Disproportionate number of SARS-CoV-2 breakthrough infections are caused by variants of concern

A study conducted by researchers in the United States has shown that among twenty patients with breakthrough infection following vaccination against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) – the agent that causes coronavirus disease 2019 (COVID-19) – all of the infections were caused by variants of concerns.

The team says that compared with SARS-CoV-2 cases circulating in the general population of Washington State over the same time period, variants of concern were significantly enriched in breakthrough infections detected at University of Washington medical hospitals.

When the researchers compared individual mutations in the viral spike protein between breakthrough and control cases, they identified a single mutation – W258L – that was 15.22-fold enriched in the breakthrough cases.

The spike protein is the main structure SARS-CoV-2 uses to infect host cells and is the primary target of neutralizing antibodies following vaccination or infection.

However, SARS-CoV-2 is now defined by a range of variants containing spike mutations that have been shown to increase transmissibility and to resist neutralization by infection- or vaccine-elicited antibodies.

The W258L mutation occurs in the so-called “N-terminal domain (NTD) antigen supersite” of the spike protein, rather than the spike receptor-binding domain (RBD), where most spike mutations that confer neutralization resistance are found.

“The impact of NTD alterations in antibody neutralization efficiency is largely unstudied,” says the team from the University of Washington and the Fred Hutchinson Cancer Research Center in Seattle.

Pavitra Roychoudhury and colleagues suggest that future studies of antibody neutralization should include NTD mutations such as W258L.

They also suggest that continued surveillance of post-vaccine breakthrough infections may help identify variants of concern for inclusion in new or booster COVID-19 vaccines.

A pre-print version of the research paper is available on the medRxiv* server, while the article undergoes peer review.

Concerns surrounding the SARS-CoV-2 variants that have emerged

Most of the COVID-19 vaccines that have been approved for emergency use contain a recombinant spike protein based on the original Wuhan-1 strain that was sequenced in January 2020.

The most widely used vaccines – Moderna’s mRNA-1273 and Pfizer-BioNTech’s BNT162b2 – have exhibited efficacies of up to 95% in preventing infection and up to 100% efficacy in preventing severe disease.

However, SARS-CoV-2 is now defined by a range of variants that harbor distinctive mutations in the spike protein.

“Variants of concern (VOCs) are those strains that show evidence of increased transmissibility, more severe disease, reduced neutralization by antibodies elicited by past infection or vaccination, reduced efficacy of treatments, or failures in diagnostic detection,” says Roychoudhury and colleagues.

Studies have shown that four VOCs originally identified in Brazil (P.1), South Africa (B.1.351), and California (B.1.427 and B.1.429) are less effectively neutralized by convalescent and post-vaccination sera.

However, “the clinical implications for post-vaccination breakthrough infection remain largely unknown,” writes the team.

What did the researchers do?

The researchers examined SARS-CoV-2 genomes isolated from 20 individuals aged 26 to 65 years (median age 43 years) who had been diagnosed with vaccine breakthrough infection between February 23rd and April 27th, 2021. The results were compared with those of 5,174 contemporaneous samples collected in Washington over the same time interval.

Cases of breakthrough post-vaccination infection were defined as patients who were vaccinated with two doses of the Pfizer-BioNTech or Moderna vaccine who subsequently tested positive for SARS-CoV-2 infection by reverse-transcription polymerase chain reaction (RT-PCR) more than two weeks following the second dose.

What did the study find?

All 20 (100%) vaccine breakthrough cases were classified as VOCs, eight (40%) of which were the UK B.1.1.7 variant, one (5%) was the South African B.1.351 variant, two (10%) were the B.1.427 (California) lineage, 8 (40%) were the B.1.429 (California) variant, and one (5%) was the P.1 (Brazil) lineage.

During the same time interval, 68% of the Washington cases were classified as VOCs, 31% of which were B.1.1.7, 1% were B.1.351, 3% were B.1.427, 27% were B.1.429, and 7% were P.1.

“Overall, variants of concern were proportionally over-represented in breakthrough cases,” says Roychoudhury and the team.

Overall, the frequency of VOCs in the breakthrough cases increased 1.47-fold compared with the control group, with 3.38-fold, 1.51-fold, and 1.29-fold increases observed for B.1.427, B.1.429, and B.1.1.7, respectively.

In vitro studies of antibody neutralization residence should include NTD mutations

When the team compared the individual mutations in the spike protein between the breakthrough and control groups, a single mutation – W258L – that lies outside of the spike RBD in the “NTD antigen supersite” was found to be 5.22-fold enriched in the breakthrough cases. No other mutations showed significant enrichment in the breakthrough group.

“Our data suggest that in vitro studies of antibody neutralization residence should include NTD alterations such as W258L,” write the researchers.

“Continued surveillance of post-vaccine breakthrough cases may help target variants of concern for inclusion in new or booster SARS-CoV-2 vaccines,” they conclude.

*Important Notice

medRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.

Journal reference:
Sally Robertson

Written by

Sally Robertson

Sally first developed an interest in medical communications when she took on the role of Journal Development Editor for BioMed Central (BMC), after having graduated with a degree in biomedical science from Greenwich University.

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