Immunological and pathological outcomes of SARS-CoV-2 challenge following formalin-inactivated vaccine in ferrets and rhesus macaques

Abstract

There is an urgent requirement for safe and effective vaccines to prevent COVID-19. A concern for the development of new viral vaccines is the potential to induce vaccine-enhanced disease (VED). This was reported in several preclinical studies with both SARS-CoV-1 and MERS vaccines but has not been reported with SARS-CoV-2 vaccines. We have used ferrets and rhesus macaques challenged with SARS-CoV-2 to assess the potential for VED in animals vaccinated with formaldehyde-inactivated SARS-CoV-2 (FIV) formulated with Alhydrogel, compared to a negative control vaccine. We showed no evidence of enhanced disease in ferrets or rhesus macaques given FIV except for mild transient enhanced disease seen 7 days after infection in ferrets. This increased lung pathology was observed at day 7 but was resolved by day 15. We also demonstrate that formaldehyde treatment of SARS-CoV-2 reduces exposure of the spike receptor binding domain providing a mechanistic explanation for suboptimal immunity.

Advances and gaps in SARS-CoV-2 infection models

“…Moreover, several experiments performed by WHO-COM scientists have utilized experimental alum-adjuvanted and formaldehyde-inactivated whole virus vaccines and subsequent SARS-CoV-2 challenge to address any evidence of VAERD. In rhesus macaques, histopathological analysis revealed no evidence of enhanced lung pathology, and a rapid rise in neutralizing antibodies was seen after challenge [ 45 ]. In hamsters and ferrets, on the other hand, a mild increase of lung pathology was observed at 5 days and 7 days postinoculation (dpi), respectively, in comparison to unvaccinated controls.…”

“…No clear influx of eosinophils was observed in either species. Noteworthy, hamsters showed no neutralizing antibodies post-immunization and no protection against challenge, but lung cytokines were markedly skewed toward Th2 [ 45 ]. In addition, a recent study in K18-hACE2 mice immunized with a very impure formalin-inactivated SARS-CoV-2 preparation and an aluminum hydroxide-based adjuvant demonstrated earlier onset of SARS-CoV-2 replication and disease in comparison to the naïve control groups or mRNA-vaccinated animals [ 46 ].…”

Influence of Aerosol Delivered BCG Vaccination on Immunological and Disease Parameters Following SARS-CoV-2 Challenge in Rhesus Macaques

“…Developed and optimised during the initial stages of the 2019 pandemic for rapid screening of SARS-CoV-2-specific vaccine candidates, the rhesus macaque SARS-CoV-2 model employs a stringent high-dose challenge protocol whereby a combined 5 × 10 6 PFU is delivered intranasally and by intrabronchial instillation, followed by measurement of viral shedding, tissue viral load, and early disease pathology readouts during the initial 6-8-day following challenge (28,32). To date, this model has proved useful in the assessment of several SARS-CoV-2-specific vaccines (29)(30)(31)33), although it is evident that the viral readouts and pathological changes observed in macaques do not fully reflect the characteristic features of severe COVID-19 seen in susceptible human patients (32). The findings of our experiment align with this view as we observed few perturbations in clinical parameters following SARS-CoV-2 challenge in either aerosol BCG-vaccinated or unvaccinated macaques, thereby demonstrating that the clinical symptoms observed in patients afflicted with severe COVID-19 are not replicated in this species.…”

“…In this study, we have used an established rhesus macaque model (28)(29)(30)(31)(32)(33) to explore the protective efficacy of aerosoldelivered BCG vaccination against experimental SARS-CoV-2 challenge and to profile a range of antigen-specific, and nonspecific, immune parameters to explore the potential mechanisms of BCG vaccination induced cross-protection.…”

SARS-CoV-2 Omicron variant causes mild pathology in the upper and lower respiratory tract of Syrian golden hamsters (Mesocricetus auratus)

“…Among the experimental animal models, the use of non-human primates or ferrets, generally offering effective models for pre-clinical evaluation of vaccines and therapeutics for respiratory infections, provide limited options for pathogenicity studies. These models mimic asymptomatic to mild COVID-19 clinical courses only and therefore should not be considered the rst choice to assess VOC Omicron pathogenicity and test COVID-19 vaccines and therapeutics [11][12][13][14][15] . The Syrian golden hamster (Mesocricetus auratus) model on the other hand, has been shown to mimic moderate to severe COVID-19 16 , for evaluation of COVID-19 vaccines and therapeutics 17 , and recently for assessment of the pathogenicity of SARS-CoV-2 variants, such as VOC Omicron 18 .…”