感染和疫苗接種在長期預防 COVID-19 中的相互作用

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

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SARS-CoV-2 omicron 變異株已迅速傳播到世界各地，包括疫苗接種率高的國家。隨著人群越來越多地包括了具有疫苗接種驅動和感染驅動免疫的個體，了解與不同免疫史相關的差異保護變得很重要。儘管評估 omicron 感染後長期免疫的研究尚不可能，但在先前所關注的變異株的背景下進行的全人群之研究可能會提供大量信息。

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在《剌胳針傳染病》中，Peter Nordström 及其同事使用瑞典國家感染和疫苗接種登記冊來評估截至 2021 年 10 月在整個人群中對 SARS-CoV-2 感染的保護。他們使用超過 200 萬人的世代，顯示感染與無免疫力者相比，在 20 個月的追蹤期間，相關免疫對隨後的再感染具有 95% 的保護性（調整後的風險比 [aHR] 0·05 [95% CI 0·05–0·05] p<0.001）。相比之下，恢復期之個案再接受一劑 COVID-19 疫苗的的再感染風險進一步降低了 58%（aHR 0·42 [95% CI 0·38–0·47]；p<0.001），儘管在接下來的 9 個月的追蹤期中它有所減弱。恢復期個案接受兩劑疫苗者僅受益於稍強之邊際性的保護（aHR 0·34 [95% CI 0·31–0·39]；P<0.001），相較於接種一劑疫苗者為（aHR 0·42 [95% CI 0·38–0·47]；p<0.001），而與僅感染組相比，再感染風險降低 66%。

這些數據顯示，在一個大型世代中，接種疫苗對從 COVID-19感染康復的個體中具有額外的保護作用。儘管一劑疫苗組和兩劑疫苗組之間的保護差異相當小，但 Nordstrom 及其同事發現了一些證據顯示，單劑疫苗組其保護作用之衰退比兩劑疫苗組要來得更大。在這兩種情況下，與恢復期世代相比，與 COVID-19 相關的住院風險至少降低了 90%。而與這項大樣本數量之全人群研究有關的一個重大好處是，能夠評估特定亞群體的再感染風險。特別是 65 歲及以上的人對既往感染的保護作用較弱，這顯示疫苗接種在某些高危人群中可能特別重要；對於 omicron 的保護可能尤其如此，其中第三劑疫苗是引發交叉反應性中和抗體的關鍵。總的來說，這些數據清楚地顯示了兩劑疫苗對恢復期個體的益處，無論是在免疫力的持久性抑或是對嚴重疾病的保護這兩方面上。

數據還顯示了單獨感染 SARS-CoV-2 的長期保護作用，在 20 個月的追蹤中保持穩定。考慮到輕度 COVID-19感染產生的廣泛中和抗體效價，在個人參與更廣泛的社會活動中這種保護水平是值得注意的。儘管這些分析無法考慮疫苗接種對病毒傳播給他人的影響，但無論先前接觸抗原的性質如何，免疫概況至少應該在評估個體隨後再感染的風險方面提供信息。隨著大流行的繼續發展，全人群對 SARS-CoV-2 之免疫力的性質將變得越來越複雜。由於 omicron 變異株的免疫逃脫導致越來越多的突破性感染，再加上對第三次或第四次疫苗接種的不同建議，許多人群將表現出具感染誘發和疫苗誘發免疫的混合狀態。儘管 Nordstrom 及其同事專注於與感染相關的保護，然後接種疫苗；但亦有許多人重點放在接種疫苗，然後感染上。然而，最近的一項研究顯示，無論感染發生在疫苗接種之前還是之後，體液免疫反應的數量、質量和廣度都得到了極大的改善。這一發現進一步支持了這樣一種觀點，即感染史應該是確定個人對抗SARS-CoV-2 是否受到保護的重要考慮因素。未來的研究將需要評估不同病毒變異株的感染是否賦予不同水平的保護性免疫，並更好地了解不同波變異株感染的流行病學影響。

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展望未來，將感染史納入個體的免疫特徵雖然是合理的，但仍會讓人質疑未來的加強免疫方案應如何規劃。例如，具有感染相關免疫力的個體是否需要再獲得兩劑才能達到在先前沒有感染但接受三劑疫苗的個體中所觀察到的免疫水平？無論如何，SARS-CoV-2 感染顯然是保護性免疫的重要貢獻者，它與疫苗接種的相互作用需要進一步長期性縱向的研究，最終為推動積極的衛生政策和措施提供見解，以便在這場大流行中實現最佳的人群免疫。

Hyon-Xhi Tan, *Jennifer A Juno jennifer.juno@unimelb.edu.au

墨爾本大學彼得.多爾蒂感染與免疫研究所微生物學和免疫學系，墨爾本，VIC 3000，澳大利亞

Interplay of infection and vaccination in long-term protection from COVID-19

    The SARS-CoV-2 omicron variant has rapidly spread throughout the world, including in countries with high vaccination rates. As populations increasingly include individuals with both vaccination-driven and infection-driven immunity, it becomes important to understand the differential protection associated with diverse immune histories. Although studies assessing long-term immunity after omicron infection are not yet possible, population-wide studies done in the context of previous variants of concern can be highly informative.

