At just over one year into the COVID-19 pandemic, evolution of SARS-CoV-2 has generated viral variants that differ in their genetic sequence from the strain first detected in December 2019. Evidence is emerging about how these variants differ in their transmission characteristics, associated clinical symptoms, and vaccine efficacy. This document is a brief summary of published evidence about characteristics of SARS-CoV-2 variants that may impact the public health response, including transmission and response to vaccination. Included are manuscripts published in peer-reviewed journals or on pre-print servers through February 5, 2021. References summarized in this report were drawn from the COVID-19 Literature Report (Lit Rep) team database. References that appeared in the daily Lit Rep are marked with an asterisk*, and the summary is shown in the annotated bibliography below. This list was cross-referenced with resource pages hosted by the Centers for Disease Control and Prevention (CDC) and World Health Organization (WHO), genomics initiatives Nextstrain and GISAID, and supplemented with studies mentioned in media articles.^1–4 We encourage readers to consult these sites and the daily Lit Rep for evidence that emerges following publication of this report.

Executive Summary of SARS-CoV-2 novel variants

• Continued evolution of SARS-CoV-2 has led to several variants with evidence or suspicion of increased transmissibility, including the B.1.1.7 variant emerging from the UK, the B.1.351 variant emerging from South Africa, and the P.1 variant emerging from Brazil.
• Early evidence indicates that the B.1.1.7 variant is still neutralized by sera from people who received the Pfizer or Moderna vaccine series. Novavax reported similar efficacy of its vaccine (85% vs 89%) against the B.1.1.7 variant and non-variant strains and the AstraZeneca-Oxford vaccine was reported to have similar efficacy against the B.1.1.7 variant and non-variant strains (74% vs 84%).
• In contrast, press releases containing preliminary findings from vaccine trial sites in South Africa during the emergence of B.1.351 suggest lower efficacy of the Novavax and Johnson & Johnson vaccines in this setting compared to sites in the US and the UK where B.1.351 was not the dominant strain, but full manuscripts have not been published.
• Additionally, laboratory evidence indicates reduced neutralization of B.1.351 and B.1.1.7 strains by convalescent plasma and monoclonal antibodies.

Overview of naming conventions for SARS-CoV-2 variants

Multiple categorizations of the genetic diversity of SARS-CoV-2 have developed across research and public health organizations, resulting in several names for each variant. Researchers emphasize the importance of referring to variants by their scientific names instead of using geographic terms to avoid stigmatizing people and places and to reduce confusion as variants are detected globally.⁵ This report refers to variants with multiple leading naming conventions (Table). One leading convention described by Rambaut and utilized by Pangolin software assigns names based on the evolutionary relationships of viruses[JMR1] [AT2]  (e.g., B.1.1.7).⁶ Another, the Nextstrain genomics project, categorizes the genetic diversity of SARS-CoV-2 into different clades, which are groups of similar viruses based on their phylogenetic relatedness, with 11 clades named thus far: 19A, 19B, 20B, 20C, 20D, 20E (EU1), 20F, 20G, 20H/501Y.V2, 20I/501Y.V1, and 20J/501Y.V3. The Global Initiative on Sharing All Influenza Data (GISAID) also uses a clade system that differs from Nextstrain (e.g., clade 20B for Nextstrain; clade GR for GISAID). Public Health England uses the ‘VOC 202012/01’ nomenclature in which VOC stands for ‘variant of concern,’ the numbers include a reference to the year and month of discovery, and variant number (01).⁷ The ‘501Y.V2’ nomenclature refers to a substitution in the 501^st amino acid site of the SARS-CoV-2 spike protein used by the team that identified the variant.

Transmission characteristics of key SARS-CoV-2 variants

Early in the pandemic, SARS-CoV-2 genomic tracking efforts identified that a variant with an amino acid change in the spike protein (D614G) had become the dominant pandemic strain by March 2020.⁸ Attention turned to other variants during the northern hemisphere autumn 2020, as COVID-19 surged in Europe and a large-scale genomic sequencing effort in the UK identified a variant known as B.1.1.7 (a.k.a. variant 20I/501Y.V1 or VOC 202012/01) associated with increased risk of transmission.⁷ Recent publications focus on B.1.1.7, B.1.351 (a.k.a. 20H/501Y.V2) emerging from South Africa, P.1 (a.k.a. 20J/501Y.V3 or descendent from B.1.1.28) emerging from Brazil, and CAL.20C, whose emergence in southern California in autumn 2020 coincided with a substantial increase in COVID-19 cases.⁹ All of these variants have been identified in samples in the US.¹

