Comparative effectiveness of different primary vaccination courses on mRNA-based booster vaccines against SARs-COV-2 infections: a time-varying cohort analysis using trial emulation in the Virus Watch community cohort.

BACKGROUND: The Omicron B.1.1.529 variant increased severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections in doubly vaccinated individuals, particularly in the Oxford-AstraZeneca COVID-19 vaccine (ChAdOx1) recipients. To tackle infections, the UK's booster vaccination programmes used messenger ribonucleic acid (mRNA) vaccines irrespective of an individual's primary course vaccine type, and prioritized the clinically vulnerable. These mRNA vaccines included the Pfizer-BioNTech COVID-19 vaccine (BNT162b2) the Moderna COVID-19 vaccine (mRNA-1273). There is limited understanding of the effectiveness of different primary vaccination courses on mRNA booster vaccines against SARs-COV-2 infections and how time-varying confounders affect these evaluations. METHODS: Trial emulation was applied to a prospective community observational cohort in England and Wales to reduce time-varying confounding-by-indication driven by prioritizing vaccination based upon age, vulnerability and exposure. Trial emulation was conducted by meta-analysing eight adult cohort results whose booster vaccinations were staggered between 16 September 2021 and 05 January 2022 and followed until 23 January 2022. Time from booster vaccination until SARS-CoV-2 infection, loss of follow-up or end of study was modelled using Cox proportional hazard models and adjusted for age, sex, minority ethnic status, clinically vulnerability and deprivation. RESULTS: A total of 19 159 participants were analysed, with 11 709 ChAdOx1 primary courses and 7450 BNT162b2 primary courses. Median age, clinical vulnerability status and infection rates fluctuate through time. In mRNA-boosted adults, 7.4% (n = 863) of boosted adults with a ChAdOx1 primary course experienced a SARS-CoV-2 infection compared with 7.7% (n = 571) of those who had BNT162b2 as a primary course. The pooled adjusted hazard ratio (aHR) was 1.01 with a 95% confidence interval (CI) of: 0.90 to 1.13. CONCLUSION: After an mRNA booster dose, we found no difference in protection comparing those with a primary course of BNT162b2 with those with a ChAdOx1 primary course. This contrasts with pre-booster findings where previous research shows greater effectiveness of BNT162b2 than ChAdOx1 in preventing infection.

Bayesian reconstruction of household transmissions to infer the serial interval of COVID-19 by variants of concern: analysis from a prospective community cohort study (Virus Watch).

BACKGROUND: The serial interval is a key epidemiological measure that quantifies the time between an infector's and an infectee's onset of symptoms. This measure helps investigate epidemiological links between cases, and is an important parameter in transmission models used to estimate transmissibility and inform control strategies. The emergence of multiple variants of concern (VOC) during the SARS-CoV-2 pandemic has led to uncertainties about potential changes in the serial interval of COVID-19. We estimated the household serial interval of multiple VOC using data collected by the Virus Watch study. This online, prospective, community cohort study followed-up entire households in England and Wales since mid-June 2020. METHODS: This analysis included 5842 symptomatic individuals with confirmed SARS-CoV-2 infection among 2579 households from Sept 1, 2020, to Aug 10, 2022. SARS-CoV-2 variant designation was based upon national surveillance data of variant prevalence by date and geographical region. We used a Bayesian framework to infer who infected whom by exploring all transmission trees compatible with the observed dates of symptoms, given assumptions on the incubation period and generation time distributions using the R package outbreaker2. FINDINGS: We characterised the serial interval of COVID-19 by VOC. The mean serial interval was shortest for omicron BA5 (2·02 days; 95% credible interval [CrI] 1·26-2·84) and longest for alpha (3·37 days; 2·52-4·04). The mean serial interval before alpha (wild-type) was 2·29 days (95% CrI 1·39-2·94), 3·11 days (2·28-3·90) for delta, 2·72 days (2·01-3·47) for omicron BA1, and 2·67 days (1·90-3·46) for omicron BA2. We estimated that 17% (95% CrI 5-26) of serial interval values are negative across all variants. INTERPRETATION: Most methods estimating the reproduction number from incidence time series do not allow for a negative serial interval by construction. Further research is needed to extend these methods and assess biases introduced by not accounting for negative serial intervals. To our knowledge, this study is the first to use a Bayesian framework to estimate the serial interval of all major SARS-CoV-2 VOC from thousands of confirmed household cases. FUNDING: UK Medical Research Council and Wellcome Trust.

