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The continued evolution of SARS-CoV-2 variants capable of subverting vaccine and infection-induced immunity suggests the advantage of a broadly protective vaccine against betacoronaviruses (β-CoVs). Recent studies have isolated monoclonal antibodies (mAbs) from SARS-CoV-2 recovered-vaccinated donors capable of neutralizing many variants of SARS-CoV-2 and other β-CoVs. Many of these mAbs target the conserved S2 stem region of the SARS-CoV-2 spike protein, rather than the receptor binding domain contained within S1 primarily targeted by current SARS-CoV-2 vaccines. One of these S2-directed mAbs, CC40.8, has demonstrated protective efficacy in small animal models against SARS-CoV-2 challenge. As the next step in the pre-clinical testing of S2-directed antibodies as a strategy to protect from SARS-CoV-2 infection, we evaluated the in vivo efficacy of CC40.8 in a clinically relevant non-human primate model by conducting passive antibody transfer to rhesus macaques (RM) followed by SARS-CoV-2 challenge. CC40.8 mAb was intravenously infused at 10mg/kg, 1mg/kg, or 0.1 mg/kg into groups (n = 6) of RM, alongside one group that received a control antibody (PGT121). Viral loads in the lower airway were significantly reduced in animals receiving higher doses of CC40.8. We observed a significant reduction in inflammatory cytokines and macrophages within the lower airway of animals infused with 10mg/kg and 1mg/kg doses of CC40.8. Viral genome sequencing demonstrated a lack of escape mutations in the CC40.8 epitope. Collectively, these data demonstrate the protective efficiency of broadly neutralizing S2-targeting antibodies against SARS-CoV-2 infection within the lower airway while providing critical preclinical work necessary for the development of pan-β-CoV vaccines., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: RA, TFR, and DRB are listed as inventors on pending patent applications describing the SARS-CoV-2 and HCoV-HKU1 S cross-reactive antibodies. DRB and RA are listed as inventors on a pending patent application describing the S2 stem epitope immunogens identified in this study. DRB is a consultant for IAVI. All other authors declare that they have no competing interests., (Copyright: This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.)

Rhesus macaques (RMs) are vital models for studying human disease, and are invaluable to pre-clinical pipelines for vaccine discovery and testing. Particularly in this regard, they are often used to study infection and vaccine-associated broadly neutralizing antibody responses. This has resulted in an increasing demand for improved genetic resources for the immunoglobulin (IG) loci, which harbor antibody-encoding genes. However, the highly polymorphic and structurally variable nature of these loci have them historically challenging to sequence and characterize at the level of both the genome and expressed repertoire. To address these challenges, we have developed a novel integrated analysis workflow for conducting the combined processing of B cell receptor repertoire sequencing data with matched whole-genome and targeted long-read genomic sequencing data. Using this novel approach, we have assembled the largest collection of IG germline alleles reported to date, amassed from 106 Indian origin RMs. Using a conservative annotation approach, requiring sample-level internal validation from both genomic and expressed datasets, we created a comprehensive resource that captures extensive diversity of IG heavy and light chain variable (V), diversity (D), and joining (J) alleles, as well as leader, intronic, and recombination signal sequences (RSSs). This publicly available, continually updated database will advance vaccine research for infectious disease, and provide a robust foundation for immunogenomics and future translational research.