Early emergence of spike protein mutation D614G, with evidence of increased transmissibility, becomes the dominant pandemic strain by March 2020. [AT3] 

• A sequence analysis of 175 SARS-CoV-2 samples early in the pandemic from a southwestern US medical center from March to May 2020 indicated that 57% of samples carried the D614G substitution.¹⁰*
• In an early study published in July 2020, Korber et al. found that patients infected with the SARS-CoV-2 strain carrying the D614G variant shed more viral nucleic acid compared to those without this mutation.⁸*
• A study published as a pre-print in September 2020 using epidemiological data and phylogenetic data (35,377 sequences) estimated that the G614 mutant of SARS-CoV-2 is 31% more transmissible than the D614 wildtype. ¹¹*

Mink culling in Denmark in response to ‘Cluster-5’ variant¹²

• A variant with 3 amino-acid changes and two deletions in the spike protein resulted in both human-to-mink and mink-to-human transmission in Denmark.¹³*
• Danish health authorities found that some of the mutations were associated with reduced response to antibodies, as described in a letter from the Danish Chief Veterinary Officer to the World Organization for Animal Health.^12,14
• Whole genome sequencing showed evidence of ongoing SARS-CoV-2 transmission in mink farms and spillover events to human in the Netherlands.¹⁵
• Denmark decided to cull all farmed mink in early November 2020 due to concern that mink were acting as a viral reservoir and contributing to ongoing SARS-CoV-2 transmission, with the potential for additional mutations as viruses were transmitted between mink and humans.¹⁶

Lineage B.1.1.7 (a.k.a. variant 20I/501Y.V1 or VOC 202012/01) identified in the UK with evidence of increased transmissibility, becomes the dominant strain in the UK by December, 2020.⁷

• 90% of samples tested across England between January 18 and 24, 2021 carried S gene target failure (SGTF), with higher proportions in London, the South East, and East of England. SGTF is used as a proxy for monitoring B.1.1.7 in the UK based on the predominant assay in UK lighthouse laboratories.⁷
• An analysis of contact tracing data by Public Health England found that the secondary attack rate was higher for SGTF, increasing from 10% to 13% of named contacts, yielding an estimate of 25% - 40% higher attack rate for the variant strain.⁷
• The receptor binding domain (RBD) of the 501Y.V1 SARS-CoV-2 variant was reported to have around a 10-times higher binding affinity for human ACE2 than the RBD of the parent N501 strain, suggesting a potential mechanism for the higher rate of contagiousness observed with this strain.¹⁷*
• An earlier mathematical modeling study for 3 regions in England estimated that VOC 202012/01 is 56% (range 50-74%) more transmissible than earlier strains using testing data and cell phone data. ¹⁸*
• CDC identified 76 reported cases of B.1.1.7 variant in US through January 13, 2021. Models predicted that B.1.1.7 may become the dominant strain in the US by March, 2021.¹⁹*

Lineage B.1.351 (a.k.a. variant 20H/501Y.V2) identified in South Africa

• This variant with multiple spike protein mutations became the dominant strain by early November 2020 in the Eastern Cape and Western Cape Provinces of South Africa.⁹²⁰
• It is estimated to be more transmissible than non-variant strains, though less quantified than B.1.1.7 variant.
• It exhibits evidence of escape from neutralization by convalescent plasma and vaccinated donor sera, as described in detail below.

P.1 variant (a.k.a. 20J/501Y.V3, branch from B.1.1.28 lineage) in Brazil

• This variant has 12 mutations to the spike protein, including three mutations of concern in common with 20H/501Y.V2 (K417N/T, E484K and N501Y) which may affect transmissibility and host immune response.¹
• Using phylogenetic analysis, Voloch et al estimate that it emerged in Rio de Janiero in July 2020 and increased in frequency among sampled genomes.²¹
• A new SARS-CoV-2 variant was one hypothesis raised to potentially explain the resurgence of COVID-19 cases in Manaus, Brazil despite high estimated seroprevalence of antibodies against SARS-CoV-2 of 76%.²²*

