COVID-19: Synopsis of three notable SARS-CoV-2 variants of concern (5 March 2021)
Three COVID-19 vaccines currently have emergency use authorization (EUA) from the Food and Drug Administration (FDA). These include Moderna’s COVID-19 vaccine, Pfizer-BioNTech’s COVID-19 vaccine, and Janssen Pharmaceutical Companies of Johnson & Johnson’s Ad26.COV2.S COVID-19 vaccine; and as of 25 February 2021, 6.2% of the U.S. population had been fully vaccinated and 13.6% had received at least one dose (1). Although each of the vaccines demonstrated protection against laboratory-confirmed symptomatic COVID-19 in clinical trials, there is concern that they may have reduced efficacy against emerging variant strains of SARS-CoV-2, the virus that causes COVID-19. In this update, I provide a synopsis of three specific viral lineages that have emerged as “variants of concern”, owing to worries over the potential for increased transmissibility, increased morbidity and mortality, decreased susceptibility to preventatives and therapeutics, etc.
By way of background, changes in the sequence of RNA or DNA, to include that of viruses is a common phenomenon. These changes, called mutations, may occur during replication (i.e. when copies of the genomic strands are made for progeny) or at other times. They may be spontaneous or may be the result of some external factor (i.e. a physical, chemical, or biological mutagen). They may involve a change in a single nucleotide base or may involve an insertion into or a deletion from the genomic strand; and they may be significant or inconsequential. The frequency with which mutations in viral genomes occurs varies between viruses and is determined by a number of factors including the nature of the genome (i.e. RNA vs. DNA, single-strand vs. double-strand, genome size, etc.), as well as the fidelity of the virus’s proofreading and post-replicative repair mechanisms (2). The rate at which the SARS-CoV-2 virus undergoes single point mutations has been estimated to be about half that of influenza and one quarter that of the Human Immunodeficiency Virus. Nonetheless, some 12,000 mutations have been catalogued to date (3). Although most of these mutations are likely to be clinically insignificant, a few are notable for their correlation with an enhanced ability to evade the host’s immune system (E484K), increased binding affinity (N501Y), hyper flexibility in the receptor binding domain (S477G/N), or enhanced transmissibility (D614G, about which I have previously written [4]).
Changes in DNA or RNA strands (e.g. due to mutations) give rise to distinct viral sequences called “variants”; and a variant with a particular geographic origin is termed a “lineage” (5). Presently, there are three lineages that are being followed by the World Health Organization and the Centers for Disease Control as “variants of concern”: B.1.1.7, B.1.351, and P.1 (6).
B.1.1.7
The B.1.1.7 lineage (also known as 20I/501Y.V1 or variant of concern [VOC] 202012/01) was first detected in the United Kingdom from a clinical sample collected in September 2020, and as of 23 February 2021 had been reported in 101 countries including the United States (7). It is characterized by 17 lineage-defining mutations, including two deletions and six substitutions in the sequences that encode the viral spike proteins (8). At least one of these mutations (N501Y) appears to be associated with a 36–75% increase in transmissibility (9) and some models depict the B.1.1.7 variant as spreading 56% faster than other lineages (10). Moreover, emerging data suggest that infection with the B.1.1.7 variant may be associated with an increased risk of hospitalization and death as compared to infection with non-variants of concern (11,12). Lastly, one study found that neutralizing antibody titers were reduced 3.85-fold against B.1.1.7 compared to wild type virus (13). However, several vaccines, including the Moderna, PfizerBioNTech, Johnson and Johnson, Novavax, and Oxford-AstraZeneca vaccines, appear to confer protection against infection with the B.1.1.7 variant (14–18).
