雙價COVID-19疫苗（原始病毒株/Omicron BA.1或BA.4/5）成效：臺灣全人口研究

Abstract

背景：2022年4月，SARS-CoV-2 Omicron變異株引發大規模社區疫情，對臺灣的醫療資源造成巨大壓力，並對公共健康產生顯著影響。隨著SARS-CoV-2的基因與抗原特徵不斷演變，疫苗組成也隨之持續調整。雖然臺灣疾病管制署（TCDC）已評估COVID-19單價疫苗的效益，但雙價疫苗（原始病毒株/Omicron BA.1或BA.4/5）對於預防中重症及死亡的真實世界中效益（Real-world effectiveness）尚未被探討。

目的：探討在大部分國人已完成3劑COVID-19疫苗接種的基礎上，量化有無接種第4劑疫苗在預防感染（確診）、中重症（住院）及死亡風險方面的具體差異，並釐清可能影響疫苗效益的因素。除聚焦於高齡族群，也進一步評估年輕族群的疫苗保護效果，讓民眾瞭解接種新版疫苗之成效，以提供更全面的疫苗政策建議。

方法：以我國全人口（Population-based）為研究對象。採用回溯性世代研究（Retrospective Cohort Study）設計，透過疾病管制署全國性預防接種資訊管理系統（NIIS）、傳染病通報系統（NIDRS），以及衛生福利部統計處2021-2023年間的死亡統計檔，以個案生日及身分證號進行資料串聯。研究對象為已接種3劑COVID-19疫苗的本國籍民眾（指第1次追加劑，非基礎加強劑），並依第4劑疫苗（第2次追加劑）接種狀態分為「未接種」、「接種單價原始病毒株」、「接種雙價BA.1」及「接種雙價BA.4/5」四組，以第4劑未接種者作為參考組進行比較。追蹤觀察期間為2022年9月24日（開放接種Moderna BA.1疫苗）至2023年3月19日止（疾病通報定義調整前），藉由羅吉斯迴歸模型計算中重症（住院）和死亡結果的勝算比（OR）及95%信賴區間（CI），測量相對於未接種參考組的相對疫苗效益（rVE）之差異。

結果：透過控制年齡、性別及重複感染等干擾因子變項後，依年齡組別區分，相較未接種者，在65歲以上族群，雙價BA.1疫苗可降低68.5%中重症風險(亦即疫苗預防中重症之保護效益為68.5％，下同）（95% CI：64.5%至72.0%）、11.8%死亡風險（95% CI：-14.0%至31.7%）；雙價BA.4/5疫苗可降低70.0%中重症風險（95% CI：65.8%至73.3%）、80.7%死亡風險（95% CI：-69.6%至87.7%）。在50-64歲族群，雙價BA.1疫苗可降低71.9%中重症風險（95% CI：62.0%至79.3%）、7.2%死亡風險（95% CI：-96.5%至56.1%）；雙價BA.4/5疫苗可降低61.3%中重症風險（95% CI：51.2%至69.3%）、85.5%死亡風險（95% CI：53.4%至95.5%）。在20-49歲族群，雙價BA.1疫苗可降低43.6%中重症風險（95% CI：16.5%至61.8%）、63.4%死亡風險（95% CI：-58.8%至91.6%）；雙價BA.4/5疫苗可降低37.4%中重症風險（95% CI：13.3%至54.8%）、88.9%死亡風險（95% CI：17.3%至98.5%）。 本研究證實COVID-19雙價疫苗對降低中重症及死亡風險具顯著保護效益，並在高齡族群中展現最佳效果。相較之下，單價原始病毒株疫苗在65歲以上族群仍具一定保護力，但在其他年齡層對抗Omicron變異株的效果較為有限。其疫苗保護效益較低，可能與疫苗效果隨時間衰減及其抗原特性與Omicron變異株差異較大有關。此外，本研究發現COVID-19雙價疫苗能顯著降低確診與重複感染風險，尤以20-49歲族群最為明顯。每百人確診率從21.5%降至3.6%，重複感染率則由6.52%降至0.23%。 疫苗保護效益（VE）受多重因素影響，包含「就醫及政府通報機制」、「接種者年齡差異」、「接種策略及優先順序」，以及「抗病毒藥物使用」。

結論：在特定Omicron變異株流行期間，選擇適當的疫苗類型並優化接種時機，對於中重症及死亡可提供額外的保護效果，接種雙價疫苗亦可減少再次感染的機率。WHO建議即便目前變異株不斷演變，建議各國政府與專業機構，無須等待特定或新的變異株疫苗而延遲接種，以高風險族群而言，儘早接種任一種現有的疫苗比起延後接種 (或未接種)，能有效降低中重症或死亡的風險。本研究結果為衛生單位推動疫苗及國家進一步投資COVID-19疫苗提供了重要參考依據。同時建議未來疫苗接種策略應聚焦於高風險族群，並推廣更新配方的疫苗，以有效應對新興變異株對公共健康構成的威脅。

Background In April 2022, the SARS-CoV-2 Omicron variant instigated a widespread community outbreak in Taiwan, exerting considerable pressure on healthcare resources and profoundly affecting public health. As the genetic and antigenic properties of SARS-CoV-2 evolved, vaccine formulations were consistently revised. The Taiwan Centers for Disease Control (TCDC) has investigated the efficacy of monovalent COVID-19 vaccinations. Nevertheless, they have not thoroughly investigated the efficacy of bivalent vaccinations (original strain/Omicron BA.1 or BA.4/5) in real-world scenarios for the prevention of severe illness and mortality.