Spike-antibody responses to COVID-19 vaccination by demographic and clinical factors in a prospective community cohort study.

Vaccination constitutes the best long-term solution against Coronavirus Disease-2019; however, vaccine-derived immunity may not protect all groups equally, and the durability of protective antibodies may be short. We evaluate Spike-antibody responses following BNT162b2 or ChAdOx1-S vaccination amongst SARS-CoV2-naive adults across England and Wales enrolled in a prospective cohort study (Virus Watch). Here we show BNT162b2 recipients achieved higher peak antibody levels after two doses; however, both groups experience substantial antibody waning over time. In 8356 individuals submitting a sample ≥28 days after Dose 2, we observe significantly reduced Spike-antibody levels following two doses amongst individuals reporting conditions and therapies that cause immunosuppression. After adjusting for these, several common chronic conditions also appear to attenuate the antibody response. These findings suggest the need to continue prioritising vulnerable groups, who have been vaccinated earliest and have the most attenuated antibody responses, for future boosters.

Nucleocapsid and spike antibody responses following virologically confirmed SARS-CoV-2 infection: an observational analysis in the Virus Watch community cohort.

OBJECTIVES: Seroprevalence studies can provide a measure of SARS-CoV-2 cumulative incidence, but a better understanding of spike and nucleocapsid (anti-N) antibody dynamics following infection is needed to assess the longevity of detectability. METHODS: Adults aged ≥18 years, from households enrolled in the Virus Watch prospective community cohort study in England and Wales, provided monthly capillary blood samples, which were tested for spike antibody and anti-N. Participants self-reported vaccination dates and past medical history. Previous polymerase chain reaction (PCR) swabs were obtained through Second Generation Surveillance System linkage data. The primary outcome variables were seropositivity and total anti-N and spike antibody levels after PCR-confirmed infection. RESULTS: A total of 13,802 eligible individuals provided 58,770 capillary blood samples. A total of 537 of these had a previous positive PCR-confirmed SARS-CoV-2 infection within 0-269 days of antibody sample date, among them 432 (80.45%) having a positive anti-N result. Median anti-N levels peaked between days 90 and 119 after PCR results and then began to decline. There is evidence of anti-N waning from 120 days onwards, with earlier waning for females and younger age categories. CONCLUSION: Our findings suggest that anti-N has around 80% sensitivity for identifying previous COVID-19 infection, and the duration of detectability is affected by sex and age.

The Alpha variant was not associated with excess nosocomial SARS-CoV-2 infection in a multi-centre UK hospital study.

OBJECTIVES: Recently emerging SARS-CoV-2 variants have been associated with an increased rate of transmission within the community. We sought to determine whether this also resulted in increased transmission within hospitals. METHODS: We collected viral sequences and epidemiological data of patients with community and healthcare associated SARS-CoV-2 infections, sampled from 16th November 2020 to 10th January 2021, from nine hospitals participating in the COG-UK HOCI study. Outbreaks were identified using ward information, lineage and pairwise genetic differences between viral sequences. RESULTS: Mixed effects logistic regression analysis of 4184 sequences showed healthcare-acquired infections were no more likely to be identified as the Alpha variant than community acquired infections. Nosocomial outbreaks were investigated based on overlapping ward stay and SARS-CoV-2 genome sequence similarity. There was no significant difference in the number of patients involved in outbreaks caused by the Alpha variant compared to outbreaks caused by other lineages. CONCLUSIONS: We find no evidence to support it causing more nosocomial transmission than previous lineages. This suggests that the stringent infection prevention measures already in place in UK hospitals contained the spread of the Alpha variant as effectively as other less transmissible lineages, providing reassurance of their efficacy against emerging variants of concern.

