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

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. Author summary: Malaria remains a serious global health problem, causing hundreds of thousands of deaths every year. An effective malaria vaccine would be an important tool to fight this disease. Previous work has shown that irradiated sporozoites, the form of the malaria parasite injected into humans by mosquitos, are not capable of progressing to a symptomatic blood stage malaria infection, and act as a protective vaccine against future malaria exposure. However the mechanisms that produce this protection are unknown. In this work, we studied individuals vaccinated with irradiated sporozoites before being exposed to live malaria parasites. Roughly half of these individual were protected against malaria. By analyzing blood samples taken at multiple points after the first vaccination using RNA sequencing and flow cytometry we identified immune responses that differed between protected and non-protected study participants. Notably, we observed a rapid increase in inflammation and interferon-associated genes in non-protected individual. We also observed protection-associated changes in T cell and NK cell associated pathways. Our study provides novel insights into immune responses associated with effective malaria vaccination, and can point the way to improved design of whole-sporozoite malaria vaccine approaches. [ABSTRACT FROM AUTHOR]