Reinfection with SARS-CoV-2: outcome, risk factors and vaccine efficacy in a Scottish cohort

BackgroundThe objective of this study was to investigate how protection against COVID-19 conferred by previous infection is modified by vaccination. MethodsIn a cohort of all 152655 individuals in Scotland alive at 90 days after a positive test for SARS-CoV-2 (confirmed by cycle threshold < 30, or two tests) followed till 22 September 2021, rate ratios for reinfection were estimated with calendar time or tests as timescale. FindingsRates of detected and hospitalised reinfection with COVID-19 while unvaccinated were respectively 6.8 (95% CI 6.4 to 7.2) and 0.18 (95% CI 0.12 to 0.25) per 1000 person-months. These rates were respectively 68% and 74% lower than in a matched cohort of individuals who had not previously tested positive. Efficacy of two doses of vaccine in those with previous infection was estimated as as 84% (95 percent CI 81% to 86%) against detected reinfection and 71% (95 percent CI 29% to 88%) against hospitalised or fatal reinfection. The rate of detected reinfection after two doses of vaccine was 1.35 (95% CI 1.02 to 1.78) times higher in those vaccinated before first infection than in those unvaccinated at first infection. InterpretationThe combination of natural infection and vaccination provides maximal protection against new infection with SARS-CoV-2: prior vaccination does not impair this protection. FundingNo specific funding was received for this work. Research in contextO_ST_ABSEvidence before this studyC_ST_ABSIn a recent systematic review of cohort studies reported up to July 2021, the average reduction in COVID-19 infection rates in those with previous infection compared with those without evidence of previous infection was 90%. There is little information about the protective effect of previous infection against severe COVID-19, or about how the protective effects of previous infection against reinfection and severe disease are modified by vaccination. What this paper addsIn unvaccinated individuals the protection against hospitalised COVID-19 conferred by previous infection is similar to that induced by vaccination. In those with previous infection, vaccination reduces the rates of reinfection and hospitalised COVID-19 by about 70%. Implications of all the available evidenceThe combination of natural infection and vaccination provides maximal protection against COVID-19: prior vaccination does not seriously impair this protection.

Efficacy of two doses of COVID-19 vaccine against severe COVID-19 in those with risk conditions and residual risk to the clinically extremely vulnerable: the REACT-SCOT case-control study

ObjectivesTo determine whether COVID-19 efficacy varies with clinical risk category and to investigate risk factors for severe COVID-19 in those who have received two doses of vaccine. DesignMatched case-control study (REACT-SCOT). SettingPopulation of Scotland from 1 December 2020 to 8 September 2021. Main outcome measureSevere COVID-19, defined as cases with entry to critical care or fatal outcome. ResultsEfficacy against severe COVID-19 of two doses of vaccine was 94% (95 percent CI 93% to 96%) in those without designated risk conditions, 89% (95 percent CI 86% to 91%) in those with moderate risk conditions, but only 73% (95 percent CI 64% to 79%) in those designated as clinically extremely vulnerable (CEV) and eligible for shielding. Of the 641 cases of severe COVID-19 in double-vaccinated individuals, 47% had moderate risk conditions and 38% were CEV. In the double-vaccinated CEV group, the rate ratio for severe disease (with no risk condition as reference category) was highest in solid organ transplants at 101 (95% CI 47 to 214) but even in this subgroup the absolute risk of severe COVID-19 was low (35 cases in 23678 person-months of follow-up). ConclusionsTwo doses of vaccine protect against severe COVID-19 in CEV individuals but the residual risk in double-vaccinated individuals remains far higher in those who are CEV than in those who are not. These results lay a basis for determining eligibility for additional measures including passive immunization to protect those at highest risk.

