1、Lauren P. Jatt ，醫學博士；2、Nyaradzo M. Mgodi ，醫學士、外科學士、醫學碩士；3、 Susan P. Buchbinder 醫學博士；4、 Glenda E. Gray 醫學士、外科學士；以及5、 James G. Kublin 醫學博士、公共衛生碩士。
2024 年 11 月，PURPOSE 2 試驗結果公佈 － 這是一項大型、隨機、策3 期試驗，評估每年兩次注射利那卡帕韋對順性別男性和性別多元化族群預防愛滋病毒效果之研究結果的發表，結果顯示，接受利那卡帕韋治療的人群的愛滋病毒發生率比每日口服恩曲他濱-富馬酸替諾福韋二吡呋酯(emtricitabine–tenofovir disoproxil fumarate) 的人群低 89%，比背景愛滋病毒發生率低 96%。 這些發現遵循 PURPOSE 1 試驗的結果顯示，每年兩次的利那卡帕韋可以完全（100%）保護順性別女性免受愛滋病毒感染。 發現一種只需每年兩次給藥高效率的 HIV 暴露前預防 (PrEP) 的選項，已導致在結束全球愛滋病毒流行上是否仍需要疫苗此一問題。
每年兩次的利那卡帕韋與理想的愛滋病疫苗有著重要的共同特徵：在 PURPOSE 試驗中觀察到的療效與許多傳統疫苗相比，它既安全且能高效地預防愛滋病。利那卡帕韋還具有熱穩定性，可以在室溫下運輸和儲存，這是相對於大多數 HIV 候選疫苗的一個重要優勢。但對於 PrEP 來說，lenacapavir 最明顯的優勢在於它不是假設性的——它現在就可以使用。儘管如此，僅依賴利那卡帕韋的愛滋病預防策略仍會存在一些限制。
因此，我們認為，發展愛滋病毒疫苗仍然是消除愛滋病毒流行全球多管齊下策略中所需的重要組成部分。
與大多數疫苗相比，利那卡帕韋提供的保護持續時間較短。人們必須每 6 個月注射一次以保持受到保護，並且必須不斷自我確認有很高的愛滋病毒接觸和感染可能性；有大量報告稱，人們因為行為改變並認為不再需要 PrEP時而停止使用 PrEP，卻從而感染了愛滋病毒。持續時間相當短的保護也意味著人們必須高度參與和堅持存留於醫療保健中接受治療。此外，他們必須能夠穩定地享受醫療保健系統；如果由於經濟困難、戰爭或環境災難等因素而失去獲取資訊的機會，他們將得不到保護。持久的免疫反應是疫苗的一個主要優勢。
疫苗和每年兩次的 PrEP 之間的另一個重要區別是，疫苗通常是普遍接種的，而 PrEP 服務則側重於高血清發生率人群。僅依賴針對特定族群的介入措施存在一些缺點。例如，在東部和南部非洲，據估計約 40% 的 HIV 感染者在感染前並不符合 PrEP 的使用標準。而符合標準的人可能會因為偏見而被臨床醫生忽略。針對特定族群的介入措施與接種疫苗等普遍性之介入措施相比也可以更加使她們更容易受到恥辱的影響。
儘管在理論上可以實現普遍地實施 PrEP，但由於成本、依從性和實施方面存在巨大障礙，尚未在任何國家推行。在某些人群中，PrEP 使用的污名化對開始和繼續使用亦產生了影響。選擇愛滋病毒預防方法很重要；並不是每個人都會選擇皮下注射 PrEP，因為這種注射有時會留下可見的結節。無論自我感知風險如何，都可以採取介入措施，這對於預防所有新的愛滋病毒病例（而不僅僅是其中一部分）至關重要（儘管不一定足夠）。
此外，許多中低收入地區缺乏實施注射PrEP所需的強大公共衛生基礎設施。有效大規模實施注射型 PrEP 計畫需要大量投資，包括皮下注射管理培訓，如果不按照方案進行，可能會很痛苦。相比之下，每個國家都有常規性的免疫接種。儘管不完善，常規性免疫系統幾十年來一直為邊緣人群引入疫苗並提供服務。
由於利那卡帕韋是一種小分子藥物，其療效可能會受到藥物與藥物間交互作用的限制。禁止將利那卡帕韋與強效 CYP3A 誘導劑一起使用，因為同時使用會導致利那卡帕韋的血漿濃度降低並降低其療效。在PURPOSE試驗中禁止同時使用某些藥物，其中包括抗驚厥藥、抗分枝桿菌藥物和全身性糖皮質激素。
抗藥性是另一個令人擔憂的領域。在PURPOSE 2試驗中，利那卡帕韋組有兩例HIV感染病例；兩名參與者在診斷時均具有 N74D 衣殼抑制劑抗性突變，這顯示試驗期間的利那卡帕韋單一療法導致了衣殼抗性的出現。 兩位參與者的利那卡帕韋濃度均在試驗的預期治療範圍內。目前還不清楚停藥後低水平接觸利那卡帕韋（由於該藥物的半衰期較長）是否會導致一些停止注射的人產生抗藥性。對利那卡帕韋產生抗藥性的 HIV 病毒株的出現，將使得僅依賴利那卡帕韋進行 PrEP 治療的 HIV 預防計畫變得無效。
