Frampton D, Rampling R, Cross A, et al. Genomic characteristics and clinical effect of the emergent SARS-CoV-2 B.1.1.7 lineage in London, UK: a whole-genome sequencing and hospital-based cohort study. Lancet Inf Dis April 12, 2021. https://www.thelancet.com/journals/laninf/article/PIIS1473-3099(21)00170-5/fulltext
It will be interesting to see whether this elegant study will gain as much media attraction as the studies showing the opposite: comparing 198 patients with B.1.1.7 infection and 143 with non-B.1.1.7 infection, the authors found NO evidence of an association between severe disease and death and lineage in unadjusted analyses or in analyses adjusted for hospital, sex, age, co-morbidities, and ethnicity. Viral load by proxy was higher in B.1.1.7 samples than in non-B.1.1.7 samples, as measured by cycle threshold value.
Ong SW, Young BE, Lye DC. Lack of detail in population-level data impedes analysis of SARS-CoV-2 variants of concern and clinical outcomes. Lancet Inf Dis April 12, 2021. https://www.thelancet.com/journals/laninf/article/PIIS1473-3099(21)00201-2/fulltext
Comment on the previous study, followed by a nice overview. What do we know about the effects of B.1.1.7 on disease severity? Not enough. Confounding factors including health care resource use, demographic changes, and socio-behavioral trends affect clinical outcomes, including mortality, and are difficult to adjust for without detailed, robust, patient-level data. According to the authors, “careful epidemiologic and clinical assessment, coupled with a healthy skepticism, is important when assessing claims of the effect of these variants”. Agreed.
Shen X, Tang H, Pajon R, et al. Neutralization of SARS-CoV-2 Variants B.1.429 and B.1.351. NEJM April 7, 2021. https://www.nejm.org/doi/full/10.1056/NEJMc2103740?query=featured_home
Vaccine-elicited neutralizing antibodies are likely to remain effective against the B.1.429 variant (“California”). The modestly lower value in neutralization titers was similar to B.1.1.7, using serum from recipients of the mRNA-1273 (Moderna) and NVX-CoV2373 (Novavax). The magnitude of resistance seen with the B.1.351 variant is of greater concern. However, this is good news, because immune escape seems to be limited in most variants.
Wang GL, Wang ZY, Duan LJ, et al. Susceptibility of Circulating SARS-CoV-2 Variants to Neutralization. NEJM April 6, 2021. https://www.nejm.org/doi/full/10.1056/NEJMc2103022?query=featured_coronavirus
B.1.1.7 showed little resistance to the neutralizing activity of convalescent or vaccinee serum (inactivated-virus vaccines from Sinopharm and Sinovac were used), whereas B.1.351 showed more resistance to the neutralization of both convalescent serum (by a factor of 2) and vaccinee serum (by a factor of 2.5 – 3.3) than to the wild-type virus. Results are in line with previous studies with mRNA vaccines.
De Oliveira T, Lutucuta S, Nkengasong J, et al. A novel variant of interest of SARS-CoV-2 with multiple spike mutations is identified from travel surveillance in Africa. https://www.medrxiv.org/content/10.1101/2021.03.30.21254323v1
Not peer reviewed: a new variant was found in Angola in three travelers arriving from Tanzania who were tested together at the airport in mid-February. The variant, named A.VOI.V2, has 31 amino acid substitutions (11 in spike) and three deletions (all in spike). According to the authors, this warrants urgent investigation as the source country has a largely undocumented epidemic and few public health measures in place to prevent spread either within or outside of the country.
Hoffmann M, Zhang L, Krüger N, et al. SARS-CoV-2 mutations acquired in mink reduce antibody-mediated neutralization. Cell Report, April 2, 2021. 109017. https://www.cell.com/cell-reports/fulltext/S2211-1247(21)00331-4
Mutations frequently found in the S proteins of SARS-CoV-2 from mink were mostly compatible with efficient entry into human cells and its inhibition by soluble ACE2. In contrast, mutation Y453F reduced neutralization by casirivimab and by sera/plasma from COVID-19 patients. Infection of mink and other animal species should be prevented and it should be continuously monitored whether SARS-CoV-2 amplification in other wild or domestic animals occurs and changes critical biological properties of the virus.
Schuit M, Biryukov J, Beck K, et al. The stability of an isolate of the SARS-CoV-2 B.1.1.7 lineage in aerosols is similar to three earlier isolates. J Inf Dis April 2, 2021, jiab171, https://academic.oup.com/jid/advance-article/doi/10.1093/infdis/jiab171/6209391?searchresult=1
The stability of SARS-CoV-2 in aerosols does not vary greatly among the currently circulating lineages, including B.1.1.7, suggesting that the increased transmissibility associated with recent SARS-CoV-2 lineages is not due to enhanced survival in the environment.
Starr TN, Greaney AJ, Dingens AS, et al. Complete map of SARS-CoV-2 RBD mutations that escape the monoclonal antibody LY-CoV555 and its cocktail with LY-CoV016. Cell Rep Med April 01, 2021. https://www.cell.com/cell-reports-medicine/fulltext/S2666-3791(21)00071-9
Future efforts should diversify the epitopes targeted by antibodies to make them more resilient to antigenic evolution. Individual mutations that escape binding by bamlanivimab (BAM) and etesevimab (ESV) are combined in the B.1.351 and P.1 lineages (E484K escapes BAM, K417N/T escapes ESV). Additionally, the L452R mutation in the B.1.429 lineage escapes BAM. The authors also identified single amino acid changes that escape the combined BAM/ESV cocktail.