Efficacy of vaccination against severe COVID-19 in relation to Delta variant and time since second dose: the REACT-SCOT case-control study

BackgroundThe objectives of this study were to investigate whether vaccine efficacy against severe COVID-19 has decreased since Delta became the predominant variant; (2) whether efficacy wanes with time since second dose. MethodsEfficacy was estimated in a matched case-control study that includes all diagnosed cases of COVID-19 in Scotland up to 19 August 2021. The main outcome measure was severe COVID-19, defined as cases with entry to critical care or fatal outcome. FindingsEfficacy of vaccination against severe COVID-19 decreased in May 2021 coinciding with the replacement of the B.1.1.7 (Alpha) by the B.1.617.2 (Delta) variant in Scotland, but this decrease was reversed over the next month. In the most recent time window, the efficacy of two doses was 91% (95 percent CI 87% to 94%) for the AstraZeneca product and 92% (95 percent CI 88% to 95%) for mRNA (Pfizer or Moderna) products. Efficacy of the AstraZeneca product against severe COVID-19 declined with time since second dose to 69% (95 percent CI 52% to 80%) at 20 weeks from second dose. Efficacy of mRNA vaccines declined in the first ten weeks from second dose but more slowly thereafter to 93% (95 percent CI 88% to 96%) at 20 weeks from second dose. InterpretationThese results are reassuring with respect to concerns that efficacy against severe COVID-19 might have fallen since the Delta variant became predominant, or that efficacy of mRNA vaccines wanes with increasing time since second dose. However it is now clear that efficacy of the AstraZeneca vaccine against severe COVID-19 wanes substantially by 20 weeks from second dose, suggesting that delivery of booster doses should initially focus on those who received this type of vaccine. FundingNo specific funding was received for this work. HC is supported by an endowed chair from the AXA Research Foundation. Research in contextO_ST_ABSEvidence before this studyC_ST_ABSSeveral reports have suggested that efficacy of COVID-19 vaccines has fallen since the Delta variant became predominant, or that efficacy wanes with time since second dose. The starting point for this study was the evidence of waning efficacy cited by the CDC, the FDA and more recently the UK Joint Committee on Vaccination and Immunisation in support of their recent recommendations for delivery of booster doses for the general population. Added value of this studyThis study shows that efficacy of both AstraZeneca and mRNA vaccines against severe COVID-19 (fatal or requiring critical care) remains high (around 90%) in the most recent time window, but that efficacy of the AstraZeneca vaccine wanes to about 70% by 20 weeks from second dose. In contrast efficacy of the mRNA vaccines wanes rapidly at first but stabilises at about 90% by 20 weeks from second dose. Implications of all the available evidenceThese results suggest that booster doses of vaccine are not needed for those who have received two doses of mRNA vaccine, except for vulnerable individuals who may require a third primary dose.

Effect of vaccination on transmission of COVID-19: an observational study in healthcare workers and their households

BackgroundThe effect of vaccination for COVID-19 on onward transmission is unknown. MethodsA national record linkage study determined documented COVID-19 cases and hospitalisations in unvaccinated household members of vaccinated and unvaccinated healthcare workers from 8th December 2020 to 3rd March 2021. The primary endpoint was COVID-19 14 days following the first dose. ResultsThe cohort comprised of 194,362 household members (mean age 31{middle dot}1 {+/-} 20{middle dot}9 years) and 144,525 healthcare workers (mean age 44{middle dot}4 {+/-} 11{middle dot}4 years). 113,253 (78{middle dot}3%) of healthcare workers received at least one dose of the BNT162b2 mRNA or ChAdOx1 nCoV-19 vaccine and 36,227 (25{middle dot}1%) received a second dose. There were 3,123 and 4,343 documented COVID-19 cases and 175 and 177 COVID-19 hospitalisations in household members of healthcare workers and healthcare workers respectively. Household members of vaccinated healthcare workers had a lower risk of COVID-19 case compared to household members of unvaccinated healthcare worker (rate per 100 person-years 9{middle dot}40 versus 5{middle dot}93; HR 0{middle dot}70, 95% confidence interval [CI] 0{middle dot}63 to 0{middle dot}78). The effect size for COVID-19 hospitalisation was similar, with the confidence interval crossing the null (HR 0{middle dot}77 [95% CI 0{middle dot}53 to 1{middle dot}10]). The rate per 100 person years was lower in vaccinated compared to unvaccinated healthcare workers for documented (20{middle dot}13 versus 8{middle dot}51; HR 0{middle dot}45 [95% CI 0{middle dot}42 to 0{middle dot}49]) and hospitalized COVID-19 (0{middle dot}97 versus 0{middle dot}14; HR 0{middle dot}16 [95% CI 0{middle dot}09 to 0{middle dot}27]). Compared to the period before the first dose, the risk of documented COVID-19 case was lower at [≥] 14 days after the second dose for household members (HR 0{middle dot}46 [95% CI 0{middle dot}30to 0{middle dot}70]) and healthcare workers (HR 0{middle dot}08 [95% CI 0{middle dot}04 to 0{middle dot}17]). InterpretationVaccination of health care workers was associated with a substantial reduction in COVID-19 cases in household contacts consistent with an effect of vaccination on transmission.