CAL.20C variant in California

• A novel SARS-CoV-2 strain, CAL.20C, emerging from Southern California, was detected through genome sequence analysis. The strain’s increasing dominance coincided with an increased positivity rate in that region. While first observed in July, CAL.20C accounted for 24% of cases by December 2020. CAL.20C is characterized by multiple mutations in the spike protein, similar to variants emerging from the UK and South Africa. Though predominant in Southern California, CAL.20C has been isolated in samples from New York and Washington DC.²³*

Implications of variants for SARS-CoV-2 re-infection and vaccine efficacy

Greaney et al. identified the E484 site in the spike protein receptor binding domain (characteristic of variants B.1.351 and P.1) as a place where mutations reduce neutralization by convalescent serum by more than 10-fold.²⁴ Convalescent plasma from people recovering from COVID-19 had attenuated neutralization to the B.1.351 variant.^25,26* The SARS-CoV-2 variant B.1.1.7 was resistant to neutralization by several monoclonal antibodies (mAbs) targeting either the N-terminal domain (NTD) of the virus’s spike protein or its receptor-binding domain (RBD).  The B.1.351 variant resisted neutralization by most NTD mAbs, multiple individual mAbs directed against the RBD, convalescent plasma (about 11-33 fold), and sera from vaccinated people (about 6.5-8.6 fold).²⁷* The SARS-CoV-2 B.1.1.7 variant was shown to reduce neutralizing activity of monoclonal antibodies (mAbs) targeting subdominant epitopes in the SARS-CoV-2 spike protein.²⁸* Cases of SARS-CoV-2 re-infection have been reported for the D614G mutation, B.1.1.7 variant, B.1.351 variant, and P.1 variant.^29–31 For B.1.1.7, the two infection episodes were separated by eight months and the second infection episode was with a B.1.1.7 variant.³⁰

Summary of vaccine efficacy by manufacturer

Pfizer-BioNTech

• Neutralizing activity of participants three weeks after receiving the first dose of the Pfizer vaccine was similar against the three key spike protein mutations in the B.1.1.7 variant, compared to the wild-type SARS-CoV-2 strain. However, neutralization titers were reduced up to 6-fold (median 3.85-fold) against a pseudovirus with the full set of 8 spike protein mutations present in the B.1.1.7 variant.³²*
• A subsequent analysis found sera from recipients who completed the 2-dose regimen of the Pfizer vaccine BNT162b2 (n=20) had similar neutralizing geometric mean titers (GMTs) against SARS-CoV-2 viruses engineered to contain key spike protein mutations from variants emerging from the UK (B.1.1.7) and South Africa (B.1.351) compared to GMTs against the wild-type virus. The authors note a limitation that the engineered viruses do not contain the full set of mutations present in variants B.1.1.7 and B.1.351.³³*

Moderna

• Sera from human subjects or non-human primates that received the mRNA-1273 (Moderna) vaccine showed no significant reduction in neutralization activity against the SARS-CoV-2 B.1.1.7 variant emerging from the UK, but reduced activity against the B.1.351 variant emerging from South Africa.³⁴*
• Using a lentivirus-based pseudovirus assay, the SARS-CoV-2 B.1.1.7 (UK) variant was shown to exhibit only modestly reduced susceptibility to neutralization from convalescent sera (1.5-fold average reduction) and sera from recipients of both the Moderna and Novavax vaccine phase 1 studies (2-fold average reduction after two inoculations).³⁵*

Novavax

• Preliminary results reported on January 28 for phase 2/3 trials for the recombinant protein-based COVID-19 vaccine NVX-CoV2373 made by Novavax showed up to 89% efficacy in the UK cohort (n >15,000), with an estimated 86% efficacy against the B.1.1.7 variant.³⁶*
• Preliminary Novavax results from the South Africa cohort (n >4,400) showed efficacy of 60% in the HIV-negative study population vs. 49% in the overall study population, with 29 COVID-19 cases observed in the placebo group vs. 15 in the vaccine group. Among 27 of the 44 cases with sequence data, mutations consistent with the B.1.351 variant were detected in 25 (93%).³⁶* 

Johnson & Johnson

• Preliminary analysis of the ENSEMBLE trial reported the efficacy of single-dose vaccination with the Johnson & Johnson vaccine was lower among trial participants in South Africa (57%) than at sites in Latin America (66%) and the US (72%) in the setting of B.1.351 emergence in South Africa.³⁷*

Oxford – AstraZeneca

• The efficacy the ChAdOx1 nCoV-19 vaccine against the B.1.1.7 variant of SARS-CoV-2 was similar to the efficacy against parent lineages, with 74% efficacy (95% CI, 42-89%) against B.1.1.7 compared to 84% efficacy (95% CI, 71-91%) against non- B.1.1.7 lineages.³⁸*

