SARS-CoV-2 variants and ending the COVID-19 pandemic
Authors: Arnaud Fontanet, Brigitte Autran, Bruno Lina, Marie Paule Kieny, Salim S Abdool Karim, Devi Sridhar
Journal: The Lancet (2021)

The COVID-19 pandemic has devastated health-care systems, shut down schools and communities, and plunged the world into an economic recession. While 2020 was a challenging year, 2021 looks to be difficult with the emergence of multiple variants of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The race to vaccinate the world will need to respond to the pathogen's constant evolution to evade immunity. What marks the path to the end of this pandemic? 2020 saw the successful development and testing of COVID-19 vaccines within timeframes not considered possible before. Two mRNA COVID-19 vaccines produced the first results, with impressive efficacy (94–95%).1Baden LR El Sahly HM Essink B et al.Efficacy and safety of the mRNA-1273 SARS-CoV-2 Vaccine.N Engl J Med. 2021; 384: 403-416Crossref PubMed Scopus (6551) Google Scholar, 2Polack FP Thomas SJ Kitchin N et al.Safety and efficacy of the BNT162b2 mRNA Covid-19 Vaccine.N Engl J Med. 2020; 383: 2603-2615Crossref PubMed Scopus (9498) Google Scholar A disadvantage of these two vaccines is their low temperature storage requirements. Although other COVID-19 vaccines developed to date that use viral vectors, subunit particles, or inactivated viruses have comparatively lower levels of efficacy, with estimates of 70% for ChAdOx1 nCoV-193Voysey M Costa Clemens SA Madhi SA et al.Safety and efficacy of the ChAdOx1 nCoV-19 vaccine (AZD1222) against SARS-CoV-2: an interim analysis of four randomised controlled trials in Brazil, South Africa, and the UK.Lancet. 2020; 397: 99-111Summary Full Text Full Text PDF PubMed Scopus (3260) Google Scholar and 92% for Gam-COVID-Vac (Sputnik V)4Logunov DY Dolzhikova IV Shcheblyaokov DV et al.Safety and efficacy of an rAd26 and rAd5 vector-based heterologous prime-boost COVIC-19 vaccine: an interim analysis of a randomized controlled phase 3 trial in Russia.Lancet. 2021; (published online Feb 2.)https://doi.org/10.1016/S0140-6736(21)00234-8Summary Full Text Full Text PDF PubMed Scopus (1204) Google Scholar adenovirus vector vaccines, they do not have the ultracold storage temperature requirements of the mRNA vaccines and are therefore easier to deliver. Data available so far for COVID-19 vaccines have shown protection only against clinical forms of infection, with the exception of recent data showing reduction in the duration of viral shedding and viral load among recipients of the ChAdOx1 nCoV-19 vaccine compared with placebo recipients, suggesting potential impact on viral transmission as well.5Emary KRW Golubchik T Aley PK et al.Efficacy of ChAdOx1 nCoV-19 (AZD1222) vaccine against SARS-CoV-2 VOC 202012/01 (B.1.1.7).SSRN. 2021; (published online Feb 4.)https://dx.doi.org/10.2139/ssrn.3779160Crossref Google Scholar In December, 2020, an unexpected rise in reported COVID-19 cases was attributed to the emergence of the new SARS-CoV-2 variants 501Y.V1 (B.1.1.7) in the UK and 501Y.V2 (B.1.351) in South Africa.6Volz E Mishra S Chand M et al.Transmission of SARS-CoV-2 lineage B.1.1.7 in England: insights from linking epidemiological and genetic data.medRxiv. 2021; (published online Jan 4.) (preprint).https://doi.org/10.1101/2020.12.30.20249034PubMed Google Scholar, 7Tegally H Wilkinson E Giovanetti M et al.Emergence and rapid spread of a new severe acute respiratory syndrome-related coronavirus 2 (SARS-CoV-2) lineage with multiple spike mutations in South Africa.MedRxiv. 2020; (published online Dec 22.) (preprint).https://doi.org/10.1101/2020.12.21.20248640Google Scholar In South Africa, high transmission in the context of high population immunity8Hsiao M Davies MA Kalk E et al.SARS-CoV-2 seroprevalence in the Cape Town Metropolitan sub-districts after the peak of infections.NICD COVID-19 Special Public Health Surveill Bull. 2020; 18: 1-9Google Scholar may have favoured the emergence and subsequent spread of the variant. Both variants had a mutation (N501Y) in the receptor-binding domain of the spike protein that is reported to contribute to increased transmission,9Gu H Chen Q Yang G et al.Adaptation of SARS-CoV-2 in BALB/c mice for testing vaccine efficacy.Science. 2020; 369: 1603-1607Crossref PubMed Scopus (517) Google Scholar with estimates ranging between 40% and 70% for increased transmission.6Volz E Mishra S Chand M et al.Transmission of SARS-CoV-2 lineage B.1.1.7 in England: insights from linking epidemiological and genetic data.medRxiv. 2021; (published online Jan 4.) (preprint).https://doi.org/10.1101/2020.12.30.20249034PubMed Google Scholar The 501Y.V2 variant has two additional mutations (E484K and K417N) in the spike protein that confer a potential immune escape to antibodies.10Wibmer CK Ayres F Hermanus T et al.SARS-CoV-2 501Y.V2 escapes neutralization by South African COVID-19 donor plasma.bioRxiv. 