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.
Highlights
Malaria is a devastating disease that results in over 200 million cases and hundreds of thousands of deaths annually
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
We studied individuals vaccinated with irradiated sporozoites before being exposed to live malaria parasites
Summary
Malaria is a devastating disease that results in over 200 million cases and hundreds of thousands of deaths annually. Plasmodium falciparum causes the most serious disease and the most deaths, especially in sub-Saharan Africa and primarily in children [1]. Multi-pronged efforts to eliminate malaria have led to substantial reductions in malaria incidence but the development of drug and insecticide resistance as well as other factors, including the current COVID-19 pandemic, are a challenge to further progress [1, 2]. Despite exciting recent progress [3], a single approved malaria vaccine exists, the RTS,S subunit vaccine, which elicited 28–33% protection in infants over a 4-year study period [4]. Especially one that prevents infection, would be a valuable tool in the effort to eliminate this disease. Understanding the immune responses that contribute to vaccine induced immune protection could aid the development of such vaccines
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