Relation of severe COVID-19 in Scotland to transmission-related factors and risk conditions eligible for shielding support: REACT-SCOT case-control study

BackgroundClinically vulnerable individuals have been advised to shield themselves during the COVID-19 epidemic. The objectives of this study were to investigate: (1) the risk of severe COVID-19 in those eligible for shielding, and (2) the relation of severe COVID-19 to transmission-related factors in those in shielding and the general population. MethodsAll 178578 diagnosed cases of COVID-19 in Scotland from 1 March 2020 to 18 February 2021 were matched for age, sex and primary care practice to 1744283 controls from the general population. This dataset (REACT-SCOT) was linked to the list of 212702 individuals identified as eligible for shielding. Severe COVID-19 was defined as cases that entered critical care or were fatal. ResultsWith those without risk conditions as reference category, the univariate rate ratio for severe COVID-19 was 3.21 (95% CI 3.01 to 3.41) in those with moderate risk conditions and 6.3 (95% CI 5.8 to 6.8) in those eligible for shielding. The highest rate was in solid organ transplant recipients: rate ratio 13.4 (95% CI 9.6 to 18.8). Risk of severe COVID-19 increased with the number of adults but decreased with the number of school-age children in the household. Severe COVID-19 was strongly associated with recent exposure to hospital (defined as 5 to 14 days before presentation date): rate ratio 12.3 (95% CI 11.5 to 13.2) overall. To test for causality, a case-crossover analysis was undertaken; with less recent exposure only (15 to 24 days before first testing positive) as reference category, the rate ratio associated with recent exposure only was 5.9 (95% CI 3.6 to 9.7). The population attributable risk fraction for recent exposure to hospital peaked at 50% in May 2020 and again at 65% in December 2020. ConclusionsThe effectiveness of shielding vulnerable individuals was limited by the inability to control transmission in hospital and from other adults in the household. For solid organ transplant recipients, in whom the efficacy of vaccines is uncertain, these results support a policy of offering vaccination to household contacts. Mitigating the impact of the epidemic requires control of nosocomial transmission.

