如果這些 mRNA 疫苗如此出色，但為何針對愛滋病毒我們仍沒有任一種疫苗呢？
蒂姆·墨菲，2021 年 8 月 19 日； 資料來源：https://www.thebody.com/article/mrna-hiv-vaccine-development-challenges ； 財團法人台灣紅絲帶基金會編譯
COVID 的外突刺（左）很容易接觸到。而愛滋病毒的外突刺，並不是那麼多——這只是製造有效的愛滋病毒疫苗真正困難的一個原因
在過去一年左右的時間裡，我從 IRL 和社交媒體上的朋友那裡聽到了很多事情：「為什麼我們在不到一年的時間內能得到多個 COVID-19 疫苗的推出，而我們已經了解 HIV 近 40 年，但我們卻仍然沒有任一 HIV疫苗？製藥公司必須阻止這種情形，因為他們已從愛滋病毒藥物中賺了太多錢了！」
我總是想回答，「嗯，是的，這是真的，製藥商確實從 HIV 藥物中賺了很多錢」——事實上，僅在 2020 年就約有 300 億美元——「但這不是我們仍沒有 HIV 疫苗的主要原因。在於製作 HIV 疫苗真的是很困難的！」
但後來我總是忘記為什麼它很難的細節。但最近我讀到了製藥商 Moderna（開發了COVID-19 其中的一種疫苗）計畫將他們用於COVID成功的 mRNA 技術應用於疫苗並將其擴展到針對玆卡病毒、癌症、流感以及 HIV 等疫苗的努力。 （事實上，他們剛剛宣布他們很快就會啟動 HIV 試驗的第一階段。）所以我決定分解為什麼 HIV 疫苗如此具有挑戰性。
我聯繫了兩位了不起的專家來做這件事——Richard Jefferys，基礎科學、疫苗和治癒計畫主任治療行動小組 (Treatment Action Group, TAG) 和國際愛滋病疫苗倡議 (the International AIDS Vaccine Initiative, IAVI) 總裁兼首席執行官 Mark Feinberg, M.D., Ph.D.，一個為 HIV、肺結核、新興傳染病、被忽視的疾病開發疫苗和抗體的非營利組織。
不過，首先讓我們談談用於疫苗的 mRNA 技術——這個想法已經存在了幾十年。mRNA名稱代表「信使 RNA」，意思是，在這種疫苗中，有一小部分具衝撞性的病毒遺傳物質，或藍圖，用於在體內生成病毒蛋白，向免疫系統「展示」，以便它知道如果它遇到真實的東西，就會對它採取行動。這不同於舊的疫苗方法，例如脊髓灰質炎疫苗疫苗，這通常需要向免疫系統「展示」實際病毒的減弱或死亡版本。
在 COVID-19 的情況下，mRNA 為免疫系統提供了花椰菜樣「刺突蛋白」(spike proteins) 的遺傳信息。
病毒表面附著在人體細胞上，尤其是在肺部。這樣，杰弗里斯說，「當真正的病毒出現時，免疫系統有特定的記憶」。
那麼為什麼這對 HIV 來說如此困難呢？
首先，杰弗里斯說，缺乏興趣和資金不再是真正的原因。「有一段時間在1990 年代初期，您可能會爭辯說 HIV 疫苗研究資金不足」，他說。「但到目前為止，這是一個實質性的預算」。根據 HIV 預防研究與開發工作組的資源追踪分析，在 HIV 疫苗倡導組織 AVAC 的計畫中，2000 年至 2019 年期間，近 153 億美元用於 HIV 疫苗研究，資金來自比爾和梅琳達·蓋茨基金會等慈善、公共和私人團體。
如果這筆錢還沒有導致研製出有效的疫苗，那麼它已經導致了大量關於愛滋病毒和愛滋病毒的信息。和在免疫系統部分地導致了 COVID 疫苗的快速發展。愛滋病毒研究有助於揭示使用改良形式的入侵者外部「剌突」蛋白製造疫苗以產生免疫反應的重要性。
HIV 疫苗研究還導致 mRNA 作為疫苗方法概念的完善——成功用於 COVID，而不是這麼多的愛滋病毒。
為什麼會有差距？簡短的回答是，HIV 是現代科學已知最詭計多端、最狡猾的病毒之一。和這個答案可分解為許多因素。
首先是 HIV 變異的速度。現在有很多關於現有的 COVID 疫苗將如何預防的討論，我們看到的 COVID 的新變種，例如 Delta 和 Lambda。但事實上，愛滋病毒會發生變異並產生新的變異比 COVID 快得多，複製得如此之快，以至於當它從一個人移動到另一個人時，它不斷地犯遺傳「錯誤」並不斷進化。這導致研製一種能夠產生所謂廣泛中和抗體 (broadly neutralizing antibodies, bNAbs)可以對抗多種 HIV 病毒株——「超過 90% 的循環變種」極端的困難，范伯格說。