B.1.351
The B.1.351 lineage (also known as 20H/501Y.V2) was first detected in South Africa in December 2020 and has become the dominant lineage there (19); and by 21 February, B.1.351 had been reported in 51 countries including the United States (20), with 65 U.S. cases reported to date (21). This variant shares several mutations with the B.1.1.7 variant including N501Y and D614G as well as several additional mutations including E484K and K417N. Collectively, these mutations appear to increase transmissibility by enhancing affinity of the virus’s receptor binding domain for ACE 2 receptors (22). Additionally, these mutations confer increased resistance to neutralizing antibodies, raising concern for both the possibility of reinfection with the B.1.351 variant as well as decreased efficacy of current spike-directed COVID-19 vaccines (23) including the Moderna, Pfizer-BioNTech, Johnson and Johnson, Oxford-AstraZeneca, and Novavax vaccines (24). For several of these vaccines (i.e. Moderna and Pfizer-BioNTech), this is a theoretical risk based on studies that showed an in vitro reduction in neutralizing activity (25–28). For others (i.e. Johnson and Johnson, Oxford-AstraZeneca, and Novavax), there are clinical and population-based studies showing reduced efficacy against the B.1.351 variant (29–32). Reduced efficacy notwithstanding, these vaccines may still confer some degree of protection against severe COVID-19 due to infection with the B.1.351 variant.
P.1
Lineage P1 (also known as B.1.1.28.1 and 20J/501Y.V3) was detected at Haneda airport outside Tokyo on 6 January 2021 in four people who had travelled from the Brazilian Amazonas on 2 January 2021 (33); and by 12 January, 13 cases had been confirmed in Manaus, Amazonas state (34). P1 appears to be descended from another variant (B.1.1.28) and has 17 unique amino acid changes, 10 of which, including N501Y and E484K, are in its spike protein (35). As of 21 February, cases had been reported in 29 countries including the United States (36). Preliminary data suggest that P.1 may have enhanced transmissibility. Additionally, decreased efficacy of vaccine against P.1 is suggested by several documented cases of reinfection (37,38). However, definitive studies are pending.
Epilogue
The incidence of COVID-19 (i.e. new cases) in the United States has been steadily down trending since a peak of 315,179 cases reported on 8 January 2021, with 50,935 cases reported on 1 March 2021 (39). The reason for this decline is not fully understood and may be multifactorial, including possibly some degree of herd immunity, seasonality of the SARS-CoV-2 virus, attenuated virulence (i.e. less severe disease), as well as the introduction of vaccines. Regarding the latter, as of 3 March 2021, only 15.6% and 7.9% of the U.S. population had received one or two doses, respectively, making it unlikely that vaccination alone is responsible for the decrease in new cases (40). Nonetheless, vaccines are likely contributing to the downward trend and the emergence of vaccine-evading variants is understandably concerning. For now, most U.S. COVID-19 cases are caused by virus that is covered by the three vaccines currently in use. Should vaccine-evading variants become increasingly prevalent and effect a resurgence in COVID-19 cases, one can anticipate the need for repeat immunization with modified vaccines. For some of these (e.g. the mRNA constructs), the necessary modifications should be fairly easy and quick. Indeed, the Food and Drug Administration has signaled that it may permit vaccine makers to forgo lengthy clinical trials for every version of their constructs — an approach similar to that taken for approval of seasonal influenza vaccines (41).
As with my prior COVID-19-themed posts, my intention here is not to politicize, sensationalize, or trivialize the pandemic, but only to provide information and thoughtful commentary.
Until my next update — regards.
