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Most of the attention in the surveillance of evolution of SARS-CoV-2 has been centered on single nucleotide substitutions in the spike glycoprotein. We show that in-frame deletions (IFDs) also play a significant role in the evolution of viral genome. The percentage of genomes and lineages with IFDs is growing rapidly and they co-occur independently in multiple lineages, including emerging variants of concerns. IFDs distribution is correlated with spike mutations associated with immune escape and concentrated in proteins involved in interactions with the host immune system. Structural analysis suggests that IFDs remodel viral proteins surfaces at common epitopes and interaction interfaces, affecting the virus interactions with the immune system. We hypothesize that the increased frequency of IFDs is an adaptive response to elevated global population immunity. SummaryMonitoring of SARS-CoV-2 genome evolution uncovers increased frequency and non-random distribution of in-frame deletions in recently emerged lineages.
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In this paper we report on genome sequencing of 154 SARS-CoV-2 samples between June and July 2021 (Summer outbreak) in the Bailiwick of Jersey, a UK channel island. We have analysed extensive data collected on 598,155 RT-qPCR tests that identified 8,950 positive cases as part of public health surveillance from September 2020 to August 2021. Our study implemented an amplicon-based sequencing approach using the Oxford Nanopore Technology (ONT) portable device. This revealed the emergence of twelve AY sublineages and were clustered into the Delta sub-clades 21I and 21J. This was integrated alongside an existing RT-qPCR diagnostic laboratory to provide a sample-to-sequence turnaround time of approximately 30 hours with significant scope for optimisation. Owing to the geographic remoteness of the island from large scale sequencing infrastructure, this presents an opportunity to provide policy makers with near real-time sequencing findings. Our analysis suggests that age and sex remained a substantial risk factor for mortality. We observe viral loads are higher in advanced ages and unvaccinated individuals. The median age of SARS-CoV-2 positive individuals was higher during winter than the summer outbreak, and the contact tracing program showed that younger individuals stayed positive for longer.
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Assessment of the unknown performance of saliva for the detection of the novel SARS-CoV-2 variant of concern (VOC) B.1.351 (501Y.V2) lineage is essential as saliva has been shown to be an equivalent, less invasive and a less costly alternative to nasopharyngeal swabs for the molecular detection of SARS-CoV-2 infection in pre-variant studies. Between 1st August 2020 and 16th January 2021, we enrolled 410 eligible ambulatory participants who presented to Groote Schuur Hospital (GSH) in Cape Town, South Africa for SARS-CoV-2 testing. Of these, 300 were enrolled prior to, and 110 after, the initial detection and replacement of wild-type by the B.1.351 variant. All participants provided a supervised self-collected mid-turbinate (MT) and saliva (SA) swab, in addition to the standard HCW collected NP swab which were all tested by RT-PCR in an accredited diagnostic laboratory. Positive percent agreement to NP swab for SA swabs pre- and post-variant were 51.5% and 72.5% respectively while these values for MT swabs were 75.8% and 77.5%. The negative percent agreement for all swab types during all periods was >98%. The basis for this marked improvement of SA swabs as a diagnostic sample for B.1.351 virus is still being investigated.
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The Omicron variant is characterised by more than 50 distinct mutations, the majority of which are located in the spike protein. The implications of these mutations for disease transmission, tissue tropism and diagnostic testing are still to be determined. We evaluated the relative performance of saliva and mid-turbinate swabs as RT-PCR samples for the Delta and Omicron variants. The positive percent agreement (PPA) of saliva swabs and mid-turbinate swabs to a composite standard was 71% (95% CI: 53-84%) and 100% (95% CI: 89-100%), respectively, for the Delta variant. However, for the Omicron variant saliva and mid-turbinate swabs had a 100% (95% CI: 90-100%) and 86% (95% CI: 71-94%) PPA, respectively. This finding supports ex-vivo data of altered tissue tropism from other labs for the Omicron variant. Reassessment of the diagnostic testing standard-of-care may be required as the Omicron variant become the dominant variant worldwide.