2021; (published online Jan 19.) (preprint).https://doi.org/10.1101/2021.01.18.427166PubMed Google Scholar In a concerning development, another set of mutations (N501Y, E484K, and K417T) in a new P.1 (501Y.V3) lineage has been identified in Manaus, Brazil.11Faria NR Claro IM Candido D et al.Genomic characterisation of an emergent SARS-CoV-2 lineage in Manaus: preliminary findings.Virological. January, 2021; https://virological.org/t/genomic-characterisation-of-an-emergent-sars-cov-2-lineage-in-manaus-preliminary-findings/586Date accessed: February 8, 2021Google Scholar A key issue is whether COVID-19 vaccines will be able to protect against infection or disease from these new SARS-CoV-2 variants. Preliminary research suggests sera from individuals immunised with the mRNA COVID-19 vaccines neutralise a 501 mutation pseudovirion, but neutralise a 501-484-417 mutant pseudovirion to a lesser extent.12Wang Z Schmidt F Weisblum Y et al.mRNA vaccine-elicited antibodies to SARS-CoV-2 and circulating variants.bioRxiv. 2021; (published online Jan 30.) (preprint).https://doi.org/10.1101/2021.01.15.426911Google Scholar Moreover, preliminary clinical trial results of ChAdOx1 nCoV-19 showed 74% efficacy in the UK3Voysey M Costa Clemens SA Madhi SA et al.Safety and efficacy of the ChAdOx1 nCoV-19 vaccine (AZD1222) against SARS-CoV-2: an interim analysis of four randomised controlled trials in Brazil, South Africa, and the UK.Lancet. 2020; 397: 99-111Summary Full Text Full Text PDF PubMed Scopus (3260) Google Scholar but only 22% in South Africa,13Cohen J South Africa suspends use of AstraZeneca's COVID-19 vaccine after it fails to clearly stop virus variant.Science. 2021; (published online Feb 8.)https://doi.org/10.1126/science.abg9559Crossref Google Scholar whereas NVX-CoV2373, a protein-based COVID-19 vaccine, showed 89% efficacy in the UK but only 49% efficacy in South Africa, where the 501Y.V2 variant predominates.14Wadman M Cohen J Novavax vaccine delivers 89% efficacy against COVID-19 in U.K.—but is less potent in South Africa.Science. 2021; (published online Jan 28.)https://doi.org/10.1126/science.abg8101Crossref PubMed Google Scholar Similarly, differences in vaccine efficacy in the USA and South Africa (72% vs 57%) were reported for the Ad26COV2.S COVID-19 vaccine.15Cohen J One-dose of COVID-19 vaccine offers solid protection against severe disease.Science. 2021; (published online Jan 29.)https://doi.org/10.1126/science.abg7115Crossref Google Scholar More encouragingly, 85% protection against severe COVID-19 has been reported for the Ad26COV2.S vaccine in South Africa, although we do not know the precision around the estimate provided in the press release.16Johnson & JohnsonJohnson & Johnson announces single-shot Janssen COVID-19 vaccine candidate met primary endpoints in interim analysis of its phase 3 ENSEMBLE trial 2021.https://www.jnj.com/johnson-johnson-announces-single-shot-janssen-covid-19-vaccine-candidate-met-primary-endpoints-in-interim-analysis-of-its-phase-3-ensemble-trialDate: Jan 29, 2021Date accessed: February 9, 2021Google Scholar If confirmed, a vaccine strategy targeting first those at risk of severe COVID-19 might therefore still be effective even in the presence of variants. The recent emergence of SARS-CoV-2 variants, after a period of relative viral genetic stability, is a cause for concern since multiple new escape variants could emerge in future and lead to severe epidemic rebound, as seen in South Africa. Increased viral transmission creates greater opportunities for the emergence of SARS-CoV-2 variants. Hence, the end of the pandemic is only possible when vaccines that are effective against circulating variants are distributed equitably across the world. As high-income countries race to immunise their populations within months, they leave themselves vulnerable to SARS-CoV-2 evolving in other countries to a new lineage that vaccines might not protect well against. Repeatedly formulating new vaccines may be needed to control some new SARS-CoV-2 variants. With the increase in basic reproduction number of more transmissible SARS-CoV-2 variants,6Volz E Mishra S Chand M et al.Transmission of SARS-CoV-2 lineage B.1.1.7 in England: insights from linking epidemiological and genetic data.medRxiv. 2021; (published online Jan 4.) (preprint).https://doi.org/10.1101/2020.12.30.20249034PubMed Google Scholar higher vaccine coverage will be required to achieve herd immunity, and vaccinating children might also be necessary to reach this coverage. The emergence of new SARS-CoV-2 variants calls for a number of important measures (panel). First, fewer new infections means less viral replication, which, in turn, lowers the risk of new variants. This situation can only be achieved by a combination of non-pharmaceutical interventions and scale-up of vaccines, both being important, until population immunity is achieved. Aiming for a COVID-19 elimination strategy is the preferred option in this context.PanelPriorities to address new SARS-CoV-2 variants•Continue