Our understanding of the deterioration in immune function in old age—immunosenescence—derives principally from studies of modern human populations and laboratory animals. The generality and significance of this process for systems experiencing complex, natural infections and environmental challenges are unknown. Here, we show that late-life declines in an important immune marker of resistance to helminth parasites in wild Soay sheep predict overwinter mortality. We found senescence in circulating antibody levels against a highly prevalent nematode worm, which was associated with reduced adult survival probability, independent of changes in body weight. These findings establish a role for immunosenescence in the ecology and evolution of natural populations.

Controlled human malaria infection (CHMI) provides a highly informative means to investigate hostpathogen interactions and enable in vivo proof-of-concept efficacy testing of new drugs and vaccines. However, unlike Plasmodium falciparum, well-characterized P. vivax parasites that are safe and suitable for use in modern CHMI models are limited. Here, two healthy malaria-naïve UK adults with universal donor blood group were safely infected with a clone of P. vivax from Thailand by mosquito-bite CHMI.Parasitemia developed in both volunteers and, prior to treatment, each volunteer donated blood to produce a cryopreserved stabilate of infected red blood cells. Following stringent safety screening, the parasite stabilate from one of these donors ("PvW1") was thawed and used to inoculate six healthy malaria-naïve UK adults by blood-stage CHMI, at three different dilutions. Parasitemia developed in all volunteers, who were then successfully drug treated. PvW1 parasite DNA was isolated and sequenced to produce a high quality genome assembly by using a hybrid assembly method. We analysed leading vaccine candidate antigens and multigene families, including the Vivax interspersed repeat (VIR) genes of which we identified 1145 in the PvW1 genome. Our genomic analysis will guide future assessment of candidate vaccines and drugs, as well as experimental medicine studies.

In endemic settings it is known that natural malaria immunity is gradually acquired following repeated exposures. Here we sought to assess whether similar acquisition of blood-stage malaria immunity would occur following repeated parasite exposure by controlled human malaria infection (CHMI). We report the findings of repeat homologous blood-stage Plasmodium falciparum (3D7 clone) CHMI studies VAC063C (ClinicalTrials.gov NCT03906474) and VAC063 (ClinicalTrials.gov NCT02927145). In total, 24 healthy, unvaccinated, malaria-naïve UK adult participants underwent primary CHMI followed by drug treatment. Ten of these then underwent secondary CHMI in the same manner, and then six of these underwent a final tertiary CHMI. As with primary CHMI, malaria symptoms were common following secondary and tertiary infection, however, most resolved within a few days of treatment and there were no long term sequelae or serious adverse events related to CHMI. Despite detectable induction and boosting of anti-merozoite serum IgG antibody responses following each round of CHMI, there was no clear evidence of anti-parasite immunity (manifest as reduced parasite growth in vivo) conferred by repeated challenge with the homologous parasite in the majority of volunteers. However, three volunteers showed some variation in parasite growth dynamics in vivo following repeat CHMI that were either modest or short-lived. We also observed no major differences in clinical symptoms or laboratory markers of infection across the primary, secondary and tertiary challenges. However, there was a trend to more severe pyrexia after primary CHMI and the absence of a detectable transaminitis post-treatment following secondary and tertiary infection. We hypothesize that this could represent the initial induction of clinical immunity. Repeat homologous blood-stage CHMI is thus safe and provides a model with the potential to further the understanding of naturally acquired immunity to blood-stage infection in a highly controlled setting.Clinical Trial RegistrationClinicalTrials.gov, identifier NCT03906474, NCT02927145.

Immunity to severe malaria is acquired quickly, operates independently of pathogen load and represents a highly effective form of disease tolerance. The mechanism that underpins tolerance in human malaria remains unknown. We developed a re-challenge model of falciparum malaria in which healthy naive adult volunteers were infected three times over a 12-month period to track the development of disease tolerance in real-time. We found that parasitaemia triggered a hardwired emergency myeloid response that led to systemic inflammation, pyrexia and hallmark symptoms of clinical malaria across the first three infections of life. In contrast, CD4+ T cell activation was quickly modified to reduce the number and diversity of effector cells upon re-challenge. Crucially, this did not silence critical helper T cell functions but instead prevented the generation of cytotoxic effectors associated with autoinflammatory disease. Tolerised hosts were thus able to prevent collateral tissue damage and injury. Host control of T cell activation can therefore be established after a single infection and in the absence of anti-parasite immunity. And furthermore, this rapid host adaptation can protect vital organs to minimise the harm caused by systemic inflammation and sequestration.