混合免疫和 COVID-19 疫苗接種策略

資料來源：www.thelancet.com/infection在線上發布，2022 年 9 月 21 日，財團法人台灣紅絲帶基金會編譯

   自 2022 年 4 月以來，受關注的 omicron (B.1.1.529) SARS-CoV-2 變體的 BA.2.12.1、BA.4 和 BA.5 亞變體隨著病毒適應性和傳播能力的增強而在全球範圍內傳播。 Omicron BA.5 亞變體目前是全球主要的 COVID-19 威脅。 隨著抗原性不同變體的出現，自然免疫或第一代疫苗誘導的免疫都未能有效阻止傳播。追加（第三或第四）劑疫苗在預防症狀性感染方面發揮著重要作用，儘管加強效果僅持續數月。 混合免疫是指接種過一劑或多劑 COVID-19 的個體的免疫保護在第一次接種疫苗之前或之後至少感染過一次 SARS-CoV-2。

   在 The Lancet Infectious Diseases 中，Sara Carazo 及其同事報告了一項新研究的結果，該研究基於來自衛生保健工作者的數據集，該數據集來自魁北克高度接種疫苗人群中 omicron BA.1 激增期間的醫護人員。 該研究採用檢測陰性病例對照設計，比較了 2022 年 3 月 27 日至 6 月 4 日 omicron BA.2 主導期間 SARS-CoV-2 核酸擴增檢測呈陽性的醫護人員（病例組），與在同一時期進行陰性測試的醫護人員相比（控制組）。 這些數據包括一個大型池，該池具有由結合疫苗接種和自然感染產生的潛在混合免疫。作者發現，先前的 BA.1 感染是針對 BA.2 感染的最具保護性的因素（與風險降低 72% 相關），並且比 pre-omicron SARS-CoV-2 的初次感染 (38%) 或之前沒有原發感染的個體接種三劑 mRNA 疫苗 (46%)兩者相比提供了更大的保護。 來自 BA.1 感染的混合免疫加上兩到三劑疫苗同樣將估計有效性提高到 96%，持續時間超過 5 個月。

   在 2021 年 12 月 23 日至 2022 年 2 月 21 日期間在卡達進行的一項全國性、匹配的、檢測陰性的病例對照研究中，在先前感染者、接種過兩劑 BNT162b2 疫苗的人和具有混合免疫力的人之間，在針對症狀性 BA.1 和 BA.2 感染的保護方面沒有差異。接種 BNT162b2 追加劑可增強對先前感染過的人的保護。先前感染產生的混合免疫和第二劑後 8 個月內的追加疫苗的接種提供了針對有症狀性 BA.1 或 BA.2 感染的最強保護。此外，既往感染以及有既往感染或未曾感染者在接種兩到三劑疫苗後可提供針對嚴重、危重或致命 BA.1 感染的強大保護（風險降低 >96%）。 相較之下，既往感染 (73·4%) 或兩劑疫苗 (76·8%) 提供的保護較弱，然而既往感染或未感染者的兩到三劑疫苗，則針對嚴重、危重 ，或致命的 BA.2 感染提供更強的保護 (>97%)。

    現在可以獲得關於 BA.4 和 BA.5 亞變體的更具體數據。 在一項評估針對 SARS-CoV-2 原始野生型分離株以及 omicron 亞變體 BA.1、BA.2、BA.2.12.1 和 BA.4 或 BA.5 的假病毒中和抗體滴度的體外研究中，在接種了三劑 mRNA 疫苗 BNT162b2 的 27 名參與者和之前感染過 BA.1 或 BA.2 亞變體的 27 名參與者中，研究人員發現 BA.2.12.1 、BA.4 和 BA.5 亞變體基本上逃脫了疫苗接種和感染誘導的中和抗體。 此外，針對 BA.4 或 BA.5 亞變體和針對 BA.2.12.1 亞變體的中和抗體效價低於針對 BA.1 和 BA.2 亞變體的效價，這顯示 SARS-CoV-2 omicron 變體，隨著中和逃逸的增加而繼續發展。葡萄牙的一項研究使用國家 COVID-19 登記處來估計曾感染過 SARS-CoV-2 變體（包括 BA.1 和 BA.2）的人群感染 BA.5 的風險，結果顯示接種疫苗的人的BA.1 或 BA.2 感染提供了比 omicron 前變體（野生型 51·6%，α [B.1.1.7] 54· 8%，和 delta [B.1.617.2] 61·3%）對抗BA.5有更高的保護（風險降低75.3%），這與測試陰性設計的兩項研究一致。總體而言，數據顯示 BA.5 亞變體的突破性感染較少在高度接種疫苗且具有 SARS-CoV-2 感染史的人群中可能發生這種情況，特別是對於之前的 BA.1 或 BA.2 感染，而不是以前沒有原發感染的人群。

   這些數據提供了免疫學背景，說明混合免疫在管理由高頻率接種疫苗和 BA.1 或 BA.2 感染的人群中 BA.2.12.1、BA.4 和 BA.5 亞變體引起的目前激增方面的重要性。降低感染風險的另一個重要因素是使用不同平台進行異源加強免疫，以最大限度地擴大疫苗誘導免疫的範圍，尤其是在主要使用滅活疫苗的國家； T 細胞免疫不受刺突蛋白變化的影響，並且在預防嚴重疾病、住院和死亡方面仍然有效。最後，在管理當前廣泛傳播的 BA.5 變種造成威脅的流行病時應考慮使用基於 BA.4 或 BA.5 的第二代疫苗。

