key: cord-0271969-lby3xhmp
authors: Taquet, M.; Dercon, Q.; Harrison, P. J.
title: Six-month sequelae of post-vaccination SARS-CoV-2 infection: a retrospective cohort study of 10,024 breakthrough infections
date: 2021-10-26
journal: nan
DOI: 10.1101/2021.10.26.21265508
sha: c202e3ef187c6bc939c9226c44ef57a56448ede6
doc_id: 271969
cord_uid: lby3xhmp

Background. Vaccination has proven effective against infection with SARS-CoV-2, as well as death and hospitalisation following COVID-19 illness. However, little is known about the effect of vaccination on other acute and post-acute outcomes of COVID-19. Methods. Data were obtained from the TriNetX electronic health records network (over 81 million patients mostly in the USA). Using a retrospective cohort study and time-to-event analysis, we compared the incidences of COVID-19 outcomes between individuals who received a COVID-19 vaccine (approved for use in the USA) at least 2 weeks before SARS-CoV-2 infection and propensity score-matched individuals unvaccinated for COVID-19 but who had received an influenza vaccine. Outcomes were ICD-10 codes representing documented COVID-19 sequelae in the 6 months after a confirmed SARS-CoV-2 infection (recorded between January 1 and August 31, 2021). Associations with the number of vaccine doses (1 vs. 2) and age (< 60 vs. [≥] 60 years-old) were assessed. Findings. Among 10,024 vaccinated individuals with SARS-CoV-2 infection, 9479 were matched to unvaccinated controls. Receiving at least one COVID-19 vaccine dose was associated with a significantly lower risk of respiratory failure, ICU admission, intubation/ventilation, hypoxaemia, oxygen requirement, hypercoagulopathy/venous thromboembolism, seizures, psychotic disorder, and hair loss (each as composite endpoints with death to account for competing risks; HR 0.70-0.83, Bonferroni-corrected p<.05), but not other outcomes, including long-COVID features, renal disease, mood, anxiety, and sleep disorders. Receiving 2 vaccine doses was associated with lower risks for most outcomes. Associations between prior vaccination and outcomes of SARS-CoV-2 infection were marked in those < 60 years-old, whereas no robust associations were observed in those [≥] 60 years-old. Interpretation. COVID-19 vaccination is associated with lower risk of several, but not all, COVID-19 sequelae in those with breakthrough SARS-CoV-2 infection. These benefits of vaccination were clear in younger people but not in the over-60s. The findings may inform service planning, contribute to forecasting public health impacts of vaccination programmes, and highlight the need to identify additional interventions for COVID-19 sequelae. Funding. National Institute for Health Research (NIHR) Oxford Health Biomedical Research Centre.

We searched PubMed on October 5, 2021 with the following terms (COVID-19 OR SARS-CoV-2 OR infection OR case* OR diagnosis) AND (vaccine OR vaccination OR breakthrough OR postvaccin*) AND (COVID-19 OR SARS-CoV-2) AND (infection OR diagnosis) AND (characteristic* OR symptom* OR outcome* OR feature* OR death OR surviv* OR admission OR hospital* OR intensive) with the first two sets of terms having to appear in the title whereas all the other terms could appear anywhere in the manuscript. Among 995 results, we found 10 articles reporting the outcomes of SARS-CoV-2 infections comparing vaccinated with unvaccinated individuals. 9 out of 10 studies focused on a combination of death, intensive care admission, hospitalisation, and mechanical ventilation. The other study investigated self-reported symptoms in 908 pairs of vaccinated and unvaccinated individuals. No study investigated how vaccination affects a broader spectrum of acute and post-acute sequelae of COVID-19 (including hypercoagulopathy, ischaemic strokes, neuropsychiatric complications, long-COVID presentations, Type 2 diabetes, renal failure, etc). In addition, unvaccinated people might display health behaviours related to vaccination hesitancy, and no study sought to address this bias.

