SARS-CoV-2 疫苗在後自然感染世界中的有效性
資料來源：www.thelancet.com/infection Vol 22 June 2022；財團法人台灣紅絲帶基金會編譯
2022 年 3 月 31 日線上發布 https://doi.org/10.1016/ S1473-3099(22)00207-9
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自然病毒感染透過一系列記憶 T 細胞和 B 細胞提供對後續感染的免疫力，除非病毒突變到一定程度而逃避記憶細胞的識別。疫苗旨在以滅活的形式代表病毒或減毒的全病毒或免疫原性之次單位，例如 SARS-CoV-2.2 中的刺突蛋白。在自然感染後，免疫系統以多種方式評估病毒，並提供抗體介導的和細胞性的保護。如SARS-CoV-2 大流行無情地發展，多波浪潮，全球人口的免疫格局已從免疫幼稚轉變為具有自然感染誘導的免疫。儘管為未具免疫人群接種疫苗是合乎邏輯的，但一個重要的問題則是是否為以前感染過 SARS-CoV-2 的人接種疫苗。透過疫苗接種提高自然免疫力的需求來自免疫力的減弱、抗體效價的下降以及具有免疫逃避特性的 SARS-CoV-2 變異株的出現。
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在《剌胳針傳染病》中，Thiago Cerqueira-Silva 及其同事解決了先前感染者的疫苗有效性問題。在這項研究中，作者使用了巴西的國家 COVID-19 通報、住院和疫苗接種數據集來評估研究期間該國使用的四種疫苗對症狀感染、住院和死亡等影響之有效性：CoronaVac (Sinovac科興) 滅活疫苗、ChAdOx1 nCoV-19 (Oxford-AstraZeneca牛津-阿斯利康) 腺病毒載體疫苗、Ad26.COV2.S (Janssen楊生) 腺病毒載體疫苗 和 BNT162b2 (Pfizer 輝瑞-生物科技）mRNA疫苗。在先前確認感染 SARS-CoV-2 的人中，作者納入了 22,566 名 RT-PCR 陽性再感染個體和 145,055 名RT-PCR 測試陰性源自於一項病例對照研究中與 68,426 名具症狀個體匹配的陰性個體。在調整了重要的干擾因素後，在前一次自然感染後完全接種之 14 天或更長時間後，針對症狀性感染的疫苗有效性於 CoronaVac為 39·4% (95% CI 36·1–42·6)，ChAdOx1 nCoV-19 為56·0% (51·4–60·2)，Ad26 COV2.S（單劑疫苗）為 44·0% (31·5–54·2) ，和 64·8% (54·9–72·4) 於BNT162b2。完全接種疫苗後針對住院或死亡的疫苗有效性更令人印象深刻：CoronaVac 為 81·3% (75·3–85·8)，ChAdOx1 nCoV-19 為 89·9% (83·5–93·8)， Ad26 為57·7%（–2·6 至 82·5）。 COV2.S，BNT162b2 為 89·7% (54·3–97·7)。
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該研究具有一些主要優勢。首先，是將用於 SARS-CoV-2 之檢測、COVID-19 之疾病監以及免疫接種三個國家數據庫連結，這展示了人口級數據的重要性和大數據分析的力量。二是對全球使用的四種疫苗的疫苗有效性進行綜合評價。第三，劑量-反應關聯性的研究。然而，據此估計疫苗有效性，一個重要的缺失信息是 SARS-CoV-2 變異。鑑於針對不同變異株的不同疫苗有效性，這種缺失很重要。
Cerqueira-Silva 及其同事在研究中對疫苗有效性的估計通常低於先前報導的未具免疫人群之有效性。但是，鑑於 Cerqueira-Silva 及其同事的估計是針對疫苗接種所提供超越或高於自然感染產生的免疫力的額外保護，預計會出現這種差異。自然感染可作為啟動或加強劑量；在之前的一項研究中，在具有自然免疫力的參與者隨後接種疫苗，在接種疫苗後 6 個月以上其再感染之保護仍保持在 90% 以上。曾感染過且接種單劑疫苗的個體，即使在接種疫苗前感染已超過12 個月以上的參與者中，亦顯示出高達 82% 的保護作用，類似於兩劑疫苗。這些臨床發現得到體外免疫學研究的證實，這些研究顯示體液和細胞免疫反應在接種疫苗後很高。自然感染和疫苗接種提供的多種抗原暴露。除了抗體介導的免疫外，細胞性的 T 細胞反應還提供了針對嚴重疾病、住院和死亡的保護。
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Cerqueira-Silva 及其同事的研究和其他近期研究的結果挑戰了僅通過自然感染對 SARS-CoV-2 進行群體免疫的概念，並顯示為先前感染的個體接種疫苗可提供進一步的保護，特別是針對嚴重疾病。這些數據應有助於指導政策之決策並減輕以前感染過 SARS-CoV-2 的人對疫苗的猶豫。
然而，一些臨床和免疫學問題仍有待解答。初次接觸抗原會導致表位特異性 B 細胞記憶，稱為免疫印記。除最初始祖之病毒感染，在隨後的由變異株引起的多波次SARS-CoV-2 感染所導致病毒抗原之異源暴露。第一次接觸（無論是病毒還是疫苗）產生的免疫印記如何影響免疫反應的持久性和廣度仍有待研究。自然感染為接種疫苗的人提供了哪些額外的保護，這種保護的持久性如何？自然感染後接種疫苗的最佳時機是什麼？鑑於全球有大量人口暴露於由 delta (B.1.617.2) 和 omicron (B.1.1.529) 變異株引起的自然感染，這些問題很重要。
由於暴露於自然感染和疫苗接種導致的混合免疫可能成為全球常態，甚至可能針對新出現的變異株提供長期保護。除了疫苗接種之外，還應針對進一步出現的變異株繼續監測其免疫逃脫性和致病性。
*Pramod Kumar Garg, Ramachandran Thiruvengadam pgarg@thsti.res.in
轉化健康科學與技術研究所，法里達巴德，NCR 德里 121001，印度
Effectiveness of SARS-CoV-2 vaccines in the post-natural infection world
Published Online March 31, 2022 https://doi.org/10.1016/ S1473-3099(22)00207-9
Natural viral infections provide immunity from subsequent infection through a repertoire of memory T cells and B cells, except when the virus mutates to an extent that it evades recognition by memory cells. Vaccines are designed to represent the virus either in the form of an inactivated or attenuated whole virus or an immunogenic subunit such as the spike protein in the case of SARS-CoV-2. After a natural infection, the immune system assesses the virus in multiple ways and provides both antibody-mediated and cellular protection. As the SARS-CoV-2 pandemic has relentlessly progressed, with multiple waves, the immune landscape of the global population has transformed from being immune naive to having natural infection-induced immunity. Although vaccinating the naive population is logical, an important question arises of whether to vaccinate those who were previously infected with SARS-CoV-2. The need for boosting natural immunity, through vaccination, comes from the waning of immunity, with declining antibody titres, and the emergence of SARS-CoV-2 variants with immune-evasion properties.
