Antigenic minimalism of SARS-CoV-2 is linked to surges in COVID-19 community transmission and vaccine breakthrough infections

“Abstract: The raging COVID-19 pandemic in India and reports of ‘vaccine breakthrough infections’ globally have raised alarm mandating the characterization of the immuno-evasive features of SARS-CoV-2. Here, we systematically analyzed over 1.3 million SARS-CoV-2 genomes from 178 countries and performed whole-genome viral sequencing from 53 COVID19 patients, including 20 vaccine breakthrough infections. We identified 116 Spike protein mutations that increased in prevalence during at least one surge in SARS-CoV-2 test positivity in any country over a three-month window. Deletions in the Spike protein N-terminal domain (NTD) are highly enriched for these ‘surge-associated mutations’… Overall, the expanding repertoire of NTD deletions throughout the pandemic and their association with case surges and vaccine breakthrough infections point to antigenic minimalism as an emerging evolutionary strategy for SARS-CoV-2 to evade immune responses. This study highlights the urgent need to sequence viral genomes at a larger scale globally and to mandate that sequences are deposited with more granular and transparent clinical annotations to ensure that therapeutic development keeps pace with the evolution of SARS-CoV-2.

Introduction: The ongoing COVID-19 pandemic has infected around 160 million people and killed more than 3 million people worldwide, as of May 20211. The continual emergence of SARS-CoV-2 variants with increased transmissibility and capacity for immune escape, such as B.1.1.7 (‘UK variant’) and P.1 (‘Brazilian variant’), threatens to prolong the pandemic through devastating outbreaks such as the one currently being witnessed in India …

Results: … This suggests that the surging SARS-CoV-2 variants in India and Chile may have acquired NTD deletions in the antigenic supersite in order to evade neutralizing antibodies and achieve immune escape. From a viral evolution standpoint, these observations raise the question of whether SARS-CoV-2 is expanding its repertoire of deletable regions in the Spike protein as the pandemic progresses.       

Discussion: The worldwide mass vaccination campaign has had a profound impact on COVID-19 transmission. However, certain variants are less susceptible to neutralization by sera from vaccinated individuals and convalescent COVID-19 patients. Such findings motivate the need to vigilantly track the emergence of new variants and to determine whether they are likely to cause surges or vaccine breakthrough infections… Thus, a concerted evolution of strategically placed deletions and substitutions appear to be conferring SARS-CoV-2 with the fitness to evade immunity and achieve efficient transmission between hosts.”