To our knowledge, this is the first study which compares the 6-month risk of a broad spectrum of 45 acute and post-acute sequelae of COVID-19 among 9479 matched pairs of vaccinated vs. unvaccinated individuals. Unvaccinated individuals were selected among those who accepted a vaccine against influenza thus limiting the bias due to health behaviours . CC-BY-NC 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted October 26, 2021. ; https://doi.org/10.1101/2021.10.26.21265508 doi: medRxiv preprint related to vaccine hesitancy. We show that vaccination is associated with a lower risk of composite endpoint of death and (i) respiratory failure, (ii) ICU admission, (iii) intubation/ventilation, (iv) hypoxaemia, (v) oxygen requirement, (vi) hypercoagulopathy/venous thromboembolism, (vii) seizures, (viii) psychotic disorder, and (ix) hair loss but with a similar risk of many other sequelae of COVID-19 including long-COVID presentations, kidney disease, type 2 diabetes mellitus, mood and anxiety disorder, and sleep disorders among others. Receiving two doses of the vaccine was associated with an even lower risk of many of the outcomes. The associations between prior vaccination and COVID-19 outcomes were strong in individuals < 60 years-old but weaker or absent in those ≥ 60 years-old.

Vaccination (especially after two doses) is associated with better outcomes among individuals infected with SARS-CoV-2. This highlights that vaccination is not only effective against SARS-CoV-2 infection, but also against its sequelae in those infected. However, the risk of several important outcomes appears to be unaffected by vaccination suggesting that different pathophysiological mechanisms might underpin these outcomes. Moreover, these benefits of vaccination were not clear in older people; this is an important factor since they are at higher absolute risks of most adverse outcomes after infection. The findings can help in determining the necessary service provision and underlines the urgency to identify other preventive or curative interventions to mitigate the impact of such sequelae of COVID-19.

The observation that individuals can be infected with SARS-CoV-2 after being vaccinated against COVID-19 (so-called breakthrough infections) has caused concerns. 1 These concerns are mitigated by abundant evidence that the risk of severe COVID-19 illness (as proxied by hospitalisation, admission to intensive care unit, and mortality) is lessened by vaccination. [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] One case-control study investigated the association between self-reported SARS-CoV-2 infection in 908 pairs of vaccinated and unvaccinated individuals and self-reported symptoms beyond 28 days. 9 It found that compared to unvaccinated individuals, those with breakthrough infection were at a lower risk of symptoms beyond 28 days.

However, how COVID-19 vaccination affects the broad spectrum of sequelae of SARS-CoV-2 infection remains elusive. In particular, it is unknown if vaccinated individuals are at the same risk as unvaccinated individuals of venous thromboembolisms, ischaemic strokes, neuropsychiatric complications, long-COVID presentations, and other post-acute sequelae following infection with SARS-CoV-2. In addition, unvaccinated people might have health behaviours related to vaccination hesitancy, 12 and this potential source of bias has not been addressed by previous studies.

This cohort study based on electronic health records compares the 6-months outcomes of SARS-CoV-2 infection among individuals who were (vs. those who were not) vaccinated against COVID-19. We investigated a range of outcomes (both acute and post-acute) with documented associations with COVID-19 across multiple body systems.

. CC-BY-NC 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)

The copyright holder for this preprint this version posted October 26, 2021. ; https://doi.org/10.1101/2021.10.26.21265508 doi: medRxiv preprint

The study used TriNetX Analytics, a federated network of linked EHRs recording anonymized data from 59 healthcare organizations (HCOs), primarily in the USA, totalling 81 million patients. Available data include demographics, diagnoses (ICD-10 codes), procedures (Current Procedural Terminology [CPT] codes), and measurements (e.g. BMI).

The HCOs in the network are a mixture of hospitals, primary care, and specialist providers, and they contribute data from uninsured and insured patients. Data de-identification is attested to through a formal determination by a qualified expert as defined in Section §164.514(b)(1) of the HIPAA Privacy Rule. This formal determination supersedes TriNetX's waiver from the Western Institutional Review Board (IRB). Via the TriNetX user interface, cohorts can be created based on inclusion and exclusion criteria, matched for confounding variables, and compared for outcomes of interest over specified time periods. For further details about TriNetX, its data provenance and functionalities, see Appendix pp. 1-2.

