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 COVID-19 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’ (Odds Ratio = 18.2, 95% CI: 7.53-48.7; p=1.465x10-18). In the recent COVID-19 surge in India, an NTD deletion (ΔF157/R158) increased over 10-fold in prevalence from February 2021 (1.1%) to April 2021 (15%). During the recent surge in Chile, an NTD deletion (Δ246-253) increased rapidly over 30-fold in prevalence from January 2021 (0.86%) to April 2021 (33%). Strikingly, these simultaneously emerging deletions associated with surges in different parts of the world both occur at an antigenic supersite that is targeted by neutralizing antibodies. Finally, we generated clinically annotated SARS-CoV-2 whole genome sequences and identified deletions within this NTD antigenic supersite in a patient with vaccine breakthrough infection (Δ156-164) and other deletions from unvaccinated severe COVID-19 patients that could represent emerging deletion-prone regions. Overall, the expanding repertoire of Spike protein 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 SARS-CoV-2 genomes at a larger scale globally and to mandate a public health policy for transparent reporting of relevant clinical annotations (e.g. vaccination status) in order to aid the development of comprehensive therapeutic strategies.

Genomic, immunological, and clinical analysis of COVID‐19 vaccine breakthrough infections in Beijing, China

“…In addition, some kinds of variants not only have decreased susceptibility to antivirals and monoclonal antibodies but also have reduced neutralizing capacity with sera from convalescent patients and vaccinated individuals. Many key amino acid mutations on the Spike protein, especially on the receptor‐binding domain (RBD) and the furin cleavage site may result in varying degrees of immune escape 12,13 . Therefore, it is highly possible for variants to cause breakthrough infections.…”

On the origin of Omicron’s unique Spike gene insertion

“…To understand which SARS-CoV-2 mutations correlate with COVID-19 test positivity, we identified "surge-associated mutations" using genomic data from GISAID (5,781,715 sequences from 203 countries/territories between December 2019 to December 2021) and epidemiology data from Our World in Data (OWID) 73 as described in our previous study. 28 A mutation is considered "surge associated" if it satisfies the following criteria: (1) it is present in at least 100 SARS-CoV-2 sequences in GISAID; (2) in a period of three consecutive months during which there was a monotonic increase of PCR positivity by at least 5% in a given country, the prevalence of the mutation in that country also monotonically increased by at least 5%.…”

Quantifying the immunological distinctiveness of emerging SARS-CoV-2 variants in the context of prior regional herd exposure

“…Perhaps the most obvious and striking examples of such "sequence loss" for SARS-CoV-2 are the in-frame deletions in the Spike protein N-terminal domain (NTD) which cluster around known binding sites for neutralizing antibodies. 19,20 Host immunity against SARS-CoV-2 is largely derived from two sources: vaccination and prior infection. All authorized COVID-19 vaccines utilize the Spike protein sequence from the ancestral Wuhan strain, with a slight modification (substitution of two prolines at positions 986-987) to stabilize the pre-fusion state of the protein product.…”

“…Perhaps the most obvious and striking examples of such “sequence loss” for SARS-CoV-2 are the in-frame deletions in the Spike protein N-terminal domain (NTD) which cluster around known binding sites for neutralizing antibodies. 19,20…”