為了終結愛滋病毒流行，我們的預防工具必須在全球範圍內負擔得起、可接受且可用。每年兩次注射 PrEP 的費用尚不清楚。目前，大多數的國家都無法獲得其他的長效 PrEP 注射劑或因價格而受限。
相關研究均持續地預測 HIV 疫苗具有成本效益。因此需要對每年兩次注射的 PrEP、假設中的 HIV 疫苗，以及兩種產品的組合等等進行成本效益之比較分析。
在 PURPOSE 試驗中，超過 4,300 名服用 lenacapavir 藥物的受試者中，只有兩例感染 HIV 病毒。幾乎消除了新的愛滋病毒感染，這是一項巨大的成就。這也引發了人們對能否進行足夠有力的第 3 期疫苗試驗的合理擔憂，因為許多臨床試驗人員認為，向任何參與 HIV 疫苗試驗的人提供 PrEP 是道德上的要求。
鑑於 HIV 疫苗的眾多潛在益處以及最近在透過疫苗接種誘導廣泛中和抗體方面取得的進展，有前景的候選疫苗值得在大規模療效試驗中進行測試。一種選擇是只招募那些在接受愛滋病預防服務後拒絕接受 PrEP 的參與者。該策略的可行性最近在 Mosaico 試驗中得到了證明，該試驗招募了 3,800 名拒絕接受 PrEP 治療的人。除了在試驗開始時接受諮詢和獲得 PrEP 服務外，參與者還可以在試驗期間的任何時間開始使用 PrEP。（獨立審查發現沒有證據顯示接種研究性疫苗的參與者感染愛滋病毒的風險降低，因此該試驗被終止。），社區參與和道德監督對於制定可接受的試驗設計至關重要。
我們與大家一樣，對長效注射 PrEP 有望大幅減少新的 HIV 感染數量抱持著極大的熱情。我們也意識到，開發一種價格合理、高效且能產生持久免疫反應的愛滋病毒疫苗將充滿挑戰。儘管最近在透過疫苗誘導廣泛中和抗體方面取得的進展，亦這些努力帶來了新的希望，但先前眾多候選疫苗的失敗清楚地提醒人們這項努力的困難。
每年只需注射兩次的 PrEP 注射劑型的存在提高了未來 HIV 疫苗的標準：它必須與現有的預防方案相比能產生持久的免疫反應，亦必須具有成本效益；並且於實施在廣泛人群上使用上必須比採用廣泛的 PrEP 管理更為可行。鑑於每年兩次注射的 PrEP 和理想的 HIV 疫苗的互補性，我們相信只有結合這些介入措施的方法才能終結 HIV 流行。
作者提供的揭露表格可在 NEJM.org 上取得。
1 華盛頓大學西雅圖分校過敏和傳染病科； 2 辛巴威大學臨床試驗研究中心，哈拉雷； 3 舊金山公共衛生局，舊金山； 4 約翰尼斯堡威特沃特斯蘭德大學健康科學學院周產期裳愛滋病毒研究組； 5 西雅圖弗雷德哈欽森癌症中心疫苗和傳染病科。
本文於 2025 年 4 月 19 日發表在 NEJM.org 上。
1. Kelley CF、Acevedo-Quiñones M、Agwu AL 等人。
每年服用兩次利那帕韋用於男性和性別多元化族群的愛滋病毒預防。《N Engl J Med 》2025； 392：1261-76。
2. Bekker L-G、Das M、Abdool Karim Q 等人。
每年服用兩次利那帕韋或每日服用 F/TAF 可預防順性別女性感染愛滋病毒。《N Engl J Med 》2024； 391：1179-92。
3. Beyrer C、Tomaras GD、Gelderblom HC 等人。
到2030年控制愛滋病疫情現實嗎？《刺胳針愛滋病毒》，2024；11(7): e489-e494。
4. Adamson B, Dimitrov D, Devine B, Barnabas R。
HIV 疫苗的潛在成本效益：系統性回顧。2017 年《藥物經濟學 – 開放獲取》； 1：1-12。
5.Williams WB、Alam SM、Ofek G 等人。
疫苗所誘導人類異源HIV-1中和抗體B細胞譜系。《細胞》2024；187(12): 2919-2934.e20。
DOI: 10.1056/NEJMp2415893
版權所有 © 2025 麻薩諸塞州醫學會。
An HIV Vaccine in the Era of Twice-Yearly Lenacapavir for PrEP — Essential or Irrelevant?
