In a recent brief report published in the prestigious New England Journal of Medicine, researchers from the Rockefeller University in New York described a case of two fully vaccinated individuals in whom they found subsequent breakthrough infections with variants of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), carrying a number of substitutions of interest.
Even though vaccines and antibody treatments gave us an upper hand in our fight against the coronavirus disease 2019 (COVID-19), these strategies are aimed at the SARS-CoV-2 spike glycoprotein. Consequently, the emergence of viral variants (most notably in the S gene) jeopardizes their continued efficacy.
Such concerns have resulted in an impetus to boost testing endeavors and viral DNA sequencing in infected individuals to fully understand the transmissibility pattern, virulence traits, and the ability of variants to circumvent the protection offered by currently available vaccines.
In recent months, there was a worrying increase in viral variants in the New York City (United States), with the newly identified B.1.526 variant accounting for 42.9% of all new cases. The already familiar United Kingdom or UK variant (B.1.1.7) accounting for 26.2% of new cases as of March 30, 2021.
Consequently, researchers from the Rockefeller University in New York, led by Dr. Ezgi Hacisuleyman, decided to address two areas of concern related to the aforementioned variants: their ability to evade vaccine-induced immunity and to result in asymptomatic infection (promoting, in turn, viral spread).
A deep dive into viral sequences
A cohort of 417 individuals who had received the second dose of either BNT162b2 (Pfizer–BioNTech) or mRNA-1273 (Moderna) vaccine at least two weeks prior to this study was tested in the period between January 21 and March 17, 2021, with continued weekly testing following the first one.
More specifically, serial polymerase chain reaction (PCR) testing of saliva samples has been conducted. The viral load per milliliter of saliva has been calculated using chemically inactivated SARS-CoV-2 spiked into saliva at various dilutions.
Furthermore, the researchers pursued reverse transcription of RNA samples and targeted sequencing, as well as neutralization assays with pseudotyped replication-defective human immunodeficiency virus type 1 modified with SARS-CoV-2 spike protein. Whole viral RNA genome sequencing has also been pursued in order to observe the repertoire of mutations fully.
SARS-CoV-2 variants of likely clinical importance
In the tested cohort, there were two women with vaccine breakthrough infections, and their clinical symptoms related to COVID-19 were observed 19 and 36 days after receiving the second dose in Patient 1 and Patient 2, respectively.
Both patients had histories in line with clinical response to a provided vaccine boost, while high titers of neutralizing antibodies were observed shortly after developing symptoms in Patient 1.
In short, both patients tested positive on saliva-based PCR, and subsequent viral sequencing demonstrated SARS-CoV-2 variants of likely clinical importance – including E484K mutation in one of them and three mutations (i.e., D614G, T95I, and del142–144) in both of them.
Rapid identification of sequence variants by utilizing targeted PCR amplification revealed that neither sequence exactly fit any known clade. Moreover, whole viral genome sequencing demonstrated several additional (and newly described) substitutions in the S gene.
An evolutionary arms race
The genetic substitutions found in this study may decrease the sensitivity of SARS-CoV-2 to convalescent serum and may harbor unique non-coding changes, which lends support to advancing a new vaccine booster (but also a so-called pan-coronavirus vaccine) in order to bestow increased protection against viral variants.
“During this critical period, our data support the need to maintain layers of mitigation strategies, including serial testing of asymptomatic persons, open publication and analysis of vaccination and infection databases (such as those accruing data in New York City), and rapid sequencing of SARS-CoV-2 RNA obtained from a variety of high-risk persons”, say study authors.
At the same time, these observations highlight the significance of the ongoing contest between immunization strategies and the natural selection of prospective viral escape mutants. In other words, the evolutionary arms race between the virus and our vaccines should not be taken lightly.
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