Effectiveness of BNT162b2, mRNA-1273, and ChAdOx1-S vaccines against severe covid-19 outcomes in a nationwide mass vaccination setting: cohort study

Objective To estimate the effectiveness of the three covid-19 vaccines by Pfizer-BioNTech (BNT162b2), Moderna (mRNA-1273), and Oxford-AstraZeneca (ChAdOx1-S) in people after receiving two doses. Design Cohort study. Setting Nationwide, population based data in France, from the French National Health Data System (Système National des Données de Santé), between 27 December 2020 and 30 April 2021. Participants Adults aged ≥50 years receiving a first dose of BNT162b2, mRNA-1273, or ChAdOx1-S were randomly selected (1:1) and matched on the date of vaccination with one unvaccinated control. Individuals were matched on year of birth, sex, region of residence, and residence in a nursing home (for individuals aged ≥75 years). All individuals were followed up until 20 August 2021. Main outcome measures Primary outcome measure was vaccine effectiveness estimated at least 14 days after the second dose against covid-19 related hospital admission using Cox proportional hazards models adjusted for baseline characteristics and comorbidities. Vaccine effectiveness against covid-19 related death in hospital was also investigated. Results 11 256 832 vaccinated individuals were included in the study (63.6% (n=7 161 658) with the BNT162b2 vaccine, 7.6% (n=856 599) with the mRNA-1273 vaccine, and 28.8% (n=3 238 575) with the ChAdOx1-S vaccine), along with 11 256 832 matched unvaccinated controls. During follow-up (up to 20 August 2021), 43 158 covid-19 related hospital admissions and 7957 covid-19 related deaths in hospital were registered. Compared with unvaccinated controls, vaccine effectiveness of two doses against covid-19 related hospital admission was 91% (95% confidence interval 91% to 92%), 95% (93% to 96%), and 91% (89% to 94%) for the BNT162b2, mRNA-1273, and ChAdOx1-S vaccines, respectively. Similar results were observed for vaccine effectiveness of two doses against covid-19 related deaths in hospital (BNT162b2, 91% (90% to 93%);mRNA-1273, 96% (92% to 98%);and ChAdOx1 nCoV-19, 88% (68% to 95%)). At 5-6 months after receiving the second dose of vaccine, effectiveness remained high at 94% (92% to 95%) for the BNT162b2 vaccine and 98% (93% to 100%) for the mRNA-1273 vaccine. Vaccine effectiveness of ChAdOx1-S estimated at 3-4 months was 90% (63% to 97%). All three vaccines remained effective at the time of circulation of the delta variant of SARS-CoV-2 between 1 July and 20 August 2021 (effectiveness between 89% and 95%). Conclusions These findings provide evidence indicating that two doses of ChAdOx1-S is as effective as two doses of mRNA vaccines in France against the alpha and delta variants of SARS-CoV-2. The effectiveness of ChAdOx1-S should be further examined with a longer follow-up and in the light of the circulation of new SARS-CoV-2 variants of concern.

Risk for Myocardial Infarction, Stroke, and Pulmonary Embolism Following COVID-19 Vaccines in Adults Younger Than 75 Years in France.

BACKGROUND: The BNT162b2 (Pfizer-BioNTech) vaccine has been shown to be safe with regard to risk for severe cardiovascular events (such as myocardial infarction [MI], pulmonary embolism [PE], and stroke) in persons aged 75 years or older. Less is known about the safety of other COVID-19 vaccines or outcomes in younger populations. OBJECTIVE: To assess short-term risk for severe cardiovascular events (excluding myocarditis and pericarditis) after COVID-19 vaccination in France's 46.5 million adults younger than 75 years. DESIGN: Self-controlled case series method adapted to event-dependent exposure and high event-related mortality. SETTING: France, 27 December 2020 to 20 July 2021. PATIENTS: All adults younger than 75 years hospitalized for PE, acute MI, hemorrhagic stroke, or ischemic stroke (n = 73 325 total events). MEASUREMENTS: Linkage between the French National Health Data System and COVID-19 vaccine databases enabled identification of hospitalizations for cardiovascular events (MI, PE, or stroke) and receipt of a first or second dose of the Pfizer-BioNTech, mRNA-1273 (Moderna), Ad26.COV2.S (Janssen), or ChAdOx1 nCoV-19 (Oxford-AstraZeneca) vaccine. The relative incidence (RI) of each cardiovascular event was estimated in the 3 weeks after vaccination compared with other periods, with adjustment for temporality (7-day periods). RESULTS: No association was found between the Pfizer-BioNTech or Moderna vaccine and severe cardiovascular events. The first dose of the Oxford-AstraZeneca vaccine was associated with acute MI and PE in the second week after vaccination (RI, 1.29 [95% CI, 1.11 to 1.51] and 1.41 [CI, 1.13 to 1.75], respectively). An association with MI in the second week after a single dose of the Janssen vaccine could not be ruled out (RI, 1.75 [CI, 1.16 to 2.62]). LIMITATIONS: It was not possible to ascertain the relative timing of injection and cardiovascular events on the day of vaccination. Outpatient deaths related to cardiovascular events were not included. CONCLUSION: In persons aged 18 to 74 years, adenoviral-based vaccines may be associated with increased incidence of MI and PE. No association between mRNA-based vaccines and the cardiovascular events studied was observed. PRIMARY FUNDING SOURCE: None.