Lauren P. Jatt, M.D.,1 Nyaradzo M. Mgodi, M.B., Ch.B., M.Med.,2 Susan P. Buchbinder, M.D.,3 Glenda E. Gray, M.B., Ch.B.,4 and James G. Kublin, M.D., M.P.H.5
In November 2024, results from the PURPOSE 2 trial — a large, randomized, phase 3 trial evaluating the efficacy of twice-yearly lenacapavir injections for HIV prevention in cisgender men and gender-diverse persons — were published, revealing that the incidence of HIV infection among people who received lenacapavir was 89% lower than the incidence among people who received daily oral emtricitabine–tenofovir disoproxil fumarate and 96% lower than the background HIV incidence. These findings followed
the results of the PURPOSE 1 trial, which showed that twice-yearly lenacapavir provided complete
(100%) protection against HIV infection in cisgender women. The discovery of a highly efficacious
option for HIV preexposure prophylaxis (PrEP) that requires only twice-yearly administration has led
to the question of whether a vaccine is still necessary to end the global HIV epidemic.
Twice-yearly lenacapavir shares important features with an ideal HIV vaccine: it is safe and highly efficacious for preventing HIV. The efficacy observed in the PURPOSE trials is similar to, if not greater
than, that of many conventionally available vaccines. Lenacapavir is also thermostable and can be shipped and stored at room temperature, an important advantage over most HIV vaccine candidates. But the most obvious advantage of lenacapavir for PrEP is that it is not hypothetical — it is available now. Nonetheless,
an HIV-prevention strategy that relied exclusively on lenacapavir would have several limitations.
We therefore believe that the development of an HIV vaccine is still an essential component of the global, multipronged strategy that is needed for ending the HIV epidemic.
Lenacapavir provides shorterlasting protection than most vaccines. People must get injections every 6 months to remain protected and must continually selfidentify as having a high likelihood of HIV exposure and acquisition; there have been numerous reports of HIV acquisition in people who stopped using PrEP because their behavior changed and they thought they no longer needed it. A fairly short duration of
protection also means that people must have high levels of health care engagement and adherence
to treatment. Furthermore, they must have stable access to the health care system; if they lose access because of factors such as economic hardship, war, or environmental disaster, they will be left unprotected. Durable immune responses are a key advantage of vaccines.
Another important difference between vaccines and twice-yearly PrEP is that vaccines are typically given universally, whereas PrEP services are focused on people in high-seroincidence groups. There are disadvantages to relying exclusively on interventions directed at specific populations. In eastern and southern Africa, for example, it’s estimated that approximately 40% of people who become infected with HIV hadn’t met the criteria for PrEP use before infection.3 People who do meet the criteria may be overlooked by their clinicians because of bias. Population-specific interventions can also be more
susceptible to the effects of stigma than universal interventions such as vaccination.
Universal administration of PrEP, although theoretically possible, hasn’t been pursued in any country, given substantial barriers related to cost, adherence, and implementation. In some populations,
stigmatization of PrEP use has had implications for initiation and continued use. Having a choice of HIV-prevention method is important; not everyone will choose a subcutaneous PrEP injection that sometimes leaves a visible nodule. Interventions that can be rolled out regardless of selfperceived risk are essential (although not necessarily sufficient) for preventing all new cases of HIV — not just some of them.
In addition, many low- and middle-income settings lack the robust public health infrastructure needed for administering injectable PrEP. Effectively implementing injectable PrEP programs at scale will require substantial investment, including training in administration of subcutaneous injections, which can be painful if they aren’t delivered according to protocol. By comparison, every country has experience with
routine immunization. Although imperfect, routine immunization systems have introduced vaccines and provided services to marginalized populations for decades.
Since lenacapavir is a smallmolecule drug, its efficacy could be limited by drug–drug interactions. Lenacapavir use with strong CYP3A inducers is contraindicated because concurrent use can result in lower plasma concentrations and reduced efficacy of lenacapavir. Simultaneous use of some medications — including anticonvulsants, antimycobacterial agents, and systemic glucocorticoids — was prohibited in the
PURPOSE trials.
