Breakthrough infection with the Pleomicron mutant induces cross-neutralizing activity against Omicron

In a recent study posted on medRxiv* Preprint server, researchers evaluated the ability to neutralize serum from patients with coronavirus disease 2019 (COVID-19).

The causative pathogen, Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), has evolved throughout the pandemic and has emerged as a feature-enhanced variant. Highly contagious or anti-avoidant SARS-CoV-2 mutants easily outperform previously predominant strains. Vaccines such as Pfizer’s BNT162b2, Modana’s mRNA-1273, Janssen’s Ad.26COV2.S, and AstraZeneca’s ChAdOx1 are effective in protecting against severe illness.

Still, protection against infection is inadequate, especially with SARS-CoV-2 delta and Omicron variants. The protection provided by previous infections with Pleomicron mutants (VOCs) against Omicron mutants is controversial.Several reports have shown that breakthrough infections with Omicron BA.1 mutants are induced. Neutralizing antibody (NAbs) For BA.1 and previous VOCs. Nevertheless, these nAbs show inadequate cross-neutralizing activity against the Omicron subline.

Omicron infections in unvaccinated people induce nAbs that are poorly neutralized for all VOCs. The widespread dissemination of SARS-CoV-2 Omicron ensures a better understanding of susceptibility to vaccination or neutralization with infection-inducing antibodies.

About research

In this study, researchers compared the sera neutralization of Omicron BA.1 in unvaccinated convalescent patients with those with breakthrough infections in the vaccine. Serum samples are 70 convalescent individuals infected with the ancestral B.1 strain (hereinafter convalescent serum) and 16 vaccinated subjects who have experienced a breakthrough infection with gamma or delta VOC. Obtained from (BTI serum). The severity of COVID-19 was classified as mild / asymptomatic, moderate, and severe.

The research team isolated the D614G strain and gamma, delta, or omicron VOCs from the patient’s remaining nasopharyngeal swabs. They added residual swab storage medium to Vero E6 cells and visually monitored their cytopathic effect (CPE). The virus supernatant was then used to reinfect Vero E6 cells (passage 2) to establish a virus stock. The remaining cotton swab SARS-CoV-2 mutants were sequenced using next-generation sequencing (NGS), and the spike (S) gene was resequenced after passage 2 to confirm conservation of the sequence. .. Finally, they conducted a live virus neutralization test.

Survey results

Most samples of convalescent serum were collected from patients with moderate or severe illness. Half of the maximum inhibition concentration (IC₅₀) Convalescent serum values ​​showed broad neutralization activity against B.1, gamma, and delta variants with comparable geometric mean.

All but one convalescent sample did not neutralize Omicron at the highest serum concentration tested.

Samples with / without neutralizing activity for one mutant often had high neutralizing activity for another. Convalescent sera from patients with moderate COVID-19 showed the highest neutralizing activity against B.1 and VOCs. They then measured antibodies directed at the S protein, its receptor binding (RBD) and N-terminal (NTD) domains, and the nucleocapsid (N) protein. All patients detected levels of anti-N, anti-S, and anti-RBD antibodies.

Anti-NTD antibodies were low / undetectable in some patients with severe illness. The authors noted that there was a moderate correlation between neutralizing activity and antibody levels. Consistently, the sera of patients with moderate COVID-19 showed higher antibodies to S, RBD, NTD, and N than in severe cases.

BTI sera were collected from 2 gamma variant infected patients and 14 delta variant cases. The median time from full vaccination was 3.06 months. BTI sera were stratified into non-neutralizing / hyponeutralizing and highly neutralizing sera (8 samples in each category). Five non / inadequately neutralized sera showed no neutralization to the B.1 strain at the highest serum concentration tested.

They found that BTI serum samples that neutralized the B.1 strain with a dilution of 1:80 or higher retained neutralization for the corresponding infected VOCs or showed higher neutralization for VOCs. I paid attention to it. Conversely, most samples that failed to neutralize the B.1 strain had no neutralizing activity against infectious mutants. More than half of BTI cases showed nAb for gamma or delta VOCs. Therefore, serum samples showed better cross-neutralizing activity against delta mutants than B.1 strains.

All BTI sera showed a substantial reduction in neutralization to the Omicron BA.1 mutant. However, 8 samples with high neutralizing activity against B.1. Gamma or delta retained partial neutralization to BA.1. Anti-S, anti-RBD, and anti-NTD antibody levels were high except for one BTI sample. Neutralizing activity against the B.1 strain was well correlated with antibodies against RBD, NTD, and S proteins, but less so with anti-N antibodies.

Conclusion

In summary, BTI sera showed higher neutralizing capacity for SARS-CoV-2 B.1 strain and VOCs containing Omicron BA.1 than convalescent sera. Of the eight BTI sera that neutralized B.1 and VOC, 6 samples partially neutralized BA.1. This revealed that breakthrough infection with the Pleomicron mutant induced antibodies that could cross-neutralize the Omicron BA.1 mutant.

In particular, lower antibodies to S, N, RBD, and NTD achieved higher neutralization in BTI sera compared to convalescent sera. This means greater neutralization. Effectiveness Achieved with lower antibody titers, probably due to improved antibody affinity. These findings highlight the qualitative differences in antibodies between unvaccinated convalescent individuals and vaccinated convalescent individuals, where breakthrough infections enhance the immune response and cross-neutralizing antibodies. It was suggested that it could be induced.

*Important Notices

medRxiv publishes unpeer-reviewed preliminary scientific reports and should not be considered definitive, guide clinical / health-related behaviors, or be treated as established information.