key: cord-0961006-3cn869v4
authors: Nguyen, Liem Binh Luong; Bauer, Rebecca; Lesieur, Zineb; Galtier, Florence; Duval, Xavier; Vanhems, Philippe; Lainé, Fabrice; Tattevin, Pierre; Durier, Christine; Launay, Odile
title: Vaccine effectiveness against COVID-19 hospitalization in adults in France: a test negative case control study
date: 2021-12-15
journal: Infect Dis Now
DOI: 10.1016/j.idnow.2021.12.002
sha: 67b11c1ac005d37317ceea2e41470040e2e3ebf4
doc_id: 961006
cord_uid: 3cn869v4

Background: Measuring vaccine effectiveness (VE) using real-life data is critical to confirm the effectiveness of licensed vaccine, which could strengthen vaccination adherence. Methods: We measured VE against adult COVID-19 hospitalization in five hospitals in France using a test negative design. We compared the odds of vaccinated patients hospitalized with COVID-19 with the odds of vaccinated patients hospitalized for the same symptoms with a negative test. Results: A total of 853 patients (463 cases and 390 controls) were included, with a total of 170 patients vaccinated (104 with one dose, 65 with two doses, and one with three doses). There were four cases of breakthrough infections, all in immunocompromised patients. The VE was 84.0% (CI0.95=[72.6 ; 90.6]) for one dose and 96.2% (CI0.95=[86.8 ; 98.9]) for two doses. Conclusion: Our results confirm the high VE of COVID-19 vaccine in France to prevent hospitalizations due to the alpha variant.

Montpellier, Lyon), has been evaluating the effectiveness of influenza vaccines against hospitalization among adults using a test negative design [2] . The Fluvac network and study design have been adapted to study COVID-19 VE, and the first results are presented here.

Between December 23, 2020 and June 15, 2021, 853 patients hospitalized for influenza-like illness ─ defined as the combination of at least one general symptom (fever, malaise, headache, myalgia, or fatigue) and one respiratory symptom (cough, sore throat, shortness of breath, or tachypnoea) ─ were included (Table 1) . Patients were prospectively screened by research staff, and detailed clinical data on comorbidities, vaccination status, and vital status were collected at baseline as well as data on hospital stay and vital status at 30 and 90 days. vs 84.6%). Oxygen therapy was required for 87.3% of cases and 67.4% of controls. Length of stay was 10 days for cases and 8 days for controls. Cases more frequently required intensive ICU admission (26.1% vs 11.3%), with an average ICU length of stay of 6 days for cases and 3 days for controls; 7% of cases required invasive mechanical ventilation versus 1% of controls ( Table 1 ). The in-hospital mortality rate was 5.5% in the case group and 5.6% in the control group.

A total of 170 patients received at least one dose of COVID-19 vaccine before symptom onset: 50 in the case group (46 received one dose and four two doses) and 120 in the control group (58 received one dose, 61 two doses, and one three doses). Most vaccinated patients (127/170, 74.7%) had received Comirnaty® (Pfizer vaccine), followed by Vaxzevria® (24/170, 14.1%). Among the four cases hospitalized for COVID-19 after two doses, there were one man admitted less than 7 days after the second dose and three patients more than 7 days after the second dose: two women aged 79 and 42 years with kidney transplants, and one man aged 72 years with multiple myeloma on third-line chemotherapy. All these patients did not require intensive care, and were alive at discharge and one month later (table 2) .

VE was estimated using a test negative design. We compared the odds of vaccinated patients hospitalized with COVID-19 with the odds of vaccinated patients hospitalized for the same symptoms but with a negative test. (Table 3) .

To test result robustness, we performed various sensitivity analyses: one that requalified negative PCR tests to cases if COVID-19 diagnosis was recorded in medical files or if the CT scan showed abnormalities suggestive of COVID-19 infection (N=46 additional cases), and one using the WHO definition of severe acute respiratory infection (SARI) cases (defined by fever 38°C and cough and onset within the past 10 days), which is more stringent (N=323 inclusions). The overall results did not change and VE estimates after the second dose were 6% and 3% lower than in the main analysis, respectively (i.e. when requalifying negative PCR tests to cases in case of COVID-19 diagnosis as mentioned above and when using the WHO definition).

A generalized additional logistic regression model was used to adjust on other covariates: time, age, and stratified on centers. Time was measured in days between January 1, 2021 and hospitalization day. It was included as a spline function to account for bias related to time differences between COVID-19 circulation and vaccine availability. VE was estimated at 96.7% (95% CI=[87.9; 99.9]) 7 days after the second dose. lineage (beta variant), respectively [7, 8] . However, the latter study had limitations: cases and controls came from two different databases, were not matched based on medical data, and were all declarative [8] . For our study, we prospectively collected clinical data at bedside, with detailed information on patients' hospitalization and careful selection of controls. We documented four hospitalized vaccine breakthrough infections, all in immunocompromised patients, in line with previous reports in kidney transplant recipients [9] . This is in line with data on HCWs reported in Israel [10] . While the epidemics is still ongoing, we carry on data Page 6 of 11 J o u r n a l P r e -p r o o f collection and are generalizing whole-genome sequencing on a random sample of patients and in all vaccine breakthroughs. We believe our study will continue to provide interesting information on COVID-19. To address misclassification and selection biases, we performed sensitivity analyses, with no impact on results. Finally, we were not able at the time of analysis to sequence samples from all patients with documented COVID-19, but national data surveillance shows that the main circulating variant at the time of patient inclusion was the alpha variant [11] .

Our results confirm the high effectiveness of COVID-19 vaccine in France to prevent hospitalizations due to the alpha variant during the first semester of 2021. Further data are expected to measure vaccine effectiveness against the delta variant. 

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