In The Lancet Infectious Diseases, Thiago Cerqueira-Silva and colleagues have addressed the issue of vaccine effectiveness among individuals who were previously infected. For this study, the authors used national COVID-19 notification, hospitalisation, and vaccination datasets from Brazil to assess effectiveness against symptomatic infection, hospitalisation, and death for the four vaccines in use in the country during the study period: CoronaVac (Sinovac), ChAdOx1 nCoV-19 (Oxford-AstraZeneca), Ad26.COV2.S (Janssen), and BNT162b2 (Pfizer-BioNtech). Of the people who had previous confirmed SARS-CoV-2 infection, the authors included 22566 symptomatic individuals with RT-PCRpositive reinfection and 145055 negative RT-PCR tests from 68426 symptomatic matched controls in a test-negative case-control study. After adjusting for important confounders, vaccine effectiveness against symptomatic infection 14 days or more from complete vaccination after a previous natural infection was 39·4% (95% CI 36·1–42·6) for CoronaVac, 56·0% (51·4–60·2) for ChAdOx1 nCoV-19, 44·0% (31·5–54·2) for Ad26. COV2.S (single-dose vaccine), and 64·8% (54·9–72·4) for BNT162b2. Vaccine effectiveness against hospitalisation or death after complete vaccination was more impressive: 81·3% (75·3–85·8) for CoronaVac, 89·9% (83·5–93·8) for ChAdOx1 nCoV-19, 57·7% (–2·6 to 82·5) for Ad26. COV2.S, and 89·7% (54·3–97·7) for BNT162b2.
The study has some major strengths. First, the linkage of three national databases for SARS-CoV-2 testing, disease surveillance for COVID-19, and immunisation. This showcases the importance of population-level data and the power of big-data analysis. Second, the comprehensive evaluation of vaccine effectiveness of four vaccines used globally. And third, the study of the dose–response relationship. However, an important missing piece of information is the SARS-CoV-2 variants against which vaccine effectiveness estimates are reported. This absence is important in view of variable vaccine effectiveness against different variants.
The vaccine effectiveness estimates in the study by Cerqueira-Silva and colleagues are generally lower than those in naive populations reported earlier. However, this discrepancy is expected given that Cerqueira-Silva and colleagues’ estimates were for additional protection provided by vaccination over and above that offered by immunity resulting from natural infection. Natural infection might act as a priming or booster dose; in a previous study, protection against reinfection was maintained at greater than 90% for more than 6 months after vaccination among participants with natural immunity who were subsequently vaccinated, even in those who were infected more than 12 months before vaccination. Protection as high as 82%, similar to two vaccine doses, was shown in individuals previously infected who had received a single dose of vaccine. These clinical findings are corroborated by in-vitro immunological studies showing that humoral and cellular immune responses are high after the multiple antigen exposure provided by natural infection and vaccination. In addition to antibody-mediated immunity, cellular T-cell responses provide protection against severe disease, hospitalisation, and death.
The results of Cerqueira-Silva and colleagues’ study and other recent studies challenge the concept of population-level herd immunity through natural infection alone against SARS-CoV-2 and suggest that vaccinating individuals who were previously infected provides further protection, particularly against severe disease. These data should help guide policy decisions and mitigate vaccine hesitancy among people who have previously had SARS-CoV-2 infection.
However, some clinical and immunological questions remain to be answered. Primary exposure to an antigen leads to epitope-specific B-cell memory known as immune imprinting. Barring the ancestral virus infection, subsequent SARS-CoV-2 infections during multiple waves caused by variants have led to heterologous exposure to virus antigens. How immune imprinting by the first exposure, either by the virus or vaccine, affects the durability and breadth of immune responses remains to be studied. What additional protection does natural infection provide to vaccinated individuals and how durable is this protection? And what is the optimal timing of vaccination after natural infection? These questions are important in view of the large swath of the global population who have been exposed to natural infections caused by delta (B.1.617.2) and omicron (B.1.1.529) variants.
Hybrid immunity due to exposure to natural infection and vaccination is likely to be the norm globally and might provide long-term protection even against emerging variants. Besides vaccination, continued surveillance for further emergence of variants for their immune evasiveness and pathogenicity should continue.
*Pramod Kumar Garg, Ramachandran Thiruvengadam pgarg@thsti.res.in Translational Health Science and Technology Institute, Faridabad, NCR Delhi 121001, India
www.thelancet.com/infection Vol 22 June 2022