Characteristics associated with the residual risk of severe COVID-19 after a complete vaccination schedule: A cohort study of 28 million people in France.

Background: Prior to the availability of vaccines, the risk factors for developing severe forms of COVID-19 were mostly older age and various comorbidities such as diabetes, cardiovascular diseases, mental disorders, transplantations, and kidney disease. Although vaccines have been shown to be highly effective in preventing severe forms of COVID-19, a residual risk may persist, despite vaccination, for certain population groups. Methods: The study was based on data from the national COVID-19 vaccination database (VAC-SI) coupled with the National Health Data System (SNDS), which contains comprehensive reimbursement and hospitalisation data for all of France. All people fully vaccinated by July 31, 2021, with a double-injection vaccine, i.e., the mRNA BNT162b2, mRNA-1273, or ChAdOx1 nCoV-19 vaccines, or a single dose for people with a previous confirmed SARS-CoV-2 infection were included and followed until August 31, 2021. Cox proportional hazard models were performed to estimate adjusted hazard ratios (aHR) for COVID-19-related hospitalisation or in-hospital death associated with age, gender, deprivation index, comorbidities, and immunosuppressive or oral corticosteroid therapy from day 14 after full-vaccination. Findings: In a population of 28,031,641 fully vaccinated individuals with an average follow-up of 80 days, 5,345 (87 hospitalisations per 100,000 person-years) were hospitalised for COVID-19 and 996 (16 in-hospital death per 100,000 person-years) died in hospital. In multivariable analysis, a higher risk was observed with increasing age, male gender, and social deprivation. Most of the 47 chronic conditions considered were positively associated with an increased risk of COVID-19-related hospitalisation and a slight excess risk of death. The risk of hospitalisation and in-hospital death for COVID-19 also increased with the use of immunosuppressants (aHR 3.3 [2.8-3.8] and 2.4 [1.7-3.5], respectively) and oral corticosteroids (aHR 2.8 [2.5-3.1] and 4.1 [3.3-5.1]).Less than 10% (519/5,345) of hospitalised cases and 2% (24/996) of those who died in hospital had no identified comorbidities. There was a strong association between an increasing number of comorbidities and the risk of hospitalisation and in-hospital death (e.g., 5+ versus none, aHR 10.1 95%CI 9.0-11.5 and 17.8 95%CI 11.5-27.4, respectively). Interpretation: Although vaccination has dramatically reduced the occurrence of severe forms of COVID-19, a residual risk remains for the elderly, immunocompromised, and polypathological populations and warrants complementary preventive measures. Funding: None.

Age and sex-specific risks of myocarditis and pericarditis following Covid-19 messenger RNA vaccines.

Cases of myocarditis and pericarditis have been reported following the receipt of Covid-19 mRNA vaccines. As vaccination campaigns are still to be extended, we aimed to provide a comprehensive assessment of the association, by vaccine and across sex and age groups. Using nationwide hospital discharge and vaccine data, we analysed all 1612 cases of myocarditis and 1613 cases of pericarditis that occurred in France in the period from May 12, 2021 to October 31, 2021. We perform matched case-control studies and find increased risks of myocarditis and pericarditis during the first week following vaccination, and particularly after the second dose, with adjusted odds ratios of myocarditis of 8.1 (95% confidence interval [CI], 6.7 to 9.9) for the BNT162b2 and 30 (95% CI, 21 to 43) for the mRNA-1273 vaccine. The largest associations are observed for myocarditis following mRNA-1273 vaccination in persons aged 18 to 24 years. Estimates of excess cases attributable to vaccination also reveal a substantial burden of both myocarditis and pericarditis across other age groups and in both males and females.

A modified self-controlled case series method for event-dependent exposures and high event-related mortality, with application to COVID-19 vaccine safety.

We propose a modified self-controlled case series (SCCS) method to handle both event-dependent exposures and high event-related mortality. This development is motivated by an epidemiological study undertaken in France to quantify potential risks of cardiovascular events associated with COVID-19 vaccines. Event-dependence of vaccinations, and high event-related mortality, are likely to arise in other SCCS studies of COVID-19 vaccine safety. Using this case study and simulations to broaden its scope, we explore these features and the biases they may generate, implement the modified SCCS model, illustrate some of the properties of this model, and develop a new test for presence of a dose effect. The model we propose has wider application, notably when the event of interest is death.

Reduced risk of severe COVID-19 in more than 1.4 million elderly people aged 75 years and older vaccinated with mRNA-based vaccines.

Randomized clinical trials have shown mRNA-based vaccines to be 92-95% effective to prevent COVID-19 in adults. We aimed to estimate the impact of vaccination on the risk of severe COVID-19 (requiring hospitalization) in elderly people. Each 1,422,461 vaccinated subject aged 75 or older was matched to two unvaccinated subjects of same age, sex, administrative region, and type of residence. They were followed from date of first injection between 27 December 2020 and 24 February 2021 to 20 March 2021 for COVID-19 hospitalization. Mean age was 82.4 years (SD, 5.7) and median follow-up was 38 days [IQR, 17-54]. Adjusted Hazard Ratio for COVID-19 hospitalization from day 7 after the second dose was estimated at 0.14 (95% confidence interval, 0.11-0.17), i.e. an estimated 86% risk reduction in people aged 75 and older, highlighting the major impact of mRNA vaccination on reducing the risk of COVID-19 among elderly people.