Impact of COVID-19 on Care-Home Mortality and Life Expectancy in Scotland

IntroductionCOVID-19 deaths are commoner among care-home residents, but the mortality burden has not been quantified. MethodsCare-home residency was identified via a national primary care registration database linked to national mortality data. Life expectancy was estimated using Makeham-Gompertz models, to (i) describe yearly life expectancy from Nov 2015 to Oct 2020 (ii) compare life expectancy (during 2016-2018) between care-home residents and the wider Scottish population and (iii) apply care-home life expectancy estimates to COVID-19 death counts to estimate years of life lost (YLL). ResultsAmong care-home residents, life expectancy in 2015/16 to 2019/20 ranged from 2.7 to 2.3 years for women and 2.3 to 1.8 years for men. Life expectancy was lowest in 2019/20. Age-sex specific life expectancy in 2016-2018 in care-home residents was lower than in the Scottish population (10 and 2.5 years in those aged 70 and 90 respectively). Rather than using national life tables, applying care-home specific life expectancies to COVID-19 deaths yields, mean YLLs for care-home residents were 2.6 and 2.2 for women and men respectively, with total care-home resident YLLs of 3,560 years in women and 2,046 years in men. In people aged over-70, approximately half of deaths and a quarter of YLL attributed to COVID-19 were accounted for by the 5% of over-70s who were care-home residents. ConclusionPrioritising care-home residents for vaccination is justified not only in terms of total deaths, but also in terms of years of life lost. Research in contextO_ST_ABSEvidence before this studyC_ST_ABSWe searched PubMed to 1st December 2020, with the terms ("nursing home" OR "care-home" OR "long-term care" OR "residential care") AND ("mortality" OR "life expectancy" OR "length of stay"). We also searched for studies specific to the impact of the COVID-19 pandemic on those living in care-homes. We restricted our search to publications in English. Usual care-home life expectancy, in a UK context, has not previously been defined. One systematic review of length of stay was identified, which found significant heterogeneity in factors and associations. The impact of COVID-19 on excess mortality among care-home residents was noted, but the impact on life expectancy was not reported. Studies evaluating life expectancy among older people in the COVID-19 pandemic have not taken account of residency in their estimates. Added value of this studyUsing Scottish national representative linked data we describe the usual life expectancy of older adults (aged [≥]70 years) living in care-homes, compared to older people living elsewhere. Deaths among care-home residents account for a considerable proportion of all mortality in older adults, around 19% for men and 30% for women. Life expectancy in care-home residents during the pandemic fell by almost 6 months, from 2.7 to 2.3 years in men and 2.1 to 1.8 years in women. In total, over 5,600 Years of Life were Lost (YLL) by care-home residents in Scotland who died with COVID-19. Around half of COVID-19 deaths and a quarter of YLL in those aged 70 years and over occurred among care-home residents. During the COVID-19 pandemic a smaller proportion of deaths among care-home residents occurred in hospitals. Implications of all the available evidencePrioritising the 5% of older adults who are care-home residents for vaccination against COVID-19 is justified both in terms of total deaths and total years of life lost. Individual and societal planning for care needs in older age relies on understanding usual care-home life expectancy and patterns of mortality. Understanding life expectancy may help clinicians, residents and their families make decisions about their health care, facilitating more informed discussions around their priorities and wishes. Population-wide estimates of YLL and burden of disease should take account of residency status, given the significant differences between life expectancy of those living in care-homes from their peers in other settings.

Sharing a household with children and risk of COVID-19: a study of over 300,000 adults living in healthcare worker households in Scotland

ObjectiveChildren are relatively protected from COVID-19, possibly due to cross-protective immunity. We investigated if contact with children also affords adults a degree of protection from COVID-19. DesignCohort study based on linked administrative data. SettingScotland Study populationAll NHS Scotland healthcare workers and their household contacts as of March 2020. Main exposureNumber of young children (0-11 years) living in the participants household. Main outcomesCOVID-19 requiring hospitalisation, and any COVID-19 (any positive test for SARS-CoV-2) in adults aged [≥]18 years between 1 March and 12 October 2020. Results241,266, 41,198, 23,783 and 3,850 adults shared a household with 0, 1, 2, and 3 or more young children respectively. Over the study period, the risk of COVID-19 requiring hospitalisation was reduced progressively with increasing numbers of household children - fully adjusted hazard ratio (aHR) 0.93 per child (95% CI 0.79-1.10). The risk of any COVID-19 was similarly reduced, with the association being statistically significant (aHR per child 0.93; 95% CI 0.88-0.98). After schools reopened to all children in August 2020, no association was seen between exposure to young children and risk of any COVID-19 (aHR per child 1.03; 95% CI 0.92-1.14). ConclusionBetween March and October 2020, living with young children was associated with an attenuated risk of any COVID-19 and COVID-19 requiring hospitalisation among adults living in healthcare worker households. There was no evidence that living with young children increased adults risk of COVID-19, including during the period after schools re-opened.