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BackgroundThe SARS-CoV-2 Beta variant, associated with immune escape and higher transmissibility, drove a more severe second COVID-19 wave in South Africa. Individual patient level characteristics and outcomes with the Beta variant are not well characterized. MethodsWe performed a retrospective cohort study comparing disease severity and inpatient mortality of COVID-19 pneumonia between the first and second wave periods at a referral hospital in Cape Town, South Africa. Beta variant infection was confirmed by genomic sequencing. Outcomes were analyzed with logistic regression and accelerated failure time models. Results1,182 patients were included: 571 during the first wave period and 611 from the second wave. Beta variant accounted for 97% of infections in the second wave. There was no difference in crude in-hospital mortality between wave periods (first wave 22.2%, second wave 22.1%; p = 0.9). Time to death was decreased with higher weekly hospital admissions (16%; 95% CI, 8 to 24 for every 50-patient increase), age (18%; 95% CI, 12 to 24 for every 10-year increase) and hypertension (31%; 95% CI, 12 to 46). Corticosteroid use delayed time to death by 2-fold (95% CI, 1.5 to 3.0). Admission during the second wave decreased time to death after adjustment for other predictors, but this did not reach statistical significance (24%; 95% CI, 47 to -2). There was no effect of HIV on survival. ConclusionsThere was a trend towards earlier mortality during the second COVID-19 wave driven by the Beta variant, suggesting a possible biological basis. Use of oral prednisone was strongly protective. Key pointsIn Cape Town, South Africa, the second wave of COVID-19, dominated by the Beta variant, was associated with decreased time to inpatient death after adjustment for age, comorbidities, steroid use, and admission numbers. Use of oral prednisone was strongly protective.
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A novel proxy for the Delta variant, RNA-dependent RNA polymerase target delay in the Seegene Allplex 2019-nCoV PCR assay, was associated with higher mortality (adjusted Odds Ratio 1.45 [95%CI 1.13-1.86]), compared to presumptive Beta infection, in the Western Cape, South Africa (April-July 2021). Prior diagnosed infection and vaccination were protective.
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Routine SARS-CoV-2 surveillance in the Western Cape region of South Africa (January-August 2021) found a reduced PCR amplification efficiency of the RdRp gene target of the Seegene, Allplex 2019-nCoV diagnostic assay when detecting the Delta variant. We propose that this can be used as a surrogate for variant detection.
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Neutralization escape by SARS-CoV-2 variants, as has been observed in the 501Y.V2 (B.1.351) variant, has impacted the efficacy of first generation COVID-19 vaccines. Here, the antibody response to the 501Y.V2 variant was examined in a cohort of patients hospitalized with COVID-19 in early 2021 - when over 90% of infections in South Africa were attributed to 501Y.V2. Robust binding and neutralizing antibody titers to the 501Y.V2 variant were detected and these binding antibodies showed high levels of cross-reactivity for the original variant, from the first wave. In contrast to an earlier study where sera from individuals infected with the original variant showed dramatically reduced potency against 501Y.V2, sera from 501Y.V2-infected patients maintained good cross-reactivity against viruses from the first wave. Furthermore, sera from 501Y.V2-infected patients also neutralized the 501Y.V3 (P.1) variant first described in Brazil, and now circulating globally. Collectively these data suggest that the antibody response in patients infected with 501Y.V2 has a broad specificity and that vaccines designed with the 501Y.V2 sequence may elicit more cross-reactive responses.
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SARS-CoV-2 variants have emerged that escape neutralization and potentially impact vaccine efficacy. T cell responses play a role in protection from reinfection and severe disease, but the potential for spike mutations to affect T cell immunity is poorly studied. We assessed both neutralizing antibody and T cell responses in 44 South African COVID-19 patients infected either with B.1.351, now dominant in South Africa, or infected prior to its emergence ( first wave), to provide an overall measure of immune evasion. We show for the first time that robust spike-specific CD4 and CD8 T cell responses were detectable in B.1.351-infected patients, similar to first wave patients. Using peptides spanning only the B.1.351 mutated regions, we identified CD4 T cell responses targeting the wild type peptides in 12/22 (54.5%) first wave patients, all of whom failed to recognize corresponding B.1.351-mutated peptides (p=0.0005). However, responses to the mutated regions formed only a small proportion (15.7%) of the overall CD4 response, and few patients (3/44) mounted CD8 responses that targeted the mutated regions. First wave patients showed a 12.7 fold reduction in plasma neutralization of B.1.351. This study shows that despite loss of recognition of immunodominant CD4 epitope(s), overall CD4 and CD8 T cell responses to B.1.351 are preserved. These observations may explain why, despite substantial loss of neutralizing antibody activity against B.1.351, several vaccines have retained the ability to protect against severe COVID-19 disease. One Sentence SummaryT cell immunity to SARS-CoV-2 B.1.351 is preserved despite some loss of variant epitope recognition by CD4 T cells.
