The Canadian VirusSeq Data Portal & Duotang: open resources for SARS-CoV-2 viral sequences and genomic epidemiology.

The COVID-19 pandemic led to a large global effort to sequence SARS-CoV-2 genomes from patient samples to track viral evolution and inform public health response. Millions of SARS-CoV-2 genome sequences have been deposited in global public repositories. The Canadian COVID-19 Genomics Network (CanCOGeN - VirusSeq), a consortium tasked with coordinating expanded sequencing of SARS-CoV-2 genomes across Canada early in the pandemic, created the Canadian VirusSeq Data Portal, with associated data pipelines and procedures, to support these efforts. The goal of VirusSeq was to allow open access to Canadian SARS-CoV-2 genomic sequences and enhanced, standardized contextual data that were unavailable in other repositories and that meet FAIR standards (Findable, Accessible, Interoperable and Reusable). The Portal data submission pipeline contains data quality checking procedures and appropriate acknowledgement of data generators that encourages collaboration. Here we also highlight Duotang, a web platform that presents genomic epidemiology and modeling analyses on circulating and emerging SARS-CoV-2 variants in Canada. Duotang presents dynamic changes in variant composition of SARS-CoV-2 in Canada and by province, estimates variant growth, and displays complementary interactive visualizations, with a text overview of the current situation. The VirusSeq Data Portal and Duotang resources, alongside additional analyses and resources computed from the Portal (COVID-MVP, CoVizu), are all open-source and freely available. Together, they provide an updated picture of SARS-CoV-2 evolution to spur scientific discussions, inform public discourse, and support communication with and within public health authorities. They also serve as a framework for other jurisdictions interested in open, collaborative sequence data sharing and analyses.

SARS-CoV-2 Surveillance of Wild Mice and Rats in North American Cities.

From July 2020 to June 2021, 248 wild house mice (Mus musculus), deer mice (Peromyscus maniculatus), brown rats (Rattus norvegicus), and black rats (Rattus rattus) from Texas and Washington, USA, and British Columbia, Canada, were tested for SARS-CoV-2 exposure and infection. Two brown rats and 11 house mice were positive for neutralizing antibodies using a surrogate virus neutralization test, but negative or indeterminate with the Multiplexed Fluorometric ImmunoAssay COVID-Plex, which targets full-length spike and nuclear proteins. Oro-nasopharyngeal swabs and fecal samples tested negative by RT-qPCR, with an indeterminate fecal sample in one house mouse. Continued surveillance of SARS-CoV-2 in wild rodents is warranted.

Rapid, high-throughput, cost-effective whole-genome sequencing of SARS-CoV-2 using a condensed library preparation of the Illumina DNA Prep kit.

The ongoing COVID-19 pandemic necessitates cost-effective, high-throughput, and timely whole-genome sequencing (WGS) of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) viruses for outbreak investigations, identifying variants of concern (VoC), characterizing vaccine breakthrough infections, and public health surveillance. In addition, the enormous demand for WGS on supply chains and the resulting shortages of laboratory supplies necessitated the use of low-reagent and low-consumable methods. Here, we report an optimized library preparation method (the BCCDC cutdown method) that can be used in a high-throughput scenario, where one technologist can perform 576 library preparations (6 plates of 96 samples) over the course of one 8-hour shift. The same protocol can also be used in a rapid turnaround time scenario, from primary samples (up to 96 samples) to loading on a sequencer in an 8-hour shift. This new method uses Freed et al.'s 1,200 bp primer sets (Biol Methods Protoc 5:bpaa014, 2020, https://doi.org/10.1093/biomethods/bpaa014) and a modified and condensed Illumina DNA Prep workflow (Illumina, CA, USA). Compared to the original protocol, the application of this new method using hundreds of clinical specimens demonstrated equivalent results to the full-length DNA Prep workflow at 45% of the cost, 15% of consumables required (such as pipet tips), 25% of manual hands-on time, and 15% of on-instrument time if performing on a liquid handler, with no compromise in sequence quality. Results demonstrate that this new method is a rapid, simple, cost-effective, and high-quality SARS-CoV-2 WGS protocol. IMPORTANCE: Sequencing has played an invaluable role in the response to the COVID-19 pandemic. Ongoing work in this area, however, demands optimization of laboratory workflow to increase sequencing capacity, improve turnaround time, and reduce cost without compromising sequence quality. This report describes an optimized DNA library preparation method for improved whole-genome sequencing of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pathogen. The workflow advantages summarized here include significant time, cost, and consumable savings, which suggest that this new method is an efficient, scalable, and pragmatic alternative for SARS-CoV-2 whole-genome sequencing.

