www.thelancet.com/infection Vol 24 November 2024 / Published Online July 19, 2024 https://doi.org/10.1016/ S1473-3099(24)00398-0
每年仍有約 130 萬新的 HIV 1 型 (HIV-1) 感染，迫切需要一種有效的疫苗來預防 HIV-1 感染。自 1980 年代末期首次疫苗試驗以來，過去四十年已經測試了多種疫苗策略。儘管 RV144 試驗為該領域帶來了希望，但隨後複製其成功的嘗試並未成功。大多數試驗都測試了旨在誘導針對 HIV-1 的非中和抗體或 T 細胞反應的免疫原。這些試驗包括最近的兩項 HIV-1 疫苗試驗 HVTN705 (Imbokodo) 和 HVTN706 (Mosaico)，這兩項試驗均因缺乏疫苗功效而在初步分析後停止。這些試驗中的每一個
測試了腺病毒26（Ad26）疫苗平台，它已被證明可以在非人類靈長類動物模型中預防 HIV-1 感染，並在人類中誘導強烈的免疫反應。
在他們的文章中， Glenda E Gray 及其同事提供了 2b 期 Imbokodo 試驗的分析。該試驗評估了四價嵌合Ad26 疫苗 (Ad26.Mos4.HIV) 與含佐劑的C 分支糖蛋白140 的結合。該研究招募了 2017 年至 2019 年間來自撒哈拉以南非洲多個醫院的 2636 名年齡在 18 至 35 歲之間且未感染 HIV-1 或 HIV-2 的女性。女性被隨機分配接受疫苗 (n=1313) 或安慰劑 (n=1323)。疫苗方案包括在一年內注射四次，主要功效是在接種疫苗後 7 個月至 24 個月之間預防 HIV-1 感染。該疫苗顯示出良好的安全性，但沒有顯著降低HIV-1 感染的發生率，因此沒有功效（估計效力為14·10% [95% CI –22·00 至39·51；p=0· 40 ]）。儘管整體結果並不理想，但該臨床試驗對於愛滋病毒疫苗的開發領域仍具有重要意義。 Imbokodo試驗堅持高道德原則，從代表性不足的高危險群中招募參與者，與當地社區密切合作，並在所有參與者中推廣使用暴露前預防等其他預防方法，可以作為一個藍圖用於未來的HIV -1 預防試驗。
迄今為止，HIV-1 疫苗的所有主要 2-3 期研究都採用了相當實證的方法，其中病原體的部分蛋白質被用作免疫原，以誘導保護性且持久的免疫反應（圖）。這個概念已成功地對抗其他病原體，並有助於確定保護的相關性，但在 HIV-1 的情況下卻失敗了。對於大多數病毒感染，中和抗體對於保護至關重要。抗體介導預防 (AMP) 試驗顯示，被動施用廣泛中和抗體 VRC01 對 VRC01 敏感菌株的 HIV-1 感染產生了 75% 的疫苗功效，但沒有針對所有病毒株的全面保護。因此，AMP 試驗為長期以來的懷疑提供了第一個證據：有效的 HIV-1 疫苗的關鍵在於存在高效價的廣泛中和抗體。因此，在過去的十年中，該領域開始研究所謂的 HIV-1 疫苗合理設計方法。在這種方法中，保護的相關性是已知的，目標是透過智慧免疫原設計引發這些免疫反應（圖）。然而，透過免疫原誘導高效價的廣泛中和抗體已被證明是一個巨大的挑戰。這一困難是因為大多數已知的廣泛中和抗體都具有一些特徵，例如體細胞超突變比率高、互補決定區［註：Complementarity-determining regions，CDRs，為抗體和T細胞受體上可變域（variable domains）的一部分，為抗原與抗體接觸的地方，故又稱抗原結合位］長度不尋常以及其可變域中存在難以由免疫原誘導的大插入或缺失。此外，開發這種疫苗的第一步需要種系靶向，以刺激來自龐大且多樣化的 B 細胞庫中最有前途的 B 細胞。然而，近年來，已經開發出許多有前途的新型候選疫苗，其中一些已進入臨床試驗，目前正在更大規模的研究中進行測試。
這些新穎的方法為開發有效的 HIV-1 疫苗帶來了希望，儘管之前有過失敗。但研發出這種疫苗的旅程將是漫長的。儘管有多種有希望的方法，但誘導一種或多種廣泛中和抗體的高效價和保護性效價很可能需要在較長時間內施用一整套免疫原（圖）。因此，HIV 疫苗開發領域必須讓股東和資助機構相信，Imbokodo 試驗等研究並不標誌著 HIV-1 疫苗探索的結束。反而的是，這些研究標誌著從經驗性疫苗研究轉向更有條理的方法的轉變。
圖：經驗與理性疫苗設計 / 圖由 BioRender.com 創建。
Env= envelope protein. （包膜蛋白）。 Gag= group-specific antigen. （群體特異性抗原）。 Nef= negative factor. （負因子）。 Pol= DNA polymerase.（聚合酶）。
科隆大學已提交了一項抗 HIV-1 廣泛中和抗體的專利申請，並將 PS 列為發明者之一。 PS 已收到科隆大學許可抗體的付款。 PS 得到了德國研究基金會 – Emmy Noether 計畫（項目號 495793173）的支持。 PS 和 CL 得到了德國感染研究中心的支持。
*Clara Lehmann, Philipp Schommers clara.lehmann@uk-koeln.de
科隆大學醫學院和科隆大學醫院科隆內科一科和分子醫學中心，科隆 50937，德國 (CL、PS)；德國感染研究中心，合作夥伴站點波昂-科隆，德國科隆（CL、PS）
The need for novel approaches to HIV-1 vaccine development
www.thelancet.com/infection Vol 24 November 2024 / Published Online July 19, 2024 https://doi.org/10.1016/ S1473-3099(24)00398-0
With approximately 1·3 million new HIV type 1 (HIV-1) infections still occurring annually, there is an urgent need for an effective vaccine against HIV-1 acquisition. Since the first vaccine trials in the late 1980s, a variety of vaccine strategies have been tested over the past four decades. However, with the exception of the RV144 trial, none of these trials has shown vaccine efficacy in humans. Although the RV144 trial raised hopes within the field, subsequent attempts to replicate its success have been unsuccessful. Most trials have tested immunogens designed to induce non-neutralising antibodies or T-cell responses against HIV-1. Among these trials were the two most recent HIV-1 vaccine trials, HVTN705 (Imbokodo) and HVTN706 (Mosaico), both of which were stopped after primary analyses due to an absence of vaccine efficacy. Each of these trials tested the adenovirus 26 (Ad26) vaccine platform, which has already been shown to protect against HIV-1 infection in a non-human primate model and to induce robust immune responses in humans.