Both the primary and control cohorts were defined as all patients who had, between January 1, 2021 and August 31, 2021, a confirmed SARS-CoV-2 infection, which we defined as either a confirmed diagnosis of COVID-19 (ICD-10 code U07.1) or a first positive PCR test for SARS-CoV-2. In the primary cohort, patients were included only if their confirmed SARS-CoV-2 infection occurred at least 14 days after a recorded administration of a COVID-19 vaccine approved for use in the USA (i.e. BNT162b2 'Pfizer/BioNTech', mRNA-1273 'Moderna', or Ad26.COV2.S 'Janssen'). In the control cohort, patients were included only if no recorded vaccine against COVID-19 was recorded before their SARS-CoV-2 infection and if they had received a vaccine against influenza at any time. In the USA, the Centers for . CC-BY-NC 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)

The copyright holder for this preprint this version posted October 26, 2021. ; https://doi.org/10.1101/2021.10.26.21265508 doi: medRxiv preprint Disease Control and Prevention (CDC) recommend yearly influenza vaccination to everyone over the age of 6 months. This inclusion criterion thus excludes patients with obvious vaccine hesitancy (so-called 'anti-vaxxers') as this is correlated with other health-related behaviours that might confound associations with COVID-19 outcomes. 12 More details are provided in the Appendix pp. 2-4.

A set of established and suspected risk factors for COVID-19 and for more severe COVID-19 illness was used: [13] [14] [15] age, sex, race, ethnicity, obesity, hypertension, diabetes, chronic kidney disease, asthma, chronic lower respiratory diseases, nicotine dependence, substance misuse, ischaemic heart disease and other forms of heart disease, socioeconomic deprivation, cancer (and haematological cancer in particular), chronic liver disease, stroke, dementia, organ transplant, rheumatoid arthritis, lupus, psoriasis, and disorders involving an immune mechanism. To capture these risk factors in patients' health records, 55 variables were used.

More details including ICD-10 codes are provided in the Appendix pp. 4-5. Cohorts were matched for all these variables, as described below. In addition, cohorts were stratified by the date of the SARS-CoV-2 infection in 2-monthly periods (January 1 to February 28, 2021, March 1 to April 30, 2021, May 1 to June 30, 2021, and July 1 to August 31, 2021) and matching was achieved independently within each period (guaranteeing that as many patients in the matched cohorts had their SARS-CoV-2 infection in every 2-month period).

We investigated the 6-month incidence of all acute and post-acute outcomes which have been shown to be significantly associated with COVID-19 in four large-scale studies based on electronic health records, [15] [16] [17] [18] namely:

. CC-BY-NC 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) Each outcome was defined as the set of corresponding ICD-10, CPT, and VA Formulary codes as specified in the original study which showed their association with COVID-19. To account for death as a competing risk and thus address survivorship bias, each outcome was analysed as part of a composite outcome with death as the other component. 19 While . CC-BY-NC 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted October 26, 2021. necessary to address survivorship bias, this approach is unlikely to provide insight into the risk of outcomes which are much rarer than death itself. The analysis was performed on October 12, 2021. More details, and ICD-10/CPT/VA Formulary codes, are provided in the Appendix pp. 5-6.

We assessed whether the associations between prior vaccinations and outcomes of SARS-CoV-2 infection were moderated by the number of vaccine doses received and by age at the time of infection. This was achieved by restricting the primary cohort to (i) those who had received only one vaccine dose at least 14 days before infection, (ii) those who had received two vaccine doses 14 days before infection, (iii) those <60 years-old, and (iv) those ≥ 60 years-old. For the latter two subgroup analyses, the control cohorts were also restricted to those <60 and ≥ 60 years-old respectively.

Propensity score matching was used to create cohorts with matched baseline characteristics, 20 and carried out within the TriNetX network. Propensity score 1:1 matching used a greedy nearest neighbour matching approach with a caliper distance of 0.1 pooled standard deviations of the logit of the propensity score. Any characteristic with a standardized mean difference (SMD) between cohorts lower than 0.1 is considered well matched. 21 The incidence of each outcome was estimated using the Kaplan-Meier estimator. Comparisons between cohorts were made using a log-rank test. Hazard ratios (HRs) with 95% confidence intervals were calculated using the Cox model. The proportional hazard assumption was tested using the generalized Schoenfeld approach. When the assumption was violated, the time-varying HR was assessed using natural cubic splines fitted to the log-cumulative . CC-BY-NC 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted October 26, 2021. ; https://doi.org/10.1101/2021.10.26.21265508 doi: medRxiv preprint hazard. 22 The contribution of the individual outcomes of interest was reported as the number of events of interest over the total number of events (e.g. the number of respiratory failures over the number of respiratory failures or deaths).