Implications of variants for diagnostic testing

• A potential consequence of emerging variants is the ability to evade detection by specific viral diagnostic tests. CDC reports that most commercial RT-PCR-based tests have multiple targets to detect the virus, so that even if a mutation impacts one of the targets, the other RT-PCR targets will still work.¹
• There is minimal impact on the performance of antigen-based tests (including rapid lateral flow devices) and there has been no impact on the performance of serological antibody tests reported on these variants.³⁹
• The World Health Organization advises laboratories using S-gene based assays to monitor for dropout and consider implementing assays specific for other genomic targets (e.g., E or RdRP genes) if not already included as part of the existing panel.⁴⁰
• Lineage B.1.1.7 (a.k.a. variant 20I/501Y.V1 or VOC 202012/01):
  • Minimal impact on performance of molecular diagnostics (69–70 deletion causes S gene dropout).⁴¹
  • A UK government assessment found that all five SARS-CoV-2 rapid antigen tests evaluated (Abbott Panbio, Fortress, Innova, Roche/SD Biosensor nasal swab, and Surescreen) were able to successfully detect the variant.⁴²
  • Abdel-Sater et al. reported the development of a rapid molecular test to identify the SARS-CoV-2 B.1.1.7 variant using a set of RT-PCR primers that were designed to confirm the deletion mutations Δ69/Δ70 in the spike and the Δ106/Δ107/Δ108 in the NSP6 gene. The large-scale screening method may help bypass the need for widespread sequencing to confirm the presence of both the B.1.1.7 variant and variants with similar deletions.⁴³* (Summarized Jan 29)
• Lineage B.1.351 (a.k.a. variant 20H/501Y.V2):
  • We did not find data on assay performance impact yet, but there is potential of impacting assays that target S gene sequences.

Current variants and clinical severity

• The UK New and Emerging Respiratory Virus Threats Advisory Group reported on January 21, 2021 that the B.1.1.7 SARS-CoV-2 variant quickly became dominant in the UK, and it is possible that infection with this variant is associated with increased risk of death. The statement cites evidence of increased case fatality from several independent UK studies of samples with s-gene target failure, a proxy for the B.1.1.7 variant.⁴⁴*
• Further evidence was published on February 3 in a pre-print by Davies et al. reporting that the B.1.1.7 variant may increase the risk of death by 30%, based on an analysis of SARS-CoV-2 community test results in the UK that identified B.1.1.7-associated infections using S gene target PCR failure.⁴⁵*
• An earlier analysis found that patients with the B.1.1.7 were equally likely to be asymptomatic.⁴⁶*
• An analysis found no association  between the proportion of the SARS-CoV-2 variant B.1.1.7 in circulation in the UK and reported disease severity, according to data obtained from reporting of symptoms and test results via the COVID Symptom Study application.⁴⁷*

Resources for tracking

• The World Health Organization (WHO) publishes weekly COVID-19 situation reports with global epidemiological and operational updates, including special coverage on novel variants. Additionally, WHO has a summary of SARS-CoV-2 variants through 12/31/2020.
• In addition to providing updated COVID-19 guideline, the US Centers for Disease Control and Prevention (CDC) has a periodically updated page on emerging SARS-CoV-2 variants.
• GISAID a global science initiative that provides open-access genomic data of influenza viruses and SARS-CoV-2. CoVsurver is a tool that allows users to perform mutation analyses based on input sequences compared to a reference strain.
• Nextstrain is an open-source project to harness the scientific and public health potential of pathogen genome data. Nextstrain provides a continually updated view of publicly available SARS-CoV-2 data and includes SARS-CoV-2 resources as well as FAQs on COVID-19.

The full report contains the following additional sections:

• Table of key characteristics of novel SARS-CoV-2 variants
• Annotated Bibliography

VIEW A PDF OF THE FULL REPORT HERE 

COVID-19 Literature Report Team: Ashley Tseng MPH, Lorenzo Tolentino MPH, Jessie Seiler MPH, Rodal Issema MPH, Molly Fisher MPH, Sherrilynne Fuller PhD FACMI, Dylan Green MPH, Diana Louden MLib, Alison Drake PhD MPH, Will Hahn MD, Brandon L. Guthrie PhD, Jennifer M. Ross MD MPH