    In The Lancet Infectious Diseases, Peter Nordström and colleagues1 use Swedish national infection and vaccination registers to assess population-wide protection from SARS-CoV-2 infection up to October, 2021. Using a cohort of more than 2 million individuals, they showed that infection-associated immunity was 95% protective against subsequent reinfection during 20 months of follow-up compared with no immunity (adjusted hazard ratio [aHR] 0·05 [95% CI 0·05–0·05] p<0.001). In comparison, convalescent individuals who received one dose of a COVID-19 vaccine exhibited a further 58% lower risk of reinfection (aHR 0·42 [95% CI 0·38–0·47]; p<0.001), albeit it with some degree of waning over the next 9 months of follow-up. Convalescent individuals receiving two doses of a vaccine benefitted from only marginally greater protection (aHR 0·34 [95% CI 0·31–0·39]; P<0.001) than those who received one dose (aHR 0·42 [95% CI 0·38–0·47]; p<0.001), with a 66% lower risk of reinfection than those in the infection-only cohort.

    These data show, in a large cohort, the added protective benefit of vaccination among individuals recovered from COVID-19. Although the difference in protection between the one-dose and two-dose vaccine groups was reasonably small, Nordstrom and colleagues found some evidence for greater waning of protection among the single-dose group than the two-dose group. In both cases, there was at least 90% reduction in the risk of COVID-19-associated hospitalisation compared with the convalescent cohort. A substantial benefit related to the large sample size of this population-wide study is the ability to also assess the risk of reinfection among specified subgroups. In particular, protection from previous infection was weaker in individuals aged 65 years and older, suggesting that vaccination might be particularly important in some high-risk populations; this is probably particularly true for protection against omicron, in which athird vaccine dose is key to eliciting cross-reactive neutralising antibodies. On balance, these data clearly show the benefits of two-dose vaccination for convalescent individuals, both in terms of the durability of immunity and protection from severe disease.

    The data also show the long-term protective effect of SARS-CoV-2 infection alone, which was stable for 20 months of follow-up. This level of protection was notable, considering the wide range of neutralising antibody titres generated by mild COVID-19. The authors note that, given these results, infection history should be accounted for when so-called immunity passports are required for individuals to partake in wider societal activities. Although these analyses cannot take into account the effect of vaccination on viral transmission to others, immune profiles should, at the very least, be informative in assessing an individual’s risk of subsequent reinfection, regardless of the nature of previous antigen exposure.

    As the pandemic continues to evolve, the nature of population-wide immunity against SARS-CoV-2 will become increasingly complex. Due to the immune evasion of the omicron variant driving an increasing number of breakthrough infections, combined with varying recommendations for third or fourth vaccine doses,6 many populations will exhibit a mixture of infection-elicited and vaccine-elicited immunity. Although Nordstrom and colleagues focus on the protection associated with infection followed by vaccination, many individuals will now have vaccination followed by infection. A recent study, however, showed that regardless of whether infection occurs before or after vaccination, the quantity, quality, and breadth of the humoral immune response were vastly improved. This finding further supports the notion that infection histories should be an important consideration in determining whether individuals are protected against SARS-CoV-2. Future studies will be required to assess whether infection by distinct viral variants imparts differing levels of protective immunity, and to better understand the epidemiological effect of infection across different variant waves.

    Looking forward, the incorporation of infection history in an immune profile of an individual, although justified, brings into question how future booster regimens should be planned for. For instance, are individuals with infection-associated immunity required to obtain two further doses to have the level of immunity observed in individuals with no previous infection but receiving three doses? Regardless, SARS-CoV-2 infection is clearly an important contributor to protective immunity, and its interplay with vaccination warrants further longitudinal studies, ultimately providing insights to drive proactive health policies and measures for optimal population-wide immunity in this pandemic.

Hyon-Xhi Tan, *Jennifer A Juno jennifer.juno@unimelb.edu.au

Department of Microbiology and Immunology, The University of Melbourne at the Peter Doherty Institute for Infection and Immunity, Melbourne, VIC 3000, Australia