We statistically tested whether the associations between prior COVID-19 vaccine and outcomes of SARS-CoV-2 infection was moderated by age. This was achieved for each outcome by testing whether the ratio between the HR in those ≥ 60 and the HR in those <60 years-old was statistically significantly different from 1. Similarly, moderation by the number of vaccine doses was achieved by testing whether the ratio between the HR in those who had received 1 dose and the HR in those who had received 2 doses at the time of infection was statistically significantly different from 1.

Further details are provided in the appendix p. 7. Statistical analyses were conducted in R version 3.6.3 except for the log-rank tests which were performed within TriNetX. Statistical significance was set at two-sided p-values <0.05. Bonferroni correction for multiple comparisons was applied to correct for the simultaneous assessments of 45 outcomes in the primary analysis. A REporting of studies Conducted using Observational Routinely-collected health Data (RECORD) statement was completed (see Appendix). Besides the outcomes shown to be significantly associated with vaccination in the primary analysis, those who had received two vaccine doses at the time of SARS-CoV-2 infection were also at a significantly lower risk of myalgia, myocarditis, cerebral haemorrhage, interstitial lung disease, urticaria, anosmia, and myoneural junction/muscle disease (each as composite endpoints with death), and at a significantly lower risk of death ( Fig. 3 and appendix pp. 14, 32-33). In those who had received only one vaccine dose, HRs followed a similar pattern, though they were generally closer to 1 (Fig. 3 and appendix pp. 15, 34-35 ).

For each of the outcome, the HR in those who had received 2 doses was not statistically significantly different from the HR in those who had received 1 vaccine dose (appendix pp.

We found a substantial effect of age on the results. Many HRs in younger individuals (< 60 years-old) were in general lower (i.e. favouring vaccination even more) for outcomes significantly associated with vaccination ( Fig. 3 and appendix pp. 16, 38-39) . These lower HRs were observed against the backdrop of lower absolute risks for most outcomes among younger individuals (appendix pp. 38-39). In contrast, in individuals >60 years-old, although most trends were similar to those in the younger group, none of the HRs were statistically significantly different from 1 after Bonferroni correction (Fig. 3 and appendix pp. 17, 40-41) .

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It is established that vaccination protects against hospitalisation, ICU admission, and death from COVID-19 2-11 but little was known about other outcomes of breakthrough SARS-CoV-2 infections. The data presented in this study, from a large-scale electronic health records network, confirm that vaccination protects against death and ICU admission following breakthrough SARS-CoV-2 infection and provide estimates of HR for these outcomes in a general population. Our study also shows that vaccination against COVID-19 is associated with lower risk of additional outcomes that had not been assessed in previous studies, namely respiratory failure, hypoxaemia, oxygen requirement, hypercoagulopathy or venous thromboembolism, seizures, psychotic disorder, and hair loss.

On the other hand, previous vaccination does not appear to be protective against several previously documented outcomes of COVID-19 such as long-COVID features, arrhythmia, joint pain, type 2 diabetes, liver disease, sleep disorders, and mood and anxiety disorders. The narrow confidence intervals (related to the high incidence of these outcomes post-COVID) rules out the possibility that these negative findings are merely a result of lack of statistical . CC-BY-NC 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted October 26, 2021. ; https://doi.org/10.1101/2021.10.26.21265508 doi: medRxiv preprint power. The inclusion of death in a composite endpoint with these outcomes rules out survivorship bias as an explanation. Instead, these negative findings might indicate that these outcomes arise through different pathophysiological mechanisms than outcomes which are affected by prior vaccination. For example, for anxiety and depression, it might be that antagonistic forces are at play with the protective effect of the vaccine being counteracted by the additional stressor of being infected despite being vaccinated.

