Systems analysis of immune responses to attenuated P. falciparum malaria sporozoite vaccination reveals excessive inflammatory signatures correlating with impaired immunity

Abstract

Immunization with radiation-attenuated sporozoites (RAS) can confer sterilizing protection against malaria, although the mechanisms behind this protection are incompletely understood. We performed a systems biology analysis of samples from the Immunization by Mosquito with Radiation Attenuated Sporozoites (IMRAS) trial, which comprised P. falciparum RAS-immunized (PfRAS), malaria-naive participants whose protection from malaria infection was subsequently assessed by controlled human malaria infection (CHMI). Blood samples collected after initial PfRAS immunization were analyzed to compare immune responses between protected and non-protected volunteers leveraging integrative analysis of whole blood RNA-seq, high parameter flow cytometry, and single cell CITEseq of PBMCs. This analysis revealed differences in early innate immune responses indicating divergent paths associated with protection. In particular, elevated levels of inflammatory responses early after the initial immunization were detrimental for the development of protective adaptive immunity. Specifically, non-classical monocytes and early type I interferon responses induced within 1 day of PfRAS vaccination correlated with impaired immunity. Non-protected individuals also showed an increase in Th2 polarized T cell responses whereas we observed a trend towards increased Th1 and T-bet+ CD8 T cell responses in protected individuals. Temporal differences in genes associated with natural killer cells suggest an important role in immune regulation by these cells. These findings give insight into the immune responses that confer protection against malaria and may guide further malaria vaccine development. Trial registration: ClinicalTrials.gov NCT01994525.

Longitudinal immune profiling after radiation-attenuated sporozoite vaccination reveals coordinated immune processes correlated with malaria protection

“…Our work stands out as the most comprehensive profiling to date of radiationattenuated sporozoite immunization and challenge in malaria naïve individuals. Previously [13], we reported that increased abundance of type I interferon-associated genes in blood were associated with a lack of protection in malaria-naïve RAS vaccinees after the first immunization.…”

“…Radiation-attenuated sporozoite vaccination is known to induce sterilizing protection against malaria, and many studies have investigated its protective efficacy and immune consequences [13,14,[36][37][38][39]. Our work stands out as the most comprehensive profiling to date of radiationattenuated sporozoite immunization and challenge in malaria naïve individuals.…”

“…The IMRAS trial (ClinicalTrials.gov NCT01994525) design has been described previously [13][14][15]. In this work, we analyzed IMRAS Cohort 1, which consisted of 11 individuals who received 5 RAS immunizations via approximately 200 mosquito bites each.…”

“…The IMRAS study design has previously been described [13][14][15]. Briefly, study participants were immunized five times with radiation attenuated P. falciparum NF54 sporozoites (RAS) delivered by mosquito bite, with roughly 200 bites per-immunization.…”

“…Notably, sporozoite administration under chemoprophylaxis has been shown to be capable of eliciting strain-transcendent protection against subsequent challenge [12]. Previous work has described the IMRAS study [13][14][15], which comprised radiation-attenuated sporozoite vaccination of malaria-naïve individuals who were predominantly male (10 male, 1 female). Studying malaria-naïve rather than malaria experienced individuals allows the clearest picture of the early events involved in protective immunity.…”