Nasopharyngeal angiotensin converting enzyme 2 (ACE2) expression as a risk-factor for SARS-CoV-2 transmission in concurrent hospital associated outbreaks.

BACKGROUND: Widespread human-to-human transmission of the severe acute respiratory syndrome coronavirus two (SARS-CoV-2) stems from a strong affinity for the cellular receptor angiotensin converting enzyme two (ACE2). We investigate the relationship between a patient's nasopharyngeal ACE2 transcription and secondary transmission within a series of concurrent hospital associated SARS-CoV-2 outbreaks in British Columbia, Canada. METHODS: Epidemiological case data from the outbreak investigations was merged with public health laboratory records and viral lineage calls, from whole genome sequencing, to reconstruct the concurrent outbreaks using infection tracing transmission network analysis. ACE2 transcription and RNA viral load were measured by quantitative real-time polymerase chain reaction. The transmission network was resolved to calculate the number of potential secondary cases. Bivariate and multivariable analyses using Poisson and Negative Binomial regression models was performed to estimate the association between ACE2 transcription the number of SARS-CoV-2 secondary cases. RESULTS: The infection tracing transmission network provided n = 76 potential transmission events across n = 103 cases. Bivariate comparisons found that on average ACE2 transcription did not differ between patients and healthcare workers (P = 0.86). High ACE2 transcription was observed in 98.6% of transmission events, either the primary or secondary case had above average ACE2. Multivariable analysis found that the association between ACE2 transcription (log2 fold-change) and the number of secondary transmission events differs between patients and healthcare workers. In health care workers Negative Binomial regression estimated that a one-unit change in ACE2 transcription decreases the number of secondary cases (ß = -0.132 (95%CI: -0.255 to -0.0181) adjusting for RNA viral load. Conversely, in patients a one-unit change in ACE2 transcription increases the number of secondary cases (ß = 0.187 (95% CI: 0.0101 to 0.370) adjusting for RNA viral load. Sensitivity analysis found no significant relationship between ACE2 and secondary transmission in health care workers and confirmed the positive association among patients. CONCLUSION: Our study suggests that ACE2 transcription has a positive association with SARS-CoV-2 secondary transmission in admitted inpatients, but not health care workers in concurrent hospital associated outbreaks, and it should be further investigated as a risk-factor for viral transmission.

Prospective, clinical comparison of self-collected throat-bilateral nares swabs and saline gargle compared to health care provider collected nasopharyngeal swabs among symptomatic outpatients with potential SARS-CoV-2 infection.

Background: In British Columbia (BC), self-collected saline gargle (SG) is the only alternative to health care provider (HCP)-collected nasopharyngeal (NP) swabs to detect SARS-CoV-2 in an outpatient setting by polymerase chain reaction (PCR). However, some individuals cannot perform a SG. Our study aimed to assess combined throat-bilateral nares (TN) swabbing as a swab-based alternative. Methods: Symptomatic individuals greater than 12 years of age seeking a COVID-19 PCR test at one of two COVID-19 collection centres in Metro Vancouver were asked to participate in this study. Participants provided a HCP-collected NP sample and a self-collected SG and TN sample for PCR testing, which were either HCP observed or unobserved. Results: Three-hundred and eleven individuals underwent all three collections. Compared against HCP-NP, SG was 99% sensitive and 98% specific (kappa 0.97) and TN was 99% sensitive and 99% specific (kappa 0.98). Using the final clinical test interpretation as the reference standard, NP was 98% sensitive and 100% specific (kappa 0.98), and both SG and TN were 99% sensitive and 100% specific (both kappa 0.99). Mean cycle threshold values for each viral target were higher in SG specimens compared to the other sample types; however, this did not significantly impact the clinical performance, because the positivity rates were similar. The clinical performance of all specimen types was comparable within the first 7 days of symptom onset, regardless of the observation method. SG self-collections were rated the most acceptable, followed by TN. Conclusions: TN provides another less invasive self-collection modality for symptomatic outpatient SARS-CoV-2 PCR testing.

