Objective To examine the relative effectiveness of a fourth dose of the Pfizer-BioNTech mRNA (BNT162b2) vaccine compared with three vaccine doses over the span of 10 weeks. Design Retrospective, test negative, case-control study, with a matched analysis and an unmatched multiple tests analysis. Setting Nationally centralised database of Maccabi Healthcare Services, an Israeli national health fund for 2.5 million people; from 10 January 2022 (seven days after the fourth dose was first given to eligible individuals) to 13 March 2022, an omicron dominant period in Israel. Participants 97 499 Maccabi Healthcare Services members aged 60 years and older, who were eligible to receive a fourth vaccine dose and obtained at least one polymerase chain reaction (PCR) test during the study. Main outcome measures Breakthrough SARS-CoV-2 infection, defined as a positive PCR test performed seven or more days after inoculation with the BNT162b2 vaccine; and breakthrough SARS-CoV-2 infection resulting in severe covid-19 disease, defined as hospital admission or death related to covid-19. Results 27 876 participants received the fourth BNT162b2 vaccine dose and 69 623 received three doses only. Of 106 participants who died during the follow-up period, 77 had had their third doses only and 23 had had their fourth doses during the first three weeks after inoculation. In the first three weeks, a fourth dose provided additional protection against both SARS-CoV-2 infection and severe disease relative to three doses of the vaccine. However, relative vaccine effectiveness against infection quickly decreased over time, peaking during the third week at 65.1% (95% confidence interval 63.0% to 67.1%) and falling to 22.0% (4.9% to 36.1%) by the end of the 10 week follow-up period. Unlike relative effectiveness against SARS-CoV-2 infection, the relative effectiveness of a fourth dose against severe covid-19 was maintained at a high level (>72%) throughout follow-up. However, severe disease was a relatively rare event, occurring in <1% of study participants who received four doses or three doses only. Conclusions A fourth dose of the BNT162b2 vaccine appears to have provided additional protection against both SARS-CoV-2 infection and severe covid-19 disease relative to three vaccine doses. However, relative effectiveness of the fourth dose against infection appears to wane sooner than that of the third dose. According to the Israel Ministry of Health regulations, individual level data cannot be shared openly. Specific requests for remote access to de-identified community level data should be referred to Kahn Sagol Maccabi Research and Innovation Centre, Maccabi Healthcare Services. Specific requests for remote access to the code used for data analysis should be referred to Kahn Sagol Maccabi Research and Innovation Centre, Maccabi Healthcare Services.

中文翻译：

---

以色列 60 岁及以上人群中四剂与三剂 BNT162b2 疫苗的短期相对有效性：回顾性、测试阴性、病例对照研究

目的 检验第四剂辉瑞 BioNTech mRNA (BNT162b2) 疫苗在 10 周内与三剂疫苗相比的相对有效性。设计回顾性、测试阴性、病例对照研究，包括匹配分析和不匹配的多重测试分析。设置 Maccabi Healthcare Services 的国家集中数据库，这是一个为 250 万人提供服务的以色列国家健康基金；从2022年1月10日（首次向符合条件的个人注射第四剂后7天）到2022年3月13日，这是以色列的omicron占主导地位的时期。参与者 97 499 名年龄在 60 岁及以上的 Maccabi Healthcare Services 成员，他们有资格接受第四剂疫苗，并在研究期间至少进行了一次聚合酶链反应 (PCR) 测试。主要成果指标 突破 SARS-CoV-2 感染，定义为接种 BNT162b2 疫苗 7 天或以上后进行的 PCR 检测呈阳性；突破性 SARS-CoV-2 感染导致严重的 covid-19 疾病，定义为与 covid-19 相关的入院或死亡。结果 27 876 名参与者接种了第四剂 BNT162b2 疫苗，69 623 名参与者仅接种了三剂。在随访期间死亡的 106 名参与者中，77 人仅接种了第三剂，23 人在接种后的前三周内接种了第四剂。在前三周内，相对于三剂疫苗，第四剂疫苗提供了针对 SARS-CoV-2 感染和严重疾病的额外保护。然而，针对感染的相对疫苗有效性随着时间的推移迅速下降，在第三周达到峰值 65.1%（95% 置信区间 63.0% 至 67.1%），并在第 10 周结束时降至 22.0%（4.9% 至 36.1%）随访期。与针对 SARS-CoV-2 感染的相对有效性不同，第四剂针对严重 covid-19 的相对有效性在整个随访过程中保持在较高水平（>72%）。然而，严重疾病是一种相对罕见的事件，在接受四剂或仅三剂的研究参与者中发生率<1%。结论 相对于三剂疫苗，第四剂 BNT162b2 疫苗似乎对 SARS-CoV-2 感染和严重的 covid-19 疾病提供了额外的保护。然而，第四剂抗感染的相对有效性似乎比第三剂更快减弱。根据以色列卫生部规定，个人层面的数据不能公开共享。有关远程访问去识别化的社区级数据的具体请求应提交给马卡比医疗服务部的卡恩·萨戈尔·马卡比研究和创新中心。远程访问用于数据分析的代码的具体请求应咨询马卡比医疗服务部的卡恩·萨戈尔·马卡比研究和创新中心。