Risk of hospitalisation with coronavirus disease 2019 in healthcare workers and their households:a nationwide linkage cohort study

ObjectiveMany healthcare staff work in high-risk settings for contracting and transmitting Severe Acute Respiratory Syndrome Coronavirus 2. Their risk of hospitalisation for coronavirus disease 2019 (COVID-19), and that of their households, is poorly understood. Design and settings and participantsDuring the peak period for COVID-19 infection in Scotland (1st March 2020 to 6th June 2020) we conducted a national record linkage study to compare the risk of COVID-19 hospitalisation among healthcare workers (age: 18-65 years), their households and other members of the general population. Main outcomeHospitalisation with COVID-19 ResultsThe cohort comprised 158,445 healthcare workers, the majority being patient facing (90,733 / 158,445; 57.3%), and 229,905 household members. Of all COVID-19 hospitalisations in the working age population (18-65-year-old), 17.2% (360 / 2,097) were in healthcare workers or their households. Adjusting for age, sex, ethnicity, socio-economic deprivation and comorbidity, the risk of COVID-19 hospitalisation in non-patient facing healthcare workers and their households was similar to the risk in the general population (hazards ratio [HR] 0.81; 95%CI 0.52-1.26 and 0.86; 95%CI 0.49-1.51 respectively). In models adjusting for the same covariates however, patient facing healthcare workers, compared to non-patient facing healthcare workers, were at higher risk (HR 3.30; 95%CI 2.13-5.13); so too were household members of patient facing healthcare workers (HR 1.79; 95%CI 1.10-2.91). On sub-dividing patient-facing healthcare workers into those who worked in front-door, intensive care and non-intensive care aerosol generating settings and other, those in front door roles were at higher risk (HR 2.09; 95%CI 1.49-2.94). For most patient facing healthcare workers and their households, the estimated absolute risk of COVID-19 hospitalisation was less than 0.5% but was 1% and above in older men with comorbidity. ConclusionsHealthcare workers and their households contribute a sixth of hospitalised COVID-19 cases. Whilst the absolute risk of hospitalisation was low overall, patient facing healthcare workers and their households had 3- and 2-fold increased risks of COVID-19 hospitalisation.

Associations of severe COVID-19 with polypharmacy in the REACT-SCOT case-control study

ObjectivesTo investigate the relation of severe COVID-19 to prior drug prescribing. DesignMatched case-control study (REACT-SCOT) based on record linkage to hospital discharges since June 2015 and dispensed prescriptions issued in primary care during the last 240 days. SettingScottish population. Main outcome measureSevere COVID-19, defined by entry to critical care or fatal outcome. ParticipantsAll 4272 cases of severe COVID-19 in Scotland since the start of the epidemic, with 36948 controls matched for age, sex and primary care practice. ResultsSevere COVID-19 was strongly associated with the number of non-cardiovascular drug classes dispensed. This association was strongest in those not resident in care homes, in whom the rate ratio (95% CI) associated with dispensing of 12 or more drug classes versus none was 10.8 (8.7, 13.2), and was not accounted for by treatment of conditions designated as conferring increased risk. Of 17 drug classes postulated at the start of the epidemic to be "medications compromising COVID", all were associated with increased risk of severe COVID-19. The largest effect was for antipsychotic agents: rate ratio 4.14 (3.39, 5.07). Other drug classes with large effects included proton pump inhibitors (rate rato 2.19 (1.70, 2.80) for >= 2 defined daily doses/day), opioids (3.62 (2.65, 4.94) for >= 50 mg morphine equivalent/day) and gabapentinoids. These associations persisted after adjusting for covariates, and were stronger with recent than with non-recent exposure. ConclusionsSevere COVID-19 is associated with polypharmacy and with drugs that cause sedation, respiratory depression or dyskinesia, have anticholinergic effects or affect the gastrointestinal system. These associations are not easily explained by co-morbidity. Although the evidence for causality is not conclusive, these results support existing guidance on reducing overprescribing of these drug classes and limiting inappropriate polypharmacy as a potential means of reducing COVID-19 risk. RegistrationENCEPP number EUPAS35558 What is already known on this topicTwo previous studies have examined the relationship of severe COVID-19 to drugs for the cardiovascular system. This is the first systematic study of the relationship of severe COVID-19 to prior drug prescribing. What this study addsSevere COVID-19 is associated with polypharmacy and with drugs that cause sedation, respiratory depression or dyskinesia, have anticholinergic effects or affect the gastrointestinal system. These associations are not easily explained by co-morbidity. These results support earlier warnings that these drug classes that these drugs might increase susceptibility to COVID-19, and reinforce existing guidance on reducing overprescribing of these drug classes.