The absence of a protective effect against long-COVID features is concerning given the high incidence and burden of these sequelae of COVID-19. 18 First, the present study used data routinely collected from a general population rather than self-selected individuals. Second, this study uses a large sample size and matches cohorts on a broad range of recorded comorbidities. To further decrease selection bias, the control cohort of this study was selected among those having received an influenza vaccine thus helping control for the confounding effect of vaccine hesitancy and related health behaviours. 12 Third, by using symptoms and diagnoses extracted from health records rather than selfreported, our study might capture the most severe presentation of symptoms and these might be less prone to demand characteristics and other forms of detection bias. Finally, there might . CC-BY-NC 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted October 26, 2021. ; https://doi.org/10.1101/2021.10.26.21265508 doi: medRxiv preprint be differences in the type of vaccines used between the two study. In particular, no ChAdOx1 nCov-19 ('Oxford/AstraZeneca') vaccine was used in our study (as this vaccine is not used in the USA).

The findings that vaccination against SARS-CoV-2 does not protect against some of the postacute outcomes of COVID-19 should not obscure the fact that vaccination remains an important protective factor against these outcomes at the population level, since the best way to prevent those outcomes is to prevent SARS-CoV-2 infection in the first place. This is also the case in those ≥ 60 years-old. 23 However, our results highlight that some post-acute outcomes of SARS-CoV-2 (and notably long-COVID presentations) are likely to persist even after successful vaccination of the population, so long as breakthrough infections occur.

These findings thus help in determining the necessary service provision. They also underline the urgency to identify other preventive or curative interventions to mitigate the impact of such COVID-19 sequelae.

Death was included in a composite endpoint with each outcome of interest to address competing risks. 19 This implies that for outcomes much rarer than death (which is the minority of outcomes investigated), HRs might be driven by death rather than the outcome of interest. For instance, the 6-month incidence of psychotic disorders in the unvaccinated cohort was 1.11% whereas the death rate was 4.5% in this cohort. Hence the HR of 0.75 for the composite endpoint of death and psychotic disorder is in part driven by differences in death rate. Observing the HR for the outcome of interest in isolation (i.e. not composed with death) is informative so long as it is lower than 1. A HR lower than 1 suggests a lower rate of the outcome of interest despite survivorship bias (which in the present study increases HRs).

If the HR is higher than 1, it is impossible to know whether the outcome is more common . CC-BY-NC 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted October 26, 2021. ; https://doi.org/10.1101/2021.10.26.21265508 doi: medRxiv preprint among vaccinated individuals or if it is a result of survivorship bias. HRs for all outcomes in isolation are provided in Appendix pp. 44-53 for the primary and secondary analyses. For instance, the HR for psychotic disorder measured in isolation was 0.79, indicating that the incidence of this outcome might indeed be lower in vaccinated than unvaccinated individuals and its significant HR might not be merely driven by differences in death rates.

Importantly, the protective effects of the vaccine against acute severity of infection and some post-acute sequelae appears to affect primarily those <60 years-old. In this group, the effects were large and robust, whereas in the ≥ 60 year-old group, effects were smaller and not statistically robust. This finding regarding age cannot be explained by differences in statistical power since the younger and older subgroups have similar sample sizes (4633 and 4657 respectively) and outcomes are in general more frequent in the older subgroup. Instead, it might be due to differences in contributions of pathophysiological pathways of breakthrough infections between younger and older individuals. In younger patients, effective B-cell response to vaccination might be followed by infection with variants against which antibodies have less neutralising activity. 24 In older patients, the B-cell response to vaccination might itself be ineffective 25 This study has several limitations beyond those inherent to research using EHRs 15, 26 (summarised in the appendix p. 2) such as the unknown completeness of records, no validation of diagnoses, and sparse information on socioeconomic and lifestyle factors. First, we do not know which SARS-CoV-2 variant individual patients were infected with and this . CC-BY-NC 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted October 26, 2021. ; https://doi.org/10.1101/2021.10.26.21265508 doi: medRxiv preprint might affect the protective effect of vaccines. There is evidence that variants of concerns are overrepresented in breakthrough infections. 27 Since such variants tend to be associated with worse outcomes, 28 their enrichment in breakthrough infections means that some HRs presented in this study might be conservative estimates. Second, it might be that vaccination status affects the probability to seek or receive medical attention, particularly for less severe outcomes. Third, this study says nothing about the outcomes in patients infected with SARS-CoV-2 but who did not get tested nor diagnosed with COVID-19. Fourth, this study did not investigate whether the association between vaccination status and outcomes of SARS-CoV-2 infection was moderated by timing of the vaccine with respect to the infection. Fifth, we could not compare the different vaccines against each other since the majority had received the Pfizer/BioNTech vaccine. Finally, as an observational study, causation cannot be inferred (though the specificity of the association with some outcomes and not others and the doseresponse relationship support causality as an explanation).

