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mRNA lipid nanoparticle (LNP) vaccines would be useful during an influenza virus pandemic since they can be produced rapidly and do not require the generation of egg-adapted vaccine seed stocks. Highly pathogenic avian influenza viruses from H5 clade 2.3.4.4b are circulating at unprecedently high levels in wild and domestic birds and have the potential to adapt to humans. Here, we generate an mRNA lipid nanoparticle (LNP) vaccine encoding the hemagglutinin (HA) glycoprotein from a clade 2.3.4.4b H5 isolate. The H5 mRNA-LNP vaccine elicits strong T cell and antibody responses in female mice, including neutralizing antibodies and broadly-reactive anti-HA stalk antibodies. The H5 mRNA-LNP vaccine elicits antibodies at similar levels compared to whole inactivated vaccines in female mice with and without prior H1N1 exposures. Finally, we find that the H5 mRNA-LNP vaccine is immunogenic in male ferrets and prevents morbidity and mortality of animals following 2.3.4.4b H5N1 challenge. Together, our data demonstrate that a monovalent mRNA-LNP vaccine expressing 2.3.4.4b H5 is immunogenic and protective in pre-clinical animal models. Highly pathogenic avian influenza viruses from H5 clade 2.3.4.4b are circulating widely in birds and have recently caused large outbreaks in mammals. Here, Furey et al. develop a clade 2.3.4.4b HA-expressing mRNA-LNP vaccine and show that it elicits strong protective immune responses in mice and ferrets.

Crimean-Congo Hemorrhagic Fever Virus (CCHFV) is a tick-borne virus that causes severe hemorrhagic disease in humans. There is a great need for effective vaccines and therapeutics against CCHFV for humans, as none are currently internationally approved. Recently, a monoclonal antibody against the GP38 glycoprotein protected mice against lethal CCHFV challenge. To show that GP38 is required and sufficient for protection against CCHFV, we used three inactivated rhabdoviral-based CCHFV-M vaccines, with or without GP38 in the presence or absence of the other CCHFV glycoproteins. All three vaccines elicited strong antibody responses against the respective CCHFV glycoproteins. However, only vaccines containing GP38 showed protection against CCHFV challenge in mice; vaccines without GP38 were not protective. The results of this study establish the need for GP38 in vaccines targeting CCHFV-M and demonstrate the efficacy of a CCHFV vaccine candidate based on an established vector platform.

Lassa fever virus (LASV), a member of the Arenavirus family, is the etiological agent of Lassa fever, a severe hemorrhagic disease that causes considerable morbidity and mortality in the endemic areas of West Africa. LASV is a rodent-borne CDC Tier One biological threat agent and is on the World Health Organization’s (WHO) Priority Pathogen list. Currently, no FDA-licensed vaccines or specific therapeutics are available. Here, we describe the efficacy of a deactivated rabies virus (RABV)-based vaccine encoding the glycoprotein precursor (GPC) of LASV (LASSARAB). Nonhuman primates (NHPs) were administered a two-dose regimen of LASSARAB or an irrelevant RABV-based vaccine to serve as a negative control. NHPs immunized with LASSARAB developed strong humoral responses to LASV-GPC. Upon challenge, NHPs vaccinated with LASSARAB survived to the study endpoint, whereas NHPs in the control group did not. This study demonstrates that LASSARAB is a worthy candidate for continued development.

Avian H5N1 influenza viruses are circulating widely in cattle and other mammals and pose a risk for a human pandemic. Previous studies suggest that older humans are more resistant to H5N1 infections due to childhood imprinting with other group 1 viruses (H1N1 and H2N2); however, the immunological basis for this is incompletely understood. Here we measured H5N1 antibody responses in sera from 157 individuals born between 1927 and 2016. We show that antibody titers to historical and recent H5N1 strains are highest in older individuals and correlate more strongly with birth year than with age, consistent with immune imprinting. Young children, who were likely not yet exposed to seasonal influenza viruses, had low levels of H5-specific antibodies. We also measured H5N1 antibody responses in sera from 100 individuals before and after receiving an A/Vietnam/1203/2004 H5N1 vaccine. We found that both younger and older humans produced H5-reactive antibodies to the A/Vietnam/1203/2004 vaccine strain and to a contemporary clade 2.3.4.4b strain, with higher seroconversion rates in young children who had lower levels of antibodies before vaccination. These studies suggest that younger individuals might benefit more from vaccination than older individuals in the event of an H5N1 pandemic. H5N1 strain-specific antibodies are higher in older individuals and correlate more with birth year than with age, suggesting that younger individuals are potentially more likely to benefit from H5N1 vaccination.

