Medigen (United States)

There is a need for safe and effective vaccines against the Venezuelan equine encephalitis virus that infects both humans and equines. However, development of a live-attenuated vaccine using the TC-83 strain has been hampered by substantial reactogenicity and the potential for neuroinvasion. In this study, we demonstrate that V4020, a new TC-83-based investigational VEEV vaccine with redundant safety features preventing neuroinvasion and reversion, exhibited no neuroinvasion potential in a murine model. Following subcutaneous or intramuscular administration, a subset of mice that received the TC-83 vaccine succumbed to central nervous system infection, with replicating virus detected in the CNS, demonstrating a low, yet detectable neuroinvasion potential of the TC-83 vaccine in vivo. Sequencing analysis of the TC-83 virus recovered from the brains identified a pseudoreversion of E2 R120I, as E2 R120 is known to confer attenuation for TC-83. In contrast, V4020 showed no evidence of virus in the CNS, highlighting one of the V4020 features, a new synonymous codon to minimize reversion to the wild-type residue. Overall, our study establishes V4020 as a rationally designed, safe vaccine candidate for VEEV with significantly reduced neuroinvasion risk.

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Annual influenza vaccination is recommended to update the variable hemagglutinin antigens. Here, we first designed a virus-like particle (VLP) displaying consensus multi-neuraminidase (NA) subtypes (cN1, cN2, B cNA) and M2 ectodomain (M2e) tandem repeat (m-cNA-M2e VLP). Vaccination of mice with m-cNA-M2e VLP induced broad NA inhibition (NAI), and M2e antibodies as well as interferon-gamma secreting T cell responses. Mice vaccinated with m-cNA-M2e VLP were protected against influenza A (H1N1, H5N1, H3N2, H9N2, H7N9) and influenza B (Yamagata and Victoria lineage) viruses containing substantial antigenic variations. Protective immune contributors include cellular and humoral immunity as well as antibody-dependent cellular cytotoxicity. Furthermore, comparable cross protection by m-cNA-M2e VLP vaccination was induced in aged mice. This study supports a novel strategy of developing a universal vaccine against influenza A and B viruses potentially in both young and aged populations by inducing multi-NA subtype and M2e immunity with a single VLP entity.