The pre-erythrocytic stage initiated by sporozoites is a population bottleneck in the parasite lifecycle, and is an attractive target for vaccine development strategies. There they multiply and over the course of 5–9 days, asymptomatically develop into thousands of merozoites which emerge from the liver and serially infect erythrocytes, resulting in blood-stage infection and disease. Malaria sporozoites develop in the mosquito and are injected into the skin during a female mosquito blood meal from where they make their way to the liver and infect hepatocytes. However, acquisition of sterilizing immunity targeting the pre-erythrocytic stage of the parasite, resulting from immunization with radiation-attenuated malaria sporozoites, has been experimentally demonstrated in animal models and in humans. Serious malaria-related complications and death occur primarily in infants and children, prior to the development of partially protective immune responses. Repeated natural malaria infections can result in acquisition of semi-protective immunity with persistent low level parasitaemia and primarily asymptomatic cases. A more effective malaria vaccine would be a valuable tool for curbing malaria, especially given the emergence of resistance to frontline artemisinin combination therapy and development of insecticide-resistant mosquito vectors. Currently, the most advanced malaria vaccine, RTS,S, exhibits 28–36% efficacy in infants and children observed over an average time period of 4 years. Some 94% of cases were in Africa, where almost all infections were caused by Plasmodium falciparum. Non-protection is associated with deviations from this model, observed in this study with over-induction of early interferon responses in IMRAS and failure to mount a cell cycle response in BSPZV1.ĭespite the existence of effective anti-parasitic drugs, malaria remains a critical global health problem, estimated at causing 409,000 deaths and 229 million cases in 2019. These comprised a moderate early interferon response peaking 2 days post vaccination, followed by a later proliferative cell cycle response steadily increasing over the first 7 days post vaccination. In summary, despite stark differences between the two studies, including route of vaccination and status of malaria exposure, responses were identified that were associated with protection after PfRAS vaccination. All individuals, except for non-protected BSPZV1 participants, showed robust upregulation of cell-cycle associated transcriptional responses post vaccination. Additionally, strongly increased induction of inflammation and interferon-associated responses was seen in non-protected IMRAS participants. A time-dependent regulatory programme of coherent blood transcriptional modular responses was observed, involving induction of inflammatory responses 1–3 days post-vaccination, with cell cycle responses apparent by day 7 in protected individuals from both trials. ResultsĪnalysis of comparable time points up to 1 week after the first vaccination revealed a shared cross-study transcriptional response programme, despite large differences in number and magnitude of differentially expressed genes between trials. Study vaccine dosings were chosen to elicit both protected and non-protected subjects, so that protection-associated responses could be identified. Observed protective efficacy was 55% in IMRAS and 20% in BSPZV1. Parasite dose and method of delivery differed between trials, and immunization regimens were designed to achieve incomplete protective efficacy. falciparum sporozoites were analysed and compared across malaria-naïve adult participants (IMRAS) and malaria-experienced adult participants (BSPZV1). Longitudinal whole blood RNAseq transcriptome responses to immunization with radiation-attenuated P. In this work, two recent radiation-attenuated sporozoite vaccination studies were used to identify potential transcriptional correlates of vaccination-induced protection. However, the mechanisms underlying this protection remain unclear. Vaccination with radiation-attenuated Plasmodium falciparum sporozoites is known to induce protective immunity.
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