BA.2.12.1, BA.4 and BA.5 escape antibodies elicited by Omicron infection

Abstract

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron sublineages BA.2.12.1, BA.4 and BA.5 exhibit higher transmissibility than the BA.2 lineage1. The receptor binding and immune-evasion capability of these recently emerged variants require immediate investigation. Here, coupled with structural comparisons of the spike proteins, we show that BA.2.12.1, BA.4 and BA.5 (BA.4 and BA.5 are hereafter referred collectively to as BA.4/BA.5) exhibit similar binding affinities to BA.2 for the angiotensin-converting enzyme 2 (ACE2) receptor. Of note, BA.2.12.1 and BA.4/BA.5 display increased evasion of neutralizing antibodies compared with BA.2 against plasma from triple-vaccinated individuals or from individuals who developed a BA.1 infection after vaccination. To delineate the underlying antibody-evasion mechanism, we determined the escape mutation profiles2, epitope distribution3 and Omicron-neutralization efficiency of 1,640 neutralizing antibodies directed against the receptor-binding domain of the viral spike protein, including 614 antibodies isolated from people who had recovered from BA.1 infection. BA.1 infection after vaccination predominantly recalls humoral immune memory directed against ancestral (hereafter referred to as wild-type (WT)) SARS-CoV-2 spike protein. The resulting elicited antibodies could neutralize both WT SARS-CoV-2 and BA.1 and are enriched on epitopes on spike that do not bind ACE2. However, most of these cross-reactive neutralizing antibodies are evaded by spike mutants L452Q, L452R and F486V. BA.1 infection can also induce new clones of BA.1-specific antibodies that potently neutralize BA.1. Nevertheless, these neutralizing antibodies are largely evaded by BA.2 and BA.4/BA.5 owing to D405N and F486V mutations, and react weakly to pre-Omicron variants, exhibiting narrow neutralization breadths. The therapeutic neutralizing antibodies bebtelovimab4 and cilgavimab5 can effectively neutralize BA.2.12.1 and BA.4/BA.5, whereas the S371F, D405N and R408S mutations undermine most broadly sarbecovirus-neutralizing antibodies. Together, our results indicate that Omicron may evolve mutations to evade the humoral immunity elicited by BA.1 infection, suggesting that BA.1-derived vaccine boosters may not achieve broad-spectrum protection against new Omicron variants.

What Omicron’s BA.4 and BA.5 variants mean for the pandemic

“…Laboratory studies [2][3][4][5][6] consistently suggest that antibodies triggered by vaccination are less effective at blocking BA.4 and BA.5 than they are at blocking earlier Omicron strains, including BA.1 and BA.2. This could leave even vaccinated and boosted people vulnerable to multiple Omicron infections, scientists say.…”

“…One explanation for this is the observation that BA.1 infection after vaccination seems to trigger infection-blocking 'neutralizing' antibodies that recognize the ancestral strain of SARS-CoV-2 (on which vaccines are based) better than they recognize Omicron variants 2,7 . "Infection with BA.1 does induce a neutralizing antibody response, but it appears to be a little bit narrower than one would expect," leaving people susceptible to immune-escaping variants such BA.4 and BA.5, says Ravindra Gupta, a virologist at the University of Cambridge, UK.…”

“…It is highly probable that additional Omicron variants will emerge," says Kei Sato, a virologist at the University of Tokyo. Researchers have identified several spots on the spike protein that are currently recognized by the antibodies that are triggered by vaccination and previous infection, but that could mutate in future Omicron strains 2 .…”

A monoclonal antibody stands out against omicron subvariants: a call to action for a wider access to bebtelovimab

“…We read with great interest the Correspondence by Daichi Yamasoba and colleagues, 1 which highlighted the efficacy of all commercially-available monoclonal antibodies against dominant omicron subvariants. In this Correspondence, similar to others, 2 one monoclonal antibody stands out, namely, bebtelovimab. Among all available monoclonal antibodies, bebtelovimab is the only one that has shown remarkably preserved in vitro activity against all SARS-CoV-2 variants, including the omicron variant and the most recent BA.4 and BA.5 subvariants that are now becoming dominant.…”

Dengue and COVID-19: two sides of the same coin

“…Therefore, although the emergence of sub-lineages of omicron such as BA.4 and BA.5 are shown to be more immune evasive than all existing variants, as a result of further mutations in the Nab binding sites. However, due to the breadth of the T cell response induced following natural infection and vaccination, infection with these variants is likely to associate with a relative reduction in clinical disease severity, despite infection, as evidenced with the global decline in COVID-19 mortality rates [ 16 ].…”