Historique: En Colombie-Britannique (C.-B.), l'autoprélèvement de gargarisme d'eau saline (GS) est la seule alternative aux écouvillons nasopharyngés (NP) prélevés par un professionnel de la santé (PdS) pour déceler le SRAS-CoV-2 par test PCR en milieu ambulatoire. Cependant, certaines personnes ne peuvent pas effectuer de GS. La présente étude visait évaluer l'écouvillonnage de la gorge et des deux narines (GN) pour remplacer le GS. Méthodologie: Les personnes symptomatiques de plus de 12 ans qui demandaient un test PCR de la COVID-19 à l'un des deux centres de dépistage de la COVID-19 du Grand Vancouver ont été invitées à participer à la présente étude. Les participants ont fourni un prélèvement NP recueilli par un PdS ainsi qu'un autoprélèvement de GS et GN en vue d'un test PCR, observés ou non par un PdS. Résultats: Au total, 311 personnes ont participé aux trois prélèvements. Par rapport au prélèvement NP-PdS, le GS avait une sensibilité de 99 % et une spécificité de 98 % (kappa 0,97) et le prélèvement GN, une sensibilité de 99 % et une spécificité de 99 % (kappa 0, 98). À l'aide de l'interprétation définitive du test clinique comme norme de référence, le prélèvement NP avait une sensibilité de 98 % et une spécificité de 100 % (kappa 0,98) et tant le GS que le prélèvement GN avaient une sensibilité de 99 % et une spécificité de 100 % (deux kappa 0,99). Les valeurs seuils du cycle moyen de chaque cible virale étaient plus élevées dans les échantillons de GS quand dans les autres types d'échantillons, mais n'avaient pas d'effet significatif sur le rendement clinique, puisque les taux de positivité étaient semblables. Le rendement clinique de tous les types d'échantillons était comparable dans les sept premiers jours suivant l'apparition de la maladie, quel que soit le mode d'observation. L'autoprélèvement de GS a été classé comme le plus acceptable, suivi du prélèvement GN. Conclusions: Le prélèvement GN est un autre mode d'autoprélèvement moins invasif chez les patients ambulatoires symptomatiques qui effectuent un test PCR du SRAS-CoV-2.

Targeted genomic sequencing of avian influenza viruses in wetland sediment from wild bird habitats.

Diverse influenza A viruses (IAVs) circulate in wild birds, including highly pathogenic strains that infect poultry and humans. Consequently, surveillance of IAVs in wild birds is a cornerstone of agricultural biosecurity and pandemic preparedness. Surveillance is traditionally done by testing wild birds directly, but obtaining these specimens is labor intensive, detection rates can be low, and sampling is often biased toward certain avian species. As a result, local incursions of dangerous IAVs are rarely detected before outbreaks begin. Testing environmental specimens from wild bird habitats has been proposed as an alternative surveillance strategy. These specimens are thought to contain diverse IAVs deposited by a broad range of avian hosts, including species that are not typically sampled by surveillance programs. To enable this surveillance strategy, we developed a targeted genomic sequencing method for characterizing IAVs in these challenging environmental specimens. It combines custom hybridization probes, unique molecular index-based library construction, and purpose-built bioinformatic tools, allowing IAV genomic material to be enriched and analyzed with single-fragment resolution. We demonstrated our method on 90 sediment specimens from wetlands around Vancouver, Canada. We recovered 2,312 IAV genome fragments originating from all eight IAV genome segments. Eleven hemagglutinin subtypes and nine neuraminidase subtypes were detected, including H5, the current global surveillance priority. Our results demonstrate that targeted genomic sequencing of environmental specimens from wild bird habitats could become a valuable complement to avian influenza surveillance programs.IMPORTANCEIn this study, we developed genome sequencing tools for characterizing avian influenza viruses in sediment from wild bird habitats. These tools enable an environment-based approach to avian influenza surveillance. This could improve early detection of dangerous strains in local wild birds, allowing poultry producers to better protect their flocks and prevent human exposures to potential pandemic threats. Furthermore, we purposefully developed these methods to contend with viral genomic material that is diluted, fragmented, incomplete, and derived from multiple strains and hosts. These challenges are common to many environmental specimens, making these methods broadly applicable for genomic pathogen surveillance in diverse contexts.