另一個原因是 HIV 以其獨特惡魔般的目標瞄準了身體通常用來擊退捕食者的部位——免疫系統。 “HIV 進入 CD4 [免疫] 細胞並阻止它們向 B 細胞 [免疫系統的另一部分] 發送正確的信號，杰弗里斯解釋說。「愛滋病毒總是領先於這場比賽」。
還有一個原因是 HIV 的表面刺突——不像 COVID 的那樣，它們毫無障礙很容易被免疫細胞鎖定——但HIV形狀奇特，包裹在一種叫做聚醣盾的棉花糖狀塗層中，這使得免疫細胞很難附著在它們上面。「這幾乎就像你在沙發底下掉了什麼東西，不得不伸手去拿，在無法看到它的情況下四處尋找」，杰弗里斯說。「這就是 [廣泛中和抗體] 與 HIV 的關係，深入到這些角落和縫隙」。
確實，狡猾的病毒！但如果它如此狡猾，為什麼我們能夠創造出有效的 HIV 治療和藥物？預防——PrEP（暴露前預防）——但不是疫苗？杰弗里斯說，就治療而言，這是因為一旦 HIV 真正進入人體細胞，這些藥物就會針對 HIV，複雜的複印工作在那裡進行複制，然後再退出以感染更多的人類細胞。「而且 HIV 的內部成分比病毒外部的包膜更不容易發生突變」，他補充說，這是一種有效的疫苗必須突破的。
至於 PrEP，它有效地阻止了HIV被稱為「反轉錄酶」的過程——將其 RNA 轉化為 DNA——病毒必須做才能真正在體內紮根。「一旦發生這種情況」，杰弗里斯說，「你體內就會有一個終生的 HIV 工廠，這是不可能擺脫的」，但 PrEP 阻止了這種情況的發生。
那麼我們現在在哪裡？值得嗎？
如果一種有效的 HIV 疫苗如此難以製造，我們能做到嗎？「這是一個非常棘手的問題」，杰弗里斯說。「在科學，總有驚喜，有好有壞。楊森的疫苗有可能擁有保護力」。
他指的是來自強生子公司楊森 (Janssen) 的疫苗，該疫苗最近處於第三階段（最大和最後）在拉丁美洲、歐洲和美國的男男性行為者和跨性別者中進行的試驗，以及在幾個非洲國家對 HIV 高危順性別女性進行的 2b 期試驗——這是由於將在 7 月分析結果。它不是一種 mRNA 疫苗，而是一種所謂的「載體」疫苗，它使用了一種改良版的不同的病毒（在本例中為腺病毒），以向人體細胞提供有關對抗 HIV 的重要信息。疫苗不是能夠誘導廣泛的中和抗體反應，而是產生其他類型的免疫反應，研究人員認為可能有機會預防愛滋病毒感染。
Feinberg 警告說，如果 Janssen 的結果是負面的，那可能是研製能激發此類免疫反應之疫苗的最後一次嘗試。 他說，未來的試驗將只會關注在免疫系統的 B 細胞翼的部份。但是，范伯格警告說，「廣泛的中和抗體必須經過多個進化步驟才能獲得可以與 HIV 結合的結構」，這意味著製造這種疫苗本身將是一個緩慢的、多步驟的過程。
他補充說，他的團隊國際愛滋病疫苗倡議 ( IAVI ) 也在與生物技術 Moderna 和 Scripps Research 合作開發一種疫苗，該疫苗可能具有引導 B 細胞產生廣泛中和抗體的潛力。
不過，儘管面臨所有挑戰，范伯格反駁了那些認為研製有效的 HIV 疫苗過於復雜的觀點。
值得挑戰，尤其是當我們現在有越來越多的全球可用的預防和治療選擇時，這些藥物正在從每天服用一次，演變為只需每月服用一次——或者很快每年一次或兩次。
「即使是這些進步也只是臨時措施」，范伯格說。「你仍然需要每年把那些東西給需要它們的每個人而不是只有一次。我們結束全球愛滋病大流行的唯一方法是，如果我們有一個疫苗」。 （據記錄，僅 2020 年全球就有 150 萬人感染了愛滋病毒，根據聯合國愛滋病毒/愛滋病綜合計畫，或聯合國愛滋病規劃署。）
Feinberg 還提醒我們，「對 HIV 疫苗的追求比起任何其他科學企業教會了我們更多關於如何開發新一代疫苗。正因為如此，我們才能盡快開發出 COVID 疫苗，而且給了我們追求更有效流感疫苗的基礎。HIV疫苗研究提高了總體複雜程度。因此，任何說沒有取得進展的人都是錯誤的」。
蒂姆·墨菲 @TimMurphyNYC
居住在布魯克林的蒂姆·墨菲 (Tim Murphy) 已經為 HIV/AIDS 撰寫文章 25 年，其出版物和組織包括 TheBody、TheBodyPro、POZ、紐約雜誌、The Nation、Housing Works 和 Lambda Legal。
If These mRNA Vaccines Are So Great, Why Don’t We Have One for HIV Yet?
