Domi, A. | Search bioRxiv

bioRxiv2026

Single-dose Efficacy of a Next-Generation Mpox Vaccine Harnessing an Immunomodulatory Peptide

Rapidly deployable, single-dose vaccines that maintain durability under operational constraints remain an unmet need in outbreak preparedness. Live viral vectors such as Modified Vaccinia Ankara (MVA) offer strong safety profiles, yet their suboptimal immunogenicity often requires multidose regimens, reducing flexibility during emergency response. To address these limitations, we developed a modular vaccine platform that leverages immune checkpoint modulation to enhance immune cell priming without compromising the established safety profile of MVA. This platform, exemplified by the recombinant virus MVA-X, was engineered to express a peptide-based PD-1 antagonist (LD10) that provides localized, transient checkpoint blockade during early antigen presentation. The approach requires no external adjuvants, is compatible with lyophilization and stockpiling, and is readily adaptable to diverse antigens and pathogens. A single immunization with MVA-X produced durable protection that matched or exceeded that of a conventional two-dose MVA regimen against the prototypic orthopoxvirus vaccinia virus. Despite modest and contracting antibody titers, single-dose MVA-X vaccination conferred complete survival following both lethal and high-dose viral challenge at early (Day 55), intermediate (Day 90), and long-term (Day 150) time points. MVA-X also restricted viral replication at the primary site of infection, reduced systemic dissemination, and preserved lung architecture during peak disease. Importantly, MVA-X maintained efficacy in the highly susceptible CAST/EiJ mouse model following challenge with highly pathogenic Clade I monkeypox virus (MPXV). Together, these findings demonstrate that vaccine-intrinsic checkpoint modulation provides a modular strategy for enhancing the potency and durability of attenuated viral vectors while preserving their favorable safety profile, supporting broader application to emerging infectious diseases beyond Mpox.

immunology↗

bioRxiv2022

The development of compulsive coping behaviors depends on the engagement of dorsolateral striatum dopamine-dependent mechanisms

Humans greatly differ in how they cope with stress, a natural behavior learnt through negative reinforcement. Some individuals engage in displacement activities, others in exercise or comfort eating, and others still in alcohol use. Across species, adjunctive behaviors, such as polydipsic drinking, are used as a form of displacement activity that reduces distress. Some individuals, in particular those that use alcohol to self-medicate, tend to lose control over such coping behaviors, which become excessive and compulsive. However, the psychological and neural mechanisms underlying this individual vulnerability have not been elucidated. Here we tested the hypothesis that the development of compulsive adjunctive behaviors stems from the functional engagement of the dorsolateral striatum (DLS) dopamine-dependent habit system after a prolonged history of adjunctive responding. We measured in longitudinal studies in male Sprague Dawley rats the sensitivity of early established vs compulsive polydipsic water or alcohol drinking to a bilateral infusion of the dopamine receptor antagonist -flupentixol into the anterior DLS (aDLS). While most rats acquired a polydipsic drinking response with water, others only did so with alcohol. Whether reliant on water or alcohol, the acquisition of this coping response was insensitive to aDLS dopamine receptor blockade. In contrast, after prolonged experience, adjunctive drinking became dependent on the aDLS dopamine-dependent habit system at a time it was compulsive in vulnerable individuals. These data suggest that habits may develop out of negative reinforcement and that the engagement of their underlying striatal system is necessary for the manifestation of adjunctive behaviors. Significance statementHarnessing the individual variability that rodents, like humans, show to engage in adaptive or maladaptive coping strategies, which can result in the development of compulsive disorders, here we demonstrate that the functional engagement of the dorsolateral striatum-dependent habit system precipitates the transition to compulsion in rats that have acquired a polydipsic adjunctive drinking response with water or alcohol as a means to cope with distress. The results of this study not only provide evidence for the emergence of instrumental habits under negative reinforcement, but they also reveal that compulsive behaviors that originate from the loss of control over coping strategies are mediated by the dorsolateral striatum-dependent habit system.

neuroscience↗