SARS-CoV-2 lineage B.1.1.7 is associated with greater disease severity among hospitalised women but not men: multicentre cohort study.

BACKGROUND: SARS-CoV-2 lineage B.1.1.7 has been associated with an increased rate of transmission and disease severity among subjects testing positive in the community. Its impact on hospitalised patients is less well documented. METHODS: We collected viral sequences and clinical data of patients admitted with SARS-CoV-2 and hospital-onset COVID-19 infections (HOCIs), sampled 16 November 2020 to 10 January 2021, from eight hospitals participating in the COG-UK-HOCI study. Associations between the variant and the outcomes of all-cause mortality and intensive therapy unit (ITU) admission were evaluated using mixed effects Cox models adjusted by age, sex, comorbidities, care home residence, pregnancy and ethnicity. FINDINGS: Sequences were obtained from 2341 inpatients (HOCI cases=786) and analysis of clinical outcomes was carried out in 2147 inpatients with all data available. The HR for mortality of B.1.1.7 compared with other lineages was 1.01 (95% CI 0.79 to 1.28, p=0.94) and for ITU admission was 1.01 (95% CI 0.75 to 1.37, p=0.96). Analysis of sex-specific effects of B.1.1.7 identified increased risk of mortality (HR 1.30, 95% CI 0.95 to 1.78, p=0.096) and ITU admission (HR 1.82, 95% CI 1.15 to 2.90, p=0.011) in females infected with the variant but not males (mortality HR 0.82, 95% CI 0.61 to 1.10, p=0.177; ITU HR 0.74, 95% CI 0.52 to 1.04, p=0.086). INTERPRETATION: In common with smaller studies of patients hospitalised with SARS-CoV-2, we did not find an overall increase in mortality or ITU admission associated with B.1.1.7 compared with other lineages. However, women with B.1.1.7 may be at an increased risk of admission to intensive care and at modestly increased risk of mortality.

Hand Hygiene Practices and the Risk of Human Coronavirus Infections in a UK Community Cohort.

Background: Hand hygiene may mitigate the spread of COVID-19 in community settings; however, empirical evidence is limited. Given reports of similar transmission mechanisms for COVID-19 and seasonal coronaviruses, we investigated whether hand hygiene impacted the risk of acquiring seasonal coronavirus infections. Methods: Data were drawn from three successive winter cohorts (2006-2009) of the England-wide Flu Watch study.  Participants ( n=1633) provided baseline estimates of hand hygiene behaviour. Coronavirus infections were identified from nasal swabs using RT-PCR. Poisson mixed models estimated the effect of hand hygiene on personal risk of coronavirus illness, both unadjusted and adjusted for confounding by age and healthcare worker status. Results: Moderate-frequency handwashing (6-10 times per day) predicted a lower personal risk of coronavirus infection (adjusted incidence rate ratio (aIRR) =0.64, p=0.04). There was no evidence for a dose-response effect of handwashing, with results for higher levels of hand hygiene (>10 times per day) not significant (aIRR =0.83, p=0.42). Conclusions: This is the first empirical evidence that regular handwashing can reduce personal risk of acquiring seasonal coronavirus infection. These findings support clear public health messaging around the protective effects of hand washing in the context of the current COVID-19 pandemic.

Seasonality and immunity to laboratory-confirmed seasonal coronaviruses (HCoV-NL63, HCoV-OC43, and HCoV-229E): results from the Flu Watch cohort study.