Drug resistance is another area of concern. In the PURPOSE 2 trial, there were two cases of HIV infection in the lenacapavir group; both participants had the N74D capsid inhibitor resistance mutation at diagnosis, which suggests that lenacapavir monotherapy during the trial led to the emergence of capsid resistance. Lenacapavir concentrations in both participants were in the expected therapeutic range for the trial. It’s also unknown whether low-level exposure to lenacapavir after discontinuation — a result of the drug’s long half-life — might lead to the emergence of resistance in some people who stop receiving injections. The emergence of HIV strains resistant to lenacapavir would render HIV-prevention programs relying exclusively on lenacapavir for PrEP ineffective.
To end the HIV epidemic, our prevention tools must be affordable, acceptable, and accessible globally. The cost of twice-yearly injectable PrEP is unknown. Other long-acting injectables for PrEP are currently unavailable or costprohibitive in most countries.
Studies have consistently predicted that an HIV vaccine would be cost-effective. An analysis comparing the cost-effectiveness of twice-yearly injectable PrEP, a hypothetical HIV vaccine, and a combination of the two products is needed.
Among the more than 4300 participants in the lenacapavir groups in the PURPOSE trials, there were only two incident cases of HIV. This near-elimination of new HIV infections is an enormous achievement. It has also led to legitimate concerns about the ability to conduct adequately powered phase 3 vaccine trials because of what many clinical trialists consider an ethical imperative to offer PrEP to anyone who would be participating in an HIV vaccine trial.
Given the numerous potential benefits of an HIV vaccine and recent progress toward achieving the induction of broadly neutralizing antibodies by means of vaccination, promising vaccine candidates merit testing in large efficacy trials. One option would be to enroll only participants who decline PrEP after being linked to HIV-prevention services. The feasibility of this strategy was recently demonstrated in the Mosaico trial, which enrolled 3800 people who had declined PrEP. In addition to receiving counseling and being offered PrEP services at the beginning of the trial, participants could start using PrEP at any point during the trial. (This trial was discontinued after an independent review found no evidence of reduced risk of HIV infection among participants receiving the investigational vaccine.) Community engagement and ethical oversight will be critical to developing acceptable trial designs.
We share the widespread enthusiasm about the potential for long-acting injectable PrEP to dramatically reduce the number of new HIV infections. We also recognize that the development of an affordable and highly effective HIV vaccine that generates a durable immune response will be rife with challenges. Although recent progress toward inducing broadly neutralizing antibodies with vaccination has brought renewed hope to these efforts, the failure of numerous previous vaccine candidates is a stark reminder of the difficulty of this endeavor.
The existence of an injectable form of PrEP that requires only twice-yearly administration raises the bar for a future HIV vaccine: it must generate a long-lasting immune response and must be cost-effective as compared with existing prevention options, and implementing it for broad population use must be more feasible than adopting widespread PrEP administration. Given the complementarity of twice-yearly injectable PrEP and an ideal HIV vaccine, we believe that only an approach that combines these interventions will end the HIV epidemic.
Disclosure forms provided by the authors are available at NEJM.org.
1 Division of Allergy and Infectious Disease, University of Washington, Seattle; 2 University of Zimbabwe Clinical Trials Research Centre, Harare; 3 San Francisco Department of Public Health, San Francisco; 4 Perinatal HIV Research Unit, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg; 5 Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Center, Seattle.
This article was published on April 19, 2025, at NEJM.org.
- Kelley CF, Acevedo-Quiñones M, Agwu AL, et al.
Twice-yearly lenacapavir for HIV prevention in men and gender-diverse persons.
N Engl J Med 2025; 392: 1261-76.
2. Bekker L-G, Das M, Abdool Karim Q, et al.
Twice-yearly lenacapavir or daily F/TAF for HIV prevention in cisgender women.
N Engl J Med 2024; 391: 1179-92.
3. Beyrer C, Tomaras GD, Gelderblom HC, et al.
Is HIV epidemic control by 2030 realistic?
Lancet HIV 2024; 11(7): e489-e494.
4. Adamson B, Dimitrov D, Devine B, Barnabas R.
The potential cost-effectiveness of HIV vaccines: a systematic review.
Pharmaco Econ Open 2017; 1: 1-12.
5. Williams WB, Alam SM, Ofek G, et al.
Vaccine induction of heterologous HIV-1-neutralizing antibody B cell lineages in humans.
Cell 2024; 187(12): 2919-2934.e20.
DOI: 10.1056/NEJMp2415893
Copyright © 2025 Massachusetts Medical Society.
