Omicron 變異株流行期間第三劑 mRNA 疫苗提供的額外保護效果：系統性回顧與統合分析

Abstract

背景：現今探討第三劑COVID-19疫苗保護效果的相關研究，仍存在相互矛盾的結果，且缺乏系統性整合的實證結論。因此，本研究旨在評估第三劑疫苗相較於兩劑基礎疫苗後所提供的額外保護效果（Vaccine effectiveness），並探討在Omicron變異株流行期間施打第三劑mRNA疫苗後之保護效果隨時間變化的情況。

方法：首先進行系統性文獻回顧（Systematic review），利用關鍵字搜尋資料庫中相關之文獻，搜尋時間至2023年3月31日，將符合篩選條件的文獻納入統合分析（Meta-analysis），並且分別估計第三劑疫苗預防Omicron變異株引起的感染、嚴重疾病，以及死亡的疫苗效果。後以統合回歸分析方法（Meta-regression），進一步探討研究間異質性影響因素，以及疫苗保護效果隨時間的變化趨勢。

結果：本研究共納入35篇文獻進行統合分析。研究結果顯示，對於預防感染Omicron變異株效果方面，在施打第三劑mRNA疫苗經過六個月後，疫苗效果從58%下降至9%；而對於預防嚴重疾病方面，施打第三劑疫苗經過五個月後，疫苗效果從80%降至55%；最後對於預防死亡方面，施打第三劑疫苗後三個月期間其疫苗效果可維持於88%。然而，疫苗保護效果在各研究間具高度異質性，分析顯示疫苗接種後的時間長短、受試者的平均年齡及第三劑疫苗廠牌的差異是影響疫苗效果的重要因素（R2 = 70.4%）。整體而言，第三劑疫苗對於預防感染的效果為中度證據品質，對於預防嚴重疾病和死亡的效果為高度證據品質。

討論及結論：在Omicron變異株流行時期，第三劑mRNA疫苗相較於兩劑基礎疫苗可產生良好的疫苗保護效果，尤其在預防嚴重疾病或死亡方面，其疫苗效果顯著。然而，針對預防感染及嚴重疾病的疫苗保護效果，在施打疫苗後的六個月內皆會隨時間逐漸下降，但整體而言，第三劑疫苗對於預防嚴重疾病仍可維持相對良好的保護效果。由於全球COVID-19持續流行，且SARS-CoV-2病毒株具高度變異性，對於公共衛生及人類健康仍造成相當程度的影響，因此，本研究建議未來仍須持續評估疫苗對於Omicron變異株的持續保護效果，以利未來防疫決策之評估。

Background: Limited and conflicting evidence exists regarding the extra protection conferred by the third dose of mRNA vaccine against COVID-19. We aim to systematically assess the effectiveness of the third mRNA vaccine, compared with the two-dose primary series vaccination, against COVID-19 and the duration of extra protection from the third mRNA vaccine dose against the SARS-CoV-2 Omicron-variant.

Methods: We search databases for all available data up to March 31, 2023. The primary outcomes were the effectiveness of the third dose compared to the primary series vaccination in preventing SARS-CoV-2 infection, severe COVID-19 disease, and COVID-19-related death by laboratory-confirmed Omicron variant or during the Omicron predominant period. We applied meta-regression to explore sources of heterogeneity between studies. The study was registered on PROSPERO (CRD42022364568).

Findings: Out of the 1,703 studies screened from the databases, 185 underwent full-text review, and 35 studies were included in the analysis. Among these, 25 studies were identified to have a moderate risk of bias, while ten studies were found to have a serious risk of bias. The effectiveness against infection was 58% (95% CI: 54% to 62%) during the first month and decreased to 9% (95% CI: -7% to 23%) by the sixth month after the third dose. The effectiveness against severe disease also decreased from 80% (95% CI: 68% to 87%) to 55% (95% CI: 49% to 60%) during a fifth-month period after the third dose. The effectiveness against COVID-19-related death remained stable at 88% (95% CI: 85% to 90%) over a three-month period after the third dose. The heterogeneity between studies can mainly be attributed to participant age, the third vaccine product used, and time elapsed after vaccination (R2 = 70.40%). Overall, moderate-certainty evidence supports the effectiveness of the third vaccine against infection, while high-certainty evidence supports the effectiveness against severe COVID-19 disease and death.

Interpretation: The third mRNA vaccine dose is highly effective in conferring extra protection against Omicron variant-associated severe COVID-19 disease or death compared with primary series vaccination. Even though protection against infection drops to a negligible level after six months, the protection against severe COVID-19 disease and death persists.