SARS-CoV-2 variants with E484K mutation show mRNA vaccine-induced antibody evasion

A recent study by researchers in Switzerland found that the Pfizer-BioNTech mRNA vaccine had limited efficacy in identifying mutated receptor-binding domains (RBDs) of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein similar to the B.1.351 and P.1 variants.

The B.1.351 variant was first detected in South Africa, and the P.1 variant in Brazil. Both variants have the E484K mutation, which decreases the neutralizing antibody response produced by vaccines, monoclonal antibody therapies, convalescent plasma, and natural infection.

The current mRNA vaccines have proven effective against the other variant of concern discovered in the United Kingdom last Fall – also known as the B.1.1.7 variant.

The study’s findings may have implications for the longevity of current vaccine models, which were based on ancestral strains of the virus

Researchers write:

Recognition may, however, be 10-fold reduced for the variants B.1.351/P.1, suggesting that the development of a new vaccine is warranted. The E484K mutation is an key hurdle for immune recognition, convalescent plasma and monoclonal antibody therapy as well as serological assays based on the wildtype sequence may therefore seriously impaired.”

The study “BNT162b2 mRNA COVID-19 vaccine induces antibodies of broader cross-reactivity than natural infection but recognition of mutant viruses is up to 10-fold reduced” is available as a preprint on the bioRxiv* server, while the article undergoes peer review.

How they did it

The team evaluated the cross-reactive binding of antibodies produced after vaccination or recovery of natural infection against RBDs of the spike protein with mutations related to the variants of concern. This included RBD mutant K417N (RBD₄₁₇), RBD mutant E484K (RBD₄₈₄), RBD mutant N501Y (RBD₅₀₁), and an RBD version with mutations at all three sites (RBD_trip).

The E484K and N501Y mutations were located in the RBD area that would allow for direct interaction with the angiotensin-converting enzyme 2 (ACE2) receptor of human host cells.

The team collected serum from 11 participants with convalescent plasma and 6 participants who were vaccinated with both Pfizer-BioNTech vaccine doses. The serum was collected from vaccinated individuals 2 weeks after the second dose. The team then performed ELISAs on the donated serum to measure antibody responses.

Reduced antibody binding against mutated RBDs

The researchers found the antibody response induced by convalescent plasma strongly decreased when faced with RBD₄₁₇ and RBD₅₀₁ . In addition, they found almost no antibody activity towards RBD₄₈₄ and RBD_trip.

Antibodies produced by the Pfizer-BioNTech vaccine showed a 2.5-3 fold reduced antibody binding to RBD₄₁₇ and RBD₅₀₁. However, there was a 10-fold binding reduction with RBD₄₈₄ and RBD_trip.

The researchers suggest the E484K is the main culprit behind reduced antibody binding as it is present in both RBD₄₈₄ and RBD_trip. They suggest this may occur because of changes from a positive to negative charge.

When evaluating the overall binding strength between the antibody and the mutated RBDs, they found convalescent plasma antibodies had limited binding strength for the wild-type version.

The antibodies produced by the Pfizer-BioNTech vaccine had a stronger binding strength towards the wild-type RBD than antibodies produced from natural infection. These also showed some residual binding to mutated RBDs, indicating low binding strength.

The avidity of vaccine-induced antibodies is much higher for RBD and the mutants than those induced by infection. This reduced affinity of antibodies induced by infection is consistent with the notion that individual RBDs are spaced by 25 nm on SARSCoV-2, too large a distance for induction of optimal antibodies,” wrote the researchers.

The research team concludes that individuals with antibodies from natural infections are may not be protected against the new coronavirus variants, especially if they contain the E484K mutation. Given the vaccine-induced antibody response was weak in identifying mutations in the receptor binding domain, they suggest more updated vaccines are necessary.

*Important Notice

bioRxiv 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.

Written by

Jocelyn Solis-Moreira

Jocelyn Solis-Moreira graduated with a Bachelor's in Integrative Neuroscience, where she then pursued graduate research looking at the long-term effects of adolescent binge drinking on the brain's neurochemistry in adulthood.