Objective This study aims to quantify the differences in infection, severe disease, and mortality risk among individuals who received a fourth COVID-19 vaccine dose compared to those who did not, within a population where the majority had already received three vaccine doses. The study further explores factors influencing vaccine effectiveness and assesses its impact not only on older populations but also among younger age groups. By providing evidence on the protective effects of updated vaccines, the study offers critical insights for future vaccination policy recommendations.

Methods This nationwide population-based retrospective cohort analysis included data from the National Immunization Information System (NIIS), the National Infectious Disease Reporting System (NIDRS), and mortality statistics from the Ministry of Health and Welfare from 2021 to 2023. Data at the individual level were correlated utilizing birthdates and national identity numbers. The study cohort consisted of Taiwanese people who had received three doses of a COVID-19 vaccination, namely the first booster dose rather than an enhanced primary series. The participants were categorized into four groups according to their fourth-dose (second booster) vaccination status: (1) unvaccinated individuals, (2) individuals vaccinated with a monovalent original strain vaccine, (3) individuals vaccinated with a bivalent BA.1 vaccine, and (4) individuals vaccinated with a bivalent BA.4/5 vaccine. The unvaccinated cohort functioned as the reference group. The observation period spanned from September 24, 2022, when the Moderna BA.1 vaccine was introduced, until March 19, 2023, prior to the amendment of case reporting definitions. Logistic regression models were employed to determine the odds ratios (ORs) and 95% confidence intervals (CIs) for severe disease (hospitalization) and mortality. We also determined the relative vaccination effectiveness (rVE) in comparison to a cohort of unvaccinated individuals.

Results Following the adjustment for confounding variables like as age, sex, and previous reinfection, the efficacy of the fourth vaccine dosage was evaluated across various age demographics. Individuals aged 65 and older who received the bivalent BA.1 vaccine saw a 68.5% reduction in the risk of severe disease (95% CI: 64.5%–72.0%) and an 11.8% decrease in the risk of mortality (95% CI: -14.0% to 31.7%). The bivalent BA.4/5 vaccine resulted in a 70.0% decrease in the probability of serious disease (95% CI: 65.8%–73.3%) and an 80.7% decrease in death risk (95% CI: -69.6% to 87.7%).The bivalent BA.1 vaccine reduced the risk of severe illness by 71.9% in individuals aged 50 to 64 (95% CI: 62.0%–79.3%) and decreased the risk of mortality by 7.2% (95% CI: -96.5% to 56.1%). The bivalent BA.4/5 vaccination diminished the risk of serious illness by 61.3% (95% CI: 51.2%–69.3%) and mortality by 85.5% (95% CI: 53.4%–95.5%).The bivalent BA.1 vaccine was associated with a 43.6% reduction in the risk of serious disease (95% CI: 16.5%–61.8%) and a 63.4% reduction in the risk of mortality (95% CI: -58.8% to 91.6%). This applied to anyone aged 20 to 49. The bivalent BA.4/5 vaccination diminished the risk of serious disease by 37.4% (95% CI: 13.3%–54.8%) and the risk of mortality by 88.9% (95% CI: 17.3%–98.5%). This research demonstrates that COVID-19 bivalent vaccines markedly diminish the chances of serious illness and death, particularly among older persons. Monovalent vaccinations provide a certain level of protection for persons aged 65 and older, but their efficacy against Omicron variants was more restricted in younger demographics. The diminished efficacy of the vaccination may be attributed to the decline of immunity over time and variations in the antigenic characteristics between the original vaccine strain and the Omicron variants. This study demonstrated that bivalent vaccinations significantly reduced the incidence of both initial infection and reinfection. This was particularly evident among individuals aged 20 to 49, with the infection rate declining from 21.5% to 3.6% and the reinfection rate decreasing from 6.52% to 0.23%. The effectiveness of vaccines is influenced by various factors, including individuals' healthcare-seeking behaviors, governmental case reporting practices, age-related vaccination uptake, immunization tactics and policies, and the administration of antiviral therapies. The efficacy of the vaccine may vary among individuals of different ages due to initial health disparities, the presence of comorbidities, and variations in immune system responses to vaccination.

Conclusion Selecting appropriate vaccine formulations and scheduling immunizations is crucial during periods when the Omicron variant predominates. This enhances protection against severe illness and mortality while simultaneously reducing the likelihood of reinfection. The World Health Organization (WHO) has underscored that, despite ongoing viral evolution, governments and health authorities should not postpone immunizations in expectation of variant-specific vaccines. For high-risk populations, prompt vaccination with any available vaccine formulation is preferable to delaying immunization, as it significantly reduces the risk of severe disease and mortality. This study's findings offer significant information to inform public health policy and immunization tactics, advocating for more investment in COVID-19 vaccination initiatives. To protect people's health from the ongoing dangers posed by new strains of SARS-CoV-2, future immunization programs should focus on those who are at the highest risk and encourage the use of updated vaccine formulations.