Background: There is currently a pandemic caused by the novel coronavirus SARS-CoV-2. The intensity and duration of this first wave in the UK may be dependent on whether SARS-CoV-2 transmits more effectively in the winter than the summer and the UK Government response is partially built upon the assumption that those infected will develop immunity to reinfection in the short term. In this paper we examine evidence for seasonality and immunity to laboratory-confirmed seasonal coronavirus (HCoV) from a prospective cohort study in England. Methods: In this analysis of the Flu Watch cohort, we examine seasonal trends for PCR-confirmed coronavirus infections (HCoV-NL63, HCoV-OC43, and HCoV-229E) in all participants during winter seasons (2006-2007, 2007-2008, 2008-2009) and during the first wave of the 2009 H1N1 influenza pandemic (May-Sep 2009). We also included data from the pandemic and 'post-pandemic' winter seasons (2009-2010 and 2010-2011) to identify individuals with two confirmed HCoV infections and examine evidence for immunity against homologous reinfection. Results: We tested 1,104 swabs taken during respiratory illness and detected HCoV in 199 during the first four seasons. The rate of confirmed HCoV infection across all seasons was 390 (95% CI 338-448) per 100,000 person-weeks; highest in the Nov-Mar 2008/9 season at 674 (95%CI 537-835). The highest rate was in February at 759 (95% CI 580-975). Data collected during May-Sep 2009 showed there was small amounts of ongoing transmission, with four cases detected during this period. Eight participants had two confirmed infections, of which none had the same strain twice. Conclusion: Our results provide evidence that HCoV infection in England is most intense in winter, but that there is a small amount of ongoing transmission during summer periods. We found some evidence of immunity against homologous reinfection.

Prevalence, incidence, and outcomes across cardiovascular diseases in homeless individuals using national linked electronic health records.

AIMS: The risk and burden of cardiovascular disease (CVD) are higher in homeless than in housed individuals but population-based analyses are lacking. The aim of this study was to investigate prevalence, incidence and outcomes across a range of specific CVDs among homeless individuals. METHODS AND RESULTS: Using linked UK primary care electronic health records (EHRs) and validated phenotypes, we identified homeless individuals aged ≥16 years between 1998 and 2019, and age- and sex-matched housed controls in a 1:5 ratio. For 12 CVDs (stable angina; unstable angina; myocardial infarction; sudden cardiac death or cardiac arrest; unheralded coronary death; heart failure; transient ischaemic attack; ischaemic stroke; subarachnoid haemorrhage; intracerebral haemorrhage; peripheral arterial disease; abdominal aortic aneurysm), we estimated prevalence, incidence, and 1-year mortality post-diagnosis, comparing homeless and housed groups. We identified 8492 homeless individuals (32 134 matched housed individuals). Comorbidities and risk factors were more prevalent in homeless people, e.g. smoking: 78.1% vs. 48.3% and atrial fibrillation: 9.9% vs. 8.6%, P < 0.001. CVD prevalence (11.6% vs. 6.5%), incidence (14.7 vs. 8.1 per 1000 person-years), and 1-year mortality risk [adjusted hazard ratio 1.64, 95% confidence interval (CI) 1.29-2.08, P < 0.001] were higher, and onset was earlier (difference 4.6, 95% CI 2.8-6.3 years, P < 0.001), in homeless, compared with housed people. Homeless individuals had higher CVD incidence in all three arterial territories than housed people. CONCLUSION: CVD in homeless individuals has high prevalence, incidence, and 1-year mortality risk post-diagnosis with earlier onset, and high burden of risk factors. Inclusion health and social care strategies should reflect this high preventable and treatable burden, which is increasingly important in the current COVID-19 context.

COVID-19 among people experiencing homelessness in England: a modelling study.

