Effectiveness of Naturally Acquired and Vaccine-Induced Immune Responses to SARS-CoV-2 Mu Variant

SARS-CoV-2 Mu variant emerged in Colombia in 2021 and spread globally. In 49 serum samples from vaccinees and COVID-19 survivors in Colombia, neutralization was significantly lower (p<0.0001) for Mu than a parental strain and variants of concern. Only the Omicron variant of concern demonstrated higher immune evasion.

pathogenicity of Mu (1). Mu was later outcompeted by Delta and Omicron, and the number of Mu-related cases gradually decreased through the end of 2021 ( Figure 1).
Recent studies relying on data from spike-based pseudovirus testing suggested substantially lower neutralization of Mu compared with the parental B.1 virus in antiserum samples from persons in Japan and China who had received either the BNT162b2 (Pfizer-BioNTech, https://www.pfizer.com) or Sinovac (http://www.sinovac.com) vaccines or recovered from COVID-19 (2,3). Because of inherent limitations in pseudovirus-based systems for reproducing response variations based on natural infection (4), regional differences of immune responses (5), and different vaccines used in Colombia, we comparatively characterized the neutralization of Mu and VOCs using fully infectious viruses and serum samples from persons in Colombia. The study was approved by the Ethics Committee of the Universidad Industrial de Santander (protocol 4110) and by the Ethics Committee of the Charité-Universitätsmedizin Berlin (protocol EA2/031/22). All participants provided written informed consent.

Effectiveness of Naturally Acquired and Vaccine-Induced
Immune  Compared with other variants, neutralizing antibody titers from serum samples of both naturally infected persons and vaccinees were lower against Mu than against all VOCs except for Omicron (Figure 2, panels A and B). Therefore, our results provide strong evidence for immune evasion of the Mu VOI on the basis of results from robust neutralization testing using full viral isolates. Neutralization of Mu by vaccine-induced antibodies was significantly lower than for Beta (p = 0.0083 by Wilcoxon text), for which immune evasion properties led to the suspension of AstraZeneca usage in South Africa (6), and Gamma, which resulted in breakthrough infections in Latin America (7). Immune evasion of Mu is consistent with shared mutations in spike protein residues associated with immune evasion in Beta and Gamma, such as E484K (8). In addition, the mutation leading to the amino acid exchange R346K in Mu is known to be involved in the evasion of monoclonal antibody-mediated neutralization (9), and genomic exchanges occurring at 3 adjacent sites (Y144T, Y145S, and insertion of the amino acid asparagine [N] between spike residues 145 and 146) have been associated with the immune escape properties of Mu (10,11).   Figure 3). Of note, antibody responses in naturally infected persons supported past infection with strains bearing similarities to early SARS-CoV-2 isolates and the Gamma variant (Figure 2, panel D). Antibody reactivity in naturally infected persons was thus in concordance with the circulation of SARS-CoV-2 variants in South America during the time of sampling in late 2020 (12), supporting the robustness of our data. Our study was limited by different time points for sampling of vaccinees and the lack of information on natural infections altering immune responses in vaccinees. However, lack of detectable N-protein antibody responses and the absence of clinical records suggestive of COVID-19 infection in vaccinees immunized with spike-based vaccines supports the robustness of our data despite the vaccinees' unclear infection histories.

Conclusions
Our data highlight the importance of continuous monitoring for the emergence of new SARS-CoV-2 variants and strains and the timely identification of those variants with potential to evade naturally elicited and vaccine-derived immune responses, using local sampling specimens in the context of regional epidemiologic conditions. Moreover, our data confirmed the potential of Mu to partially evade immune responses, which may affect the efficacy of vaccination programs in southern America and other areas (7,13). Further studies are warranted to evaluate the pathogenicity of and cell-mediated immunity against Mu and the ability of immune responses associated with Mu to neutralize other SARS-CoV-2 variants. However, because vaccination boosters still provide some degree of protection against severe disease from Omicron (3,14), which shows more immunity evasion than Mu, vaccination will likely still provide protection against severe disease from Mu.

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incubation, an overlay containing DMEM with 1% FCS and 2% Avicell was added, and cells were further incubated for 3 d for Mu and 2 d for the other variants. The overlay medium was removed, and cells were fixated with 6% paraformaldehyde and stained with crystal violet. PRNT50endpoint titers were calculated using a logistic regression function in GraphPad prism6 (www.graphpad.com).

Antigenic Cartography
Antigenic cartography was done using the R package Racmacs   Vaccine  AZ2  204  41  154  79  64  77  13  129  64  AstraZeneca  AZ3 453 123 *AZ, AstraZeneca; PF, Pfizer; SVN, Sinovac †Because we followed the Colombian vaccination program, it was not possible to collect samples the same time after completing the recommended vaccination scheme and the subjects' age were variable.