Comparison of transcriptional signatures in human and non-human primates during malaria sporozoite vaccination with concurrent chemoprophylaxis 2330945

Abstract Introduction Developing a highly effective, durable malaria vaccine remains a global health priority. A promising approach is the chemo-attenuated, live whole sporozoite (SPZ) vaccine, in which SPZ is co-administered with an antimalarial agent, often chloroquine, that kills liver-emerging parasites to abrogate blood-stage progression while allowing effective immune responses against late liver-stage antigens. In malaria-naive adults, this approach using Plasmodium falciparum SPZ (PfSPZ-CVac) confers complete, sterile protection against subsequent challenge with controlled human malaria infection (CHMI), but trials conducted in malaria-exposed adults have shown reduced vaccine efficacy. Studies in mice and non-human primates (NHP) have revealed that long-lived, liver-resident memory T cells are critical to protection conferred by whole-sporozoite vaccination. However, immune correlates of protection in the more accessible peripheral blood compartment remain unknown. Methods Here, we identified whole-blood transcriptional signatures that are associated with a protective chemo-attenuated, SPZ vaccine regimen in both NHP and malaria-naïve adults enrolled in a clinical trial (PMID 34048504). Comparative analyses of protective signatures across distinct cell types using single-cell RNA-seq of liver and blood lymphocytes from NHP are ongoing. Results Natural killer (NK) cell signatures were significantly enriched in those receiving the protective regimen at early immunization time points and post-challenge in both NHP and humans. In NHP, this signature was reflected in both the liver and blood, with liver-resident CD16+ and CD16- NK cells correlating positively and negatively with protection respectively. Conclusion Our findings suggest that early innate immune activation, particularly NK cells, is conducive to functional adaptive immunity. Funding Source National Institutes of Health Topic Categories Vaccines and Immunotherapy (VAC)