulates monocyte phagocytic capacity of sporo...
(A) Plots of actual values with linear regression fits. (B) Perspective plots using fitted values from the logistic regression model in Supplemental Table 7 showing that CSP-specific IgG and CD14+ monocytes have differing effects on protection for placebo and 1.8 × 106 PfSPZ groups. (C) Baseline expression of innate-related BTMs in nonprotected (NP) and protected (P) infants who received 1.8 × 106 PfSPZ and lacked baseline CSP-specific IgG. (D) In vitro sporozoite phagocytosis assay design. (E) Representative images of PfSPZ uptake by primary monocytes stained with anti-PfCSP 2A10 Ab after pretreatment with indicated conditions. (F) Odds ratios with 95% CIs for number of monocytes containing phagocytosed PfSPZ over total monocytes for indicated treatment versus medium-only control. Opsonization with anti-PfCSP L9LS mAb is shown as a positive control, where reference was isotype control mAb. Significance determined by Fisher’s exact test. Data shown are representative of 2 independent experiments.