In their Article, Glenda E Gray and colleagues provide the analysis of the phase 2b Imbokodo trial. This trial evaluated the tetravalent mosaic Ad26 vaccine (Ad26. Mos4.HIV) in conjunction with an adjuvanted clade C glycoprotein 140. The study enrolled 2636 women aged 18–35 years without HIV-1 or HIV-2 from multiple hospital sites in sub-Saharan Africa between 2017 and 2019. Women were randomly assigned to receive either the vaccine (n=1313) or placebo (n=1323). The vaccine regimen included four injections over 1 year, with primary efficacy measured as the prevention of HIV-1 acquisition between months 7 and 24 post vaccination. The vaccine showed a favourable safety profile but did not significantly reduce the incidence of HIV-1 acquisition and thus showed no efficacy (estimated efficacy of 14·10% [95% CI –22·00 to 39·51; p=0·40]). Although the overall result was unfavourable, this clinical trial remains of great importance for the field of HIV vaccine development. The Imbokodo trial adhered to high ethical principles by recruiting participants from under-represented high-risk groups, engaging closely with local communities, and promoting the use of other prevention methods such as pre-exposure prophylaxis among all participants, and could serve as a blueprint for future HIV-1 prevention trials.
All major phase 2–3 studies of HIV-1 vaccines to date used a rather empirical approach, in which parts of the pathogen’s proteins are used as immunogens to induce a protective and long-lasting immune response (figure). This concept has worked successfully against other pathogens and helped to identify the correlate of protection but has failed in the case of HIV-1. For most viral infections, neutralising antibodies are crucial for protection. The Antibody-Mediated Prevention (AMP) trials have shown that passively administrating broadly neutralising antibody VRC01 resulted in a 75% vaccine efficacy for HIV-1 infections with VRC01-susceptible strains, but there was no overall protection against all strains. Thus, the AMP trials provided the first evidence of a long-held suspicion: the key to an effective HIV-1 vaccine lies in the presence of high titers of broadly neutralising antibodies. Hence, over the past decade, the field has started to work on a so-called rational approach to HIV-1 vaccine design. In this approach, the correlate of protection is known, and the goal is to elicit these immune responses through intelligent immunogen design (figure). However, inducing high titres of broadly neutralising antibodies through immunogens has been shown to be a substantial challenge. This difficulty is because most known broadly neutralising antibodies share characteristics such as high rates of somatic hypermutation, unusual complementarity-determining region lengths, and large insertions or deletions in their variable domain that are difficult to induce by immunogens. Moreover, the first step of developing such a vaccine would require germline targeting that stimulates the most promising B cells from the large and diverse B-cell repertoire. In recent years, however, many promising novel vaccine candidates have been developed, and some have progressed to clinical trials and are now being tested in larger studies.
These novel approaches offer hope for the development of an effective HIV-1 vaccine, despite previous failures. But the journey to such a vaccine will be long. Despite the multitude of promising approaches, the induction of high and protective titers of one or more broadly neutralising antibodies will most probably need a whole set of immunogens administered over an extended period (figure). Thus, it is imperative that the HIV vaccine development field convinces shareholders and funding agencies that studies such as the Imbokodo trial do not mark the end of the search for an HIV-1 vaccine. Instead, these studies mark the transition away from empirical vaccine studies towards a more methodical approach.
Figure: Empirical versus rational vaccine design Neutralisation breadth and potency Passive administration Eliciting broadly neutralising antibodies through rational immunogen design Figure created with BioRender.com. Env=envelope protein. Gag=group-specific antigen. Nef=negative factor. Pol=DNA polymerase.
A patent application for anti-HIV-1 broadly neutralising antibodies has been f iled by the University of Cologne and lists PS as one of the inventors. PS has received payments from the University of Cologne for licensed antibodies. PS was supported by the German Research Foundation–Emmy Noether Programme (project number 495793173). PS and CL were supported by the German Center for Infection Research.
*Clara Lehmann, Philipp Schommers clara.lehmann@uk-koeln.de
Department I of Internal Medicine and Center for Molecular Medicine Cologne, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne 50937, Germany (CL, PS); German Center for Infection Research, Partner Site Bonn–Cologne, Cologne, Germany (CL, PS)