The SARS-CoV-2 variant with lineage B.1.351 clusters investigation team. Linked transmission chains of imported SARS-CoV-2 variant B.1.351 across mainland France, January 2021. Euro Surveill 2021;26(13):pii=2100333. https://www.eurosurveillance.org/content/10.2807/1560-7917.ES.2021.26.13.2100333
Two cases had travelled in mid-December 2020 with a group to Mozambique where they participated in a religious gathering and returned with the B.1.351 variant. A joint team of epidemiologists, public health workers and clinical and virological specialists co-operated across France to urgently investigate and initiate control measures. A total of 36 cases were analyzed. Believe it or not: “Another challenge was that some members of the clusters did not agree to answer questions”.
Graham C, Seow J, Huettner I, et al. Neutralization potency of monoclonal antibodies recognizing dominant and subdominant epitopes on SARS-CoV-2 Spike is impacted by the B.1.1.7 variant. Immunity April 01, 2021. https://www.cell.com/immunity/fulltext/S1074-7613(21)00135-7
To understand how mutations affect Spike antigenicity, the authors isolated and characterized > 100 monoclonal antibodies targeting epitopes on SARS-CoV-2 spike receptor-binding domain (RBD), N-terminal domain (NTD) and S2 from SARS-CoV-2-infected individuals. Mutations present in B.1.1.7 spike frequently conferred neutralization resistance to NTD-specific antibodies. Neutralization by RBD-specific nAbs remained largely unchanged.
Peng J, Liu J, Mann SA, et al. Estimation of secondary household attack rates for emergent spike L452R SARS-CoV-2 variants detected by genomic surveillance at a community-based testing site in San Francisco. Clinical Infectious Diseases 31 March 2021, ciab283, https://academic.oup.com/cid/advance-article/doi/10.1093/cid/ciab283/6206738?searchresult=1
The new lineages B.1.427 and B.1.429 (the “California” or “West Coast” variants) share S gene non-synonymous mutations at sites 13, 152, 452, and 614 and were seen during the December 2020 to February 2021 period when California was experiencing a huge peak. Whereas no instances of B.1.1.7, or independent N501Y mutations were detected in the sample population, the authors found a modest transmissibility increase of the West Coast variants. Household contacts exposed to these variants were at higher risk of infection compared to those exposed to lineages lacking these variants (0.36 vs 0.29, RR = 1.28; 95% CI: 1.00-1.64). Ct values did not differ.
Dejnirattisai W, Zhou D, Supasa P, et al. Antibody evasion by the P.1 strain of SARS-CoV-2. Cell March 30, 2021. https://www.cell.com/cell/fulltext/S0092-8674(21)00428-1
All new strains (P.1 from Brazil, B.1.351 from South Africa and B.1.1.7 from the UK) have mutations in the ACE2 binding site with P.1 and B.1.351 having a virtually identical triplet: E484K, K417N/T and N501Y, conferring similar increased affinity for ACE2. Surprisingly, P.1 was significantly less resistant to naturally acquired or vaccine induced antibody responses than B.1.351, suggesting that changes outside the receptor-binding domain impact neutralization.
Francisco MA, Zavascki AP, Lamb WP, et al. Detection of SARS-CoV-2 lineage P.1 in patients from a region with exponentially increasing hospitalisation rate, February 2021, Rio Grande do Sul, Southern Brazil. Euro Surveill Accepted: 25 Mar 2021, 2021. Full text: https://doi.org/10.2807/1560-7917.ES.2021.26.12.2100276
From epidemiological week 6, starting on 7 February 2021, until 6 March, the number of hospitalizations for COVID-19 in Rio Grande do Sul, the southernmost state of Brazil in the South region, increased from 1738 inpatients to 6995 (3.8-fold). This resulted in the collapse of the state healthcare system. The overwhelming increase in hospitalizations temporally coincided with the finding that lineage P.1 became predominant (although a small number of specimens was taken).
Until late last fall, public health departments had no federal mandate or additional funding to sequence samples, although new variants were an inevitability.
McCormick KD, Jacobs JL, Mellors JW. The emerging plasticity of SARS-CoV-2. Science 2021, published 26 March. Full text: https://doi.org/10.1126/science.abg4493
Volz E, Mishra S, Chand M, et al. Assessing transmissibility of SARS-CoV-2 lineage B.1.1.7 in England. Nature (2021). Full text: https://doi.org/10.1038/s41586-021-03470-x
The preprint we presented on 13 January now published in Nature: the authors describe the new SARS-CoV-2 lineage B.1.1.7 (AKA VOC 202012/01) which originated in England, late Summer to early Autumn 2020. The data indicate a transient shift in the age composition of reported cases, with a larger share of under-20-year-olds among B.1.1.7 cases than among historical cases. B.1.1.7 has a substantial transmission advantage with a 50% to 100% higher reproduction number.
Edara VV, Norwood C, Floyd K, et al. Infection and vaccine-induced antibody binding and neutralization of the B.1.351 SARS-CoV-2 variant. Cell Host Microbe 2021, published 20 March. Full text: https://doi.org/10.1016/j.chom.2021.03.009
Despite reduced antibody titers against the B.1.351 variant (first detected in South Africa), sera from infected and vaccinated individuals containing polyclonal antibodies to the spike protein could still neutralize SARS-CoV-2 B.1.351. The authors conclude that protective humoral immunity may be retained against this variant.
