Biology subjects

Heath, W. R.

Publications and source records attributed to Heath, W. R..

6 recordsLinked to original sources

bioRxiv2026

Optimization of a liver Trm cell-inducing mRNA vaccine by reduction of type I interferon response

CD8+ tissue-resident memory T cells provide rapid frontline protection at pathogen invasion sites, making them attractive targets for vaccine-mediated immunity. We previously developed an NKT cell-adjuvanted mRNA lipoplex vaccine capable of inducing liver Trm cells and sterile protection against malaria in mice. Here, we show that type I interferon (IFN-I) signalling through dendritic cells -- not T cells -- is a key brake on liver Trm induction by this vaccine. Optimising mRNA manufacturing to reduce immunostimulatory contaminants substantially dampened IFN-I production, boosted antigen expression in the lymphoid tissues, and drove significantly greater Trm accumulation. These enhanced responses translated into superior protection against parasite challenge. Our findings identify DC-intrinsic IFN-I signalling as a tractable target, and mRNA manufacturing quality as a critical and underappreciated lever, for maximising Trm-based vaccine efficacy.

immunology↗

bioRxiv2026

Temporal expression of liver-stage malaria antigens shapes vaccine efficacy

Vaccine-induced cytotoxic T cells can prevent malaria by killing parasite-infected hepatocytes during the liver stage. While several antigenic targets have been identified, little consideration has been given to their temporal expression. Here, we identified SERA1 of Plasmodium berghei as a late liver-stage target in rodent malaria and further showed that the classic vaccine antigen thrombospondin-related adhesion protein (TRAP) is only an early target. While vaccination with either antigen alone was modestly protective, combining these antigens enabled killing over the entire liver-stage, greatly improving efficacy. Given the relatively long liver-stage in human malaria, our findings imply TRAP-dependent vaccines likely utilize only a small proportion of the available liver-stage to eradicate parasites. Our findings further indicate that considerations of temporal coverage when selecting vaccine antigens will improve efficacy. One-Sentence SummaryTemporally defining presentation of liver-stage antigens informs rational combinations that maximize malaria vaccine efficacy.

immunology↗

bioRxiv2025

Chemovaccination with a novel antimalarial targeting the late liver stage induces durable immunity against malaria

Vaccination with Plasmodium falciparum, the most lethal malaria parasite, using sporozoites that arrest during liver stage infection either by irradiation, genetic attenuation or chemotherapy have been developed, with late liver stage arrest providing very high efficacy. Such vaccines require complex manufacture, deployment and intravenous administration. Here, we report an alternative strategy of chemo-attenuation of malaria parasites at the late liver stage using first-in-class antimalarials under clinical development that target the parasite aspartyl proteases plasmepsin IX and X. A single low-dose infection with virulent Plasmodium berghei sporozoites followed by drug treatment cleared infection by producing chemo-attenuated liver merozoites (CALM) that induced sterile immunity in mice for up to 21 months. Protection arose from humoral responses to circumsporozoite protein and robust CD8+ T cell responses, including liver-resident memory cells reactive to diverse antigens including SERA1 and RPL6. Drug treatment also attenuated the human pathogen P. falciparum by preventing liver merozoites from infecting human erythrocytes in humanized chimeric liver mice, confirming that the mechanism of liver-stage merozoite attenuation (ie, CALM) via inhibition of plasmepsins IX and X is conserved, likely due to conservation of binding site amino acids of both proteases across the Plasmodium genus. Therefore, plasmepsin IX/X-targeting antimalarials offer a new approach to achieving late liver stage arrest against all circulating Plasmodium species and strains. This study establishes the basis for clinical trials assessing CALM for chemoprevention and chemovaccination against diverse Plasmodium species to advance new therapeutic strategies in malaria control. It also suggests the prospect of chemovaccination by natural exposure to mosquito-borne parasites if development of a long-acting injectable formulation of plasmepsin IX/X inhibitors proves feasible.

