Improving the representativeness of UKs national COVID-19 Infection Survey through spatio-temporal regression and post-stratification (preprint)

Population-representative estimates of SARS-CoV-2 infection prevalence and antibody levels in specific geographic areas at different time points are needed to optimise policy responses. However, even population-wide surveys are potentially impacted by biases arising from differences in participation rates across key groups. Here, we use spatio-temporal regression and post-stratification models to UKs national COVID-19 Infection Survey (CIS) to obtain representative estimates of PCR positivity (6,496,052 tests) and antibody prevalence (1,941,333 tests) for different regions, ages and ethnicities (7-December-2020 to 4-May-2022). Not accounting for vaccination status through post-stratification led to small underestimation of PCR positivity, but more substantial overestimations of antibody levels in the population (up to 21%), particularly in groups with low vaccine uptake in the general population. There was marked variation in the relative contribution of different areas and age-groups to each wave. Future analyses of infectious disease surveys should take into account major drivers of outcomes of interest that may also influence participation, with vaccination being an important factor to consider.

Correlates of protection against SARS-CoV-2 Omicron variant and anti-spike antibody responses after a third/booster vaccination or breakthrough infection in the UK general population (preprint)

Following primary SARS-CoV-2 vaccination, understanding the relative extent of protection against SARS-CoV-2 infection from boosters or from breakthrough infections (i.e. infection in the context of previous vaccination) has important implications for vaccine policy. In this study, we investigated correlates of protection against Omicron BA.4/5 infections and anti-spike IgG antibody trajectories after a third/booster vaccination or breakthrough infection following second vaccination in 154,149 adults [≥]18y from the United Kingdom general population. We found that higher anti-spike IgG antibody levels were associated with increased protection against Omicron BA.4/5 infection and that breakthrough infections were associated with higher levels of protection at any given antibody level than booster vaccinations. Breakthrough infections generated similar antibody levels to third/booster vaccinations, and the subsequent declines in antibody levels were similar to or slightly slower than those after third/booster vaccinations. Taken together our findings show that breakthrough infection provides longer lasting protection against further infections than booster vaccinations. For example, considering antibody levels associated with 67% protection against infection, a third/booster vaccination did not provide long-lasting protection, while a Delta/Omicron BA.1 breakthrough infection could provide 5-10 months of protection against Omicron BA.4/5 reinfection. 50-60% of the vaccinated UK population with a breakthrough infection would still be protected by the end of 2022, compared to <15% of the triple-vaccinated UK population without previous infection. Although there are societal impacts and risks to some individuals associated with ongoing transmission, breakthrough infection could be an efficient immune-boosting mechanism for subgroups of the population, including younger healthy adults, who have low risks of adverse consequences from infection.

The challenge of limited vaccine supplies: impact of prior infection on anti-spike IgG antibody trajectories after a single COVID-19 vaccination (preprint)

Given high SARS-CoV-2 incidence, coupled with slow and inequitable vaccine roll-out, there is an urgent need for evidence to underpin optimum vaccine deployment, aiming to maximise global population immunity at speed. We evaluate whether a single vaccination in previously infected individuals generates similar initial and subsequent antibody responses to two vaccinations in those without prior infection. We compared anti-spike IgG antibody responses after a single dose of ChAdOx1, BNT162b2, or mRNA-1273 SARS-CoV-2 vaccines in the COVID-19 Infection Survey in the UK general population. In 100,849 adults who received at least one vaccination, 13,404 (13.3%) had serological and/or PCR evidence of prior infection. Prior infection significantly boosted antibody responses for all three vaccines, producing a higher peak level and longer half-life, and a response comparable to those without prior infection receiving two vaccinations. In those with prior infection, median time above the positivity threshold was estimated to last for >1 year after the first dose. Single-dose vaccination targeted to those previously infected may provide protection in populations with high rates of previous infection faced with limited vaccine supply, as an interim measure while vaccine campaigns are scaled up.

Impact of Delta on viral burden and vaccine effectiveness against new SARS-CoV-2 infections in the UK (preprint)

The effectiveness of BNT162b2, ChAdOx1, and mRNA-1273 vaccines against new SARS-CoV-2 infections requires continuous re-evaluation, given the increasingly dominant Delta variant. We investigated the effectiveness of the vaccines in a large community-based survey of randomly selected households across the UK. We found that the effectiveness of BNT162b2 and ChAd0x1 against any infections (new PCR positives) and infections with symptoms or high viral burden is reduced with the Delta variant. A single dose of the mRNA-1273 vaccine had similar or greater effectiveness compared to a single dose of BNT162b2 or ChAdOx1. Effectiveness of two doses remains at least as great as protection afforded by prior natural infection. The dynamics of immunity following second doses differed significantly between BNT162b2 and ChAdOx1, with greater initial effectiveness against new PCR-positives but faster declines in protection against high viral burden and symptomatic infection with BNT162b2. There was no evidence that effectiveness varied by dosing interval, but protection was higher among those vaccinated following a prior infection and younger adults. With Delta, infections occurring following two vaccinations had similar peak viral burden to those in unvaccinated individuals. SARS-CoV-2 vaccination still reduces new infections, but effectiveness and attenuation of peak viral burden are reduced with Delta.