Hoffmann M, Arora P, Groß R, et al. SARS-CoV-2 variants B.1.351 and P.1 escape from neutralizing antibodies. Cell 2021, accepted 16 March. Full-text: https://doi.org/10.1016/j.cell.2021.03.036
The authors show that entry of all variants into human cells is susceptible to blockade by the entry inhibitors soluble ACE2, Camostat, EK-1 and EK-1-C4. In contrast, entry of B.1.351 and P.1 was partially (casirivimab) or fully (bamlanivimab) resistant to monoclonal antibodies. Moreover, entry of these variants was less efficiently inhibited by plasma from convalescent COVID-19 patients and sera from individuals vaccinated with the Pfizer-BioNTech vaccine.
Grint DJ, Wing K, Williamson E, et al. Case fatality risk of the SARS-CoV-2 variant of concern B.1.1.7 in England, 16 November to 5 February. Volume 26, Issue 11, 18 March 2021. https://www.eurosurveillance.org/content/10.2807/1560-7917.ES.2021.26.11.2100256
Evidence grows that B.1.1.7 is more dangerous. In this data drawn from the OpenSAFELY electronic health records secure research platform (covering 40% of England’s population registered with a general practitioner), there was a consistently higher (about two thirds) absolute risk of death by 28 days after a SARS-CoV-2-positive test in all groups stratified by age, sex and presence of co-morbidities.
Paper of the Day
Wu K, Werner AP, Koch M. Serum Neutralizing Activity Elicited by mRNA-1273 Vaccine. NEJM March 17, 2021. https://www.nejm.org/doi/full/10.1056/NEJMc2102179
What about Moderna’s mRNA vaccine and the new variants? This study saw a decrease in titers of neutralizing antibodies against the P.1 variant, the B.1.427/B.1.429 variant, the B.1.1.7+E484K variant, and the B.1.351 variant as well as a subset of its mutations in the RBD. Protection against these lineages remains “to be determined”.
Challen R, Brooks-Pollock E, Read JM, Dyson L, Tsaneva-Atanasova K, Danon L. Risk of mortality in patients infected with SARS-CoV-2 variant of concern 202012/1: matched cohort study. BMJ. 2021 Mar 9;372:n579. PubMed: https://pubmed.gov/33687922. Full-text: https://doi.org/10.1136/bmj.n579
Is B.1.1.7 more lethal? In this large study from the UK, mortality hazard ratio associated with infection with “B.1.1.7” (S gene negative) was 1.64 (95% CI: 1.32 to 2.04) in the community, compared with previously circulating variants. However, even though the authors controlled for some biases, their matched control approach bears several limitations. Let’s take it as a first hint, but not as proof.
Garcia-Beltran WF, Lam EC, Denis KS, et al. Multiple SARS-CoV-2 variants escape neutralization by vaccine-induced humoral immunity. Cell March 12, 2021. https://www.cell.com/cell/fulltext/S0092-8674(21)00298-1
Among 99 individuals who received one or two doses of mRNA vaccines, most individuals receiving a single dose did not raise sufficient antibody titers to provide detectable cross neutralization to B.1.351. This supports the importance of 2-dose regimens to acheive protective titers.
Altman DM, Boyton RJ, Beale R. Immunity to SARS-CoV-2 variants of concern. Science 12 Mar 2021: Vol. 371, Issue 6534, pp. 1103-1104. https://science.sciencemag.org/content/371/6534/1103
Brilliant brief review about not only immunity to variants but also on methodological issues. Assessment of variants on neutralization are complicated by the variability of pseudotype assays used.
Li Y, Ma ML, Lei Q, et al. Linear epitope landscape of the SARS-CoV-2 Spike protein constructed from 1,051 COVID-19 patients. Cell Reports March 12, 2021. DOI:https://doi.org/10.1016/j.celrep.2021.108915
What part of the spike protein is highly immunogeneic? By analyzing the serum IgG response of 1051 COVID-19 patients with a peptide microarray, the authors built a comprehensive epitope landscape that covers the entire sequence of the SARS-CoV-2 spike protein. A set of 16 highly immunogenic epitopes outside of the RBD region were identified. The antibody responses against several epitopes are associated with severity. Little neutralization activity was observed for the antibodies against the highly immunogenic epitopes.
Grint DJ, Wing K, Williamson E, et al. Case fatality risk of the SARS-CoV-2 variant of concern B.1.1.7 in England. MedRxiv 2021, posted 8 March. Full-text: https://doi.org/10.1101/2021.03.04.21252528
The authors draw data from a research platform that covers 40% of England’s population registered with a general practitioner. B.1.1.7 status was known for 184,786 people. The B.1.1.7 group was younger with a lower proportion of older cases (80+: 0.9% VOC vs. 1.6% non-B.1.1.7 cases), with fewer Comorbidities (2+ Comorbidities: 2.9% vs. 3.8%). After controlling for Comorbidities, age, week, region & other sociodemographics, the authors found an increased risk of death for B.1.1.7 compared with non-B.1.1.7 cases (HR: 1.67; 95% CI: 1.34 – 2.09; P < 0.0001).
