Fast and fierce versus slow and smooth: Heterogeneity in immune responses to Plasmodium in the controlled human malaria infection model.

Controlled human malaria infection (CHMI) is an established model in clinical malaria research. Upon exposure to Plasmodium falciparum parasites, malaria-naive volunteers differ in dynamics and composition of their immune profiles and subsequent capacity to generate protective immunity. CHMI volunteers are either inflammatory responders who have prominent cellular IFN-γ production primarily driven by adaptive T cells, or tempered responders who skew toward antibody-mediated humoral immunity. When exposed to consecutive CHMIs under antimalarial chemoprophylaxis, individuals who can control parasitemia after a single immunization (fast responders) are more likely to be protected against a subsequent challenge infection. Fast responders tend to be inflammatory responders who can rapidly induce long-lived IFN-γ+ T cell responses. Slow responders or even non-responders can also be protected, but via a more diverse range of responses that take a longer time to reach full protective efficacy, in part due to their tempered phenotype. The latter group can be identified at baseline before CHMI by higher expression of inhibitory ligands CTLA-4 and TIM-3 on CD4+ T cells. Delineating heterogeneity in human immune responses to P. falciparum will facilitate rational design and strategy towards effective malaria vaccines.

Serologic Markers of Previous Malaria Exposure and Functional Antibodies Inhibiting Parasite Growth Are Associated With Parasite Kinetics Following a Plasmodium falciparum Controlled Human Infection.

BACKGROUND: We assessed the impact of exposure to Plasmodium falciparum on parasite kinetics, clinical symptoms, and functional immunity after controlled human malaria infection (CHMI) in 2 cohorts with different levels of previous malarial exposure. METHODS: Nine adult males with high (sero-high) and 10 with low (sero-low) previous exposure received 3200 P. falciparum sporozoites (PfSPZ) of PfSPZ Challenge by direct venous inoculation and were followed for 35 days for parasitemia by thick blood smear (TBS) and quantitative polymerase chain reaction. Endpoints were time to parasitemia, adverse events, and immune responses. RESULTS: Ten of 10 (100%) volunteers in the sero-low and 7 of 9 (77.8%) in the sero-high group developed parasitemia detected by TBS in the first 28 days (P = .125). The median time to parasitemia was significantly shorter in the sero-low group than the sero-high group (9 days [interquartile range {IQR} 7.5-11.0] vs 11.0 days [IQR 7.5-18.0], respectively; log-rank test, P = .005). Antibody recognition of sporozoites was significantly higher in the sero-high (median, 17.93 [IQR 12.95-24] arbitrary units [AU]) than the sero-low volunteers (median, 10.54 [IQR, 8.36-12.12] AU) (P = .006). Growth inhibitory activity was significantly higher in the sero-high (median, 21.8% [IQR, 8.15%-29.65%]) than in the sero-low group (median, 8.3% [IQR, 5.6%-10.23%]) (P = .025). CONCLUSIONS: CHMI was safe and well tolerated in this population. Individuals with serological evidence of higher malaria exposure were able to better control infection and had higher parasite growth inhibitory activity. CLINICAL TRIALS REGISTRATION: NCT03496454.

Declining Malaria Transmission Differentially Impacts the Maintenance of Humoral Immunity to Plasmodium falciparum in Children.

Background: We investigated the poorly understood impact of declining malaria transmission on maintenance of antibodies to Plasmodium falciparum merozoite antigens and infected erythrocytes (IEs), including functional immunity. Methods: In a 3-year longitudinal cohort of 300 Kenyan children, antibodies to different AMA1 and MSP2 alleles of merozoites, IE surface antigens, and antibody functional activities were quantified. Results: Over a period in which malaria transmission declined markedly, AMA1 and MSP2 antibodies decreased substantially; estimated half-lives of antibody duration were 0.8 year and 1-3 years, respectively. However, 69%-74% of children maintained their seropositivity to AMA1 alleles and 42%-52% to MSP2 alleles. Levels and prevalence of antimerozoite antibodies were consistently associated with increasing age and concurrent parasitemia. Antibodies promoting opsonic phagocytosis of merozoites declined rapidly (half-life, 0.15 years). In contrast, complement-fixing antibodies to merozoites did not decline and antibodies to IE surface antigens expressing virulent phenotypes were much better maintained (half-life, 4-10 years). Conclusions: A decline in malaria transmission is associated with reduction in naturally acquired immunity. However, loss of immunity is not universal; some key functional responses and antibodies to IEs were better maintained and these may continue to provide some protection. Findings have implications for malaria surveillance and control measures and informing vaccine development.

