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

Introduction/Rationale: 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.