Rapid Epidemiological Analysis of Comorbidities andTreatments as risk factors for COVID-19 in Scotland(REACT-SCOT): a population-based case-control study

BackgroundThe objectives of this study were to identify risk factors for severe COVID-19 and to lay the basis for risk stratification based on demographic data and health records. Methods and FindingsThe design was a matched case-control study. Severe COVID-19 was defined as either a positive nucleic acid test for SARS-CoV-2 in the national database followed by entry to a critical care unit or death within 28 days, or a death certificate with COVID-19 as underlying cause. Up to ten controls per case matched for sex, age and primary care practice were selected from the population register. All diagnostic codes from the past five years of hospitalisation records and all drug codes from prescriptions dispensed during the past nine months were extracted. Rate ratios for severe COVID-19 were estimated by conditional logistic regression. There were 4272 severe cases. In a logistic regression using the age-sex distribution of the national population, the odds ratios for severe disease were 2.87 for a 10-year increase in age and 1.63 for male sex. In the case-control analysis, the strongest risk factor was residence in a care home, with rate ratio (95% CI) 21.4 (19.1, 23.9). Univariate rate ratios (95% CIs) for conditions listed by public health agencies as conferring high risk were 2.75 (1.96, 3.88) for Type 1 diabetes, 1.60 (1.48, 1.74) for Type 2 diabetes, 1.49 (1.37, 1.61) for ischemic heart disease, 2.23 (2.08, 2.39) for other heart disease, 1.96 (1.83, 2.10) for chronic lower respiratory tract disease, 4.06 (3.15, 5.23) for chronic kidney disease, 5.4 (4.9, 5.8) for neurological disease, 3.61 (2.60, 5.00) for chronic liver disease and 2.66 (1.86, 3.79) for immune deficiency or suppression. 78% of cases and 52% of controls had at least one listed condition (NA of cases and NA of controls under age 40). Severe disease was associated with encashment of at least one prescription in the past nine months and with at least one hospital admission in the past five years [rate ratios 3.10 (2.59, 3.71)] and 2.75 (2.53, 2.99) respectively] even after adjusting for the listed conditions. In those without listed conditions significant associations with severe disease were seen across many hospital diagnoses and drug categories. Age and sex provided 2.58 bits of information for discrimination. A model based on demographic variables, listed conditions, hospital diagnoses and prescriptions provided an additional 1.25 bits (C-statistic 0.825). A limitation of this study is that records from primary care were not available. ConclusionsAlong with older age and male sex, severe COVID-19 is strongly associated with past medical history across all age groups. Many comorbidities beyond the risk conditions designated by public health agencies contribute to this. A risk classifier that uses all the information available in health records, rather than only a limited set of conditions, will more accurately discriminate between low-risk and high-risk individuals who may require shielding until the epidemic is over. Author summaryMost people infected with the SARS-CoV-2 coronavirus do not become seriously ill. It is The risk of severe or fatal illness is higher in older than in younger people, and is higher in people with conditions such as asthma and diabetes than in people without these conditions. Using Scotlands capability for linking electronic health records, we report the first systematic study of the relation of severe or fatal COVID-19 to pre-existing health conditions and other risk factors. We show that the strongest risk factor, apart from age, is residence in a care home. The conditions associated with increased risk include not only those already designated by public health agencies - asthma, diabetes, heart disease, disabling neurological disease, kidney disease - but many other diagnoses, associated with frailty and poor health. This lays a basis for constructing risk scores based on electronic health records that can be used to advise people at high risk of severe disease to shield themselves when there cases in their neighbourhood.