Publisher Correction: SARS-CoV-2 Omicron is an immune escape variant with an altered cell entry pathway (Nature Microbiology, (2022), 7, 8, (1161-1179), 10.1038/s41564-022-01143-7)

In the version of this article initially published, the author affiliation information was incomplete, neglecting to note that Brian J. Willett, Joe Grove, Oscar A. MacLean, Craig Wilkie, Giuditta De Lorenzo, Wilhelm Furnon, Diego Cantoni, Sam Scott, Nicola Logan and Shirin Ashraf contributed equally and that John Haughney, David L. Robertson, Massimo Palmarini, Surajit Ray and Emma C. Thomson jointly supervised the work, as now indicated in the HTML and PDF versions of the article

Viral coinfections in hospitalized coronavirus disease 2019 patients recruited to the international severe acute respiratory and emerging infections consortium WHO clinical characterisation protocol UK study

Background We conducted this study to assess the prevalence of viral coinfection in a well characterized cohort of hospitalized coronavirus disease 2019 (COVID-19) patients and to investigate the impact of coinfection on disease severity. Methods Multiplex real-time polymerase chain reaction testing for endemic respiratory viruses was performed on upper respiratory tract samples from 1002 patients with COVID-19, aged <1 year to 102 years old, recruited to the International Severe Acute Respiratory and Emerging Infections Consortium WHO Clinical Characterisation Protocol UK study. Comprehensive demographic, clinical, and outcome data were collected prospectively up to 28 days post discharge. Results A coinfecting virus was detected in 20 (2.0%) participants. Multivariable analysis revealed no significant risk factors for coinfection, although this may be due to rarity of coinfection. Likewise, ordinal logistic regression analysis did not demonstrate a significant association between coinfection and increased disease severity. Conclusions Viral coinfection was rare among hospitalized COVID-19 patients in the United Kingdom during the first 18 months of the pandemic. With unbiased prospective sampling, we found no evidence of an association between viral coinfection and disease severity. Public health interventions disrupted normal seasonal transmission of respiratory viruses; relaxation of these measures mean it will be important to monitor the prevalence and impact of respiratory viral coinfections going forward

SARS-CoV-2 Omicron is an immune escape variant with an altered cell entry pathway

Vaccines based on the spike protein of SARS-CoV-2 are a cornerstone of the public health response to COVID-19. The emergence of hypermutated, increasingly transmissible variants of concern (VOCs) threaten this strategy. Omicron (B.1.1.529), the fifth VOC to be described, harbours multiple amino acid mutations in spike, half of which lie within the receptor-binding domain. Here we demonstrate substantial evasion of neutralization by Omicron BA.1 and BA.2 variants in vitro using sera from individuals vaccinated with ChAdOx1, BNT162b2 and mRNA-1273. These data were mirrored by a substantial reduction in real-world vaccine effectiveness that was partially restored by booster vaccination. The Omicron variants BA.1 and BA.2 did not induce cell syncytia in vitro and favoured a TMPRSS2-independent endosomal entry pathway, these phenotypes mapping to distinct regions of the spike protein. Impaired cell fusion was determined by the receptor-binding domain, while endosomal entry mapped to the S2 domain. Such marked changes in antigenicity and replicative biology may underlie the rapid global spread and altered pathogenicity of the Omicron variant

SARS-CoV-2: can isolation be limited to those who are truly infectious?