BACKGROUND: People experiencing homelessness are vulnerable to COVID-19 due to the risk of transmission in shared accommodation and the high prevalence of comorbidities. In England, as in some other countries, preventive policies have been implemented to protect this population. We aimed to estimate the avoided deaths and health-care use among people experiencing homelessness during the so-called first wave of COVID-19 in England-ie, the peak of infections occurring between February and May, 2020-and the potential impact of COVID-19 on this population in the future. METHODS: We used a discrete-time Markov chain model of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection that included compartments for susceptible, exposed, infectious, and removed individuals, to explore the impact of the pandemic on 46 565 individuals experiencing homelessness: 35 817 living in 1065 hostels for homeless people, 3616 sleeping in 143 night shelters, and 7132 sleeping outside. We ran the model under scenarios varying the incidence of infection in the general population and the availability of prevention measures: specialist hotel accommodation, infection control in homeless settings, and mixing with the general population. We divided our scenarios into first wave scenarios (covering Feb 1-May 31, 2020) and future scenarios (covering June 1, 2020-Jan 31, 2021). For each scenario, we ran the model 200 times and reported the median and 95% prediction interval (2·5% and 97·5% quantiles) of the total number of cases, the number of deaths, the number hospital admissions, and the number of intensive care unit (ICU) admissions. FINDINGS: Up to May 31, 2020, we calibrated the model to 4% of the homeless population acquiring SARS-CoV-2, and estimated that 24 deaths (95% prediction interval 16-34) occurred. In this first wave of SARS-CoV-2 infections in England, we estimated that the preventive measures imposed might have avoided 21 092 infections (19 777-22 147), 266 deaths (226-301), 1164 hospital admissions (1079-1254), and 338 ICU admissions (305-374) among the homeless population. If preventive measures are continued, we projected a small number of additional cases between June 1, 2020, and Jan 31, 2021, with 1754 infections (1543-1960), 31 deaths (21-45), 122 hospital admissions (100-148), and 35 ICU admissions (23-47) with a second wave in the general population. However, if preventive measures are lifted, outbreaks in homeless settings might lead to larger numbers of infections and deaths, even with low incidence in the general population. In a scenario with no second wave and relaxed measures in homeless settings in England, we projected 12 151 infections (10 718-13 349), 184 deaths (151-217), 733 hospital admissions (635-822), and 213 ICU admissions (178-251) between June 1, 2020, and Jan 31, 2021. INTERPRETATION: Outbreaks of SARS-CoV-2 in homeless settings can lead to a high attack rate among people experiencing homelessness, even if incidence remains low in the general population. Avoidance of deaths depends on prevention of transmission within settings such as hostels and night shelters. FUNDING: National Institute for Health Research, Wellcome, and Medical Research Council.

Public activities preceding the onset of acute respiratory infection syndromes in adults in England - implications for the use of social distancing to control pandemic respiratory infections.

Background: Social distancing measures may reduce the spread of emerging respiratory infections however, there is little empirical data on how exposure to crowded places affects risk of acute respiratory infection. Methods: We used a case-crossover design nested in a community cohort to compare self-reported measures of activities during the week before infection onset and baseline periods. The design eliminates the effect of non-time-varying confounders. Time-varying confounders were addressed by exclusion of illnesses around the Christmas period and seasonal adjustment.  Results: 626 participants had paired data from the week before 1005 illnesses and the week before baseline. Each additional day of undertaking the following activities in the prior week was associated with illness onset: Spending more than five minutes in a room with someone (other than a household member) who has a cold (Seasonally adjusted OR 1·15, p=0·003); use of underground trains (1·31, p=0·036); use of supermarkets (1·32, p<0·001); attending a theatre, cinema or concert (1·26, p=0·032); eating out at a café, restaurant or canteen (1·25, p=0·003); and attending parties (1·47, p<0·001). Undertaking the following activities at least once in the previous week was associated with illness onset: using a bus, (aOR 1.48, p=0.049), shopping at small shops (1.9, p<0.002) attending a place of worship (1.81, p=0.005).    Conclusions: Exposure to potentially crowded places, public transport and to individuals with a cold increases risk of acquiring circulating acute respiratory infections. This suggests social distancing measures can have an important impact on slowing transmission of emerging respiratory infections.