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.

Mathematical Analysis of the Ross-Macdonald Model with Quarantine.

People infected with malaria may receive less mosquito bites when they are treated in well-equipped hospitals or follow doctors' advice for reducing exposure to mosquitoes at home. This quarantine-like intervention measure is especially feasible in countries and areas approaching malaria elimination. Motivated by mathematical models with quarantine for directly transmitted diseases, we develop a mosquito-borne disease model where imperfect quarantine is considered to mitigate the disease transmission from infected humans to susceptible mosquitoes. The basic reproduction number [Formula: see text] is computed and the model equilibria and their stabilities are analyzed when the incidence rate is standard or bilinear. In particular, the model system may undergo a subcritical (backward) bifurcation at [Formula: see text] when standard incidence is adopted, whereas the disease-free equilibrium is globally asymptotically stable as [Formula: see text] and the unique endemic equilibrium is locally asymptotically stable as [Formula: see text] when the infection incidence is bilinear. Numerical simulations suggest that the quarantine strategy can play an important role in decreasing malaria transmission. The success of quarantine mainly relies on the reduction of bites on quarantined individuals.