Arenaviruses represent a rapidly expanding group of rodent-borne emerging human pathogens with significant pandemic potential. Diseases caused by these viruses, such as the Old-World Arenavirus (OWA) Lassa virus (LASV), which causes Lassa Fever, and the New-World Arenavirus (NWA) Junin virus (JUNV), which causes hemorrhagic fevers, currently lack effective therapeutics or vaccines. Members of the Arenaviridae family possess bi- or tri-segmented genomes encoding three to four viral proteins: glycoprotein (GP), nucleoprotein (NP), RNA polymerase (L) and matrix protein (Z). A robust T-cell immune response is critical for viral clearance and for limiting disease severity during the early stages of the infection.
Using a primary in vitro immunogenicity assay, we identified Conserved T cell Epitope Regions (CTERs) derived from conserved sequences within OWA and NWA, using LASV and JUNV as respective prototypes. These CTER epitopes were strongly recognized by human CD4+ T cells in vitro and were predicted to provide broad population coverage across diverse ethnicities. CTER constructs were designed based on the number of viral proteins included (GP+N+L, N+L, or L) and were assembled using AlphaFold into stable and unstable forms. Plasmids for OWA and NWA were codon-optimized and subsequently packaged into mRNA constructs.
Our ongoing BDF1 mouse studies demonstrate that the CTER-based T-cell vaccine is both safe and immunogenic, as assessed using a combined activation-induced marker (AIM) and intracellular cytokine (ICS) assay. AIM+ T cells isolated from the spleen and lymph nodes show strong cross-reactive potential across the Arenaviridae family.
With further in vitro and in vivo evaluation, this work represents an initial step toward the development of a pan-arenavirus T-cell vaccine.
CEPI, NIH
Vaccines and Immunotherapy (VAC)
Ziyin Wang, Margret Kim, A. Zúñiga et al.· Journal of Immunology· 0 citations
The COVID-19 pandemic highlighted the need for vaccines strategies that elicit broad T cell-mediated immunity against emerging viral families. BetaCoronaviruses - including severe acute respiratory syndrome coronavirus (SARS-CoV), Middle East respiratory syndrome (MERS) and SARS-CoV-2 — pose significant pandemic risks due to their zoonotic potential and genetic diversity. In previous work, we identified conserved Spike T cell epitope regions (S-CTERs) within the ancestral Wuhan S protein sequence that demonstrated strong cross-reactive potential across diverse BetaCoronaviruses.
Here, we investigated whether bivalent vaccination (Beta + Omicron) preferentially enhances T cell responses targeting CTERs and improves cross-reactivity across Betacoronavirus subgenera. PBMC samples were collected at baseline (day 0) and post-vaccination (day 90) from a cohort of 60 adults receiving either the Pfizer or Moderna bivalent vaccine. Antigen-specific CD4+ and CD8+ T cell responses were assessed using a combined activation-induced marker (AIM) and intracellular cytokine (ICS) assay in a 25-colour-flow cytometry panel.
Overall, bivalent vaccination did not increase the response magnitude to spike or the relative fraction of S-CTER responses within total spike responses. A trend toward increased cytokine polyfunctionality was observed post-vaccination, but no significant differences were observed between pre- and post-vaccination samples across CTER pools derived from multiple BetaCoV isolates.
These findings suggest that spike-based bivalent vaccination alone cannot direct a T-cell focused response to achieve broad immunity across the BetaCoronaviruses family. Incorporation of additional protein sequences will likely be required to shift response toward the CTER approach. Understanding how bivalent vaccinations shape T cell recognition of CTER pools will be critical for advancing universal BetaCoronavirus vaccine design.
NIH
Vaccines and Immunotherapy (VAC)
Ziyin Wang, Nematullah Waseem, Naomi Peisajovich et al.· Journal of Immunology· 0 citations
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