Michael Zapor, MD, PhD, CTropMed, FACP, FIDSA
(5 March 2021)
References
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5. Mary Kearney, PhD (personal communication)
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11. Investigation of novel SARS-CoV-2 variant — Variant of Concern 202012/01.19
12. https://assets.publishing.service.gov.uk/government/uploads/system/uploads/attachment_data/file/961042/S1095_NERVTAG_update_note_on_B.1.1.7_severity_20210211.pdf (Accessed 2 March 2021)
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17. Xie X, Liu Y, Liu J, Zhang X, Zou J, Fontes-Garfias CR, et al. Neutralization of SARS-CoV-2 spike 69/70 deletion, E484K and N501Y variants by BNT162b2 vaccine-elicited sera. Nature Medicine. 2021:1–2. https://www.nature.com/articles/s41591-021-01270-4
18. https://www.pfizer.com/news/press-release/press-release-detail/vitro-study-shows-pfizer-biontech-covid-19-vaccine-elicits (Accessed 2 March 2021)
19. https://cov-lineages.org/global_report_B.1.351.html (Accessed 2 March 2021)
20. file://r04.med.va.gov/v05/MWV/Users/VHAMWVZAPORM/Desktop/20210223_Weekly_Epi_Update_28.pdf (Accessed 2 March 2021)
21. https://www.cdc.gov/coronavirus/2019-ncov/transmission/variant-cases.html (Accessed 3 March 2021)
22. https://asm.org/Articles/2021/February/SARS-CoV-2-Variants-vs-Vaccines
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25. Wu K, Werner AP, Koch M, Choi A, Narayanan E, Stewart-Jones GBE, et al. Serum Neutralizing Activity Elicited by mRNA-1273 Vaccine — Preliminary Report. N Engl J Med. 2021.
https://www.ncbi.nlm.nih.gov/pubmed/33596346
26. Moderna COVID-19 Vaccine Retains Neutralizing Activity Against Emerging Variants First Identified in the U.K. and the Republic of South Africa.
27. Wang Z, Schmidt F, Weisblum Y, Muecksch F, Barnes CO, Finkin S, et al. mRNA vaccine-elicited antibodies to SARS-CoV-2 and circulating variants. bioRxiv. 2021. http://www.ncbi.nlm.nih.gov/pubmed/33501451
28. Xie X, Liu Y, Liu J, Zhang X, Zou J, Fontes-Garfias CR, et al. Neutralization of SARS-CoV-2 spike 69/70 deletion, E484K and N501Y variants by BNT162b2 vaccine-elicited sera. Nature Medicine.
29. Johnson & Johnson Announces Single-Shot Janssen COVID-19 Vaccine Candidate Met Primary Endpoints in Interim Analysis of its Phase 3 ENSEMBLE Trial | Johnson & Johnson. Content Lab US.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-trial
30. Mahase E. Covid-19: Novavax vaccine efficacy is 86% against UK variant and 60% against South African variant. BMJ. 2021:n296. https://www.bmj.com/lookup/doi/10.1136/bmj.n296
31. ChAdOx1 nCov-19 provides minimal protection against mild-moderate COVID-19 infection from B.1.351 coronavirus variant in young South African adults | University of Oxford.https://www.ox.ac.uk/news/2021-02-07-chadox1-ncov-19-provides-minimal-protection-against-mild-moderate-covid-19-infection
32. Latest — Oxford Covid-19 vaccine trial results — Wits University. https://www.wits.ac.za/covid19/covid19-news/latest/oxford-covid-19-vaccine-trial-results.html
33. “Japan finds new coronavirus variant in travelers from Brazil”. Japan Today. Japan. 11 January 2021.
34. https://virological.org/t/genomic-characterisation-of-an-emergent-sars-cov-2-lineage-in-manaus-preliminary-findings/586 (Accessed 3 March 2021)
35. Ibid.
36. file://r04.med.va.gov/v05/MWV/Users/VHAMWVZAPORM/Desktop/20210223_Weekly_Epi_Update_28.pdf (Accessed 2 March 2021)
37. SARS-CoV-2 reinfection by the new Variant of Concern (VOC) P.1 in Amazonas, Brazil — SARS-CoV-2 coronavirus / nCoV-2019 Genomic Epidemiology. Virological. 2021.https://virological.org/t/sars-cov-2-reinfection-by-the-new-variant-of-concern-voc-p-1-in-amazonas-brazil/596
38. Sabino EC, Buss LF, Carvalho MPS, Prete CA, Crispim MAE, Fraiji NA, et al. Resurgence of COVID-19 in Manaus, Brazil, despite high seroprevalence. The Lancet. 2021;397(10273):452–5 https://linkinghub.elsevier.com/retrieve/pii/S0140673621001835
39. https://covid.cdc.gov/covid-data-tracker/#trends_dailytrendscases (Accessed 3 March 2021)
40. Ibid.
