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. 2025 May:115:105698.
doi: 10.1016/j.ebiom.2025.105698. Epub 2025 Apr 12.

A replicating RNA vaccine confers protection against Crimean-Congo hemorrhagic fever in cynomolgus macaques

David W Hawman  1 , Shanna Leventhal  2 , Kimberly Meade-White  2 , William Graham  3 , Karen Gaffney  4 , Amit Khandhar  4 , Justin Murray  2 , Jessy Prado-Smith  5 , Carl Shaia  5 , Greg Saturday  5 , Henry Buda  3 , Lenny Moise  3 , Jesse Erasmus  4 , Heinz Feldmann  6
Affiliations

A replicating RNA vaccine confers protection against Crimean-Congo hemorrhagic fever in cynomolgus macaques

David W Hawman et al. EBioMedicine. 2025 May.

Abstract

Background: Crimean-Congo hemorrhagic fever is a tick-borne febrile illness with wide geographic distribution. In recent years the geographic range of CCHFV and its tick vector have increased, placing an increasing number of people at risk of CCHFV infection. Currently there are no widely available vaccines and although the World Health Organization recommends ribavirin for treatment, its efficacy is unclear. Vaccines are critically needed for CCHFV.

Methods: Here we evaluated a promising replicating RNA vaccine for CCHFV in a Cynomolgus macaque model of disease.

Findings: In primed and boosted macaques, we found that our replicating RNA vaccine expressing the CCHFV nucleoprotein (repNP) was highly immunogenic, eliciting a robust non-neutralizing antibody response that conferred significant protection against CCHFV challenge. Macaques receiving a single repNP vaccination were partially protected against CCHFV challenge.

Interpretation: Our data demonstrate that our repNP vaccine and NP-specific antibody can protect against CCHFV in non-human primates.

Funding: This study was supported by the Intramural Research Program of the NIAID/NIH and the Medical CBRN Defense Consortium grant #MCDC2204-011.

Keywords: Antibody; Crimean-Congo; Non-human primates; RNA vaccine; Vaccine.

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Conflict of interest statement

Declaration of interests J.E. and A.K. have equity interest in HDT Bio. J.E. and A.K. are co-inventors on U.S. patent application no. 62/993,307 “Compositions and methods for delivery of RNA” pertaining to formulations for RNA delivery. DWH, JE and HF are inventors on U.S. patent application number 63/365,015 “Replicating RNA vaccine for Crimean-Congo hemorrhagic fever virus” regarding the repRNA for use against CCHFV. WG, HB, LM have equity interest in Seromyx systems.

Figures

Fig. 1
Fig. 1
repNP is immunogenic in cynomolgus macaques. Groups of cynomolgus macaques were sham-vaccinated or vaccinated with repNP-alone or repNP + repGc (a). CCHFV-specific IgG to whole-virus antigen (b) or recombinant antigen (c) was quantified by ELISA. CCHFV-specific IFNγ responses at day −14 to overlapping peptide pools spanning the CCHFV GPC (G1-14) or NP (N1-5) was measured by ELISpot (d). The isotype of CCHFV NP-specific antibody was measured (e) and the ability of NP-specific antibody to bind Fc-receptors, TRIM21 or complement component C1q measured (f). Line connects means (b,d,e,f). (c) Data presented as mean and SD.
Fig. 2
Fig. 2
repNP protects against CCHFV challenge in CM. Animals were comprehensively scored daily after challenge for signs of clinical disease (a). Viral RNA in the blood (b), nasal swabs (c), oral swabs (d) and tissues (e) was quantified by qRT-PCR. Platelet count (f) and AST levels (g) are shown. (f). Lines represent mean and SD (a–d, f,g). (e) Data presented as mean and SD.
Fig. 3
Fig. 3
Histological examination of vaccinated animals. (a) Representative images for H&E and IHC for CCHFV NP antigen in the liver and spleen of sham, repNP and repNP + repGc animals is shown. (b) H&E stained sections were scored by pathologists blinded to study groups and scored as 0 = no lesions, 1 = minimal, 2 = mild, 3 = moderate, 4 = marked and 5 = severe. (c) Sections were stained for CCHFV NP antigen and scored by pathologists blinded to study groups and presence of antigen scored as 0 = none, 1 = rare, 2 = scattered, 3 = moderate, 4 = numerous, 5 = diffuse. (b and c) Data shown as mean and SD.
Fig. 4
Fig. 4
Vaccinated animals develop anamnestic antibody responses to the NP and Gc. (a) IgG to recombinant NP, Gn and Gc was measured by ELISA at indicated timepoints relative to CCHFV challenge. (b) NP specific antibody was evaluated for its isotype and ability to bind Fc-receptors, C1q or TRIM21. Day 0 data is duplicated from Fig. 1 for comparison. (c) An IFNγ ELISpot was used to quantify anamnestic IFNγ responses to CCHFV peptides in PBMCs collected from animals at day 6 PI. (b,c) Line indicates mean.
Fig. 5
Fig. 5
Single immunization with repNP is partially protective against CCHFV challenge. Groups of cynomolgus macaques were sham-vaccinated or vaccinated with repNP-alone (a). (b) CCHFV-specific IgG to whole-virus antigen was quantified by ELISA at indicated timepoint. On day 23 after vaccination, animals were challenged with CCHFV and animals were comprehensively scored daily for signs of clinical disease (c) and AST (d), ALT (e) and platelet levels in the blood enumerated (f). Viral loads in the blood (g) or various tissues collected on day 5 or 6 PI (h) were quantified by qRT-PCR. Formalin fixed tissue sections were stained for CCHFV NP antigen (i) or with H&E (j) and scored by pathologists blinded to study group for presence of viral antigen or lesions. (h–j) Data shown as mean and SD. (b) Line indicates mean.
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References

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