EBioMedicine · 2026
Immunogenicity and protective efficacy of single-dose adenoviral vaccines expressing Crimean-Congo haemorrhagic fever virus GP38, Gc, or nucleoprotein antigens in mice: a preclinical study.
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Saunders Jack E, Gilbride Ciaran, Sampson Alex, Dowall Stuart, Kennedy Emma, Webster Sarah, Fotheringham Susan, Findlay-Wilson Stephen, Al-Dainy Fahad, Camara Susana, Hussain Khiyam, Ruedas-Torres Ines, Salguero Francisco J, Hewson Roger, Gilbert Sarah C, Bibi Sagida, Wright Daniel, Belij-Rammerstorfer Sandra, Lambe Teresa
Аннотация
BACKGROUND: Crimean-Congo haemorrhagic fever virus (CCHFV) is a highly pathogenic, tick-borne orthonairovirus responsible for severe human disease, yet no approved vaccines or therapeutics exist. The glycoprotein precursor (GPC), including its GP38, Gn, and Gc components, and the nucleoprotein (NP) have been explored as vaccine targets with varying success. A chimpanzee adenoviral vector (ChAdOx) vaccine encoding full-length GPC previously conferred complete protection in mice, supporting Phase I evaluation. However, the essential protective components and mechanisms of vaccine-induced immunity remain unclear.
METHODS: We evaluated ChAdOx2 vaccines encoding individual GPC subunits (GP38, Gn, or Gc), full-length GPC, or NP in a lethal interferon receptor-deficient mouse model. Protective efficacy and immune responses were assessed to define protective immunogens and mechanisms.
FINDINGS: Single-dose vaccination with ChAdOx2-GP38 or ChAdOx2-Gc conferred complete survival (6/6 per group; both p = 0.0005 vs PBS), with minimal histopathology and viral RNA burden at the 21-day study endpoint, comparable to full-length GPC (6/6; p = 0.0005 vs PBS). ChAdOx2-NP likewise conferred complete survival (6/6; p = 0.0008 vs PBS) and elicited robust NP-specific immune responses. In contrast, ChAdOx2-Gn conferred partial survival (2/6; p = 0.0101 vs PBS), while low-dose GPC vaccination provided limited protection (1/6; p = 0.0617 vs PBS) with impaired IgG responses while preserving T-cell responses. Immunological analyses showed that GP38, Gc, and full-length GPC constructs induced robust antibody responses with similar Fcγ receptor engagement and limited neutralising activity.
INTERPRETATION: These findings identify GP38 and Gc as individually protective immunogens while reinforcing GPC and NP as effective vaccine targets. Together, these data support roles for non-neutralising antibodies and T-cell responses in protection against CCHFV and continued development of ChAdOx-vectored vaccines for clinical use.
FUNDING: This research was supported by the Biotechnology and Biological Sciences Research Council.
METHODS: We evaluated ChAdOx2 vaccines encoding individual GPC subunits (GP38, Gn, or Gc), full-length GPC, or NP in a lethal interferon receptor-deficient mouse model. Protective efficacy and immune responses were assessed to define protective immunogens and mechanisms.
FINDINGS: Single-dose vaccination with ChAdOx2-GP38 or ChAdOx2-Gc conferred complete survival (6/6 per group; both p = 0.0005 vs PBS), with minimal histopathology and viral RNA burden at the 21-day study endpoint, comparable to full-length GPC (6/6; p = 0.0005 vs PBS). ChAdOx2-NP likewise conferred complete survival (6/6; p = 0.0008 vs PBS) and elicited robust NP-specific immune responses. In contrast, ChAdOx2-Gn conferred partial survival (2/6; p = 0.0101 vs PBS), while low-dose GPC vaccination provided limited protection (1/6; p = 0.0617 vs PBS) with impaired IgG responses while preserving T-cell responses. Immunological analyses showed that GP38, Gc, and full-length GPC constructs induced robust antibody responses with similar Fcγ receptor engagement and limited neutralising activity.
INTERPRETATION: These findings identify GP38 and Gc as individually protective immunogens while reinforcing GPC and NP as effective vaccine targets. Together, these data support roles for non-neutralising antibodies and T-cell responses in protection against CCHFV and continued development of ChAdOx-vectored vaccines for clinical use.
FUNDING: This research was supported by the Biotechnology and Biological Sciences Research Council.