Protection of second booster vaccinations and prior infection against SARS-CoV-2 in the UK SIREN healthcare worker cohort (preprint)

Background The protection of fourth dose mRNA vaccination against SARS-CoV-2 is relevant to current global policy decisions regarding ongoing booster roll-out. We estimate the effect of fourth dose vaccination, prior infection, and duration of PCR positivity in a highly-vaccinated and largely prior-COVID-19 infected cohort of UK healthcare workers. Methods Participants underwent fortnightly PCR and regular antibody testing for SARS-CoV-2 and completed symptoms questionnaires. A multi-state model was used to estimate vaccine effectiveness (VE) against infection from a fourth dose compared to a waned third dose, with protection from prior infection and duration of PCR positivity jointly estimated. Results 1,298 infections were detected among 9,560 individuals under active follow-up between September 2022 and March 2023. Compared to a waned third dose, fourth dose VE was 13.1% (95%CI 0.9 to 23.8) overall; 24.0% (95%CI 8.5 to 36.8) in the first two months post-vaccination, reducing to 10.3% (95%CI -11.4 to 27.8) and 1.7% (95%CI -17.0 to 17.4) at 2-4 and 4-6 months, respectively. Relative to an infection >2 years ago and controlling for vaccination, 63.6% (95%CI 46.9 to 75.0) and 29.1% (95%CI 3.8 to 43.1) greater protection against infection was estimated for an infection within the past 0-6, and 6-12 months, respectively. A fourth dose was associated with greater protection against asymptomatic infection than symptomatic infection, whilst prior infection independently provided more protection against symptomatic infection, particularly if the infection had occurred within the previous 6 months. Duration of PCR positivity was significantly lower for asymptomatic compared to symptomatic infection. Conclusions Despite rapid waning of protection, vaccine boosters remain an important tool in responding to the dynamic COVID-19 landscape; boosting population immunity in advance of periods of anticipated pressure, such as surging infection rates or emerging variants of concern. Funding UK Health Security Agency, Medical Research Council, NIHR HPRU Oxford, and others.

Adapting COVID-19 research infrastructure to capture Influenza and Respiratory Syncytial Virus alongside SARS-CoV-2 in UK healthcare workers Winter 2022/23 and beyond: protocol for a pragmatic sub-study (preprint)

IntroductionDuring the COVID-19 pandemic, extensive research was conducted on SARS-CoV-2, however important questions about other respiratory pathogens remain unanswered. A severe influenza season in 2022-2023 with simultaneous circulation of SARS-CoV2 and Respiratory Syncytial Virus (RSV) is anticipated. This sub-study aims to determine the incidence and impact of these respiratory viruses on healthcare workers (HCW), the symptoms they experienced, the effectiveness of both COVID-19 and influenza vaccination and the burden of these infections on the National Health Service (NHS) workforce. Methods and analysisThis is a longitudinal prospective cohort sub-study, utilising the population and infrastructure of SIREN, which focuses on hospital staff in the UK. Participants undergo fortnightly Nucleic Acid Amplification Testing (NAAT) on a multiplex assay including SARS-CoV-2, Influenza A&B and RSV, regardless of symptoms. Questionnaires are completed every two weeks, capturing symptoms, sick days, exposures, and vaccination records. Serum samples are collected monthly or quarterly from participants associated with a SIREN site. This sub-study commenced on 28/11/22 to align with the predicted influenza season and participants influenza vaccine status. The SIREN Participant Involvement Panel (PIP) shaped the aims and methods for the study, highlighting its acceptability. UK Devolved Administrations were supported to develop local protocols. Analysis plans include incidence of asymptomatic and symptomatic infection, comparisons of vaccination coverage; assessment of sick day burden, and effectiveness of seasonal influenza against infection and time off work. Data are also integrated into UKHSA nosocomial modelling. Ethics and disseminationThe protocol was approved by the Berkshire Research Ethics Committee (IRAS ID 284460, REC Reference 20SC0230) on 14/11/2022. Participants were informed in advance. As the frequency and method of sampling remained the same, implied consent processes were approved by the committee. Participants returning to the study give informed consent. Regular reports to advisory groups and peer-reviewed publications are planned to disseminate findings and inform decision making. Trial registration number: ISRCTN11041050. Strengths and limitations of this study- The positioning of this sub-study, led by public health agencies in collaboration with a network of NHS sites, facilitates horizon scanning enabling rapid adaptation of the study protocol and deployment to conduct relevant scientific research in a cohort of healthcare workers - To achieve target recruitment, deployment of a new postal pathway is underway, allowing for more direct communication between the central research team and participants - The multi-disciplinary partnerships including a network of academic centres established and embedded by SIREN can now be leveraged and extended to explore Flu and RSV - Decentralised study delivery, with testing at a network of NHS sites has both strengths and limitations. This includes enabling more in-depth relationships and communications between participants and their local research teams, however, introduce additional communication, governance, and data sharing requirements. - Some demographics are over-represented such as female staff, nurses and doctors, and some are under-represented such as staff from ethnic minorities, porters and estates. This is partly the consequence of a rapid recruitment drive at the beginning of the COVID-19 pandemic.

