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SARS-CoV-2 Lambda Variant Remains Susceptible to Neutralization by mRNA
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Vaccine-elicited Antibodies and Convalescent Serum
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Takuya Tada
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*
, Hao Zhou
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*
, Belinda M. Dcosta
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, Marie I. Samanovic
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, Mark J. Mulligan
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,
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and Nathaniel R. Landau
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**
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Affiliation:
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Department of Microbiology, NYU Grossman School of Medicine, New York, NY, USA.
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NYU Langone Vaccine Center and Department of Medicine, NYU Grossman School of
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Medicine, New York, NY, USA.
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*Contributed equally to this study
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**Corresponding author:
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Nathaniel R. Landau, Ph.D.
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NYU Grossman School of Medicine
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430 East 29th Street, Alexandria West Building, Rm 509, New York, NY 10016
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Email: nathaniel.landau@med.nyu.edu
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Phone: (212) 263-9197
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was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission.
The copyright holder for this preprint (whichthis version posted July 3, 2021. ; https://doi.org/10.1101/2021.07.02.450959doi: bioRxiv preprint
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Abstract
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The SARS-CoV-2 lambda variant (lineage C.37) was designated by the World Health
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Organization as a variant of interest and is currently increasing in prevalence in South
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American and other countries. The lambda spike protein contains novel mutations within
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the receptor binding domain (L452Q and F490S) that may contribute to its increased
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transmissibility and could result in susceptibility to re-infection or a reduction in protection
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provided by current vaccines. In this study, the infectivity and susceptibility of viruses with
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the lambda variant spike protein to neutralization by convalescent sera and vaccine-
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elicited antibodies was tested. Virus with the lambda spike had higher infectivity and was
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neutralized by convalescent sera and vaccine-elicited antibodies with a relatively minor
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2.3-3.3-fold decrease in titer on average. The virus was neutralized by the Regeneron
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therapeutic monoclonal antibody cocktail with no loss of titer. The results suggest that
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vaccines in current use will remain protective against the lambda variant and that
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monoclonal antibody therapy will remain effective.
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was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission.
The copyright holder for this preprint (whichthis version posted July 3, 2021. ; https://doi.org/10.1101/2021.07.02.450959doi: bioRxiv preprint
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Introduction
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The continued emergence of severe acute respiratory syndrome coronavirus 2 (SARS-
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CoV-2) variants with increased transmissibility poses concerns with regards to re-
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infection and diminished vaccine protection. The spread of variants also raises concerns
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regarding potential decrease in the efficacy of anti-spike protein monoclonal antibody
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therapy that has been shown to reduce disease symptoms and the rate of hospitalization
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.
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Variants B.1.351 (Beta), B.1.617.2 (Delta), B.1.427/B.1.429 (Epsilon), B.1.526 (Iota), and
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B.1.1.248 (Gamma) encode spike proteins with L452R, E484K, E484Q mutations in the
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spike protein receptor binding domain (RBD) that provide a degree of resistance to
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neutralization by serum antibodies of vaccinated and convalescent individuals
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.
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The lambda variant is prevalent in Peru and is increasing in prevalence in neighboring
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Argentina, Ecuador, Chile and Brazil
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. In June, the World Health Organization designated
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the variant (C.37 lineage) a variant of interest
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. The variant spike protein is characterized
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by a novel deletion and mutations (Δ246-252, G75V, T76I, L452Q, F490S, T859N),
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L452Q and F490S of which are novel mutations in the RBD.
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The increasing prevalence of the lambda variant raises concerns as to whether the
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current vaccines will contain its spread. In this study, we tested the sensitivity of viruses
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with the lambda variant spike protein to neutralization by convalescent sera, vaccine-
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elicited antibodies and Regeneron therapeutic monoclonal antibodies REGN10933 and
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REGN10987.
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was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission.
The copyright holder for this preprint (whichthis version posted July 3, 2021. ; https://doi.org/10.1101/2021.07.02.450959doi: bioRxiv preprint
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Results
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Lambda spike protein-pseudotyped lentiviruses. The lambda spike protein has
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mutations L452Q and F490S in the RBD, and G75V, T76I mutations and 246-252
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deletions in the N-terminal domain (NTD) (Figure S1A). To analyze antibody
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neutralization of the variant spike protein, we generated expression vectors for the variant
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and its constituent mutations and used these to produce pseudotyped lentiviral virions
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encoding GFP and nano-luciferase reporters. The use of such pseudotypes to determine
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antibody neutralizing titers has been shown to yield results consistent with those obtained
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with the live virus plaque reduction neutralization test
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. Immunoblot analysis of
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transfected pseudotype virus producer cells and virus-containing supernatants showed
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that the variant spike proteins were well expressed, proteolytically processed and
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incorporated into lentiviral virions at a level similar to that of the parental D614G spike
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protein (Figure S1B). Analysis of the infectivity of the pseudotyped viruses on ACE2.293T
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cells, normalized for particle number, showed that the lambda spike protein increased
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infectivity by 2-fold. The increase was due to the L452Q mutation; the other mutations
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(G75V-T76I, F490S, T859N and D246-252) had no significant effect on infectivity (Figure
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S1C).
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Neutralization of the lambda variants by convalescent sera and vaccine-elicited
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antibody. Analysis of serum specimens from convalescent patients who had been
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infected prior to the emergence of the variants showed that viruses with the lambda
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variant spike protein were 3.3-fold resistant to neutralization by convalescent sera as
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was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission.
The copyright holder for this preprint (whichthis version posted July 3, 2021. ; https://doi.org/10.1101/2021.07.02.450959doi: bioRxiv preprint
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compared to neutralization of virus with the parental D614G spike, similar to the 4.9-fold
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resistance of the B.1.351 variant to neutralization (Figure 1A).
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Analysis of serum samples from individuals vaccinated with Pfizer BNT162b2 showed
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that virus with the lambda spike was about 3-fold resistant to neutralization (Figure 1B).
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Serum samples from individuals vaccinated with the Moderna mRNA-1273 vaccine were
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on average 2.3-fold resistant to neutralization (Figure 1C). The resistance was attributed
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to the L452Q and F490S mutations in the lambda spike protein (Figure 1A, B, C).
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L452Q increases spike protein affinity for ACE2. N501Y and L452R mutations in the
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RBD of earlier variants increase spike protein affinity for ACE2, an effect that most likely
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is a primary contributor to the increased transmissibility of the alpha, beta and delta
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variants
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. To determine whether the lambda variant has an increased affinity for ACE2,
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we used a sACE2 neutralization assay in which pseudotyped virions were incubated with
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different concentrations of sACE2 and the infectivity of the treated virions was measured
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on ACE2.293T cells. The results showed that the lambda spike caused a 3-fold increase
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sACE2 binding. The increase was caused by the L452Q mutation and was similar to the
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increase provided by the N501Y mutation
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(Figure 1D). The F490S mutation did not
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have a detectable effect on sACE2 binding. The findings suggest that L452Q, like L452R
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in the delta variant, increases virus affinity for ACE2, likely contributing to increased
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transmissibility.
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was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission.
The copyright holder for this preprint (whichthis version posted July 3, 2021. ; https://doi.org/10.1101/2021.07.02.450959doi: bioRxiv preprint