Foodborne Botulism, Canada, 2006-20211.

During 2006-2021, Canada had 55 laboratory-confirmed outbreaks of foodborne botulism, involving 67 cases. The mean annual incidence was 0.01 case/100,000 population. Foodborne botulism in Indigenous communities accounted for 46% of all cases, which is down from 85% of all cases during 1990-2005. Among all cases, 52% were caused by botulinum neurotoxin type E, but types A (24%), B (16%), F (3%), and AB (1%) also occurred; 3% were caused by undetermined serotypes. Four outbreaks resulted from commercial products, including a 2006 international outbreak caused by carrot juice. Hospital data indicated that 78% of patients were transferred to special care units and 70% required mechanical ventilation; 7 deaths were reported. Botulinum neurotoxin type A was associated with much longer hospital stays and more time spent in special care than types B or E. Foodborne botulism often is misdiagnosed. Increased clinician awareness can improve diagnosis, which can aid epidemiologic investigations and patient treatment.

The utility of SARS-CoV-2 genomic data for informative clustering under different epidemiological scenarios and sampling.

OBJECTIVES: Clustering pathogen sequence data is a common practice in epidemiology to gain insights into the genetic diversity and evolutionary relationships among pathogens. We can find groups of cases with a shared transmission history and common origin, as well as identifying transmission hotspots. Motivated by the experience of clustering SARS-CoV-2 cases using whole genome sequence data during the COVID-19 pandemic to aid with public health investigation, we investigated how differences in epidemiology and sampling can influence the composition of clusters that are identified. METHODS: We performed genomic clustering on simulated SARS-CoV-2 outbreaks produced with different transmission rates and levels of genomic diversity, along with varying the proportion of cases sampled. RESULTS: In single outbreaks with a low transmission rate, decreasing the sampling fraction resulted in multiple, separate clusters being identified where intermediate cases in transmission chains are missed. Outbreaks simulated with a high transmission rate were more robust to changes in the sampling fraction and largely resulted in a single cluster that included all sampled outbreak cases. When considering multiple outbreaks in a sampled jurisdiction seeded by different introductions, low genomic diversity between introduced cases caused outbreaks to be merged into large clusters. If the transmission and sampling fraction, and diversity between introductions was low, a combination of the spurious break-up of outbreaks and the linking of closely related cases in different outbreaks resulted in clusters that may appear informative, but these did not reflect the true underlying population structure. Conversely, genomic clusters matched the true population structure when there was relatively high diversity between introductions and a high transmission rate. CONCLUSION: Differences in epidemiology and sampling can impact our ability to identify genomic clusters that describe the underlying population structure. These findings can help to guide recommendations for the use of pathogen clustering in public health investigations.

Emergence of SARS-CoV-2 Delta Variant and Effect of Nonpharmaceutical Interventions, British Columbia, Canada.