In summary, the present data show that prior vaccination against COVID-19, especially after two doses, is associated with significantly less risk of many but not all outcomes of COVID-19, in younger but not older individuals. These findings may inform service planning, contribute to forecasting public health impacts of vaccination programmes, and highlight the urgent need to identify or develop additional preventive and curative interventions for sequelae of COVID-19.

The funding source had no role in study design; in the collection, analysis, and interpretation of data; in the writing of the report; and in the decision to submit the paper for publication.

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The authors declare no conflict of interest.

The TriNetX system returned the results of these analyses as csv files which were downloaded and archived. Data presented in this paper and the Appendix can be freely accessed at [URL to be added on publication]. Additionally, TriNetX will grant access to researchers if they have a specific concern (via the third-party agreement option).

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The copyright holder for this preprint this version posted October 26, 2021. ; https://doi.org/10.1101/2021.10.26.21265508 doi: medRxiv preprint Table 1 -Baseline characteristics and major outcomes for the vaccinated and unvaccinated cohorts, before and after propensity score matching. Only characteristics with an overall prevalence above 5% after matching are presented here; for additional baseline characteristics see appendix pp. 18 . CC-BY-NC 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted October 26, 2021. ; https://doi.org/10.1101/2021.10.26.21265508 doi: medRxiv preprint Fig. 3 -Hazard ratios for the outcomes within 6 months of infection with SARS-CoV-2 between individuals who received one dose of the vaccine (vs. unvaccinated individuals), those who received two doses of the vaccine (vs. unvaccinated individuals), vaccinated vs. unvaccinated individuals under the age of 60, and vaccinated vs. unvaccinated individuals over the age of 60. HR lower than 1 indicate outcomes less common among vaccinated individuals. Horizontal bars represent 95% confidence intervals. Each outcome is a composite endpoint with death as a component to address competing risks. The contribution of the outcome of interest to the overall incidence of the composite endpoint is encoded by the colour. Only a subset of representative outcomes is displayed. The same figures with all outcomes are presented in the appendix pp. 14-17.

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The copyright holder for this preprint this version posted October 26, 2021. ; https://doi.org/10.1101/2021.10.26.21265508 doi: medRxiv preprint

Vaccine breakthrough infections with SARS-CoV-2 variants

Vaccination reduces need for emergency care in breakthrough COVID-19 infections: A multicenter cohort study

EAVE II): a prospective cohort study

Mask usage, social distancing, racial, and gender correlates of COVID-19 vaccine intentions among adults in the US

Risk factors for SARS-CoV-2 among patients in the Oxford Royal College of General Practitioners Research and Surveillance Centre primary care network: a cross-sectional study

OpenSAFELY: factors associated with COVID-19 death in 17 million patients

6-month neurological and psychiatric outcomes in 236 379 survivors of COVID-19: a retrospective cohort study using electronic health records

Risk of clinical sequelae after the acute phase of SARS-CoV-2 infection: retrospective cohort study

High-dimensional characterization of post-acute sequalae of COVID-19

Incidence, cooccurrence, and evolution of long-COVID features: A 6-month retrospective cohort study of 273,618 survivors of COVID-19

Criteria for use of composite end points for competing risks-a systematic survey of the literature with recommendations

An Introduction to Propensity Score Methods for Reducing the Effects of Confounding in Observational Studies

The propensity score

Flexible parametric proportional-hazards and proportionalodds models for censored survival data, with application to prognostic modelling and estimation of treatment effects

Safety and efficacy of the BNT162b2 mRNA Covid-19 vaccine

Serum neutralizing activity elicited by mRNA-1273 vaccine

B-cell responses to vaccination at the extremes of age