Tablizo FA, Kim KM, Lapid CM, et al. Genome sequencing and analysis of an emergent SARS-CoV-2 variant characterized by multiple spike protein mutations detected from the Central Visayas Region of the Philippines. medRxiv 2021, posted 6 March. Full-text: https://doi.org/10.1101/2021.03.03.21252812
The authors describe the emergence of a new SARS-CoV-2 lineage, mainly from the Central Visayas region of the Philippines: 13 lineage-defining mutations, including the co-occurrence of the E484K, N501Y, and P681H mutations at the spike protein region, as well as three additional radical amino acid replacements towards the C-terminal end of the said protein. A three amino acid deletion at positions 141 to 143 (LGV141_143del) in the spike protein is reminiscent of a region preceding the 144Y deletion found in the B.1.1.7 variant. See also the ‘P.3’ proposition by Andrew Rambaut: https://github.com/cov-lineages/pango-designation/issues/27.
Paper of the Day
Collier DA, De Marco A, Ferreira IA, et al. Sensitivity of SARS-CoV-2 B.1.1.7 to mRNA vaccine-elicited antibodies. Nature March 11, 2021. https://www.nature.com/articles/s41586-021-03412-7
A pseudovirus bearing S protein with the full set of mutations present in the B.1.1.7 variant did result in a small reduction in neutralization by sera from vaccinees that was more marked following the first dose vs the second dose. Worryingly, Dami A. Collier and colleagues measured further reduction in neutralization titers by vaccine sera when E484K was present alongside the B.1.1.7 S mutations. They conclude that “E484K emergence on a B.1.1.7 background represents a threat to the vaccine BNT162b”.
Borges V, Sousa C, Menezes L, et al. Tracking SARS-CoV-2 lineage B.1.1.7 dissemination: insights from nationwide spike gene target failure (SGTF) and spike gene late detection (SGTL) data, Portugal, week 49 2020 to week 3 2021. Eurosurveillance Mar 11, 2021, Article Volume 26, Issue 10. https://www.eurosurveillance.org/content/10.2807/1560-7917.ES.2021.26.10.2100130
Dissemination of the B.1.1.7 lineage in Portugal. Both SGTF and SGTL (a proxy for monitoring trends of B.1.1.7) samples had significantly lower median Ct values of N and ORF1ab gene targets (ca 3.5 and 1.8 Ct units, respectively) compared with samples where the S gene was unbiasedly detected.
Paper of the Day
Tegally H, Wilkinson E, Giovanetti M. et al. Emergence of a SARS-CoV-2 variant of concern with mutations in spike glycoprotein. Nature March 9, 2021. https://www.nature.com/articles/s41586-021-03402-9_reference.pdf
The future “reference” paper on the detection of B.1.351 (or 501Y.V2), characterized by eight lineage-defining mutations in the spike protein, including three at important residues in the receptor-binding domain (K417N, E484K and N501Y). This lineage was identified in South Africa after the first epidemic wave in a severely affected metropolitan area, and spread rapidly. The genomic data, showing the rapid expansion and displacement of other lineages in multiple regions, suggest that this lineage is associated with a selection advantage, most plausibly as a result of increased transmissibility or immune escape. Nevertheless, congrats to co-author Wolfgang Preiser!
Paper of the Day
Wang P, Nair MS, Liu L, et al. Antibody Resistance of SARS-CoV-2 Variants B.1.351 and B.1.1.7. Nature March 8, 2021. https://www.nature.com/articles/s41586-021-03398-2
For younger readers: once upon a time, in the stone age (c. 1996), David Ho from the Aaron Diamond Center was deemed “man of the year” (Time Magazine), after explaining the dynamics of HIV replication to the world. Today he explains why B.1.351 is so worrisome. While B.1.1.7 is refractory to neutralization by many mAbs but not more resistant to convalescent plasma (CP) or vaccinee sera (VS), B.1.351 is not only refractory to neutralization by almost all mAbs but also by CP (9.4 fold) and VS (10.3-12.4 fold). SARS-CoV-2 “is traveling in a direction that could ultimately lead to escape from our current therapeutic and prophylactic interventions directed to the viral spike”.
Alexandre G, Bosetti P, Feri A, et al. Early assessment of diffusion and possible expansion of SARS-CoV-2 Lineage 20I/501Y.V1 (B.1.1.7, variant of concern 202012/01) in France, January to March 2021. Euro Surveill. 2021;26(9):pii=2100133. https://doi.org/10.2807/1560-7917.ES.2021.26.9.2100133
Spread of B.1.1.7. in France, in January. The authors estimate the population-level effective reproduction number will be respectively 39% (95%: 33–45%) and 56% (95%: 50–62%) higher on 1 March and 1 April 2021 than what would be expected if only the classical lineages were circulating.
Firestone MJ, Lorentz AJ, Meyer S, et al. First Identified Cases of SARS-CoV-2 Variant P.1 in the United States — Minnesota, January 2021. MMWR Morb Mortal Wkly Rep. ePub: 3 March 2021. https://www.cdc.gov/mmwr/volumes/70/wr/mm7010e1.htm?s_cid=mm7010e1_x
The arrival of P.1 in the US. Both guys had returned from southeastern Brazil. According to the authors, this “underscores the importance of community prevention strategies to slow transmission of SARS-CoV-2 including use of well-fitting masks, physical distancing, washing hands, quarantine, testing of persons who have had contact with a person with laboratory-confirmed COVID-19, isolating persons with symptoms of COVID-19 or with diagnosed COVID-19 and” (drumroll, please) “adhering to CDC recommendations to delay travel”. Maybe it’s not the best idea to vacation in Brazil (or anywhere!) right now.