我聲明沒有相互競爭的利益。

許大衛 dschui@cuhk.edu.hk

香港中文大學醫學院醫學與治療學系和何鴻燊新興傳染病中心，中國香港

Hybrid immunity and strategies for COVID-19 vaccination 

www.thelancet.com/infection Vol 23 January 2023

  Since April, 2022, BA.2.12.1, BA.4, and BA.5 subvariants of the omicron (B.1.1.529) SARS-CoV-2 variant of concern have been spreading globally with increased viral fitness and transmissibility. Omicron BA.5 subvariant is currently the predominant COVID-19 threat worldwide.1 With the emergence of the antigenically distinct variants of concern, either natural immunity or first-generation vaccine-induced immunity has failed to prevent transmission effectively. Booster (third or fourth) doses of vaccine play an important role in preventing symptomatic infection, although the boosting effect only lasts for several months.2 Hybrid immunity refers to the immune protection in individuals who have had one or more doses of a COVID-19 vaccine and at least one SARS-CoV-2 infection before or after the first vaccination. 

  In The Lancet Infectious Diseases, Sara Carazo and colleagues report the findings of a novel study based on a dataset derived from health-care workers during the omicron BA.1 surge among the highly vaccinated Quebec population. The study used a test-negative case-control design and compared health-care workers who had a positive SARS-CoV-2 nucleic acid amplification test (cases) during the period of omicron BA.2 dominance from March 27 to June 4, 2022, versus health-care workers who had a negative test during the same period (controls). The data consisted of a large pool with potential hybrid immunity resulting from combined vaccination and natural infection. The authors found that previous BA.1 infection was the most protective factor against BA.2 infection (associated with a risk reduction of 72%), and gave greater protection than primary infection with pre-omicron SARS-CoV-2 (38%) or three doses of mRNA vaccine in individuals with no previous primary infection (46%). Hybrid immunity from BA.1 infection plus two to three vaccine doses similarly increased the estimated effectiveness to 96% for longer than 5 months. 

  In a national, matched, test-negative, case-control study in Qatar from Dec 23, 2021, to Feb 21, 2022, no differences in protection against symptomatic BA.1 and BA.2 infection were noted between people with previous infection, people who had been vaccinated with two doses of BNT162b2, and people with hybrid immunity. Vaccination with a BNT162b2 booster enhanced protection among people who had previous infection. Hybrid immunity resulting from previous infection and a booster vaccination within 8 months after the second dose conferred the strongest protection against symptomatic BA.1 or BA.2 infection. Additionally, previous infection and two to three vaccine doses with or without previous infection conferred strong protection (risk reduction of >96%) against severe, critical, or fatal BA.1 infection. By contrast, previous infection (73·4%) or two doses of vaccine (76·8%) gave weaker protection, while two to three vaccine doses with or without previous infection conferred stronger protection (>97%), against severe, critical, or fatal BA.2 infection. 

  More specific data on BA.4 and BA.5 subvariants are now available. In an in-vitro study evaluating pseudovirus neutralising antibody titres against the original wild-type isolate of SARS-CoV-2 along with omicron subvariants BA.1, BA.2, BA.2.12.1, and BA.4 or BA.5 in 27 participants who had been vaccinated with three doses of mRNA vaccine BNT162b2, and in 27 participants who had previous infection with the BA.1 or BA.2 subvariant a median of 29 days earlier, the investigators found that the BA.2.12.1, BA.4, and BA.5 subvariants substantially escaped neutralising antibodies induced by both vaccination and infection. Moreover, neutralising antibody titres against the BA.4 or BA.5 subvariant and against the BA.2.12.1 subvariant were lower than titres against the BA.1 and BA.2 subvariants, which suggests that the SARS-CoV-2 omicron variant has continued to evolve with increasing neutralisation escape. A study in Portugal using the national COVID-19 registry to estimate the risk of BA.5 infection among people with documented infection with past SARS-CoV-2 variants, including BA.1 and BA.2, has shown that BA.1 or BA.2 infection in vaccinated people provided higher protection (risk reduction of 75·3%) against BA.5 infection than did infection with pre-omicron variants (wild type 51·6%, alpha [B.1.1.7] 54·8%, and delta [B.1.617.2] 61·3%), in line with the two studies with a test-negative design. Overall, the data suggested that breakthrough infections with the BA.5 subvariant were less likely to occur among people with a previous SARS-CoV-2 infection history in a highly vaccinated population, especially for previous BA.1 or BA.2 infection, than among people with no previous primary infection. 

  These data provide immunological context for the importance of hybrid immunity in managing the current surges caused by the BA.2.12.1, BA.4, and BA.5 subvariants in populations with high frequencies of vaccination and BA.1 or BA.2 infection. Another important factor in reducing infection risk is heterologous booster vaccination with different platforms to maximise the breadth of vaccine-induced immunity, especially in countries primarily using inactivated vaccine; T-cell immunity is not affected by changes in spike protein and remains effective in preventing severe disease, hospitalisation, and death.7–9 Finally, second-generation BA.4 or BA.5-based vaccines should be considered in managing the current threat due to the widely circulating BA.5 variant. 

I declare no competing interests.

David S Hui dschui@cuhk.edu.hk 

Department of Medicine and Therapeutics and Stanley Ho Centre for Emerging Infectious Diseases, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, China