In British Columbia, Canada, initial growth of the SARS-CoV-2 Delta variant was slower than that reported in other jurisdictions. Delta became the dominant variant (>50% prevalence) within ≈7-13 weeks of first detection in regions within the United Kingdom and United States. In British Columbia, it remained at <10% of weekly incident COVID-19 cases for 13 weeks after first detection on March 21, 2021, eventually reaching dominance after 17 weeks. We describe the growth of Delta variant cases in British Columbia during March 1-June 30, 2021, and apply retrospective counterfactual modeling to examine factors for the initially low COVID-19 case rate after Delta introduction, such as vaccination coverage and nonpharmaceutical interventions. Growth of COVID-19 cases in the first 3 months after Delta emergence was likely limited in British Columbia because additional nonpharmaceutical interventions were implemented to reduce levels of contact at the end of March 2021, soon after variant emergence.

A comparison of sampling and testing approaches for the surveillance of SARS-CoV-2 in farmed American mink.

Surveillance for SARS-CoV-2 in American mink (Neovison vison) is a global priority because outbreaks on mink farms have potential consequences for animal and public health. Surveillance programs often focus on screening natural mortalities; however, significant knowledge gaps remain regarding sampling and testing approaches. Using 76 mink from 3 naturally infected farms in British Columbia, Canada, we compared the performance of 2 reverse-transcription real-time PCR (RT-rtPCR) targets (the envelope [E] and RNA-dependent RNA polymerase [RdRp] genes) as well as serology. We also compared RT-rtPCR and sequencing results from nasopharyngeal, oropharyngeal, skin, and rectal swabs, as well as nasopharyngeal samples collected using swabs and interdental brushes. We found that infected mink were generally RT-rtPCR-positive on all samples; however, Ct values differed significantly among sample types (nasopharyngeal < oropharyngeal < skin < rectal). There was no difference in the results of nasopharyngeal samples collected using swabs or interdental brushes. For most mink (89.4%), qualitative (i.e., positive vs. negative) serology and RT-rtPCR results were concordant. However, mink were positive on RT-rtPCR and negative on serology and vice versa, and there was no significant correlation between Ct values on RT-rtPCR and percent inhibition on serology. Both the E and RdRp targets were detectable in all sample types, albeit with a small difference in Ct values. Although SARS-CoV-2 RNA can be detected in multiple sample types, passive surveillance programs in mink should focus on multiple target RT-rtPCR testing of nasopharyngeal samples in combination with serology.

Impact of Age and Severe Acute Respiratory Syndrome Coronavirus 2 Breakthrough Infection on Humoral Immune Responses After Three Doses of Coronavirus Disease 2019 mRNA Vaccine.

Background: Longer-term immune response data after 3 doses of coronavirus disease 2019 (COVID-19) mRNA vaccine remain limited, particularly among older adults and after Omicron breakthrough infection. Methods: We quantified wild-type- and Omicron-specific serum immunoglobulin (Ig)G levels, angiotensin-converting enzyme 2 displacement activities, and live virus neutralization up to 6 months after third dose in 116 adults aged 24-98 years who remained COVID-19 naive or experienced their first severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection during this time. Results: Among the 78 participants who remained COVID-19 naive throughout follow up, wild-type- and Omicron-BA.1-specific IgG concentrations were comparable between younger and older adults, although BA.1-specific responses were consistently significantly lower than wild-type-specific responses in both groups. Wild-type- and BA.1-specific IgG concentrations declined at similar rates in COVID-19-naive younger and older adults, with median half-lives ranging from 69 to 78 days. Antiviral antibody functions declined substantially over time in COVID-19-naive individuals, particularly in older adults: by 6 months, BA.1-specific neutralization was undetectable in 96% of older adults, versus 56% of younger adults. Severe acute respiratory syndrome coronavirus 2 infection, experienced by 38 participants, boosted IgG levels and neutralization above those induced by vaccination alone. Nevertheless, BA.1-specific neutralization remained significantly lower than wild-type, with BA.5-specific neutralization lower still. Higher Omicron BA.1-specific neutralization 1 month after third dose was an independent correlate of lower SARS-CoV-2 infection risk. Conclusions: Results underscore the immune benefits of the third COVID-19 mRNA vaccine dose in adults of all ages and identify vaccine-induced Omicron-specific neutralization as a correlate of protective immunity. Systemic antibody responses and functions however, particularly Omicron-specific neutralization, decline rapidly in COVID-19-naive individuals, particularly in older adults, supporting the need for additional booster doses.