Ojelade M, Rodriguez A, Gonzalez D, et al. Travel from the United Kingdom to the United States by a Symptomatic Patient Infected with the SARS-CoV-2 B.1.1.7 Variant — Texas, January 2021. MMWR Morb Mortal Wkly Rep. ePub: 3 March 2021. https://www.cdc.gov/mmwr/volumes/70/wr/mm7010e2.htm?s_cid=mm7010e2_w
Another jerk who traveled from UK to US after experiencing COVID-19–compatible symptoms, infected with the B.1.1.7 variant. “Persons should not travel if they are experiencing symptoms compatible with COVID-19 or if they have received a positive SARS-CoV-2 test result and have not met criteria to discontinue isolation, have had close contact with a person with suspected or confirmed COVID-19 and have not subsequently met criteria to end quarantine, or have a pending SARS-CoV-2 viral test result”. Questions?
Fujino T, Nomoto H, Kutsuna S, Ujiie M, Suzuki T, Sato R, et al. Novel SARS-CoV-2 variant identified in travelers from Brazil to Japan. Emerg Infect Dis. 2021 Apr [date cited]. https://doi.org/10.3201/eid2704.210138
A family of four, traveling in early January to Tokyo, Japan, from Amazonas state in Brazil via Istanbul, Turkey (by the way, wouldn’t it have been shorter heading west?). Souvenir: A new lineage, resembling P.1, but with some interesting new mutations. Cringe.
Maggi F, Novazzi F, Genoni A, Baj A, Spezia PG, Focosi D, et al. Imported SARS-CoV-2 variant P.1 detected in traveler returning from Brazil to Italy. Emerg Infect Dis. 2021 Apr [date cited]. https://doi.org/10.3201/eid2704.210183
A family of three, flying from São Paulo, Brazil, via Madrid, Spain, to Milan (Malpensa Airport) in Italy, in mid-January. In the luggage: P.1.
Paper of the Day
De Souza WM, Amorm MR, Sesti-Costa R, et al. Levels of SARS-CoV-2 Lineage P.1 Neutralization by Antibodies Elicited after Natural Infection and Vaccination. Lancet Preprints 2021, posted 1 March. Full-text: https://papers.ssrn.com/sol3/papers.cfm?abstract_id=3793486
William de Souza and colleagues isolated two P.1-containing specimens from nasopharyngeal and bronchoalveolar lavage samples of patients in Manaus, Brazil. They found that the immune plasma of COVID-19 convalescent blood donors had 6-fold less neutralizing capacity against the P.1 than against the B lineage. Moreover, five months after booster immunization with the Chinese CoronaVac vaccine, plasma from vaccinated individuals failed to efficiently neutralize P.1 lineage isolates.
Faria NR, Mellan TA, Whittaker C, et al. Genomics and epidemiology of a novel SARS-CoV-2 lineage in Manaus, Brazil. MedRxiv 2021, posted 3 March. Full-text: https://doi.org/10.1101/2021.02.26.21252554
Using a combination of genomic and epidemiological data, Nuno Faria and colleagues characterize the emergence and characteristics of P.1 that acquired 17 mutations, including the trio in the spike protein (K417T, E484K and N501Y) associated with increased binding to the human ACE2 receptor. The authors show that P.1 emerged around early November 2020. They estimate that P.1 could be 1.4–2.2 times more transmissible and able to evade 25-61% of protective immunity elicited by previous infection with non-P.1 lineages.
Wang P, Wang M, Yu J, et al. Increased Resistance of SARS-CoV-2 Variant P.1 to Antibody Neutralization. bioRxiv 2021, posted 2 March. Full-text: https://doi.org/10.1101/2021.03.01.433466
David D. Ho, Pengfei Wang and colleagues report that P.1 is not only refractory to multiple neutralizing monoclonal antibodies, but also more resistant to neutralization by convalescent plasma (6.5-fold) and vaccinee sera (2.2-2.8-fold).
Cele S, Gazy I, Jackson L, et al. Escape of SARS-CoV-2 501Y.V2 from neutralization by convalescent plasma. MedRxiv 2021, posted 27 February. Full-text: https://doi.org/10.1101/2021.01.26.21250224
We already knew that people previously infected with the non-B.1.351 variant don’t neutralize B.1.351 very effectively. Now Alex Sigal, Tulio de Oliveira, Sandile Cele and colleagues show that people infected with B.1.351 can neutralize both B.1.351 and (to a slightly lesser extent) ‘regular’ non-B.1.351 viruses (Cele 2021). If these data are confirmed, a variant B.1.351-targeted booster vaccine could be a solution for countries where B.1.351 is the dominant strain.
Starr TN, Greaney AJ, Dingens AS, Bloom JD. Complete map of SARS-CoV-2 RBD mutations that escape the monoclonal antibody LY-CoV555 and its cocktail with LY-CoV016. bioRxiv 2021, posted 21 February. Full-text: https://doi.org/10.1101/2021.02.17.431683
Jesse Bloom, Tyler Starr and colleagues completely map all mutations to the SARS-CoV-2 spike receptor binding domain (RBD) that escape binding by LY-CoV555 (bamlanivimab, a monoclonal antibody manufactured by Lilly), and its cocktail combination with LY-CoV016. Individual mutations that escape binding are present in B.1.351 and P.1 (E484K escapes LY-CoV555, K417N/T escape LY-CoV016). Additionally, the L452R mutation in the B.1.429 lineage escapes LY-CoV555.