Effectiveness and durability of protection against future SARS-CoV-2 infection conferred by COVID-19 vaccination and previous infection; findings from the UK SIREN prospective cohort study of healthcare workers March 2020 to September 2021 (preprint)

BackgroundUnderstanding the duration and effectiveness of infection and vaccine-acquired SARS-CoV-2 immunity is essential to inform pandemic policy interventions, including the timing of vaccine-boosters. We investigated this in our large prospective cohort of UK healthcare workers undergoing routine asymptomatic PCR testing. MethodsWe assessed vaccine effectiveness (VE) (up to 10-months after first dose) and infection-acquired immunity by comparing time to PCR-confirmed infection in vaccinated and unvaccinated individuals using a Cox regression-model, adjusted by prior SARS-CoV-2 infection status, vaccine-manufacturer/dosing-interval, demographics and workplace exposures. ResultsOf 35,768 participants, 27% (n=9,488) had a prior SARS-CoV-2 infection. Vaccine coverage was high: 97% had two-doses (79% BNT162b2 long-interval, 8% BNT162b2 short-interval, 8% ChAdOx1). There were 2,747 primary infections and 210 reinfections between 07/12/2020 and 21/09/2021. Adjusted VE (aVE) decreased from 81% (95% CI 68%-89%) 14-73 days after dose-2 to 46% (95% CI 22%-63%) >6-months; with no significant difference for short-interval BNT162b2 but significantly lower aVE (50% (95% CI 18%-70%) 14-73 days after dose-2 from ChAdOx1. Protection from infection-acquired immunity showed evidence of waning in unvaccinated follow-up but remained consistently over 90% in those who received two doses of vaccine, even in those infected over 15-months ago. ConclusionTwo doses of BNT162b2 vaccination induce high short-term protection to SARS-CoV-2 infection, which wanes significantly after six months. Infection-acquired immunity boosted with vaccination remains high over a year after infection. Boosters will be essential to maintain protection in vaccinees who have not had primary infection to reduce infection and transmission in this population. Trial registration numberISRCTN11041050

Effectiveness of BNT162b2 mRNA Vaccine Against Infection and COVID-19 Vaccine Coverage in Healthcare Workers in England, Multicentre Prospective Cohort Study (the SIREN Study) (preprint)

