Potency of Moderna, Pfizer vaccines weaker against epsilon COVID-19 variant

The novel epsilon variant of SARS-CoV-2, first detected in California, US, carries mutations in the spike (S) protein and N-terminal (NTD) and receptor-binding (RBD) domains that could render neutralizing antibodies (nAbs) induced by mRNA-based vaccines weaker, according to a recent study.

“Understanding the newfound mechanism of immune evasion of the emerging variants, such as the signal peptide modification described herein, is as important as sequence surveillance itself to successfully counter the ongoing pandemic,” the researchers said.

Drawing from the databases of the Global Initiative on Sharing Avian Influenza Data, they retrieved 8,441 sequenced genomes of the SARS-CoV-2 B.1.427 lineage and 21,072 genomes of the B.1.429 lineage. Both lineages shared three key mutations: S13I in the S protein, W125C in the NTD, and L452R in the RBD.

To look at the potential impact of the S mutations, the researchers used a murine leukaemia virus pseudotyping system. They compared the neutralization potencies of mRNA vaccine-induced Abs against the B.1.427/B.1.429 variant vs the G614 variant, which had become highly prevalent worldwide since it was first discovered. Plasma samples from 15 patients immunized with the Moderna vaccines and 15 with the Pfizer/BioNtech shots were used for the analysis.

Relative to the G614 variant, the Moderna vaccines demonstrated an average neutralization potency 2.4-fold weaker against the B.1.426/B.1.429 variant. The potency of the Pfizer/BioNtech vaccines, in comparison, were reduced 2.3-fold. [Science 2021;doi:10.1126/science.abi7994]

Using different pseudotyping systems yielded similar results, with both mRNA-based vaccines showing at least a twofold reduction in potency against the novel variants.

Plasma from nine convalescent donors who had had symptomatic disease likewise showed reduced neutralization potency against the B.1.427/B.1.429 variant.

These findings agreed with previous findings, which showed that the L452R mutation “reduced the binding or neutralizing activity of some monoclonal antibodies (mAbs),” the researchers said. “The acquisition of [the said] substitution by multiple lineages across multiple continents … is suggestive of positive selection, which might result from the selective pressure of RBD-specific nAbs.” [Cell Host Microbe 2021;29:477-488.e4; bioRxiv 2021;doi:10.1101/2021.02.22.432189]

The researchers then sought to identify the contributions of the RBD and NTD mutations to the weaker neutralization potencies of vaccines and used a panel of 34 mAbs against RBD and 10 against NTD.

They found 10 RBD mAbs that had neutralization potencies tenfold weaker against the B.1.427/B.1.429 variant relative to D614, another viral variant, an effect driven to the poor binding to the L452R mutation at this region. In addition, all 10 tested NTD mAbs had their neutralizing activities completely eliminated due to both the S13I and W152C mutations.

“These data indicate that the decreased potency of neutralization of the B.1.427/B.1.429 variant results from evasion of both RBD- and NTD-specific mAb-mediated neutralization,” the researchers explained. “The data herein showing immune evasion of all tested NTD-specific mAbs by the B.1.427/B.1.429 variant also support that the NTD antigenic supersite is under host immune pressure.”