No abstract available

Prevalence of endemic respiratory viruses during the COVID-19 pandemic in urban and rural Malawi

Background Non-pharmaceutical interventions (NPI) during the COVID-19 pandemic disrupted respiratory virus circulation. Malawi employed multiple NPI but did not impose a “lockdown”. We aimed to investigate endemic respiratory virus circulation patterns in urban and rural Malawi during this period. Methods Within a prospective cohort of randomly selected households in an urban and rural community in Malawi, adult participants provided upper respiratory tract samples at four timepoints, between February 2021 and April 2022. PCR for SARS-CoV-2, influenza and other endemic respiratory viruses was performed. Results 1626 URT samples from 945 participants in 542 households were included. Overall, 7.6% (n = 123) of samples were PCR-positive for 1 respiratory virus; SARS-CoV-2 (4.4%) and rhinovirus (2.0%) were most frequently detected. No influenza A virus was detected. Influenza B and RSV were rare. Significantly higher levels of virus positivity were detected in the rural setting, and at earlier timepoints. Co-infections were infrequent (0.2%; n = 3). Conclusion Endemic respiratory viruses circulated in the community in Malawi during the pandemic, although influenza and RSV were rarely detected. Distinct differences in virus positivity and demographics were observed between urban and rural cohorts. Ongoing surveillance is needed to monitor the impact of continuing co-circulation of SARS-CoV-2 with endemic respiratory viruses

Prevalence of endemic respiratory viruses during the COVID-19 pandemic in urban and rural Malawi

Background Non-pharmaceutical interventions (NPI) during the COVID-19 pandemic disrupted respiratory virus circulation. Malawi employed multiple NPI but did not impose a “lockdown”. We aimed to investigate endemic respiratory virus circulation patterns in urban and rural Malawi during this period. Methods Within a prospective cohort of randomly selected households in an urban and rural community in Malawi, adult participants provided upper respiratory tract samples at four timepoints, between February 2021 and April 2022. PCR for SARS-CoV-2, influenza and other endemic respiratory viruses was performed. Results 1626 URT samples from 945 participants in 542 households were included. Overall, 7.6% (n = 123) of samples were PCR-positive for 1 respiratory virus; SARS-CoV-2 (4.4%) and rhinovirus (2.0%) were most frequently detected. No influenza A virus was detected. Influenza B and RSV were rare. Significantly higher levels of virus positivity were detected in the rural setting, and at earlier timepoints. Co-infections were infrequent (0.2%; n = 3). Conclusion Endemic respiratory viruses circulated in the community in Malawi during the pandemic, although influenza and RSV were rarely detected. Distinct differences in virus positivity and demographics were observed between urban and rural cohorts. Ongoing surveillance is needed to monitor the impact of continuing co-circulation of SARS-CoV-2 with endemic respiratory viruses

The SARS-CoV-2 Alpha variant was associated with increased clinical severity of COVID-19 in Scotland: A genomics-based retrospective cohort analysis

Objectives The SARS-CoV-2 Alpha variant was associated with increased transmission relative to other variants present at the time of its emergence and several studies have shown an association between Alpha variant infection and increased hospitalisation and 28-day mortality. However, none have addressed the impact on maximum severity of illness in the general population classified by the level of respiratory support required, or death. We aimed to do this. Methods In this retrospective multi-centre clinical cohort sub-study of the COG-UK consortium, 1475 samples from Scottish hospitalised and community cases collected between 1st November 2020 and 30th January 2021 were sequenced. We matched sequence data to clinical outcomes as the Alpha variant became dominant in Scotland and modelled the association between Alpha variant infection and severe disease using a 4-point scale of maximum severity by 28 days: 1. no respiratory support, 2. supplemental oxygen, 3. ventilation and 4. death. Results Our cumulative generalised linear mixed model analyses found evidence (cumulative odds ratio: 1.40, 95% CI: 1.02, 1.93) of a positive association between increased clinical severity and lineage (Alpha variant versus pre-Alpha variants). Conclusions The Alpha variant was associated with more severe clinical disease in the Scottish population than co-circulating lineages. :</p

Mapping of SARS-CoV-2 IgM and IgG in gingival crevicular fluid: antibody dynamics and linkage to severity of COVID-19 in hospital inpatients.