Paper of the Day
Shen X, Tang H, McDanal C, et al. SARS-CoV-2 variant B.1.1.7 is susceptible to neutralizing antibodies elicited by ancestral Spike vaccines. Cell Host Microbe March 03, 2021. https://www.cell.com/cell-host-microbe/fulltext/S1931-3128(21)00102-5
Good news. Using a lentivirus-based pseudovirus assay, Xiaoying Shen and colleagues from Duke, Durham, US, show that B.1.1.7 is probably not a neutralization escape variant of concern for COVID-19 vaccines. Moreover, B.1.1.7 is unlikely to increase the risk of SARS-CoV-2 re-infection.
Wibmer CK, Ayres F, Hermanus T, et al. SARS-CoV-2 501Y.V2 escapes neutralization by South African COVID-19 donor plasma. Nature Medicine 02 March 2021. https://www.nature.com/articles/s41591-021-01285-x
B.1.351 is a bigger problem. This study (for months available as a pre-print only, now as a beautiful paper in Nature Medicine) shows that this lineage completely escapes three classes of therapeutically relevant antibodies. The B.1.351 pseudovirus also exhibited substantial to complete escape from neutralization, but not binding, by convalescent plasma. The overwhelming majority of monoclonal antibodies already on the path to licensure target residues K417 or E484 and are therefore likely to be futile against this variant.
Paper of the Day
Davies NG, Abbott S, Barnard RS, et al. Estimated transmissibility and impact of SARS-CoV-2 lineage B.1.1.7 in England. Science 03 Mar 2021: eabg3055. Full-text: https://science.sciencemag.org/content/early/2021/03/03/science.abg3055
Difficult months ahead: the B.1.1.7 variant emerged in southeast England in November 2020 and is rapidly spreading toward dominance. In this brilliant article, Nicholas Davies and colleagues from London estimate that this variant has a 43–90% (range of 95% credible intervals 38–130%) higher reproduction number than pre-existing variants. A fitted two-strain dynamic transmission model shows that B.1.1.7. will lead to large resurgences of COVID-19 cases. Without stringent control measures, including limited closure of educational institutions and a greatly accelerated vaccine roll-out, COVID-19 hospitalizations and deaths across England in 2021 will exceed those in 2020.
Plante JA, Mitchell BM, Plante KS, et al. The Variant Gambit: COVID’s Next Move. Cell Host Microbe March 01, 2021. https://www.cell.com/cell-host-microbe/fulltext/S1931-3128(21)00099-8
Nice review that outlines factors driving SARS-CoV-2 variant evolution, explores the potential impact of specific mutations and examines the risk of further mutations. Jessica A. Plante and colleagues from the World Reference Center for Emerging Viruses and Arboviruses consider also the experimental studies needed to understand the threat these variants pose.
Paper of the Day
WHO 20210223. Weekly epidemiological update – 23 February 2021. WHO 2021, published 23 February. Full-text: https://www.who.int/publications/m/item/weekly-epidemiological-update—23-february-2021
If you are interested in variants, read the Special Focus: Update on SARS-CoV-2 Variants of Concern on page 7 to 13 with an excellent table on the current information we have on B.1.1.7, B.1.351 and P.1.
Naveca F, Nascimento V, Souza V, et al. COVID-19 epidemic in the Brazilian state of Amazonas was driven by long-term persistence of endemic SARS-CoV-2 lineages and the recent emergence of the new Variant of Concern P.1. Research Square 2021, posted 25 February. Full-text: https://doi.org/10.21203/rs.3.rs-275494/v1
The second wave in the Northern Brazilian state of Amazonas coincides with the emergence of the P.1 variant in late November 2020. P.1 replaced the parental lineage in less than two months. The authors report that successive lineage replacements in Amazonas were driven by a complex combination of variable levels of social distancing measures and the emergence of a more transmissible VOC P.1 virus. They provide insights to understanding the mechanisms that underlie COVID-19 waves and the risk of disseminating P.1 in Brazil and potentially worldwide.
Faria NR, Mellan TA, Whittaker C, et al. Genomics and epidemiology of a novel SARS-CoV-2 lineage in Manaus. GitHub 2021, posted 27 February. Full-text: https://github.com/CADDE-CENTRE/Novel-SARS-CoV-2-P1-Lineage-in-Brazil/blob/main/manuscript/FINAL_P1_MANUSCRIPT_25-02-2021_combined.pdf
Using a combination of genomic and epidemiological data, Nuno Faria and colleagues characterize the emergence and characteristics of P.1 that acquired 17 mutations, including the trio in the spike protein (K417T, E484K and N501Y) associated with increased binding to the human ACE2 receptor. The authors show that P.1 emerged around early November 2020. They estimate that P.1 could be 1.4–2.2 times more transmissible and able to evade 25-61% of protective immunity elicited by previous infection with non-P.1 lineages. These data need to be confirmed by further studies.
Paper of the Day
Zhou D, Dejnirattisai W, Supasa P, et al. Evidence of escape of SARS-CoV-2 variant B.1.351 from natural and vaccine induced sera. Cell February 23, 2021. Full-text: https://www.cell.com/action/showPdf?pii=S0092-8674%2821%2900226-9
The new variants have multiple changes in the immunodominant spike protein which facilitates viral cell entry via the ACE receptor. Mutations in the receptor recognition site on the spike are of great concern due to their potential for immune escape. Daming Zhou and colleagues from Oxford, UK describe a structure-function analysis of B.1.351 using a large cohort of convalescent and vaccinee serum samples. The receptor binding domain mutations provide tighter ACE2 binding and widespread escape from monoclonal antibody neutralization largely driven by E484K although K417N and N501Y act together against some important antibody classes. The neutralization titer for B.1.351 reduced 8 to 9-fold for both the Pfizer and AstraZeneca vaccinees. E484K, K417N and N501Y caused widespread escape from monoclonal antibodies. However, let‘s keep in mind that even if antibody responses to the new variants are not able to prevent infection, they may moderate severity. Moreover, T cell responses to spike may not be disrupted by the mutational changes described here.
