Biology subjects

Holz, L. E.

Publications and source records attributed to Holz, L. E..

2 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↗