Effect of COVID-19 on inequalities in premature mortality in England: an analysis of excess mortality by deprivation and ethnicity (preprint)

Objectives: To examine the impact of the COVID-19 pandemic on inequalities in premature mortality in England by deprivation and ethnicity. Design: A statistical model to estimate increased mortality in population sub-groups during the COVID-19 pandemic by comparing observed with expected mortality in each group based on trends over the previous five years. Setting: Information on deaths registered in England since 2015 was used, including age, sex, area of residence, and cause of death. Ethnicity was obtained from Hospital Episode Statistics (HES) records linked to death registration data. Participants: Population study of England, including all 569,824 deaths from all causes registered between 21 March 2020 and 26 February 2021. Main outcome measures: Excess mortality in each sub-group over and above the number expected based on trends in mortality in that group over the previous five years. Results: The gradient in excess mortality by deprivation was greater in the under 75s (most deprived had 1.25 times as many deaths as expected, least deprived 1.14) than in all ages (most deprived had 1.24 times as many deaths as expected, least deprived 1.20). Among the Black and Asian groups, all deprivation quintiles had significantly larger excesses than the most deprived White group and there were no clear gradients across quintiles. Among the White group, only the most deprived had more excess deaths than deaths directly involving COVID-19. Among the Black group all deprivation quintiles experienced more excess deaths than deaths directly involving COVID-19. Conclusion: The COVID-19 pandemic has widened inequalities in premature mortality by deprivation. Among those under 75, the direct and indirect effects of the pandemic on deaths have disproportionately impacted ethnic minority groups irrespective of deprivation, and the most deprived White group. Statistics limited to deaths directly involving COVID-19 understate the pandemic's impact on inequalities by deprivation and ethnic group at younger ages.

Impact of vaccination on SARS-CoV-2 cases in the community: a population-based study using the UK COVID-19 Infection Survey (preprint)

Objectives: To assess the effectiveness of COVID-19 vaccination in preventing SARS-CoV-2 infection in the community. Design: Prospective cohort study. Setting: The UK population-representative longitudinal COVID-19 Infection Survey. Participants: 373,402 participants aged [≥]16 years contributing 1,610,562 RT-PCR results from nose and throat swabs between 1 December 2020 and 3 April 2021. Main outcome measures: New RT-PCR-positive episodes for SARS-CoV-2 overall, by self-reported symptoms, by cycle threshold (Ct) value (<30 versus [≥]30), and by gene positivity (compatible with the B.1.1.7 variant versus not). Results: Odds of new SARS-CoV-2 infection were reduced 65% (95% CI 60 to 70%; P<0.001) in those [≥]21 days since first vaccination with no second dose versus unvaccinated individuals without evidence of prior infection (RT-PCR or antibody). In those vaccinated, the largest reduction in odds was seen post second dose (70%, 95% CI 62 to 77%; P<0.001).There was no evidence that these benefits varied between Oxford-AstraZeneca and Pfizer-BioNTech vaccines (P>0.9).There was no evidence of a difference in odds of new SARS-CoV-2 infection for individuals having received two vaccine doses and with evidence of prior infection but not vaccinated (P=0.89). Vaccination had a greater impact on reducing SARS-CoV-2 infections with evidence of high viral shedding Ct<30 (88% reduction after two doses; 95% CI 80 to 93%; P<0.001) and with self-reported symptoms (90% reduction after two doses; 95% CI 82 to 94%; P<0.001); effects were similar for different gene positivity patterns. Conclusion: Vaccination with a single dose of Oxford-AstraZeneca or Pfizer-BioNTech vaccines, or two doses of Pfizer-BioNTech, significantly reduced new SARS-CoV-2 infections in this large community surveillance study. Greater reductions in symptomatic infections and/or infections with a higher viral burden are reflected in reduced rates of hospitalisations/deaths, but highlight the potential for limited ongoing transmission from asymptomatic infections in vaccinated individuals. Registration: The study is registered with the ISRCTN Registry, ISRCTN21086382.

Correlation of Computerized Tomography (CT) Severity Score for COVID-19 pneumonia with Clinical Outcomes (preprint)