Li Q, Nie J, Wu J. No higher infectivity but immune escape of SARS-CoV-2 501Y.V2 variants. Cell February 23, 2021. https://www.cell.com/action/showPdf?pii=S0092-8674%2821%2900231-2
More experiments on B.1.351 (also known as 501Y.V2). These variants DO NOT confer increased infectivity in multiple cell types except for murine (not human!) ACE2-overexpressing cells, where a substantial increase in infectivity was observed. As seen in the other paper, the susceptibility of the variants to neutralizing monoclonal antibodies was substantially diminished, and the neutralization ability of the sera from convalescent patients and immunized mice was also reduced. The neutralization resistance was mainly caused by E484K and N501Y mutations in the receptor-binding domain of Spike.
Vasques Nonaka CK, Franco MM, Gräf T, et al. Genomic evidence of SARS-CoV-2 reinfection involving E484K spike mutation, Brazil. Emerg Infect Dis. February 19, 2021. https://wwwnc.cdc.gov/eid/article/27/5/21-0191_article
A case of reinfection from distinct virus lineages in Brazil harboring the E484K mutation, a variant associated with escape from neutralizing antibodies (see above). Both episodes were considered to be mild.
Liu Y, Liu J, Xia H, et al. Neutralizing Activity of BNT162b2-Elicited Serum – Preliminary Report. N Engl J Med. 2021 Feb 17. PubMed: https://pubmed.gov/33596352. Full-text: https://doi.org/10.1056/NEJMc2102017
Some more in vitro data on vaccine efficacy in SARS-CoV-2 variants. The authors produced different recombinant viruses, among them one with all the mutations found in the S gene in the B.1.351 lineage. After a single shot of BNT162b2 from Pfizer/BioNTech, neutralization of the B.1.351-spike virus was weaker by approximately two thirds. However, according to Yang Liu and colleagues, it remains unclear what this reduction means in terms of protection.
Wu K, Werner AP, Koch M, et al. Serum Neutralizing Activity Elicited by mRNA-1273 Vaccine – Preliminary Report. N Engl J Med. 2021 Feb 17. PubMed: https://pubmed.gov/33596346. Full-text: https://doi.org/10.1056/NEJMc2102179
Same with Moderna’s vaccine. In vitro reductions by a factor of 2,7-6,4 in titers of neutralizing antibodies against the partial or full panel of mutations. Again, protection against B.1.351 remains to be determined.
Twitter: Some more in vitro data on vaccine efficacy in SARS-CoV-2 variants (in particular B.1.351), after BNT162b2 from Pfizer/BioNTech https://doi.org/10.1056/NEJMc2102017 and Moderna https://doi.org/10.1056/NEJMc2102179
Paper of the Day
Garcia-Beltran WF, Lam EC, St. Denis K, et al. Circulating SARS-CoV-2 variants escape neutralization by vaccine-induced humoral immunity. medRxiv 2021, posted 18 February. Full-text: https://doi.org/10.1101/2021.02.14.21251704
While many strains, such as B.1.1.7, B.1.1.298, or B.1.429, continue to be potently neutralized despite the presence of individual receptor-binding domain (RBD) mutations, other circulating SARS-CoV-2 variants escape vaccine-induced humoral immunity. The P.2 variant, which contains an E484K mutation within the RBD region, was capable of significantly reducing the neutralization potency of fully vaccinated individuals. Similarly, the P.1 strain, which has three RBD mutations, more effectively escaped neutralization. Finally, B.1.351 variants exhibited remarkable resistance to neutralization, largely due to three mutations in RBD but with a measurable contribution from non-RBD mutations. The magnitude of the effect is such that B.1.351 strains escape neutralizing vaccine responses like SARS-CoV-1 (SARS 2002/2003) and bat-derived WIV1-CoV, suggesting that a relatively small number of mutations can mediate potent escape from vaccine responses. Alejandro Balazs, Wilfredo F. Garcia-Beltran and colleagues emphasize the need to develop broadly protective interventions against the evolving pandemic.
Resende PC, Delatorre D, Gräf T, et al. Evolutionary Dynamics and Dissemination Pattern of the SARS-CoV-2 Lineage B.1.1.33 During the Early Pandemic Phase in Brazil. Front. Microbiol 2021, 17 February. Full-text: https://www.frontiersin.org/articles/10.3389/fmicb.2020.615280/
Paula Cristina Resende et al. investigated the origin of the major and most widely disseminated SARS-CoV-2 Brazilian lineage B.1.1.33 that evolved from an ancestral clade, here designated B.1.1.33-like. The B.1.1.33-like lineage may have been introduced from Europe or may have arisen in Brazil in early February 2020 and a few weeks later gave origin to the lineage B.1.1.33.
