Decoupling of omicron variant infections and severe COVID-19

Abstract

SARS-CoV-2 omicron (B.1.1.529) was designated a variant of concern by WHO because of specific mutations that might increase transmissibility, risk of reinfection, or vaccine breakthrough infection. Many of these mutations affect the receptor-binding domain and N-terminal domain of the spike protein, which might, paradoxically, increase binding to ACE-2 while evading antibody recognition.1Gong SY Chatterjee D Richard J et al.Contribution of single mutations to selected SARS-CoV-2 emerging variants spike antigenicity.Virology. 2021; 563: 134-145Google Scholar Emergence of omicron appears to have parallels with the beta variant (B.1.351) in South Africa. It was demonstrated that there are decreased neutralising antibody titres with beta in infection-naive individuals who received two doses of AZD1222 (ChAdOx1 nCoV-19) or BNT162b.2Madhi SA Baillie V Cutland CL et al.Efficacy of the ChAdOx1 nCoV-19 Covid-19 vaccine against the B.1.351 variant.N Engl J Med. 2021; 384: 1885-1898Google Scholar, 3Bates TA Leier HC Lyski ZL et al.Neutralization of SARS-CoV-2 variants by convalescent and BNT162b2 vaccinated serum.Nat Commun. 2021; 125135Google Scholar Nevertheless, real-world data showed more than 80% effectiveness against severe disease and hospitalisations.4Abu-Raddad LJ Chemaitelly H Butt AA Effectiveness of the BNT162b2 Covid-19 vaccine against the B.1.1.7 and B.1.351 variants.N Engl J Med. 2021; 385: 187-189Google Scholar, 5Nasreen S Chung H He S et al.Effectiveness of mRNA and ChAdOx1 COVID-19 vaccines against symptomatic SARS-CoV-2 infection and severe outcomes with variants of concern in Ontario.Nat Microbiol. 2022; (published online Feb 7.)https://doi.org/10.1038/s41564-021-01053-0Google Scholar Although preliminary evidence suggests booster doses might enhance protection against omicron,6Andrews N Stowe J Kirsebom F et al.Effectiveness of COVID-19 vaccines against the omicron (B.1.1.529) variant of concern.medRxiv. 2021; (published online Dec 14.) (preprint).https://doi.org/10.1101/2021.12.14.21267615Google Scholar studies are underway to fully determine vaccine effectiveness. Given the natural lag between infection and severe outcomes, we await further data on omicron for effectiveness of vaccinations in preventing severe disease—the key intended outcome of vaccination.7McIntyre PB Aggarwal R Jani I et al.COVID-19 vaccine strategies must focus on severe disease and global equity.Lancet. 2022; 399: 406-410Google Scholar In the meantime, the South Africa National Institute for Communicable Diseases has shared preliminary data indicating a decoupling of infection rates from hospitalisations and deaths with omicron. These data suggest underlying immune responses following infection and that primary and booster vaccination might attenuate the course of illness. Complementary humoral (antibody) and cellular (T cell) immune responses are activated following natural SARS-CoV-2 infection or vaccination. T-cell responses encompass a broad range of spike-protein-specific T-cell receptors that recognise multiple epitopes both within and outside of mutated regions in variants of concern.8Swanson 2nd, PA Padilla M Hoyland W et al.AZD1222/ChAdOx1 nCoV-19 vaccination induces a polyfunctional spike protein-specific TH1 response with a diverse TCR repertoire.Sci Transl Med. 2021; 13abj7211Google Scholar Thus, even if spike protein mutations enable neutralising antibody escape, non-neutali-sing antibodies or T-cell-mediated responses can provide protection. The beta variant has only a few mutations in the spike gene that affect T-cell epitopes, meaning T-cell response is maintained; this is expected to be the case with omicron.1Gong SY Chatterjee D Richard J et al.Contribution of single mutations to selected SARS-CoV-2 emerging variants spike antigenicity.Virology. 2021; 563: 134-145Google Scholar, 8Swanson 2nd, PA Padilla M Hoyland W et al.AZD1222/ChAdOx1 nCoV-19 vaccination induces a polyfunctional spike protein-specific TH1 response with a diverse TCR repertoire.Sci Transl Med. 2021; 13abj7211Google Scholar At this stage of the pandemic, omicron is spreading in populations where many individuals have been previously infected with SARS-CoV-2 and are now being vaccinated, or where many have received two or three COVID-19 vaccine doses. These populations might be expected to have greater depth of antibody response and a broader and deeper poly-epitopic T-cell response,9Dan JM Mateus J Kato Y et al.Immunological memory to SARS-CoV-2 assessed for up to 8 months after infection.Science. 2021; 371eabf4063Google Scholar, 10Milne G Hames T Scotton C et al.Does infection with or vaccination against SARS-CoV-2 lead to lasting immunity?.Lancet Respir Med. 2021; 9: 1450-1466Google Scholar which should overcome some of the anticipated antibody evasion of omicron. In these scenarios, protection against severe disease is anticipated. Most cases of severe disease and hospitalisation with omicron are among the unvaccinated; we recommend an accelerated and equitable roll-out of COVID-19 vaccines, which have a continued role in enhancing protection against omicron. For more on omicron see https://www.who.int/news/item/26–11–2021-classification-of-omicron-(b.1·1.529)-sars-cov-2-variant-of-concernFor more on preliminary data see https://www.nicd.ac.za/diseases-a-z-index/disease-index-covid-19/surveillance-reports/daily-hospital-surveillance-datcov-report/For more on Good Publication Practice guidelines see https://www.ismpp.org/gpp3 For more on omicron see https://www.who.int/news/item/26–11–2021-classification-of-omicron-(b.1·1.529)-sars-cov-2-variant-of-concern For more on preliminary data see https://www.nicd.ac.za/diseases-a-z-index/disease-index-covid-19/surveillance-reports/daily-hospital-surveillance-datcov-report/ For more on Good Publication Practice guidelines see https://www.ismpp.org/gpp3 SAM's institution received grants from the Bill & Melinda Gates Foundation, South African Medical Research Council, Pfizer, European & Developing Countries Clinical Trials Partnership, Minervax, and Novavax. SAM also received advisory fees from the Bill & Melinda Gates Foundation and participated on a Data Safety Monitoring Board or Advisory Board for PATH and Centre for the AIDS Programme of Research in South Africa. AJP's institution received grants from National Institute for Health Research (NIHR) and AstraZeneca. AJP is Chair of UK Department of Health and Social Care's Joint Committee on Vaccination and Immunisation, member of the WHO Scientific Advisory Group for Emergencies, an NIHR Senior Investigator and Chief Investigator on clinical trials of Oxford University's COVID-19 vaccine. CI and HR declare no competing interests. The authors acknowledge Jon Moran of Ashfield MedComms, an Ashfield Health company, part of UDG Healthcare, for medical writing support that was funded by AstraZeneca in accordance with Good Publication Practice guidelines.