IntroductionVarious CT severity scores have already been described in literature since the start of this pandemic. One pertinent issue with all of the previously described severity scores is their relative challenging calculation and variance in inter-observer agreement. The severity score proposed in our study is relatively simpler, easier to calculate and apart from a trained radiologist, can easily be calculated even by physicians with good inter-observer agreement. Therefore, a rapid CT severity score calculation can give a clue to physician about possible clinical outcome without being dependent on radiologist who may not be readily available especially in third world countries. ObjectiveThe objective of this study is to develop a simple CT severity score (CT-SS) with good inter-observer agreement and access its correlation with clinical outcome. MethodsThis retrospective study was conducted by the Department of Radiology and Internal Medicine, at the Aga Khan University Hospital Karachi, from April 2020 to August 2020. Non-probability consecutive sampling was used to include all patients who were positive for COVID-19 on PCR, and underwent CT chest examination at AKUH. Severity of disease was calculated in each lobe on the basis of following proposed CT severity scoring system (CT-SS). For each lobe the percentage of involvement by disease was scored - 0% involvement was scored 0, <50% involvement was scored 1 and >50% involvement was scored 2. Maximum score for one lobe was 2 and hence total maximum overall score for all lobes was 10. Continuous data was represented using mean and standard deviation, and compared using independent sample t-tests. Categorical data was represented using frequencies and percentages, and compared using Chi-squared tests. Inter-observer reliability between radiologist and COVID intensivist for the 10 point CT-SS rated on 0-10 was assessed using the Kappa statistic. A p-value < 0.05 was considered significant for all analyses. ResultsA total of 73 patients were included, the majority male (58.9%) with mean age 55.8 {+/-} 13.93 years. The CT-SS rated on 0-10 showed substantial inter-observer reliability between radiologist and intensivist with a Kappa statistic of 0.78. Patients with CT-SS 8-10 had a significantly higher ICU admission & intubation rate (53.8% vs. 23.5%) and mortality rate (35.9% vs. 11.8%; p = 0.017), as compared to those with CT-SS 0-7. ConclusionWe conclude that the described CT severity score (CT-SS) is a quick, effective and easily reproducible tool for prediction of adverse clinical outcome in patients with COVID 19 pneumonia. The tool shows good inter-observer agreement when calculated by radiologist and physician independently.

Increased infections, but not viral burden, with a new SARS-CoV-2 variant (preprint)

BackgroundA new variant of SARS-CoV-2, B.1.1.7/VOC202012/01, was identified in the UK in December-2020. Direct estimates of its potential to enhance transmission are limited. MethodsNose and throat swabs from 28-September-2020 to 2-January-2021 in the UKs nationally representative surveillance study were tested by RT-PCR for three genes (N, S and ORF1ab). Those positive only on ORF1ab+N, S-gene target failures (SGTF), are compatible with B.1.1.7/VOC202012/01. We investigated cycle threshold (Ct) values (a proxy for viral load), percentage of positives, population positivity and growth rates in SGTF vs non-SGTF positives. Results15,166(0.98%) of 1,553,687 swabs were PCR-positive, 8,545(56%) with three genes detected and 3,531(23%) SGTF. SGTF comprised an increasing, and triple-gene positives a decreasing, percentage of infections from late-November in most UK regions/countries, e.g. from 15% to 38% to 81% over 1.5 months in London. SGTF Ct values correspondingly declined substantially to similar levels to triple-gene positives. Population-level SGTF positivity remained low (<0.25%) in all regions/countries until late-November, when marked increases with and without self-reported symptoms occurred in southern England (to 1.5-3%), despite stable rates of non-SGTF cases. SGTF positivity rates increased on average 6% more rapidly than rates of non-SGTF positives (95% CI 4-9%) supporting addition rather than replacement with B.1.1.7/VOC202012/01. Excess growth rates for SGTF vs non-SGTF positives were similar in those up to high school age (5% (1-8%)) and older individuals (6% (4-9%)). ConclusionsDirect population-representative estimates show that the B.1.1.7/VOC202012/01 SARS-CoV-2 variant leads to higher infection rates, but does not seem particularly adapted to any age group.

Community prevalence of SARS-CoV-2 in England: Results from the ONS Coronavirus Infection Survey Pilot (preprint)

Objective: To estimate the percentage of individuals infected with severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) over time in the community in England and to quantify risk factors. Design: Repeated cross-sectional surveys of population-representative households with longitudinal follow-up if consent given. Setting: England. Participants: 34,992 Individuals aged 2 years and over from 16,722 private residential households. Data were collected in a pilot phase of the survey between 26 April and 28 June 2020. Main outcome measures: Percentage of individuals in the community testing positive for SARS-CoV-2 RNA using throat and nose swabs. Individuals were asked about any symptoms and potential risk factors. Results: The percentage of people in private-residential households testing positive for SARS-CoV-2 reduced from 0.32% (95% credible interval (CrI) 0.19% to 0.52%) on 26 April to 0.08% (95% CrI 0.05% to 0.12%) on 28 June, although the prevalence stabilised near the end of the pilot. Factors associated with an increased risk of testing positive included having a job with direct patient contact (relative exposure (RE) 4.06, 95% CrI 2.42 to 6.77)), working outside the home (RE 2.49, 95% CrI 1.39 to 4.45), and having had contact with a hospital (RE 2.20, 95% CrI 1.09 to 4.16 for having been to a hospital individually and RE 1.95, 95% CrI 0.81 to 4.09 for a household member having been to a hospital). In 133 visits where individuals tested positive, 82 (61%, 95% CrI 53% to 69%) reported no symptoms, stably over time. Conclusion: The percentage of SARS-CoV-2 positive individuals declined between 26 April and 28 June 2020. Positive tests commonly occurred without symptoms being reported. Working outside your home was an important risk factor, indicating that continued monitoring for SARS-CoV-2 in the community will be essential for early detection of increases in infections following return to work and other relaxations of control measures.