ABSTRACT
In late 2022, the SARS-CoV-2 Omicron subvariants have highly diversified, and XBB is spreading rapidly around the world. Our phylogenetic analyses suggested that XBB emerged by recombination of two co-circulating BA.2 lineages, BJ.1 and BM.1.1.1 (a progeny of BA.2.75), during the summer of 2022 around India. In vitro experiments revealed that XBB is the most profoundly resistant variant to BA.2/5 breakthrough infection sera ever and is more fusogenic than BA.2.75. Notably, the recombination breakpoint is located in the receptor-binding domain of spike, and each region of recombined spike conferred immune evasion and augmented fusogenicity to the XBB spike. Finally, the intrinsic pathogenicity of XBB in hamsters is comparable to or even lower than that of BA.2.75. Our multiscale investigation provided evidence suggesting that XBB is the first documented SARS-CoV-2 variant increasing its fitness through recombination rather than single mutations.
ABSTRACT
In late 2022, although the SARS-CoV-2 Omicron subvariants have highly diversified, some lineages have convergently acquired amino acid substitutions at five critical residues in the spike protein. Here, we illuminated the evolutionary rules underlying the convergent evolution of Omicron subvariants and the properties of one of the latest lineages of concern, BQ.1.1. Our phylogenetic and epidemic dynamics analyses suggest that Omicron subvariants independently increased their viral fitness by acquiring the convergent substitutions. Particularly, BQ.1.1, which harbors all five convergent substitutions, shows the highest fitness among the viruses investigated. Neutralization assays show that BQ.1.1 is more resistant to breakthrough BA.2/5 infection sera than BA.5. The BQ.1.1 spike exhibits enhanced binding affinity to human ACE2 receptor and greater fusogenicity than the BA.5 spike. However, the pathogenicity of BQ.1.1 in hamsters is comparable to or even lower than that of BA.5. Our multiscale investigations provide insights into the evolutionary trajectory of Omicron subvariants.
ABSTRACT
SARS-CoV-2 Omicron BA.2.75 emerged in May 2022. BA.2.75 is a BA.2 descendant but is phylogenetically different from BA.5, the currently predominant BA.2 descendant. Here, we showed that the effective reproduction number of BA.2.75 is greater than that of BA.5. While the sensitivity of BA.2.75 to vaccination- and BA.1/2 breakthrough infection-induced humoral immunity was comparable to that of BA.2, the immunogenicity of BA.2.75 was different from that of BA.2 and BA.5. Three clinically-available antiviral drugs were effective against BA.2.75. BA.2.75 spike exhibited a profound higher affinity to human ACE2 than BA.2 and BA.5 spikes. The fusogenicity, growth efficiency in human alveolar epithelial cells, and intrinsic pathogenicity in hamsters of BA.2.75 were comparable to those of BA.5 but were greater than those of BA.2. Our multiscale investigations suggest that BA.2.75 acquired virological properties independently of BA.5, and the potential risk of BA.2.75 to global health is greater than that of BA.5.
Subject(s)
Adenocarcinoma, Bronchiolo-AlveolarABSTRACT
Unremitting emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants imposes us to continuous control measurement. Given the rapid spread, new Omicron subvariant named BA.5 is urgently required for characterization. Here we analyzed BA.5 with the other Omicron variants BA.1, BA.2, and ancestral B.1.1 comprehensively. Although in vitro growth kinetics of BA.5 is comparable among the Omicron subvariants, BA.5 become much more fusogenic than BA.1 and BA.2. The airway-on-a-chip analysis showed that the ability of BA.5 to disrupt the respiratory epithelial and endothelial barriers is enhanced among Omicron subvariants. Furthermore, in our hamster model, in vivo replication of BA.5 is comparable with that of the other Omicrons and less than that of the ancestral B.1.1. Importantly, inflammatory response against BA.5 is strong compared with BA.1 and BA.2. Our data suggest that BA.5 is still low pathogenic compared to ancestral strain but evolved to induce enhanced inflammation when compared to prior Omicron subvariants.
Subject(s)
Coronavirus Infections , InflammationABSTRACT
After the global spread of SARS-CoV-2 Omicron BA.2 lineage, some BA.2-related variants that acquire mutations in the L452 residue of spike protein, such as BA.2.9.1 and BA.2.13 (L452M), BA.2.12.1 (L452Q), and BA.2.11, BA.4 and BA.5 (L452R), emerged in multiple countries. Our statistical analysis showed that the effective reproduction numbers of these L452R/M/Q-bearing BA.2-related Omicron variants are greater than that of the original BA.2. Neutralization experiments revealed that the immunity induced by BA.1 and BA.2 infections is less effective against BA.4/5. Cell culture experiments showed that BA.2.12.1 and BA.4/5 replicate more efficiently in human alveolar epithelial cells than BA.2, and particularly, BA.4/5 is more fusogenic than BA.2. Furthermore, infection experiments using hamsters indicated that BA.4/5 is more pathogenic than BA.2. Altogether, our multiscale investigations suggest that the risk of L452R/M/Q-bearing BA.2-related Omicron variants, particularly BA.4 and BA.5, to global health is potentially greater than that of original BA.2.
Subject(s)
Adenocarcinoma, Bronchiolo-AlveolarABSTRACT
We estimated the seroprevalence of anti-SARS-COV-2 IgG in different island groups in Okinawa and described its changes over time. A cross-sectional sero-survey was repeated in three distinct periods between July 2020 and February 2021. A total of 2683 serum samples were collected from six referral medical centers, each covering a separate region in Okinawa. Patients who visited the emergency department for any reason and underwent blood collection were eligible for the study. Samples were analyzed using an FDA-authorized two-step enzyme-linked immunosorbent assay (ELISA) protocol. The case detection ratio was computed by dividing the seroprevalence by the attack rate obtained from publicly available surveillance data. In the main island, the seroprevalence was 0.0% (0/392, 95% CI: 0.0-0.9), 0.6% (8/1448, 0.2-1.1), and 1.4% (8/582, 0.6-2.7) at the 1 st , 2 nd , and 3 rd sero-survey, respectively. In the remote islands, the seroprevalence was 0.0% (0/144, 95% CI: 0.0-2.5) and 1.6% (2/123, 0.2-5.8) at the 2 nd and 3 rd survey, respectively. The overall case detection ratios at the 3 rd survey were 2.7 (95% CI: 1.3-5.3) in the main island and 2.8 (0.7-11.1) in the remote islands. The highest age-specific case detection ratio was observed in people aged 20-29 years (8.3, 95% CI: 3.3-21.4) in the main island and in those aged 50-59 years (14.1, 2.1-92.7) in the remote islands. The low seroprevalence at the latest survey suggested that a large-scale epidemic had not yet occurred in Okinawa by February 2021. The case detection ratios imply that the cumulative number of incident cases in Okinawa should be 2-3 times higher than that reported by routine surveillance. The ratio was particularly high in young people probably due to a frequent asymptomatic/mild COVID-19 disease in this age group. To accurately measure the scale of the COVID-19 epidemic, it is crucially important to conduct a sero-survey targeting the young.