Realizing the value in "non-standard" parts of the qPCR standard curve by integrating fundamentals of quantitative microbiology.

The real-time polymerase chain reaction (PCR), commonly known as quantitative PCR (qPCR), is increasingly common in environmental microbiology applications. During the COVID-19 pandemic, qPCR combined with reverse transcription (RT-qPCR) has been used to detect and quantify SARS-CoV-2 in clinical diagnoses and wastewater monitoring of local trends. Estimation of concentrations using qPCR often features a log-linear standard curve model calibrating quantification cycle (Cq) values obtained from underlying fluorescence measurements to standard concentrations. This process works well at high concentrations within a linear dynamic range but has diminishing reliability at low concentrations because it cannot explain "non-standard" data such as Cq values reflecting increasing variability at low concentrations or non-detects that do not yield Cq values at all. Here, fundamental probabilistic modeling concepts from classical quantitative microbiology were integrated into standard curve modeling approaches by reflecting well-understood mechanisms for random error in microbial data. This work showed that data diverging from the log-linear regression model at low concentrations as well as non-detects can be seamlessly integrated into enhanced standard curve analysis. The newly developed model provides improved representation of standard curve data at low concentrations while converging asymptotically upon conventional log-linear regression at high concentrations and adding no fitting parameters. Such modeling facilitates exploration of the effects of various random error mechanisms in experiments generating standard curve data, enables quantification of uncertainty in standard curve parameters, and is an important step toward quantifying uncertainty in qPCR-based concentration estimates. Improving understanding of the random error in qPCR data and standard curve modeling is especially important when low concentrations are of particular interest and inappropriate analysis can unduly affect interpretation, conclusions regarding lab performance, reported concentration estimates, and associated decision-making.

The DataHarmonizer: a tool for faster data harmonization, validation, aggregation and analysis of pathogen genomics contextual information.

Pathogen genomics is a critical tool for public health surveillance, infection control, outbreak investigations as well as research. In order to make use of pathogen genomics data, they must be interpreted using contextual data (metadata). Contextual data include sample metadata, laboratory methods, patient demographics, clinical outcomes and epidemiological information. However, the variability in how contextual information is captured by different authorities and how it is encoded in different databases poses challenges for data interpretation, integration and their use/re-use. The DataHarmonizer is a template-driven spreadsheet application for harmonizing, validating and transforming genomics contextual data into submission-ready formats for public or private repositories. The tool's web browser-based JavaScript environment enables validation and its offline functionality and local installation increases data security. The DataHarmonizer was developed to address the data sharing needs that arose during the COVID-19 pandemic, and was used by members of the Canadian COVID Genomics Network (CanCOGeN) to harmonize SARS-CoV-2 contextual data for national surveillance and for public repository submission. In order to support coordination of international surveillance efforts, we have partnered with the Public Health Alliance for Genomic Epidemiology to also provide a template conforming to its SARS-CoV-2 contextual data specification for use worldwide. Templates are also being developed for One Health and foodborne pathogens. Overall, the DataHarmonizer tool improves the effectiveness and fidelity of contextual data capture as well as its subsequent usability. Harmonization of contextual information across authorities, platforms and systems globally improves interoperability and reusability of data for concerted public health and research initiatives to fight the current pandemic and future public health emergencies. While initially developed for the COVID-19 pandemic, its expansion to other data management applications and pathogens is already underway.

Hands off the Mink! Using Environmental Sampling for SARS-CoV-2 Surveillance in American Mink.

