Virus World

Continued evolution of SARS-CoV-2 has led to the emergence of several new Omicron subvariants, including BQ.1, BQ. 1.1, BA.4.6, BF.7 and BA.2.75.2. Here we examine the neutralization resistance of these subvariants, as well as their ancestral BA.4/5, BA.2.75 and D614G variants, against sera from 3-dose vaccinated health care workers, hospitalized BA.1-wave patients, and BA.5-wave patients. We found enhanced neutralization resistance in all new subvariants, especially the BQ.1 and BQ.1.1 subvariants driven by a key N460K mutation, and to a lesser extent, R346T and K444T mutations, as well as the BA.2.75.2 subvariant driven largely by its F486S mutation.

The BQ.1 and BQ.1.1 subvariants also exhibited enhanced fusogenicity and S processing dictated by the N460K mutation. Interestingly, the BA.2.75.2 subvariant saw an enhancement by the F486S mutation and a reduction by the D1199N mutation to its fusogenicity and S processing, resulting in minimal overall change. Molecular modelling revealed the mechanisms of receptor-binding and non-receptor binding monoclonal antibody-mediated immune evasion by R346T, K444T, F486S and D1199N mutations. Altogether, these findings shed light on the concerning evolution of newly emerging SARS-CoV-2 Omicron subvariants.

Preprint available in bioRxiv (October 20, 2022):

https://doi.org/10.1101/2022.10.19.512891 

Highlights

Summary

Infection with a pre-Omicron SARS-CoV-2 variant protects against reinfection with a second, although the effect fades almost completely after three years.  Natural immunity induced by infection with SARS-CoV-2 provides a strong shield against reinfection by a pre-Omicron variant for 16 months or longer, according to a study1. This protection against catching the virus dwindles over time, but immunity triggered by previous infection also thwarts the development of severe COVID-19 symptoms — and this safeguard shows no signs of waning. The study1, which analyses cases in the entire population of Qatar, suggests that although the world will continue to be hit by waves of SARS-CoV-2 infection, future surges will not leave hospitals overcrowded with people with COVID-19. The research was posted on the medRxiv preprint server on 7 July. It has not yet been peer reviewed. The study is “solid”, says Shane Crotty, an immunologist at the La Jolla Institute for Immunology in California. “The data make sense and are in line with multiple other studies and previous work by this group.”

Better late than never

But scientists also warn that the study’s results do not mean that infected people can skip vaccination. A separate study2 by many of the same authors found that “people who had both natural immunity and vaccine immunity were substantially more protected against the virus than people who had only natural immunity alone or vaccine immunity”, says Laith Abu-Raddad, an infectious-disease epidemiologist at Weill Cornell Medicine–Qatar in Doha and a co-author of both studies. “It was very clear-cut.” Studies3,4 on the effectiveness of COVID-19 vaccines suggest that protection against the virus SARS-CoV-2 decreases over time, waning considerably after six months. To learn about the course of naturally acquired immunity, the authors examined COVID-19 data gathered in Qatar between 28 February 2020 and 5 June 2022. “Our study is the first to have such a long time of follow-up,” says co-author Hiam Chemaitelly, an epidemiologist also at Weill Cornell Medicine–Qatar. The researchers compared COVID-19 cases in unvaccinated individuals who’d had one previous SARS-CoV-2 infection with cases in unvaccinated people who’d never previously caught the virus. They found that infection with a pre-Omicron variant prevented reinfection by another pre-Omicron variant with an average effectiveness of 85.5% for the period covering the 4th through the 16th month following the initial infection. Effectiveness peaked at 90.5% in the 7th month after the first infection and fell to about 70% at 16 months (see ‘Immunity fades away’). By extrapolating this trend, the authors predict that effectiveness against reinfection will fall to less than 10% 32 months after the first infection. Pre-Omicron infection was only 38% effective at preventing infection by an Omicron variant in the first 6 months after Omicron emerged. Modelling suggests that the number will drop to 10% at 15 months. All the same, infection with any SARS-CoV-2 variant is highly effective at combating severe, critical or fatal COVID-19 after reinfection: effectiveness was around 100% up to the 14th month after primary infection and showed no signs of declining.

Published  in Nature July 15, 2022

 https://doi.org/10.1038/d41586-022-01914-6 

Recent emergence of SARS-CoV-2 Omicron sublineages BA.2.12.1, BA.2.13, BA.4 and BA.5 all contain L452 mutations and show potential higher transmissibility over BA.2. The new variants' receptor binding and immune evasion capability require immediate investigation, especially on the role of L452 substitutions. Herein, coupled with structural comparisons, we showed that BA.2 sublineages, including BA.2.12.1 and BA.2.13, exhibit increased ACE2-binding affinities compared to BA.1; while BA.4/BA.5 shows the weakest receptor-binding activity due to F486V and R493Q reversion. Importantly, compared to BA.2, BA.2.12.1 and BA.4/BA.5 exhibit stronger neutralization escape from the plasma of 3-dose vaccinees and, most strikingly, from vaccinated BA.1 convalescents.

To delineate the underlying evasion mechanism, we determined the escaping mutation profiles, epitope distribution and Omicron sublineage neutralization efficacy of 1640 RBD-directed neutralizing antibodies (NAbs), including 614 isolated from BA.1 convalescents. Interestingly, post-vaccination BA.1 infection mainly recalls wildtype (WT) induced humoral memory and elicits antibodies that neutralize both WT and BA.1. These cross-reactive NAbs are significantly enriched on non-ACE2-competing epitopes; and surprisingly, the majority are undermined by R346 and L452 substitutions, namely R346K (BA.1.1), L452M (BA.2.13), L452Q (BA.2.12.1) and L452R (BA.4/BA.5), suggesting that R346K and L452 mutations appeared under the immune pressure of Omicron convalescents. Nevertheless, BA.1 infection can also induce new clones of BA.1-specific antibodies that potently neutralize BA.1 but do not respond to WT SARS-CoV-2, due to the high susceptibility to N501, N440, K417 and E484. However, these NAbs are largely escaped by BA.2 sublineages and BA.4/BA.5 due to D405N and F486V, exhibiting poor neutralization breadths.

As for therapeutic NAbs, LY-CoV1404 (Bebtelovimab) and COV2-2130 (Cilgavimab) can still effectively neutralize BA.2.12.1 and BA.4/BA.5, while the S371F, D405N and R408S mutations carried by BA.2/BA.4/BA.5 sublineages would undermine most broad sarbecovirus NAbs. Together, our results indicate that Omicron can evolve mutations to specifically evade humoral immunity elicited by BA.1 infection. The continuous evolution of Omicron poses great challenges to SARS-CoV-2 herd immunity and suggests that BA.1-derived vaccine boosters may not be ideal for achieving broad-spectrum protection.

Preprint available in bioRxiv (May 02, 2022):

 https://doi.org/10.1101/2022.04.30.489997