Variants in the SARS-CoV-2 viral sequence may pose a risk for the development of COVID-19 despite successful vaccination, according to authors of a brief report published in the New England Journal of Medicine.

Although current vaccines and antibody therapies target the viral spike protein, viral variants, especially in the S gene of SARS-CoV-2, have raised concerns regarding trends in viral transmissibility, virulence, and how well these variants could potentially evade current vaccines.

A team of investigators, aiming to better understand the capability of SARS-CoV-2 variants to evade current vaccines and the cause of asymptomatic infection, collected saliva samples from 417 employees and students at Rockefeller University in New York who had received the second dose of either the BNT162b2 (Pzfizer-BioNTech) vaccine or the mRNA-1273 (Moderna) vaccine at least 2 weeks before baseline.

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Following sequencing analyses, 2 participants tested positive for SARS-CoV-2 infection and subsequently developed COVID-19-related symptoms despite complete vaccination.

The first patient was a healthy 51-year-old woman who received her first dose of the mRNA-1273 vaccine on January 21, 2021, and her second dose on February 19, 2021. Following her second dose, she developed flu-like muscle aches that resolved the following day. However, 19 days after receiving her second dose, she presented with a sore throat, congestion, and headache. On day 20 following her second dose, the patient lost her sense of smell. She tested positive for SARS-CoV-2 RNA on day 19, and her symptoms resolved gradually over the subsequent week.

The second patient was a healthy 65-year-old woman who received her first dose of the BNT162b2 vaccine on January 19, 2021, and her second dose on February 9, 2021. She experienced pain in the arm in which the vaccine was administered that lasted for 2 days. Her unvaccinated partner tested positive for SARS-CoV-2 on March 3, and on March 16 the patient developed fatigue, sinus congestion, and headache. On March 17, upon symptom exacerbation, she tested positive for SARS-CoV-2 RNA, 36 days after receiving her second vaccine dose. Her symptoms plateaued and started to resolve on March 20.

RNA obtained from saliva samples from both patients was sequenced after reverse transcription and targeted polymerase chain reaction amplification of the S gene. Test results confirmed several differences between the patients’ sequences and the original sequence that was first identified in Wuhan, China. Several of these mutations were of possible clinical concern: E484K in patient 1 and S477N mutation in patient 2. Both patients also had a D614G mutation.

The investigators performed additional RNA testing on saliva samples from patient 1 and found that the infection was caused by a SARS-CoV-2 variant “that is related to but distinct from the known variants of concern,” namely the B.1.1.7 variant first identified in the United Kingdom and the B.1.526 variant first identified in New York City.  After testing of a serum sample from patient 1 to measure its effectiveness against the wild-type virus, the E484K mutant (which is associated with a commonly elicited class of neutralizing antibodies), and the B.1.526 variant, they found that the serum “was equally effective in each,” suggesting that “antibody response in patient 1 recognized these variants but was nonetheless insufficient to prevent a breakthrough infection.”

“These observations in no way undermine the importance of the urgent efforts being taken at the federal and state levels to vaccinate the US population,” the investigators noted, adding that the findings support efforts to advance both a new vaccine booster and a pancoronavirus vaccine.

“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 … and rapid sequencing of SARS-CoV-2 RNA obtained from a variety of high-risk persons,” they wrote.

Disclosure: Some study authors declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of authors’ disclosures.


Hacisuleyman E, Hale C, Saito Y, et al. Vaccine breakthrough infections with SARS-CoV-2 variants. N Engl J Med. Published online April 21, 2021. doi: 10.1056/NEJMoa2105000