Background: BNT162b2 mRNA and ChAdOx1 nCOV-19 adenoviral vector vaccines have been rapidly rolled out in the UK. We determined the factors associated with vaccine coverage for both vaccines and documented the vaccine effectiveness of the BNT162b2 mRNA vaccine in our healthcare worker (HCW) cohort study of staff undergoing regular asymptomatic testing.Methods: The SIREN study is a prospective cohort study among staff working in publicly funded hospitals. Baseline risk factors, vaccination status (from 8/12/2020-5/2/2021), and symptoms are recorded at 2 weekly intervals and all SARS-CoV-2 polymerase chain reaction (PCR) and antibody test results documented. A mixed effect proportional hazards frailty model using a Poisson distribution was used to calculate hazard ratios to compare time to infection in unvaccinated and vaccinated participants to estimate the impact of the BNT162b2 vaccine on all (asymptomatic and symptomatic) infection.Findings: Vaccine coverage was 89% on 5/2/2021. Significantly lower coverage was associated with prior infection (aOR 0.59 95% confidence interval [CI] 0.54-0.64), female (aOR 0.72, 95% CI 0.63-0.82), aged under 35 years, being from minority ethnic groups (especially Black, aOR 0.26, 95% CI 0.21-0.32), porters/security guards (aOR 0.61, 95% CI 0.42-0.90),or midwife (aOR 0.74, 95% CI 0.57-0.97), and living in more deprived neighbourhoods (IMD 1 (most) vs. 5 (least) (aOR 0.75, 95% CI 0.65-0.87). A single dose of BNT162b2 vaccine demonstrated vaccine effectiveness of 72% (95% CI 58-86) 21 days after first dose and 86% (95% CI 76-97) seven days after two doses in the antibody negative cohort.Conclusion: Our study demonstrates that the BNT162b2 vaccine effectively prevents both symptomatic and asymptomatic infection in working age adults; this cohort was vaccinated when the dominant variant in circulation was B1.1.7 and demonstrates effectiveness against this variant.Trial Registration: IRAS ID 284460, REC reference 20/SC/0230 Berkshire Research Ethics Committee, Health Research Authority and Health and Care Research Wales approval granted 22 May 2020. Trial registered with ISRCTN, Trial ID: ISRCTN11041050. https://www.isrctn.com/ISRCTN11041050Funding: The study is funded by the United Kingdom’s Department of Health and Social Care and Public Health England, with contributions from the Scottish, Welsh and Northern Irish governments. Funding is also provided by the National Institute for Health Research (NIHR) as an Urgent Public Health Priority Study (UPHP). SH, VH are supported by the National Institute for Health Research Health Protection Research Unit (NIHR HPRU) in Healthcare Associated Infections and Antimicrobial Resistance at the University of Oxford in partnership with Public Health England (PHE) (NIHR200915). AC is supported by NIHR HealthProtection Research Unit in Behavioural Science and Evaluation at University of Bristol in partnership with Public Health England. MR, NA, AC are supported by NIHR HealthProtection Research Unit in Immunisation at the London School of Hygiene and Tropical Medicine in partnership with Public Health England.Conflict of Interest: The Immunisation and Countermeasures Division has provided vaccine manufacturers(including Pfizer) with post-marketing surveillance reports on pneumococcal andmeningococcal infection which the companies are required to submit to the UK Licensing authority in compliance with their Risk Management Strategy. A cost recovery charge is made for these reports.Ethical Approval: The study was approved by the Berkshire Research Ethics Committee, Health Research Authority (IRAS ID 284460, REC reference 20/SC/0230) on 22 May 2020; the vaccine amendment was approved on 12/1/2021.

Do antibody positive healthcare workers have lower SARS-CoV-2 infection rates than antibody negative healthcare workers? Large multi-centre prospective cohort study (the SIREN study), England: June to November 2020 (preprint)

BackgroundThere is an urgent need to better understand whether individuals who have recovered from COVID-19 are protected from future SARS-CoV-2 infection. MethodsA large multi-centre prospective cohort was recruited from publicly funded hospital staff in the UK. Participants attended regular SARS-CoV-2 PCR and antibody testing (every 2-4 weeks) and completed fortnightly questionnaires on symptoms and exposures. At enrolment, participants were assigned to either the positive cohort (antibody positive or prior PCR/antibody test positive) or negative cohort (antibody negative, not previously known to be PCR/antibody positive). Potential reinfections were clinically reviewed and classified according to case definitions (confirmed, probable, possible (subdivided by symptom-status)) depending on hierarchy of evidence. Individuals in the primary infection were excluded from this analysis if infection was confirmed by antibody only. Reinfection rates in the positive cohort were compared against new PCR positives in the negative cohort using a mixed effective multivariable logistic regression analysis. FindingsBetween 18 June and 09 November 2020, 44 reinfections (2 probable, 42 possible) were detected in the baseline positive cohort of 6,614 participants, collectively contributing 1,339,078 days of follow-up. This compares with 318 new PCR positive infections and 94 antibody seroconversions in the negative cohort of 14,173 participants, contributing 1,868,646 days of follow-up. The incidence density per 100,000 person days between June and November 2020 was 3.3 reinfections in the positive cohort, compared with 22.4 new PCR confirmed infections in the negative cohort. The adjusted odds ratio was 0.17 for all reinfections (95% CI 0.13-0.24) compared to PCR confirmed primary infections. The median interval between primary infection and reinfection was over 160 days. InterpretationA prior history of SARS-CoV-2 infection was associated with an 83% lower risk of infection, with median protective effect observed five months following primary infection. This is the minimum likely effect as seroconversions were not included. FundingDepartment of Health and Social Care and Public Health England, with contributions from the Scottish, Welsh and Northern Irish governments.