to suppress and push to eliminate SARS-CoV-2 while rolling out COVID-19 vaccines•Improve surveillance of SARS-CoV-2 variants through global sequencing and sharing of variant-specific PCR primers•Create a central repository of samples of sera and cells from individuals with past infection or past immunisation with available COVID-19 vaccines for seroneutralisation and cellular immunity functional testing against newly discovered variants•Produce COVID-19 vaccines reactively and adapt them to newly emerging lineages•Ensure global access, availability, and affordability of COVID-19 vaccines to ensure no countries are left behind •Continue to suppress and push to eliminate SARS-CoV-2 while rolling out COVID-19 vaccines•Improve surveillance of SARS-CoV-2 variants through global sequencing and sharing of variant-specific PCR primers•Create a central repository of samples of sera and cells from individuals with past infection or past immunisation with available COVID-19 vaccines for seroneutralisation and cellular immunity functional testing against newly discovered variants•Produce COVID-19 vaccines reactively and adapt them to newly emerging lineages•Ensure global access, availability, and affordability of COVID-19 vaccines to ensure no countries are left behind Second, for surveillance of the circulation of SARS-CoV-2 variants, sharing of variant-specific PCR primers could help to monitor their spread, particularly in resource-limited countries. In addition, every country should include genomic sequencing of SARS-CoV-2 variants in their plans. For resource-limited countries, support from WHO, the Africa Centres for Disease Control and Prevention, and other partner institutions will be necessary to help develop expertise and capacity as well as strengthen health systems. All genetic sequences should be posted on international platforms such as GISAID for shared analyses. Infections in people who were previously infected or vaccinated should be carefully examined for escape variants. Third, a central repository of samples of sera and cells from individuals with past infection or past immunisation with available COVID-19 vaccines should be established for seroneutralisation and cellular immunity functional testing against newly discovered variants. This repository could release regular advisories to provide guidance on a minimum set of epitopes to be included in new COVID-19 vaccines. Fourth, the production of COVID-19 vaccines should be reactive and adapted to newly emerging lineages. This flexibility is likely to be easier to achieve with the new COVID-19 vaccine technologies currently being deployed and based on nucleic acids (mRNA vaccines or viral vector vaccines).17Muik A Wallisch AK Sänger B et al.Neutralization of SARS-CoV-2 lineage B.1.1.7 pseudovirus by BNT162b2 vaccine-elicited human sera.Science. 2021; (published online Jan 29.)https://doi.org/10.1126/science.abg6105Crossref PubMed Scopus (361) Google Scholar Finally, vaccines need to be available, affordable, and accessible at a global scale. Several high-income countries have purchased vaccine doses, sometimes close to nine doses per person,18Mullard A How COVID vaccines are being divided up around the world.Nature. 2020; (published online Nov 30.)https://doi.org/10.1038/d41586-020-03370-6Crossref PubMed Google Scholar while WHO has called for greater equity and stronger support for the COVAX initiative and its mandate of equitable vaccine access, especially for resource-limited countries. Of note is an initiative of the African Union to independently purchase and distribute COVID-19 vaccines to countries over the continent to supplement the COVAX programme.19Africa NewsAfrican Union secures 400 million vaccine doses.https://www.africanews.com/2021/01/28/african-union-secures-additional-400-million-vaccine-doses/Date: Jan 28, 2021Date accessed: February 9, 2021Google Scholar Whether vaccine delivery should be prioritised to countries with high SARS-CoV-2 prevalence and continued transmission—eg, South Africa, Brazil, Mexico, or India—to prevent further emergence of new variants has to be considered. This pandemic is a reminder to high-income countries that infectious diseases have a tremendous impact on economies and lives, and rapid development and implementation of effective vaccines against these diseases should remain priorities globally. Global cooperation to ensure equity and responsiveness to local contexts is essential on the difficult path ahead to ending the COVID-19 pandemic. AF and BL are members of the French COVID-19 Scientific Council. AF, BA, and MPK are members of the French COVID-19 Vaccine Strategy Committee. MPK is Chair of the French COVID-19 Vaccine Committee and Chair of the COVAX Independent Product Group. SSAK is Co-Chair of the South African Ministerial Advisory Committee on COVID-19. DS is a member of the Scottish COVID-19 Advisory Group and the UK Cabinet Office COVID-19 Advisory Group. We declare no other competing interests.