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

Area of Science:

• Immunology
• Vaccinology
• Systems Biology

Background:

• Differential immunogenicity and protective efficacy of the radiation-attenuated whole-sporozoite Plasmodium falciparum sporozoite (PfSPZ) vaccine were observed in African infants.
• Understanding the molecular mechanisms is crucial for optimizing malaria vaccine strategies.

Purpose of the Study:

• To investigate the molecular mechanisms underlying the variable responses to the PfSPZ vaccine in a clinical trial.
• To identify host immune signatures that predict vaccine efficacy or susceptibility to malaria.

Main Methods:

• A systems analysis approach was employed, integrating clinical trial data with molecular profiling.
• Machine learning algorithms were utilized to identify predictive immune signatures at prevaccination baseline.
• In vivo experiments in malaria-naive mice were conducted to validate findings.

Main Results:

• Prevaccination innate immune activation and myeloid signatures correlated with protection in placebo recipients but with susceptibility in high-dose vaccine recipients.
• Machine learning identified spliceosome, proteasome, and resting dendritic cell signatures as predictive of protection with the highest vaccine dose.
• Baseline circumsporozoite protein-specific (CSP-specific) IgG predicted nonprotection, while innate signatures correlated with higher sporozoite-specific IgG but undetectable CD8+ T cell responses.
• Innate stimulation in mice conferred protection but diminished CD8+ T cell responses to sporozoites.

Conclusions:

• Innate immune stimulation plays a dichotomous role in malaria protection and the induction of protective immunity by whole-sporozoite vaccines.
• The PfSPZ vaccine's efficacy may be limited by opposing antigen presentation pathways, uncoupling antibody-mediated protection from CD8+ T cell responses.