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BackgroundEmerging data suggest that SARS-CoV-2 Omicron variant of concern (VOC)is associated with reduced risk of severe disease. The extent to which this reflects a difference in the inherent virulence of Omicron, or just higher levels of population immunity, is currently not clear. MethodsRdRp target delay (RTD: a difference in cycle threshold value of RdRp - E > 3.5) in the Seegene Allplex 2019-nCoV PCR assay is a proxy marker for the Delta VOC. The absence of this proxy marker in the period of transition to Omicron was used to identify suspected Omicron VOC infections. Cox regression was performed for the outcome of hospital admission in those who tested positive for SARS-CoV-2 on the Seegene Allplex assay from 1 November to 14 December 2021 in the Western Cape Province, South Africa, public sector. Vaccination status at time of diagnosis, as well as prior diagnosed infection and comorbidities, were adjusted for. Results150 cases with RTD (proxy for Delta) and 1486 cases without RTD (proxy for Omicron) were included. Cases without RTD had a lower hazard of admission (adjusted Hazard Ratio [aHR] of 0.56, 95% confidence interval [CI] 0.34-0.91). Complete vaccination was protective of admission with an aHR of 0.45 (95%CI 0.26-0.77). ConclusionOmicron has resulted in a lower risk of hospital admission, compared to contemporaneous Delta infection in the Western Cape Province, when using the proxy marker of RTD. Under-ascertainment of reinfections with an immune escape variant like Omicron remains a challenge to accurately assessing variant virulence.
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The Johnson and Johnson Ad26.COV2.S single dose vaccine represents an attractive option for COVID-19 vaccination in resource limited countries. We examined the effect of prior infection with different SARS-CoV-2 variants on Ad26.COV2.S immunogenicity. We compared participants who were SARS-CoV-2 naive with those either infected with the ancestral D614G virus, or infected in the second wave when Beta predominated. Prior infection significantly boosted spike binding antibodies, antibody-dependent cellular cytotoxicity and neutralizing antibodies against D614G, Beta and Delta, however neutralization cross-reactivity varied by wave. Robust CD4 and CD8 T cell responses were induced after vaccination, regardless of prior infection. T cell recognition of variants was largely preserved, apart from some reduction in CD8 recognition of Delta. Thus, Ad26.COV2.S vaccination following infection may result in enhanced protection against COVID-19. The impact of the infecting variant on neutralization breadth after vaccination has implications for the design of second-generation vaccines based on variants of concern.
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Continued uncontrolled transmission of the severe acute respiratory syndrome-related coronavirus 2 (SARS-CoV-2) in many parts of the world is creating the conditions for significant virus evolution. Here, we describe a new SARS-CoV-2 lineage (501Y.V2) characterised by eight lineage-defining mutations in the spike protein, including three at important residues in the receptor-binding domain (K417N, E484K and N501Y) that may have functional significance. This lineage emerged in South Africa after the first epidemic wave in a severely affected metropolitan area, Nelson Mandela Bay, located on the coast of the Eastern Cape Province. This lineage spread rapidly, becoming within weeks the dominant lineage in the Eastern Cape and Western Cape Provinces. Whilst the full significance of the mutations is yet to be determined, the genomic data, showing the rapid displacement of other lineages, suggest that this lineage may be associated with increased transmissibility.
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The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) epidemic in southern Africa has been characterised by three distinct waves. The first was associated with a mix of SARS-CoV-2 lineages, whilst the second and third waves were driven by the Beta and Delta variants respectively1-3. In November 2021, genomic surveillance teams in South Africa and Botswana detected a new SARS-CoV-2 variant associated with a rapid resurgence of infections in Gauteng Province, South Africa. Within three days of the first genome being uploaded, it was designated a variant of concern (Omicron) by the World Health Organization and, within three weeks, had been identified in 87 countries. The Omicron variant is exceptional for carrying over 30 mutations in the spike glycoprotein, predicted to influence antibody neutralization and spike function4. Here, we describe the genomic profile and early transmission dynamics of Omicron, highlighting the rapid spread in regions with high levels of population immunity.
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The progression of the SARS-CoV-2 pandemic in Africa has so far been heterogeneous and the full impact is not yet well understood. Here, we describe the genomic epidemiology using a dataset of 8746 genomes from 33 African countries and two overseas territories. We show that the epidemics in most countries were initiated by importations, predominantly from Europe, which diminished following the early introduction of international travel restrictions. As the pandemic progressed, ongoing transmission in many countries and increasing mobility led to the emergence and spread within the continent of many variants of concern and interest, such as B.1.351, B.1.525, A.23.1 and C.1.1. Although distorted by low sampling numbers and blind-spots, the findings highlight that Africa must not be left behind in the global pandemic response, otherwise it could become a breeding ground for new variants.
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Investment in Africa over the past year with regards to SARS-CoV-2 genotyping has led to a massive increase in the number of sequences, exceeding 100,000 genomes generated to track the pandemic on the continent. Our results show an increase in the number of African countries able to sequence within their own borders, coupled with a decrease in sequencing turnaround time. Findings from this genomic surveillance underscores the heterogeneous nature of the pandemic but we observe repeated dissemination of SARS-CoV-2 variants within the continent. Sustained investment for genomic surveillance in Africa is needed as the virus continues to evolve, particularly in the low vaccination landscape. These investments are very crucial for preparedness and response for future pathogen outbreaks. One-Sentence SummaryExpanding Africa SARS-CoV-2 sequencing capacity in a fast evolving pandemic.