Science Spotlight

SARS-CoV-2 variants of concern break through vaccination barriers

From the University of Washington and the Fred Hutch Vaccine and Infectious Disease Division

Amidst the SARS-CoV-2 pandemic, several vaccines were rapidly developed and granted emergency use authorization to prevent infection and spread of COVID-19 disease. The two most widely implemented mRNA vaccines are up to 95% effective at preventing clinical cases and up to 100% effective at preventing severe disease. However, these vaccines were designed to recognize a SARS-CoV-2 recombinant spike protein derived from a viral strain isolated in January 2020 in Wuhan, but rapidly emerging SARS-CoV-2 variants more than a year later, may be distinct enough from the original spike protein to allow for escape from immune responses elicited from the existing vaccines. Despite the effectiveness of current vaccines against the initial strains of SARS-CoV-2, novel, these highly pathogenic variants of concern (VOC) could overcome vaccine-induced immunity and cause infection, disease, or viral transmission.

As of May 2021, the U.S. SARS-CoV-2 Interagency Group reported 4 VOC that are less effectively neutralized in vitro by the antibodies produced by vaccinated or naturally infected individuals. However, the potential for real-life, post-vaccination breakthrough infections by these four strains is undefined. Dr. Pavitra Roychoudhury, along with colleagues from the University of Washington Virology Lab and the Fred Hutch Vaccine and Infectious Disease Division, analyzed the SARS-CoV-2 viruses collected from 20 individuals vaccinated with either Pfizer or Moderna who had breakthrough infections—15 of whom reported mild symptoms— between February and April 2021. By performing whole viral genome sequencing of nasal swabs collected from these patients, they determined that all breakthrough infections were caused by VOC. They recently published this work in Clinical Infectious Diseases.

“Our lab (UW Virology) has been sequencing SARS-CoV-2 since the start of the pandemic. We have deposited over 20,000 sequences to public repositories, and a large proportion of WA state’s sequences have come from our lab. In late Feb 2021, we started to receive requests to sequence samples from vaccinated individuals (mostly healthcare workers) who had tested positive for SARS-CoV-2. By late April, we had hit 20 such cases where we could confirm vaccination status,” Dr. Roychoudhury explained. Notably, while VOC caused 100% of breakthrough infections, VOC only accounted for 68% of Washington cases in unvaccinated people during the same time period. This discrepancy suggests that the 100% VOC incidence in breakthrough infections was not random and that VOC disproportionately cause infections (but not severe disease) in vaccinated people. Additionally, the incidence of some individual VOC were even more highly overrepresented in breakthrough infections compared to infections in unvaccinated people, demonstrating that some VOC may be more transmissible despite vaccination. The authors followed up on this finding by asking if a specific single mutation in the spike protein was overrepresented in breakthrough versus unvaccinated groups. Although a specific single mutation was over 15-fold enriched in breakthrough cases, it was present in only two people. This demonstrates that multiple single mutations could lead to vaccine immunity-evading VOC, but a larger sample size is needed to identify such mutations.

Viral lineages assigned to each breakthrough cases in vaccinated people (top) vs the overall distribution of viral lineages from samples collected at the same time from unvaccinated people in Washington (bottom).
Viral lineages assigned to each breakthrough cases in vaccinated people (top) vs the overall distribution of viral lineages from samples collected at the same time from unvaccinated people in Washington (bottom). Figure provided by Pavitra Roychoudhury, from the original publication.

Although VOC are sometimes able to escape vaccine immunity and cause infection, it is important to remember that vaccines still effectively prevent severe disease. They were also struck by the relatively low Ct values (high viral loads) among breakthrough samples, “which seemed to run counter to predictions at the time that all vaccine breakthroughs would have low viral loads. Yet, none of the cases required hospitalization and there were no deaths, showing that vaccines are effective and they work as advertised! However, the viral loads tell us that these cases, even though mild, could result in onward transmission and it underscores the need to continue sequencing and surveillance of all post-vaccination breakthrough cases, not just the ones that lead to hospitalization,” Dr. Roychoudhury explained.

These findings have critical implications for ongoing pandemic control. Although breakthrough infections in vaccinated people are relatively rare, these events may increase as VOC increasingly circulate and acquire mutations that further evade neutralization by vaccine-elicited antibodies. This discouraging result means that additional, targeted boosted vaccines may need to be developed and administered to maintain protection from SARS-CoV-2 in vaccinated people. Furthermore, additional methods to prevent transmission, such as masking and physical distancing, may be necessary even in vaccinated groups.

In the future, continued surveillance of breakthrough infection viral strains is important to inform the need for additional SARS-CoV-2 vaccines. Additionally, the breakthrough infections sequenced in this study were identified primarily because of active hospital employee surveillance programs or after self-reported symptoms in vaccinated individuals; therefore, the incidence of asymptomatic breakthrough infection in the public could be underestimated in this work, and further studies implementing random community sampling could identify more breakthrough infections. “Going forward, we will continue to sequence as many positive samples as we can, which will likely include many post-vaccination infections. The genomic data we gather will be crucial for outbreak tracking, identification of any future variants of concern, and for potential redesign of vaccines in the future,” said Dr. Roychoudhury.

McEwen AE, Cohen S, Bryson-Cahn C, Liu C, Pergam SA, Lynch J, Schippers A, Strand K, Whimbey E, Mani NS, Zelikoff AJ, Makarewicz VA, Brown ER, Bakhash SAM, Baker NR, Castor J, Livingston RJ, Huang ML, Jerome KR, Greninger AL, Roychoudhury P. Variants of concern are overrepresented among post-vaccination breakthrough infections of SARS-CoV-2 in Washington State. Clinical Infectious Diseases.  2021 Jun 24;ciab581.doi: 10.1093/cid/ciab581. 

UW/Fred Hutch Cancer Consortium members Steven Pergam, Keith Jerome, and Catherine Liu contributed to this work.

This work was supported by the National Institutes of Health and the UW-Fred Hutch CFAR New Investigator Award.