Crimean-Congo Hemorrhagic Fever virus (CCHFV) is an emerging, tickborne, zoonotic virus with an expansive global distribution. CCHFV is a biosafety level 4 (BSL-4) pathogen and classified as an NIH/NIAID Category A and WHO high-priority pathogen, thus of great risk to public health. There are currently no globally licensed therapeutics or vaccines available. The goal of this thesis was to use rhabdoviral vectors to develop CCHFV vaccines. Rabies virus (RABV) and vesicular stomatitis virus (VSV) were chosen as vaccine vectors given their safety record, easily manipulated genomes and ability to incorporate foreign glycoproteins. The CCHFV-GP38 protein was shown to be indispensable for virus replication and an anti-GP38 monoclonal antibody protected mice against wildtype (WT) CCHFV challenge. Thus, GP38 was hypothesized to be a protective antigen. RABV- and VSV-based CCHFV vaccines with or without GP38, either alone or with the other CCHFV glycoproteins were developed to test this hypothesis. The vaccine viruses were characterized to look for incorporation of the desired glycoproteins and then inactivated, administered to mice, and shown to elicit a humoral response through enzyme-linked immunosorbent assay. A VSV with its native glycoprotein replaced by the CCHFV glycoprotein gene (M) (VSV-ΔG-coM) was used as a non-BSL-4 surrogate challenge model for CCHFV. Interferon α/β receptor 1 knockout mice immunized with a GP38 only vaccine were protected against VSV-ΔG-coM challenge compared to controls, demonstrating vaccine efficacy and utility of the surrogate challenge model. Additionally, rhabdoviral-based CCHFV vaccines were tested in a WT CCHFV challenge model, in which only mice immunized with vaccines containing GP38 were protected. Thus, GP38 is required and sufficient for protection against CCHFV. Strikingly, the GP38 only vaccine did not induce CCHFV neutralizing antibodies or significant GP38-specific T cell responses, indicating that the mechanism of protection is likely mediated by non-neutralizing antibody functions. The results presented here advance the effort to design a successful CCHFV vaccine by defining a protective target antigen.

Clade 2.3.4.4b H5NX influenza viruses have spread widely in birds since 2020. In addition to causing disease in birds, these viruses have infected a variety of mammals, including humans. Clade 2.3.4.4b H5N1 viruses are currently causing an outbreak among dairy cattle in the United States, and it is important to determine if other mammals have been exposed to H5NX viruses. Cats, specifically outdoor and feral cats, frequently predate wild birds. Recent studies have shown that cats living on dairy cattle farms can be infected with H5N1. Here, we completed serological studies to determine if owned and feral cats living in an urban environment in the United States have evidence of past H5N1 exposures. We used multianalyte bead-based assays to measure clade 2.3.4.4b hemagglutinin (HA) antibody levels in serum samples collected in July 2023 to June 2025 from 417 feral and 228 owned cats from the greater Philadelphia area. We also measured antibody levels against a panel of HAs from other human and non-human influenza viruses, and the receptor binding domain (RBD) of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). We completed additional H5N1 and SARS-CoV-2 neutralization assays using samples that had detectable antibodies in the multianalyte bead-based assays. One cat (0.16%) was positive for H5 antibodies and twenty cats (3.1%) were positive for SARS-CoV-2 antibodies in both binding and neutralization assays. These data suggest that cats in the Philadelphia area have not been routinely exposed to clade 2.3.4.4b H5N1 viruses but have been more commonly exposed to SARS-CoV-2.

Introduction: Aberrant DNA methylation is frequently observed in colorectal cancer (CRC), but the underlying mechanisms are poorly understood. Ten-Eleven Translocation (TET) dioxygenases and DNA repair enzyme Thymine DNA Glycosylase (TDG) are involved in active DNA demethylation by generating and removing, respectively, novel oxidized cytosine species. Mutations of TET1 and TDG, and alterations of the levels of oxidized cytosine species have been identified in human CRC cases, but the biological significance of the TET-TDG demethylation axis in intestinal tumorigenesis is unclear. Material and Methods: We generated ApcMin mice with additional inactivation of Tet1 and/or Tdg, and characterized the methylome and transcriptome of intestinal adenomas by DREAM and RNA sequencing, respectively. Results: Tet1- and/or Tdg-deficient ApcMin mice show enhanced intestinal tumorigenesis in comparison to wild type Tet1 and Tdg ApcMin mice. Specifically, Tet1 and/or Tdg-deficient ApcMin adenomas manifested increased size or features of erosion and stroma activation. Methylome analysis revealed progressive loss of global DNA hypomethylation in colonic adenomas from Tet1- and Tdg-deficient ApcMin mice, and hypermethylation of CpG islands in Tet1-deficient ApcMin mice. In addition, RNA sequencing showed upregulation of genes in inflammatory and immune response pathways in Tet1- and Tdg-mutant colonic adenomas compared to control ApcMin adenomas. Conclusions: Taken together, these findings demonstrate the important role of active DNA demethylation mediated by TET-TDG in reducing intestinal tumor formation, by modulating the epigenome and inflammatory/immune responses. This study highlights a novel mechanism of epigenetic deregulation during intestinal tumorigenesis with diagnostic, therapeutic and prognostic implications.