Biomarkers of cellular aging during a controlled human malaria infection.

Cellular aging is difficult to study in individuals with natural infection, given the diversity of symptom duration and clinical presentation, and the high interference of aging-related processes with host and environmental factors. To address this challenge, we took advantage of the controlled human malaria infection (CHMI) model. This approach allowed us to characterize the relationship among cellular aging markers prior, during and post malaria pathophysiology in humans, controlling for infection dose, individual heterogeneity, previous exposure and co-infections. We demonstrate that already low levels of Plasmodium falciparum impact cellular aging by inducing high levels of inflammation and redox-imbalance; and that cellular senescence reversed after treatment and parasite clearance. This study provides insights into the complex relationship of telomere length, cellular senescence, telomerase expression and aging-related processes during a single malaria infection.

TH1-Polarized TFH Cells Delay Naturally-Acquired Immunity to Malaria.

Humoral immunity is a critical effector arm for protection against malaria but develops only slowly after repeated infections. T cell-mediated regulatory dynamics affect the development of antibody responses to Plasmodium parasites. Here, we hypothesize that T follicular helper cell (TFH) polarization generated by repeated Plasmodium asexual blood-stage infections delays the onset of protective humoral responses. IFN-γ production promotes polarization toward TFH1 and increased generation of regulatory follicular helper cells (TFR). Delineating the mechanisms that drive TH1 polarization will provide clues for appropriate induction of lasting, protective immunity against malaria.

Dendritic Cell Responses and Function in Malaria.

Malaria remains a serious threat to global health. Sustained malaria control and, eventually, eradication will only be achieved with a broadly effective malaria vaccine. Yet a fundamental lack of knowledge about how antimalarial immunity is acquired has hindered vaccine development efforts to date. Understanding how malaria-causing parasites modulate the host immune system, specifically dendritic cells (DCs), key initiators of adaptive and vaccine antigen-based immune responses, is vital for effective vaccine design. This review comprehensively summarizes how exposure to Plasmodium spp. impacts human DC function in vivo and in vitro. We have highlighted the heterogeneity of the data observed in these studies, compared and critiqued the models used to generate our current understanding of DC function in malaria, and examined the mechanisms by which Plasmodium spp. mediate these effects. This review highlights potential research directions which could lead to improved efficacy of existing vaccines, and outlines novel targets for next-generation vaccine strategies to target malaria.

Different Life Cycle Stages of Plasmodium falciparum Induce Contrasting Responses in Dendritic Cells.

Dendritic cells are key linkers of innate and adaptive immunity. Efficient dendritic cell activation is central to the acquisition of immunity and the efficacy of vaccines. Understanding how dendritic cells are affected by Plasmodium falciparum blood-stage parasites will help to understand how immunity is acquired and maintained, and how vaccine responses may be impacted by malaria infection or exposure. This study investigates the response of dendritic cells to two different life stages of the malaria parasite, parasitized red blood cells and merozoites, using a murine model. We demonstrate that the dendritic cell responses to merozoites are robust whereas dendritic cell activation, particularly CD40 and pro-inflammatory cytokine expression, is compromised in the presence of freshly isolated parasitized red blood cells. The mechanism of dendritic cell suppression by parasitized red blood cells is host red cell membrane-independent. Furthermore, we show that cryopreserved parasitized red blood cells have a substantially reduced capacity for dendritic cell activation.