Abstract
BackgroundVaccination with radiation-attenuated Plasmodium falciparum sporozoites is known to induce protective immunity. However, the mechanisms underlying this protection remain unclear. In this work, two recent radiation-attenuated sporozoite vaccination studies were used to identify potential transcriptional correlates of vaccination-induced protection.MethodsLongitudinal whole blood RNAseq transcriptome responses to immunization with radiation-attenuated P. falciparum sporozoites were analysed and compared across malaria-naïve adult participants (IMRAS) and malaria-experienced adult participants (BSPZV1). Parasite dose and method of delivery differed between trials, and immunization regimens were designed to achieve incomplete protective efficacy. Observed protective efficacy was 55% in IMRAS and 20% in BSPZV1. Study vaccine dosings were chosen to elicit both protected and non-protected subjects, so that protection-associated responses could be identified.ResultsAnalysis 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. 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. Additionally, strongly increased induction of inflammation and interferon-associated responses was seen in non-protected IMRAS participants. All individuals, except for non-protected BSPZV1 participants, showed robust upregulation of cell-cycle associated transcriptional responses post vaccination.ConclusionsIn 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. 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. 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.
Highlights
Vaccination with radiation-attenuated Plasmodium falciparum sporozoites is known to induce protective immunity
Challenge trials The IMRAS trial was performed in Bethesda, MD, USA with malaria-naive participants immunized by four rounds of ~ 190 bites of P. falciparum RAS (PfRAS)-infected mosquitoes at 4-week intervals followed by a fifth immunization a further 5 weeks later
Study design Participants were recruited as part of two independent radiation-attenuated sporozoites (RAS)-vaccination studies: IMRAS, [NCT01994525], [15] and BSPZV1 [16]
Summary
Vaccination with radiation-attenuated Plasmodium falciparum sporozoites is known to induce protective immunity. Despite 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. Repeated natural malaria infections can result in acquisition of semi-protective immunity with persistent low level parasitaemia and primarily asymptomatic cases [5]. Serious malaria-related complications and death occur primarily in infants and children, prior to the development of partially protective immune responses [6]. 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 [7,8,9,10]
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