microbiology↗

bioRxiv2024

Vgamma1+ gammadelta T cell-derived IL-4 initiates CD8 T cell immunity

Dendritic cells (DC) are pivotal for initiating adaptive immunity, a process triggered by the activation of DC via pathogen products or damage. Here, we describe an additional layer to this process, essential when pathogen-derived signals alone cannot directly achieve full DC activation. Immunisation with sporozoites from Plasmodium leads to CD8 T cell priming in a complex response that is initiated by a collaboration between conventional type 1 DC (cDC1) and {gamma}{delta} T cells. We unveil a pivotal initiating role for V{gamma}1+ {gamma}{delta} T cells, as they directly supply IL-4 to DC and CD8 T cells. IL-4 synergises with a CD4 T cell-derived CD40L signal to induce IL-12 production by cDC1. Both IL-12 and IL-4 then directly signal CD8 T cells, with synergy between these cytokines driving enhanced IL-12 receptor expression and expansion of responding CD8 T cells. This study reveals a key role for V{gamma}l+ {gamma}{delta} T cells in initiating CD8 T cell immunity to Plasmodium. More broadly, it shows that responses to some pathogens require help from innate-like T cells to pass an initiation threshold and further amplify the response in a process underscored by IL-4 production.

immunology↗

bioRxiv2024

Long lived liver-resident memory T cells of biased specificities for abundant sporozoite antigens drive malaria protection by radiation-attenuated sporozoite vaccination

Vaccination with radiation-attenuated sporozoites (RAS) can provide highly effective protection against malaria in both humans and mice. To extend understanding of malaria immunity and inform the development of future vaccines, we studied the protective response elicited by this vaccine in C57BL/6 mice. We reveal that successive doses of Plasmodium berghei RAS favour the generation of liver CD8+ tissue-resident memory T cells (TRM cells) over circulating memory cells, and markedly enhance their longevity. Importantly, RAS immunisation strongly skews the composition of the liver CD8+ TRM compartment towards cells specific for abundant sporozoite antigens, such as thrombospondin-related adhesive protein (TRAP) and circumsporozoite protein (CSP), which become major mediators of protection. The increased prevalence of sporozoite specificities is associated with limited intrahepatic parasite development and inhibition of naive T cell responses to all parasite antigens in previously vaccinated mice. This leads to the exclusive expansion of effector T cells formed upon initial immunisation, ultimately reducing the diversity of the liver TRM pool later established. These findings provide novel insights into the mechanisms governing malaria immunity induced by attenuated sporozoite vaccination and highlight the susceptibility of this vaccine to limitations imposed by strain-specific immunity associated with the abundant, yet highly variable sporozoite antigens CSP and TRAP. Author SummaryMalaria remains a significant global health challenge. An efficient vaccine could significantly enhance malaria control. Vaccination with radiation-attenuated sporozoites (RAS) can induce highly efficient protection against malaria, and our study brings critical insights into the protective mechanisms elicited by this vaccine. We show that RAS stimulates the formation of parasite-specific cytotoxic memory T cells that permanently reside in the liver (liver TRM cells). These cells are critical mediators of protection. Interestingly, multiple doses of RAS extend the lifespan of these memory cells, potentially improving long term immunity. However, we found that the induced memory T cell response is strongly skewed towards abundant, but highly variable, sporozoite proteins. Thus, this phenomenon exposes a potential limitation of the RAS vaccine against the great parasite diversity in the field, as it focuses the T cell response away from less abundant, but more conserved, parasite antigens.

immunology↗

bioRxiv2019

Systemic inflammation suppresses lymphoid tissue remodelling and B cell immunity during concomitant local infection

Concurrent infection with multiple pathogens occurs frequently in individuals and can result in exacerbated infections and altered immunity. However, the impact of such coinfections on immune responses remains poorly understood. Here we reveal that systemic infection results in an inflammation-induced suppression of local immunity. During localized infection or vaccination in barrier tissues including the skin or respiratory tract, concurrent systemic infection induced a type I interferon-dependent lymphopenia that impairs lymphocyte recruitment to the draining lymph node (dLN). This leads to suppressed lymphoid stromal cell expansion and dLN remodeling and impaired induction of B cell responses and antibody production. Our data suggest that contemporaneous systemic inflammation constrains the induction of regional immunity.Competing Interest StatementThe authors have declared no competing interest.View Full Text

immunology↗