Novel highly divergent SARS-CoV-2 lineage with the Spike substitutions L249S and E484K

Laiton‐Donato, Katherine; Usme-Ciro, José A.; Franco-Muñoz, Carlos; Álvarez-Díaz, Diego A.; Ruiz-Moreno, Héctor Alejandro; Reales-González, Jhonnatan; Prada, Diego Andrés; Corchuelo, Sheryll; Herrera-Sepúlveda, María T.; Naizaque, Julian; Santamaría, Gerardo del Cerro; Wiesner, Magdalena; Walteros, Diana Marcela; Martinez, Martha; Mercado-Reyes, Marcela

doi:10.1101/2021.03.12.21253000

Cited by 5 publications

(6 citation statements)

References 14 publications

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“…Efficacy of bamlanivimab was preserved against VOC alpha (also named B.1.1.7 by PANGOLIN and 20I/501Y.V1 by NextStrain) [ 21 ], but was lost in the related E484K-positive eta VOI (also named B.1.525 in PANGOLIN and 21D in NextStrain) [ 26 ]. This evidence confirms that the E484K mutation, occurring in 64 out of the 800 clades reported as of March 2021 and hence being a dramatic example of convergent evolution [ 27 ], inevitably leads to full resistance to bamlanivimab [ 23 ] as well as to many other class 2 RBD-directed mAbs [ 28 ].…”

Section: Discovery Strategy and Preclinical Developmentsupporting

confidence: 64%

An overview of the preclinical discovery and development of bamlanivimab for the treatment of novel coronavirus infection (COVID-19): reasons for limited clinical use and lessons for the future

Tuccori

Convertino

Ferraro

et al. 2021

Expert Opinion on Drug Discovery

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Introduction : In the COVID-19 pandemic emergency, research has been oriented toward the development of therapies that could cure critically ill patients and treatments that can reduce the number of hospitalized patients, in order to ease the pressure on health-care systems. Bamlanivimab, developed from human convalescent plasma, was the first monoclonal antibody to become available for emergency use in several countries. Expectations related to its use in COVID-19 patients as a single agent have been largely disregarded, especially against E484K-carrying SARS-CoV-2 variants. Areas covered : In this drug discovery case history, the development of the drug is described starting from the identification and selection of the antibody, from the pre-clinical and clinical trials up to the post-authorization phase. Expert opinion : Bamlanivimab has shown some efficacy in patients with mild to moderate COVID-19. Initially approved as a monotherapy, due to poor efficacy it is currently only usable in combination with etesevimab. Pharmacokinetic limitations and mainly the onset of SARS-CoV-2 variants are the main reasons for this limited clinical use. The use in preventing hospitalization also has ethical limits related to the sustainability of care, especially if, considering similar effectiveness, bamlanivimab is compared with convalescent plasma.

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Section: Discovery Strategy and Preclinical Developmentsupporting

confidence: 64%

An overview of the preclinical discovery and development of bamlanivimab for the treatment of novel coronavirus infection (COVID-19): reasons for limited clinical use and lessons for the future

Tuccori

Convertino

Ferraro

et al. 2021

Expert Opinion on Drug Discovery

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“…Until December 2020, over thirty lineages were circulating inside the country without evidence of VOC and VOI importation. However, a lineage turnover accompanied the third epidemic peak during March and April 2021, involving the emergence of B.1 lineage descendants with high mutation accumulation (B.1.621 and the provisionally assigned B.1 + L249S + E484K) ( Laiton-Donato et al, 2021 ), as well as the introduction of the B.1.1.7, P.1 and VOI in some cities.…”

Section: Introductionmentioning

confidence: 99%

Characterization of the emerging B.1.621 variant of interest of SARS-CoV-2

Laiton‐Donato

Franco-Muñoz

Álvarez-Díaz

et al. 2021

Infection, Genetics and Evolution

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116

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SARS-CoV-2 genetic diversity has the potential to impact the virus transmissibility and the escape from natural infection- or vaccine-elicited neutralizing antibodies. Here, we report the emergence of the B.1.621 lineage, considered a variant of interest (VOI) with the accumulation of several substitutions affecting the Spike protein, including the amino acid changes I95I, Y144T, Y145S and the insertion 146 N in the N-terminal domain, R346K, E484K and N501Y in the Receptor Binding Domain and P681H in the S1/S2 cleavage site of the Spike protein. The rapid increase in frequency and fixation in a relatively short time in some cities that were near the theoretical herd immunity suggests an epidemiologic impact. Further studies will be required to assess the biological and epidemiologic roles of the substitution pattern found in the B.1.621 lineage.