Hodcroft EB, Domman DB, Snyder DJ, et al. Emergence in late 2020 of multiple lineages of SARS-CoV-2 Spike protein variants affecting amino acid position 677. medRxiv 2021, posted 14 January. Full-text: https://doi.org/10.1101/2021.02.12.21251658
Emma Hodcroft et al. describe 7 newly identified coronavirus variants in the US with a mutation in spike position 677 (also named after birds, Mockingbird to Yellowhammer). The authors promise to keep an eye on S:677 polymorphisms for effects on proteolytic processing, cell tropism, and transmissibility.
Hoffmann M, Arora P, Groß R, et al. SARS-CoV-2 variants B.1.351 and B.1.1.248: Escape from therapeutic antibodies and antibodies induced by infection and vaccination. medRxiv 2021, posted 11 February. Full-text: https://doi.org/10.1101/2021.02.11.430787
Stefan Pöhlmann, Markus Hoffmann and colleagues show that B1351 (first detected in South Africa) and P1 (alias B11248, first detected in Brazil) were partially (casirivimab, in REGN-COV2, Regeneron) or fully (bamlanivimab, Lilly) resistant to monoclonal antibodies and was less efficiently inhibited by serum/plasma from convalescent individuals or those vaccinated with the Pfizer-BioNTech vaccine.
Paper of the Day
NERVTAG 20210211. Update note on B.1.1.7 severity. New and Emerging Respiratory Virus Threats Advisory Group (NERVTAG) 2021, published 12 February. Full-text: https://www.gov.uk/government/publications/nervtag-update-note-on-b117-severity-11-february-2021
It is now likely that infection with B.1.1.7 is associated with an increased risk of hospitalization and death compared to infection with previously circulating viruses.
Variants – 13 February update. COVID Reference 2021, published 13 February. Full-text: https://covidreference.com/variants | See also the Comparison document with new content added between 7 and 13 February: http://www.bsk1.com/CR_Variants_Update.html
In most of continental Europe and the US, Easter 2021 (4 April) may be recalled later as a B.1.1.7 Easter.
Fontanet A, Autran B, Lina B, et al. SARS-CoV-2 variants and ending the COVID-19 pandemic. Lancet 2021, published 11 February. Full-text: https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(21)00370-6/fulltext
Arnaud Fontanet from the Pasteur Institute in Paris outlines the priorities to address in an environment with 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 immunization with available COVID-19 vaccines for sero-neutralization 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
Zhang W, Davis BD, Chen SS, Sincuir Martinez JM, Plummer JT, Vail E. Emergence of a Novel SARS-CoV-2 Variant in Southern California. JAMA. 2021 Feb 11. PubMed: https://pubmed.gov/33571356. Full-text: https://doi.org/10.1001/jama.2021.1612
In California, the proportion of SARS-CoV-2 cases associated with the CAL.20C variant rose from 3,8% to 25% between mid-November and late December. By then, it accounted for 24% of samples in one study, and 36,4% (66/181) of samples in a local Los Angeles cohort. The emerging predominance of this strain is temporally related to the time of onset of the current spike in SARS-CoV-2 infections in Southern California. CAL.20C is defined by mutations in the S protein (L452R, S13I, W152C) and in the ORF1a (I4205V) and ORF1b protein (D1183Y).
Althaus C, et al. Transmission of SARS-CoV-2 variants in Switzerland. Institute of Social and Preventive Medicine (ISPM), University of Bern 2021, reported 5 February. Full-text: https://ispmbern.github.io/covid-19/variants/
For 5 February, the authors estimated the proportion of SARS-CoV-2 variants (501Y, B.1.1.7) to have reached 67% in Geneva and 35% in Zurich. They also estimated the increase in transmissibility slightly above 50%.
Paper of the Day
Washington NL, Gangavarapu K, Zeller M, et al. Genomic epidemiology identifies emergence and rapid transmission of SARS-CoV-2 B.1.1.7 in the United States. medRxiv 2021, posted 7 February. Full-text: https://www.medrxiv.org/content/10.1101/2021.02.06.21251159v1
Kristian Andersen, Nicole L. Washington, Karthik Gangavarapu and colleagues from Helix and the Scripps Research Institute, La Jolla, sequenced 212 B117 genomes collected in the U.S. from December 2020 to January 2021. They found a doubling rate of a little over a week and an increased transmission rate of 35-45%. The authors show that the U.S. is on a similar trajectory as other countries where B117 rapidly became the dominant SARS-CoV-2 variant and warn that immediate and decisive action to minimize COVID-19 morbidity and mortality. Authorities in Germany, France, Italy, Spain and other countries should listen too.
With viruses, some mutations emerge while others recede. Rarely does one or more mutations confer a “selective advantage” to a new variant, for example enhanced transmissibility. Such variants can then become the new dominant virus.
Over the last two months, several new SARS-CoV-2 variants have been described that are more transmissible, may escape both natural and vaccine-induced immunity and could impact COVID-19 morbidity and mortality. It is too early to assert that these variants will create a new pandemic within the pandemic, however, in countries like England, South Africa, Brazil, Ireland, Portugal and Israel, they may have modified the dynamic of the latest outbreaks for the worse. More transmissible SARS-CoV-2 variants will replace older variants – everywhere! Countries where the prevalence of these new variants is still low should anticipate rapid spread within the next weeks and months and plan ahead accordingly, ie closing/restricting borders, etc.
The current trio infernale:
- B117 (first described in England; Rambaut 2020)
- B1351 (first described in South Africa; Tegally 2020)
- P1 (first described in Brazil; Faria 2021)