SARS-CoV-2 Hospital Epidemiology, Risks, Responses and Viral Dynamics Study

Abstract

Background: Healthcare workers (HCW) are at increased risk for SARS-CoV-2 infection compared to the general community. The HERD study hypothesises that host, occupational and social factors influence this infection risk. I aimed to describe the clinical presentation, demographics, occupational details and social circumstances of St. James's Hospital HCWs with confirmed COVID-19 during Wave 1 of the pandemic. I investigated the contemporaneous risks associated with confirmed SARS-CoV-2 infection amongst HCWs following in-work exposure to a confirmed COVID-19 case during Waves 1-3 of the pandemic. I examined risk factors for HCW SARS-CoV-2 seropositivity, the durability of antibody responses in a highly vaccinated HCW cohort and the neutralisation capacity of detected antibodies, prior to booster COVID-19 vaccination. A nested-substudy assessed how rapid point of care anti-SARS-CoV-2 antibody testing can be compared to a standard laboratory assay, examining its effectiveness in neutralisation assessment and explored its uses into the future of the pandemic. I proposed that some individuals have particularly effective innate immune systems that can protect against SARS-CoV-2 infection in the absence of SARS-CoV-2-specific T-cells or B-cell produced antibodies. I investigated the mechanisms of resistance to SARS-CoV-2 infection, with a focus on genetic polymorphisms, in individuals with significant exposure to a known COVID-19 case. Methods: A retrospective case series of all confirmed COVID-19 cases in St. James's Hospital during Wave 1 of the pandemic was undertaken, utilising occupational health databases. Clinical, demographic, occupational and social factors associated were recorded. A retrospective nested case-control study utilising digital contact tracing and occupational health data identified COVID-19 index cases, their HCW contacts and the consequences of this exposure i.e. SARS-CoV-2 infection or non-infection, during Waves 1-3 of the pandemic. A cross-sectional seroprevalence study of anti-SARS-CoV-2 antibodies across two hospital sites was undertaken. Serology samples were analysed using the Roche Elecsys/-S Anti-SARS-CoV-2 assays to detect anti-nucleocapsid (N)/anti-spike (S) antibodies. Paired serology results from prior study phases were used to analyse changes in individual HCW serostatus over time. Demographic and work-related risk-factors for SARS-CoV-2 seropositivity were assessed. Antibody neutralisation capacity was assessed in a subset of samples via an in vitro ACE2 binding enzyme-linked immunosorbent assay. A point of care (POC) lateral flow immunoassay (LFA) detecting anti-SARS-CoV-2 spike (S)-receptor binding domain (RBD) neutralising antibodies was compared to the Roche Elecsys/-S anti-SARS-CoV-2 antibody assays and the in vitro surrogate neutralisation assay. A correlation between anti-S, anti-N titres and in vitro neutralisation was also assessed. Participants with potential resistance to SARS-CoV-2 were identified and assessed clinically for their degree of exposure to COVID-19. DNA extraction from whole blood and genotyping for key single nucleotide polymorphisms (SNPs) was performed. SNP allelic distributions were compared to two large international control cohorts. Whole blood interferon gamma (IFN-gamma) release assays assessed T-cell IFN-gamma release in response to SARS-CoV-2 antigens. In a subset of samples, whole blood was stimulated using the TruCulture system to assess induced innate immune responses. Simoa was performed to assess levels of interferon-gamma and Luminex was performed to assess cytokine production. Results: Clinical manifestations of HCW SARS-CoV-2 infection during Wave 1 of the pandemic are consistent with those reported in contemporaneous studies. A median of 21 work days was lost per infection. Testing algorithms developed rapidly and may have underestimated early asymptomatic cases. Approximately 25% of Wave 1 SARS-CoV-2-infected HCWs meet the definition for Long-COVID following infection. Within the hospital setting, male sex, Eastern European nationality, exposure location, PPE use and vaccination status all impacted the likelihood of SARS-CoV-2 infection following nosocomial exposure to a known COVID-19 case during Waves 1-3 of the pandemic. Seroprevalence of SARS-CoV-2 antibodies in November 2021 was 23.4% across study sites. Factors associated with seropositivity were HCW age category 18-19 years, India as country of birth, education level and healthcare assistant job role. All vaccinated HCWs maintained anti-S positivity prior to COVID-19 booster vaccination, however anti-N positivity was more dynamic over time. Antibody neutralisation capacity was highest in participants with COVID-19 vaccination plus prior SARS-CoV-2 infection. High sensitivity (97.7%), specificity (100%), and PPV (100%) were demonstrated for the POC LFA for the detection of anti-S-RBD antibodies in comparison to the commercial assay. The LFA was not a reliable determinant of the neutralisation capacity of identified antibodies. In a significantly SARS-CoV-2 exposed, pre-COVID-19 vaccine cohort, a signal for the genetic underpinning to innate immune resistance to SARS-CoV-2 infection is identified via the rs7251 SNP in the interferon regulatory factor 3 gene, that is known to be associated with increased type-1 IFN activity. Conclusion: HCW remain at increased risk of infection with SARS-CoV-2 compared to the general community. COVID-19 vaccination is an important tool in controlling infection, however waning immune responses and viral evolution means that institutional infection prevention and control (IPC) measures such as PPE use remain key in preventing HCW infection. Institutional communications and IPC measures must acknowledge high risk HCW subgroups and ensure barriers to guideline compliance are addressed. Social factors such as living with other HCW impacts SARS-CoV-2 infection risk. While a select number of HCW may demonstrate innate protection from SARS-CoV-2 via heightened innate immune responses, the proposed mechanism will need further investigation in larger cohorts for confirmation and is impacted by viral evolution. HCW will be key in future SARS-CoV-2 and other viral outbreaks. Future pandemic preparedness requires the establishment of prospective research cohorts to fully understand HCW infection.