SARS-CoV-2 疫苗有效性的观察性研究很容易出现混淆，这可以使用阴性对照方法来说明。全国人群队列研究包括两组 60-90 岁的丹麦居民，年龄和性别按 1:1 匹配：已接种疫苗和未接种疫苗的队列，包括 2021 年 3 月 1 日至 7 月 1 日期间接种 SARS-CoV-2 疫苗的 61052 名个体和 2021 年 7 月 1 日之前未接种疫苗的 61052 名个体。从这两个队列中，我们构建了诊断为 SARS-CoV-2 的个体的阴性对照队列SARS-CoV-2 感染或急性心肌梗死、中风、癌症、低能量骨折或头部外伤。结果包括 SARS-CoV-2 感染、阴性对照结果（例如乳房 X 光检查、前列腺活检、白内障手术、恶性黑色素瘤、眼睛和耳朵检查）和死亡。我们使用 Cox 回归来计算调整后的发病率和死亡率比率（aIRR 和 aMRR）。在接种疫苗的人群中，SARS-CoV2 感染的风险和所有阴性对照结果均升高，aIRR 为 1.15（95% CI：1.09-1.21） ）对于眼科检查，对于恶性黑色素瘤，为 3.05（95% CI：2.24-4.14）。相反，在 SARS-CoV-2 感染队列和所有阴性对照队列中，接种疫苗的个体的死亡风险较低，从 SARS-CoV-2 感染后的 aMRR 为 0.23（95% CI：0.19-0.26）到中风后为 0.50（95% CI：0.37-0.67）。我们的研究结果表明，SARS-CoV-2 疫苗有效性的观察性研究可能会受到严重混杂的影响。因此，在出现新的 SARS-CoV-2 变种和推出多种加强疫苗后，随机试验对于确定疫苗功效至关重要。© 2024 Obel 等人。

Observational studies of SARS-CoV-2 vaccine effectiveness are prone to confounding, which can be illustrated using negative control methods.Nationwide population-based cohort study including two cohorts of Danish residents 60-90 years of age matched 1:1 on age and sex: A vaccinated and a non-vaccinated cohort, including 61052 SARS-CoV-2 vaccinated individuals between 1 March and 1 July 2021 and 61052 individuals not vaccinated preceding 1 July 2021. From these two cohorts, we constructed negative control cohorts of individuals diagnosed with SARS-CoV-2 infection or acute myocardial infarction, stroke, cancer, low energy fracture, or head-trauma. Outcomes were SARS-CoV-2 infection, negative control outcomes (eg, mammography, prostate biopsy, operation for cataract, malignant melanoma, examination of eye and ear), and death. We used Cox regression to calculate adjusted incidence and mortality rate ratios (aIRR and aMRR).Risks of SARS-CoV2 infection and all negative control outcomes were elevated in the vaccinated population, ranging from an aIRR of 1.15 (95% CI: 1.09-1.21) for eye examinations to 3.05 (95% CI: 2.24-4.14) for malignant melanoma. Conversely, the risk of death in the SARS-CoV-2 infected cohort and in all negative control cohorts was lower in vaccinated individuals, ranging from an aMRR of 0.23 (95% CI: 0.19-0.26) after SARS-CoV-2 infection to 0.50 (95% CI: 0.37-0.67) after stroke.Our findings indicate that observational studies of SARS-CoV-2 vaccine effectiveness may be subject to substantial confounding. Therefore, randomized trials are essential to establish vaccine efficacy after the emergence of new SARS-CoV-2 variants and the rollout of multiple booster vaccines.© 2024 Obel et al.