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“…Remarkably, the genomic surveillance and laboratory studies with the emerging lineage B1+L249S+E484K identified simultaneously with the Mu variant in the same geographic region of Colombia, evidenced reduced neutralization of convalescent sera accompanied by a decline of cases associated with this variant, demonstrating that this lineage does not represent a concern for public health in Colombia [16][9]. Therefore, the escape of vaccine antibodies and the dramatic increase in cases associated with Mu in Colombia, even with a greater impact than the VOC Gamma, suggest that Mu can be classified as VOC, depending on the dispersion and global cases in the incoming months.…”

Section: Discussionmentioning

confidence: 99%

“…The spatiotemporal distribution of SARS-CoV-2 lineages circulating in Colombia between January and August 2021 was determined following the National Program for the Genomic Characterization of SARS-CoV-2 based on representativeness and virologic criteria for probabilistic sampling [3,8]. Then, we isolated the three most predominant SARS-CoV-2 lineages during this period, used to evaluate the titer of neutralizing antibodies by microneutralization assays (MN) as previously described [9],…”

Section: Methodsmentioning

confidence: 99%

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Low neutralizing antibody titers against the Mu variant of SARS-CoV-2 in BNT162b2 vaccinated individuals

Álvarez-Díaz

Muñoz²,

Tavera-Rodríguez

et al. 2021

Preprint

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SummaryBackgroundGlobal surveillance programs for the virus that causes COVID-19 are showing the emergence of variants with mutations in the Spike protein, including the Mu variant, recently declared a Variant of Interest (VOI) by the World Health Organization. Genomic and laboratory surveillance is important in these types of variants because they may be more infectious or less susceptible to antiviral treatments and vaccine-induced antibodies.ObjectivesTo evaluate the sensitivity of the Mu variant (B.1.621) to neutralizing antibodies induced by the BNT162b2 vaccine.Study designThree of the most predominant SARS-CoV-2 variants in Colombia during the epidemiological peaks of 2021 were isolated. Microneutralization assays were performed by incubating 120 TCDI50 of each SARS-CoV-2 isolate with five 2-fold serial dilutions of sera from 14 BNT162b2 vaccinated volunteers. The MN50 titer was calculated by the Reed-Muench formulaResultsThe three isolated variants were Mu, a Variant of Interest (VOI), Gamma, a variant of concern (VOC), and B.1.111 that lacks genetic markers associated with greater virulence. At the end of August, the Mu and Gamma variants were widely distributed in Colombia. Mu was predominant (49%), followed by Gamma (25%). In contrast, B.1.111 became almost undetectable. The evaluation of neutralizing antibodies suggests that patients vaccinated with BNT162-2 generate neutralizing antibody titers against the Mu variant at significantly lower concentrations relative to B.1.111 and Gamma.ConclusionsThis study shows the importance of continuing with surveillance programs of emerging variants as well as the need to evaluate the neutralizing antibody response induced by other vaccines circulating in the country against Mu and other variants with high epidemiological impact.HighlightsMu and Gamma variants represented 49% and 25% of cases in Colombia by August 2021.Increased proportion of SARS-COV-2 cases were mostly associated with Mu variant, despite being detected simultaneously with the VOC GammaThe Mu variant remarkably escapes from neutralizing antibodies elicited by the BNT162b2-vaccineLaboratory studies of neutralizing antibodies are useful to determine the efficacy of SARS-CoV-2 vaccines against VOC and VOI.

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Novel highly divergent SARS-CoV-2 lineage with the Spike substitutions L249S and E484K

Cited by 5 publications

References 14 publications

An overview of the preclinical discovery and development of bamlanivimab for the treatment of novel coronavirus infection (COVID-19): reasons for limited clinical use and lessons for the future

An overview of the preclinical discovery and development of bamlanivimab for the treatment of novel coronavirus infection (COVID-19): reasons for limited clinical use and lessons for the future

Characterization of the emerging B.1.621 variant of interest of SARS-CoV-2

Low neutralizing antibody titers against the Mu variant of SARS-CoV-2 in BNT162b2 vaccinated individuals

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