Throughout the COVID-19 pandemic, numerous non-human species were shown to be susceptible to natural infection by SARS-CoV-2, including farmed American mink. Once infected, American mink can transfer the virus from mink to human and mink to mink, resulting in a high rate of viral mutation. Therefore, outbreak surveillance on American mink farms is imperative for both mink and human health. Historically, disease surveillance on mink farms has consisted of a combination of mortality and live animal sampling; however, these methodologies have significant limitations. This study compared PCR testing of both deceased and live animal samples to environmental samples on an active outbreak premise, to determine the utility of environmental sampling. Environmental sampling mirrored trends in both deceased and live animal sampling in terms of percent positivity and appeared more sensitive in some low-prevalence instances. PCR CT values of environmental samples were significantly different from live animal samples' CT values and were consistently high (mean CT = 36.2), likely indicating a low amount of viral RNA in the samples. There is compelling evidence in favour of environmental sampling for the purpose of disease surveillance, specifically as an early warning tool for SARS-CoV-2; however, further work is needed to ultimately determine whether environmental samples are viable sources for molecular epidemiology investigations.

Clinical severity of Omicron subvariants BA.1, BA.2, and BA.5 in a population-based cohort study in British Columbia, Canada.

The SARS-CoV-2 variant Omicron emerged in late 2021. In British Columbia (BC), Canada, and globally, three genetically distinct subvariants of Omicron, BA.1, BA.2, and BA.5, emerged and became dominant successively within an 8-month period. SARS-CoV-2 subvariants continue to circulate in the population, acquiring new mutations that have the potential to alter infectivity, immunity, and disease severity. Here, we report a propensity-matched severity analysis from residents of BC over the course of the Omicron wave, including 39,237 individuals infected with BA.1, BA.2, or BA.5 based on paired high-quality sequence data and linked to comprehensive clinical outcomes data between December 23, 2021 and August 31, 2022. Relative to BA.1, BA.2 cases were associated with a 15% and 28% lower risk of hospitalization and intensive care unit (ICU) admission (aHRhospital = 1.17; 95% confidence interval [CI] = 1.096-1.252; aHRICU = 1.368; 95% CI = 1.152-1.624), whereas BA.5 infections were associated with an 18% higher risk of hospitalization (aHRhospital = 1.18; 95% CI = 1.133-1.224) after accounting for age, sex, comorbidities, vaccination status, geography, and social determinants of health. Phylogenetic analysis revealed no specific subclades associated with more severe clinical outcomes for any Omicron subvariant. In summary, BA.1, BA.2, and BA.5 subvariants were associated with differences in clinical severity, emphasizing how variant-specific monitoring programs remain critical components of patient and population-level public health responses as the pandemic continues.

People With Human Immunodeficiency Virus Receiving Suppressive Antiretroviral Therapy Show Typical Antibody Durability After Dual Coronavirus Disease 2019 Vaccination and Strong Third Dose Responses.

BACKGROUND: Longer-term humoral responses to 2-dose coronavirus disease 2019 (COVID-19) vaccines remain incompletely characterized in people living with human immunodeficiency virus (HIV) (PLWH), as do initial responses to a third dose. METHODS: We measured antibodies against the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein receptor-binding domain, angiotensin-converting enzyme 2 (ACE2) displacement, and viral neutralization against wild-type and Omicron strains up to 6 months after 2-dose vaccination, and 1 month after the third dose, in 99 PLWH receiving suppressive antiretroviral therapy and 152 controls. RESULTS: Although humoral responses naturally decline after 2-dose vaccination, we found no evidence of lower antibody concentrations or faster rates of antibody decline in PLWH compared with controls after accounting for sociodemographic, health, and vaccine-related factors. We also found no evidence of poorer viral neutralization in PLWH after 2 doses, nor evidence that a low nadir CD4+ T-cell count compromised responses. Post-third-dose humoral responses substantially exceeded post-second-dose levels, though Omicron-specific responses were consistently weaker than responses against wild-type virus. Nevertheless, post-third-dose responses in PLWH were comparable to or higher than controls. An mRNA-1273 third dose was the strongest consistent correlate of higher post-third-dose responses. CONCLUSION: PLWH receiving suppressive antiretroviral therapy mount strong antibody responses after 2- and 3-dose COVID-19 vaccination. Results underscore the immune benefits of third doses in light of Omicron.

