Conserved Structures in the Viral Macrodomain of Rubella Virus Confers Protection Against SARS-CoV-2-Induced Pulmonary Pathology

Background: The goal of vaccine development against SARS-CoV-2 is to target a reliably conserved structure that will elicit a strong and durable T-cell response but prevent mutational escape. The evolution of the omicron variant with its 30 mutations in the spike protein reaffirms that SARS-CoV-2 may eventually evade antibody and T cell responses induced by the current vaccines. Accordingly, there is a need for vaccines that target more conserved structures than the spike protein. Structures that are conserved across different viruses may be least prone to mutations as they are essential for virus stability. Methods: K18-hACE-2 mice were vaccinated with the MMR vaccine and challenged intranasally with SARS-CoV-2. Viral tires were measured using PCR and pathological samples of the lungs were stained for viral antigen as well as macrophage and T-cell infiltration. A synthetic gene encoding residues 805-983 of rubella virus p150 (GenScript) was cloned into the pET24a plasmid. Crystals were grown by sitting drop vapour diffusion. Human dendritic cells were loaded ex vivo with macrodomains of severe acute respiratory syndrome coronavirus (SARS-CoV-2) and the rubella virus. Proteomics were performed on MHC class I and class II loaded peptides. Human plasma from patients challenged with SARS-CoV-2 were screened for IgG against the macrodomain of both rubella and SARS-CoV-2. Findings: The measles, mumps and rubella (MMR) vaccine MMR provides protection against severe lung pathology in SARS-CoV-2 infection. The crystal structure of the macro domain from rubella virus p150 shares almost identical structural homology to the Macro1 domain from SARS-CoV-2 NSP3. MHC Class II presentation of peptides by human dendritic cell presented epitopes spanning the regions of structural homology between the macro domains. Human serum from patients challenged with SARS-CoV-2 produced antibodies that recognised the macrodomain of both viruses. Interpretation: Recognition of the conserved macro domain of rubella offers protection against SARS-CoV-2 infection. Given the level of stability of this viral structure, it should be considered as a vaccine target to prevent future evolutional escape from SARS-CoV-2 vaccines.Funding: This work was supported by funding from Jan and David Baszucki (AY, YM, RF), a Wellcome Trust Investigator Award 108045/Z/15/Z (CB), The Adelson Medical Research Foundation (RF), a Wellcome Trust PhD Fellowship for Clinicians (AY), Wellcome Trust Senior Research Fellowship 217191/Z/19/Z (YM), MRC Research Grant MR/S021604/1 (YM) and a core support grant from the Wellcome Trust and MRC to the Wellcome Trust-Medical Research Council Cambridge Stem Cell Institute (203151/Z/16/Z). We are grateful to the technical staff in the Histology Laboratory, Institute of Veterinary Pathology, Vetsuisse Faculty, University of Zurich, for excellent technical support.Declaration of Interest: YM is a consultant for Related Sciences LLC. The other authorsdeclare that there are no competing interests.Ethical Approval: Animal work was approved by the local University of Liverpool Animal Welfare and Ethical Review Body and performed under UK Home Office Project Licence PP4715265. Mice carrying the human ACE2 gene under the control of the keratin 18 promoter (K18-hACE-2; formally B6.Cg-Tg(K18-ACE2)2Prlmn/J) were purchased from Jackson Laboratories.