Objectives: To characterise the acute and early convalescent antibody responses in gingival crevicular fluid (GCF) from patients hospitalised with COVID-19. Methods: IgM and IgG antibody against the SARS-CoV-2 Nucleoprotein (NP) and components of the Spike protein were analysed in GCF samples. The association between antibody reactivity and disease severity was also investigated. Results: IgM and IgG reactivity were detectable in GCF samples as early as week one post symptom onset. Differential patterns of antibody reactivity across the NP and Spike proteins were noted. Antibody responses to NP appeared earlier, a trend noted for both the IgM and IgG; however, the NP IgM response was not as robust as IgM responses to Spike proteins. There was some evidence that higher levels of antibody in GCF in the first 14 days post symptom onset were associated with a more severe disease and for this association to be more significant with the IgM response. Conclusions: Gingival crevicular fluid forms a useful analyte for the detection and monitoring of SARS-CoV-2 antibody responses. The data demonstrates a dynamic antibody response across different protein targets and indicates an association between severe disease and higher levels of antibody

Adeno-associated virus 2 infection in children with non-A-E hepatitis

An outbreak of acute hepatitis of unknown aetiology in children was reported in Scotland in April 2022$^{1}$ and has now been identified in 35 countries$^{2}$. Several recent studies have suggested an association with human adenovirus (HAdV), a virus not commonly associated with hepatitis. Here we report a detailed case-control investigation and find an association between adeno-associated virus (AAV2) infection and host genetics in disease susceptibility. Using next-generation sequencing (NGS), reverse transcription-polymerase chain reaction (RT-PCR), serology and in situ hybridisation (ISH), we detected recent infection with AAV2 in the plasma and liver samples of 26/32 (81%) hepatitis cases versus 5/74 (7%) of controls. Further, AAV2 was detected within ballooned hepatocytes alongside a prominent T cell infiltrate in liver biopsies. In keeping with a CD4+ T-cell-mediated immune pathology, the Human Leucocyte Antigen (HLA) class II DRB1*04:01 allele was identified in 25/27 cases (93%), compared with a background frequency of 10/64 (16%; p=5.49 x 10$^{-12}$). In summary, we report an outbreak of acute paediatric hepatitis associated with AAV2 infection (most likely acquired as a coinfection with HAdV which is required as a "helper virus" to support AAV2 replication) and HLA class II-related disease susceptibility

SARS-CoV-2 antibody responses associate with sex, age and disease severity in previously uninfected people admitted to hospital with COVID-19: an ISARIC4C prospective study

The SARS-CoV-2 pandemic enables the analysis of immune responses induced against a novel coronavirus infecting immunologically naïve individuals. This provides an opportunity for analysis of immune responses and associations with age, sex and disease severity. Here we measured an array of solid-phase binding antibody and viral neutralising Ab (nAb) responses in participants (n=337) of the ISARIC4C cohort and characterised their correlation with peak disease severity during acute infection and early convalescence. Overall, the responses in a Double Antigen Binding Assay (DABA) for antibody to the receptor binding domain (anti-RBD) correlated well with IgM as well as IgG responses against viral spike, S1 and nucleocapsid protein (NP) antigens. DABA reactivity also correlated with nAb. As we and others reported previously, there is greater risk of severe disease and death in older men, whilst the sex ratio was found to be equal within each severity grouping in younger people. In older males with severe disease (mean age 68 years), peak antibody levels were found to be delayed by one to two weeks compared with women, and nAb responses were delayed further. Additionally, we demonstrated that solid-phase binding antibody responses reached higher levels in males as measured via DABA and IgM binding against Spike, NP and S1 antigens. In contrast, this was not observed for nAb responses. When measuring SARS-CoV-2 RNA transcripts (as a surrogate for viral shedding) in nasal swabs at recruitment, we saw no significant differences by sex or disease severity status. However, we have shown higher antibody levels associated with low nasal viral RNA indicating a role of antibody responses in controlling viral replication and shedding in the upper airway. In this study, we have shown discernible differences in the humoral immune responses between males and females and these differences associate with age as well as with resultant disease severity