Antibody response durability following three-dose coronavirus disease 2019 vaccination in people with HIV receiving suppressive antiretroviral therapy.

BACKGROUND: Limited data exist regarding longer term antibody responses following three-dose coronavirus disease 2019 (COVID-19) vaccination, and the impact of a first SARS-CoV-2 infection during this time, in people with HIV (PWH) receiving suppressive antiretroviral therapy (ART). We quantified wild-type-specific, Omicron BA.1-specific and Omicron BA.5-specific responses up to 6 months post-third dose in 64 PWH and 117 controls who remained COVID-19-naive or experienced their first SARS-CoV-2 infection during this time. DESIGN: Longitudinal observational cohort. METHODS: We quantified wild-type-specific and Omicron-specific anti-Spike receptor-binding domain IgG concentrations, ACE2 displacement activities and live virus neutralization at 1, 3 and 6 months post-third vaccine dose. RESULTS: Third doses boosted all antibody measures above two-dose levels, but BA.1-specific responses remained significantly lower than wild-type-specific ones, with BA.5-specific responses lower still. Serum IgG concentrations declined at similar rates in COVID-19-naive PWH and controls post-third dose (median wild-type-specific and BA.1-specific half-lives were between 66 and 74 days for both groups). Antibody function also declined significantly yet comparably between groups: 6 months post-third dose, BA.1-specific neutralization was undetectable in more than 80% of COVID-19 naive PWH and more than 90% of controls. Breakthrough SARS-CoV-2 infection boosted antibody concentrations and function significantly above vaccine-induced levels in both PWH and controls, though BA.5-specific neutralization remained significantly poorer than BA.1 even post-breakthrough. CONCLUSION: Following three-dose COVID-19 vaccination, antibody response durability in PWH receiving ART is comparable with controls. PWH also mounted strong responses to breakthrough infection. Due to temporal response declines, however, COVID-19-naive individuals, regardless of HIV status, would benefit from a fourth dose within 6 months of their third.

Clinical Severity of Severe Acute Respiratory Syndrome Coronavirus 2 Omicron Variant Relative to Delta in British Columbia, Canada: A Retrospective Analysis of Whole-Genome Sequenced Cases.

BACKGROUND: In late 2021, the Omicron severe acute respiratory syndrome coronavirus 2 variant emerged and rapidly replaced Delta as the dominant variant. The increased transmissibility of Omicron led to surges in case rates and hospitalizations; however, the true severity of the variant remained unclear. We aimed to provide robust estimates of Omicron severity relative to Delta. METHODS: This retrospective cohort study was conducted with data from the British Columbia COVID-19 Cohort, a large provincial surveillance platform with linkage to administrative datasets. To capture the time of cocirculation with Omicron and Delta, December 2021 was chosen as the study period. Whole-genome sequencing was used to determine Omicron and Delta variants. To assess the severity (hospitalization, intensive care unit [ICU] admission, length of stay), we conducted adjusted Cox proportional hazard models, weighted by inverse probability of treatment weights (IPTW). RESULTS: The cohort was composed of 13 128 individuals (7729 Omicron and 5399 Delta). There were 419 coronavirus disease 2019 hospitalizations, with 118 (22%) among people diagnosed with Omicron (crude rate = 1.5% Omicron, 5.6% Delta). In multivariable IPTW analysis, Omicron was associated with a 50% lower risk of hospitalization compared with Delta (adjusted hazard ratio [aHR] = 0.50, 95% confidence interval [CI] = 0.43 to 0.59), a 73% lower risk of ICU admission (aHR = 0.27, 95% CI = 0.19 to 0.38), and a 5-day shorter hospital stay (aß = -5.03, 95% CI = -8.01 to -2.05). CONCLUSIONS: Our analysis supports findings from other studies that have demonstrated lower risk of severe outcomes in Omicron-infected individuals relative to Delta.