By Sam Rydberg-Cox, Winter 2021.

The world changed last March when the COVID-19 pandemic completely altered day to day life in the United States and around the world. Since then, people have been working from home, students have been learning on Zoom, and friends have gone months without seeing each other in person. Everyone has yearned for an end to the era of social distancing. When the Pfizer-BioNTech and Moderna COVID-19 vaccines were found to be safe and extremely effective[1,2] and received Emergency Use Authorization from the FDA in December, these vaccines provided a glimmer of home; the end to the pandemic was in sight. However, the virus that causes COVID-19, SARS-Cov-2, is mutating, therefore instilling uncertainty surrounding the vaccine’s efficacy.

The Pfizer-BioNTech and Moderna COVID-19 vaccines use groundbreaking mRNA technology. After the SARS-Cov-2 RNA was sequenced in early January 2020, BioNTech and Moderna each used this sequence to create a slightly altered version of this mRNA molecule that encodes the SARS-Cov-2 spike protein as a transmembrane-anchored protein.[3] The vaccines consist of this mRNA molecule encased in a lipid nanoparticle. When someone receives the vaccine, the lipid capsule releases the mRNA molecule into cells. The mRNA is then translated by budded ribosomes on the rough endoplasmic reticulum, therefore forming a transmembrane spike protein that is exported to the cell membrane and displayed on the cell surface.[1] The immune system can then recognize this spike protein as a foreign molecule and develops an immune response to it. Therefore, if a vaccinated individual is infected with SARS-Cov-2, the body will be able to recognize the spike protein on the surface of the virus and fight it. While these vaccines may seem like silver bullets for stopping the pandemic, SARS-Cov-2 can mutate such that the immune response caused by the vaccines is less effective. 

Each time a living thing reproduces, it can randomly mutate. When there is a selective pressure on an organism, new mutations could provide the organism with a survival or reproductive advantage. Therefore, any organism with an advantageous mutation would be more likely to survive and reproduce than other organisms of the same species. Over the course of many generations, all organisms in this species without this advantageous trait would die off, and only mutated organisms would remain. This process is called natural selection. Even though viruses aren’t technically living things, SARS-Cov-2 undergoes natural selection. 

The vaccines could be a selective pressure on SARS-Cov-2. Mutations in the spike protein could lead to a strain of SARS-Cov-2 that is somewhat resistant to the immune response developed from receiving a mRNA COVID-19 vaccine. Dr. Paul Bieniasz, a Howard Hughes Investigator at the Rockefeller University, told NPR that he believes the time between the first and second doses of the vaccine could “serve as a sort of a breeding ground for the virus to acquire new mutations.”[4] During this time, the vaccine provides a selective pressure on the virus, therefore fostering an environment in which mutations that confer resistance are likely to persist.

Various studies have investigated the potential for these kinds of mutations. Drs. David A. Kennedy and Andrew F. Read advocated for sequencing SARS-Cov-2 samples taken from vaccine clinical trial participants in order to screen for new mutants that might be resistant to the vaccine.[5] Another study has found deletions in the spike protein in immunocompromised patients with persistent COVID-19 infection; these deletions confer resistance to neutralizing antibodies.[6] Deletions are especially dangerous mutations because they cause widespread changes in the amino acid sequence of the spike protein. The new spike protein would be significantly different from the spike protein encoded by the mRNA molecules in the Pfizer-BioNTech and Moderna COVID-19 vaccines. Therefore, the immune response generated by these vaccines is perhaps less able to fight a strain of SARS-Cov-2 that has a deletion in the spike protein. 

Mutant strains of SARS-Cov-2 are already emerging. In the United Kingdom, a new variant known as B.1.1.7 has mutations (including deletions) in the spike protein, and is associated with increased transmissibility and risk of death, but none of its mutations confer vaccine resistance.[7] The new variant from South Africa known as B.1.351 has 10 mutations in the spike protein that confer some resistance to the Moderna vaccine, but the vaccine is still effective enough to fight this mutant.[8] There is also evidence that the P.1 variant originating in Brazil has some mutations in the spike protein that confer some resistance to the antibodies generated by the vaccines.[9]

However, no widespread mutant has been identified yet that is completely resistant to any of the mRNA vaccines. A mutant that is able to avoid vaccine-induced immunity is called an escape mutant. Currently, there is no evidence that an escape mutant is evolving. In order for an escape mutant to evolve, the mutated spike protein would have to be different from the original spike protein in hundreds of locations. However, due to the nature of the virus, experts do not believe this will happen.[9] In addition, while the vaccine is still effective against the B.1.351 mutant, Moderna is already working on a booster shot to induce an additional immune response against this mutant.[8] Because of the versatility of the mRNA vaccine technology, Moderna and Pfizer-BioNTech will simply be able to adjust the mRNA sequences in the vaccines according to the mutated sequences to fight future vaccine-resistant mutants if they do emerge. 

 

While mutant strains of SARS-Cov-2 that have some resistance to the Pfizer-BioNTech and Moderna mRNA vaccines are developing, these mutants are unlikely to impact the efficacy of these vaccines for ending the COVID-19 pandemic. As long as as many people as possible receive the vaccine, maintain social distancing, and wear masks, the COVID-19 pandemic will, after many tumultuous months, finally come to an end. 

 

[1] Polack, Fernando P., et al. 2020. “Safety and Efficacy of the BNT162b2 mRNA Covid-19 Vaccine.” The New England Journal of Medicine 383, no. 27 (December): 2603-2615. doi:10.1056/NEJMoa2034577.

[2] Baden, Lindsey R., et al. 2021. “Efficacy and Safety of the mRNA-1273 SARS-CoV-2 Vaccine.” The New England Journal of Medicine 384, no. 5 (February): 403-416. doi:10.1056/NEJMoa2035389.

[3] Corbett, Kizzmekia S., et al. 2020. “SARS-CoV-2 mRNA Vaccine Development Enabled by Prototype Pathogen Preparedness.” Biorxiv (June). https://doi.org/10.1101/2020.06.11.145920.

[4] Harris, Richard. 2021. “COVID-19 Vaccines Could Add Fuel To Evolution Of Coronavirus Mutations.” NPR (February). https://www.npr.org/sections/health-shots/2021/02/10/965940914/covid-19-vaccines-could-add-fuel-to-evolution-of-more-coronavirus-mutations

[5] Kennedy, David A. and Read, Andrew F. 2020. “Monitor for COVID-19 vaccine resistance evolution during clinical trials.” PLoS Biology 18, no. 11 (November): e3001000. doi:10.1371/journal.pbio.3001000.

[6] McCarthy, Kevin R., et al. 2021. “Recurrent deletions in the SARS-CoV-2 spike glycoprotein drive antibody escape.” Science (February). DOI: 10.1126/science.abf6950.

[7] Wu, Kai et al. 2021. “mRNA-1273 vaccine induces neutralizing antibodies against spike mutants from global SARS-CoV-2 variants.” Biorxiv (January). https://doi.org/10.1101/2021.01.25.427948.

[8] Moderna. 2021. “Moderna COVID-19 Vaccine Retains Neutralizing Activity Against Emerging Variants First Identified in the U.K. and the Republic of South Africa.” Posted January 25, 2021. https://investors.modernatx.com/news-releases/news-release-details/moderna-covid-19-vaccine-retains-neutralizing-activity-against.

[9] Centers for Disease Control and Prevention (CDC). 2021. “Emerging SARS-CoV-2 Variants.” Updated Jan. 28, 2021. https://www.cdc.gov/coronavirus/2019-ncov/more/science-and-research/scientific-brief-emerging-variants.html#ref4