Virus World

The Orthocoronaviridae subfamily is large comprising four highly divergent genera. Four seasonal coronaviruses were circulating in humans prior to the coronavirus disease 2019 (COVID-19) pandemic. Infection with these viruses induced antibody responses that are relatively narrow with little cross-reactivity to spike proteins of other coronaviruses. Here, we report that infection with and vaccination against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) induces broadly crossreactive binding antibodies to spikes from a wide range of coronaviruses including members of the sarbecovirus subgenus, betacoronaviruses including Middle Eastern respiratory syndrome coronavirus (MERS CoV), and extending to alpha-, gamma- and delta-coronavirus spikes. These data show that the coronavirus spike antibody landscape in humans has profoundly been changed and broadened as a result of the SARS-CoV-2 pandemic. While we do not understand the functionality of these crossreactive antibodies, they may lead to enhanced resistance of the population to infection with newly emerging coronaviruses with pandemic potential.

Preprunt in medRxiv (August 6, 2023):

https://doi.org/10.1101/2023.08.01.23293522 

The Omicron SARS-CoV-2 has three distinct sublineages, among which sublineage BA.1 is responsible for the initial Omicron surge and is now being replaced by BA.2 worldwide, whereas BA.3 is currently at a low frequency. The ongoing BA.1-to-BA.2 replacement underscores the importance to understand the cross-neutralization among the three Omicron sublineages. Here we tested the neutralization of BA.1-infected human sera against BA.2, BA.3, and USA/WA1-2020 (a strain isolated in late January 2020). The BA.1-infected sera neutralized BA.1, BA.2, BA.3, and USA/WA1-2020 SARS-CoV-2s with geometric mean titers (GMTs) of 445, 107, 102, and 16, respectively. Thus, the neutralizing GMTs against heterologous BA.2, BA.3, and USA/WA1-2020 were 4.2-, 4.4-, and 28.4-fold lower than the GMT against homologous BA.1, respectively. These findings have implications for vaccine strategy.

Preprint available in bioRxiv (March 31, 2022):

https://doi.org/10.1101/2022.03.30.486409 

The SARS-CoV-2 Omicron variant largely escapes neutralizing antibodies elicited by vaccines or infection. However, whether Omicron triggers humoral responses that are cross-reactive to other variants of concern (VOCs) remains largely unknown. We use plasma from 20 unvaccinated and seven vaccinated individuals infected during the Omicron wave in South Africa to test binding, antibody-dependent cellular cytotoxicity (ADCC), antibody-dependent cellular phagocytosis (ADCP) and neutralization against VOCs. In unvaccinated individuals, Fc effector function and binding antibodies target Omicron and other VOCs at comparable levels. However, Omicron-triggered neutralization is not extensively cross-reactive to VOCs, with 20 to 43-fold reductions in titer. In contrast, vaccination followed by breakthrough Omicron infection improved cross-neutralization of VOCs, with titers exceeding 1:2,900. This has important implications for the vulnerability of unvaccinated Omicron-infected individuals to reinfection by circulating and emerging VOCs. Further, while Omicron-based immunogens may be adequate boosters, they are unlikely to be superior to existing vaccines for priming in SARS-CoV-2 naïve individuals.

Preprint available (Feb. 14, 2022):

https://www.medrxiv.org/content/10.1101/2022.02.10.22270789v1 

Omicron is the evolutionarily most distinct SARS-CoV-2 variant of concern (VOC) to date. We report that Omicron BA.1 breakthrough infection in BNT162b2-vaccinated individuals resulted in strong neutralizing activity against Omicron BA.1, BA.2 and previous SARS-CoV-2 VOCs, but not against the Omicron sublineages BA.4 and BA.5. BA.1 breakthrough infection induced a robust recall response, primarily expanding BMEM cells against epitopes shared broadly amongst variants, rather than inducing BA.1-specific B cells. The vaccination-imprinted BMEM cell pool had sufficient plasticity to be remodeled by heterologous SARS-CoV-2 spike glycoprotein exposure. While selective amplification of BMEM cells recognizing shared epitopes allows for effective neutralization of most variants that evade previously established immunity, susceptibility to escape by variants that acquire alterations at hitherto conserved sites may be heightened.

Published in Science (June 2, 2022):

https://doi.org/10.1126/sciimmunol.abq2427 

In comparing breakthrough infections from the SARS-CoV-2 Delta and Omicron variants, the latter, though milder than Delta infections, were associated with lower antibody titers and limited cross-neutralizing immunity, suggesting reduced protection against re-infection or infection from a future variant.

Summary

Virus-like particle (VLP) and live virus assays were used to investigate neutralizing immunity against Delta and Omicron SARS-CoV-2 variants in 259 samples from 128 vaccinated individuals. Following Delta breakthrough infection, titers against WT rose 57-fold and 3.1-fold compared to uninfected boosted and unboosted individuals, respectively, versus only a 5.8-fold increase and 3.1-fold decrease for Omicron breakthrough infection. Among immunocompetent, unboosted patients, Delta breakthrough infections induced 10.8-fold higher titers against WT compared to Omicron (p=0.037). Decreased antibody responses in Omicron breakthrough infections relative to Delta were potentially related to a higher proportion of asymptomatic or mild breakthrough infections (55.0% versus 28.6%, respectively), which exhibited 12.3-fold lower titers against WT compared to moderate-severe infections (p=0.020). Following either Delta or Omicron breakthrough infection, limited variant-specific cross-neutralizing immunity was observed. These results suggest that Omicron breakthrough infections are less immunogenic than Delta, thus providing reduced protection against reinfection or infection from future variants.

Highlights

1. In breakthrough infections, variant-specific cross-neutralizing immunity is limited.

2. Higher antibody titers are observed in severe versus mild breakthrough infections.

3. Delta breakthroughs exhibited 10.8X higher antibody titers compared to Omicron.

4. The rise in antibody titers from Omicron breakthroughs was 1/3 of that from boosting.

Published in Cell (March 17, 2022):

https://doi.org/10.1016/j.cell.2022.03.019