Tim Murphy CONTRIBUTING EDITOR Aug. 19, 2021
One thing I’ve heard a lot of in the past year or so from friends both IRL and on social media, is: “How could we get multiple COVID-19 vaccines in less than a year, while we’ve known about HIV for nearly 40 years and we still don’t have an HIV vaccine? The pharmaceuticals must be stopping it because they’re making too much money off the HIV drugs!”
To which I always want to reply, “Well, yes, it’s true, drugmakers do make a lot of money from HIV drugs”—about $30 billion in 2020 alone , in fact—“but that’s not the main reason we don’t have an HIV vaccine yet. Making an HIV vaccine is really hard!”
But then I always forget the details of exactly why it’s hard. But then I recently read about how drugmaker Moderna (which developed one of the COVID-19 vaccines) plans to take the mRNA technology they successfully applied to a vaccine for COVID and extend it to efforts at a vaccine for things like Zika, cancer, flu—and, yes, HIV. (In fact, they just announced that they’ll soon launch Phase I of an HIV trial.) So I decided to break down just why an HIV vaccine is so challenging.
I reached out to two terrific experts to do it—Richard Jefferys, the Basic Science, Vaccines, and Cure Project director at Treatment Action Group (TAG), and Mark Feinberg, M.D., Ph.D., president and CEO of the International AIDS Vaccine Initiative (IAVI), a nonprofit that develops vaccines and antibodies for HIV, tuberculosis, emerging infectious diseases, and neglected diseases.
First, though, let’s have a word about mRNA technology for vaccines—an idea that’s been around a few decades. The term mRNA stands for “messenger RNA,” meaning that, in such vaccines, a tiny piece of the offending virus’ genetic material, or blueprint, is used to generate a virus protein inside the body that is “shown” to the immune system so that it’ll know to spring into action against the real thing if it encounters it. This differs from older vaccine methods, such as the polio vaccine, which usually required “showing” the immune system a weakened or dead version of the actual virus.
In the case of COVID-19, mRNA delivers the immune system the genetic info for the broccoli-like “spike proteins” on the virus’ surface that latch onto human cells, especially in the lungs. That way, said Jefferys, “when the real virus shows up, the immune system has a specific memory.”
So Why Is That So Hard to Do With HIV?
First of all, said Jefferys, lack of interest and funding are no longer really among the reasons. “There was a period in the early 1990s when you could argue that HIV vaccine research was underfunded,” he said. “But by now, it’s a substantial budget.” According to an analysis by the Resource Tracking for HIV Prevention Research & Development Working Group, a project of the HIV vaccine advocacy group AVAC, nearly $15.3 billion was spent on HIV vaccine research between 2000 and 2019. The money comes from philanthropic, public, and private groups like the Bill & Melinda Gates Foundation.
And if that money hasn’t led yet to an effective vaccine, it has led to an enormous amount of information about both HIV and the immune system that led, in part, to the rapid development of COVID vaccines. HIV research helped reveal the importance of creating a vaccine using modified forms of invader’s outer “spike” proteins to generate immune responses.
HIV vaccine research also led to the perfection of mRNA as a vaccine method concept—used successfully for COVID, not so much for HIV.
Why the disparity? The short answer is that HIV is one of the wiliest, most slippery viruses known to modern science. And that answer breaks down into many factors.
The first is how quickly HIV mutates. There is much talk now about how well existing COVID vaccines will protect against the ever-new variants of COVID we are seeing, such as Delta and Lambda. But in fact, HIV mutates and creates new variants much, much faster than COVID, replicating so quickly that it is constantly making genetic “mistakes” and evolving as it moves from person to person. This has led to extreme difficulty in creating a vaccine that can make what are called broadly neutralizing antibodies (bNAbs), which would fight diverse strains of HIV—“more than 90% of circulating variants,” said Feinberg.
Another reason is HIV’s uniquely diabolical targeting of the very part of the body that usually fights off predators—the immune system. “HIV goes into CD4 [immune] cells and prevents them from sending the right signals to the B cells [another part of the immune system],” explained Jefferys. “HIV is always ahead of the game.” And yet another reason is that HIV’s surface spikes—unlike COVID’s, which are unobstructed and easily latched onto by immune cells—are oddly shaped and swathed in a cotton-candy–like coating called a glycan shield, which makes them extremely hard for immune cells to attach to. “It’s almost as if you dropped something under your couch and have to reach around for it without being able to see it,” said Jefferys. “That’s what [broadly neutralizing antibodies] have to do with HIV, reach into these nooks and crannies.”
Indeed, a wily virus! But if it’s so wily, why have we been able to create both effective HIV treatment and pharmaceutical prevention—PrEP (pre-exposure prophylaxis)—but not a vaccine? In the case of treatment, said Jefferys, it’s because those drugs are targeting HIV once it’s actually inside human cells, stopping it from doing the complex Xerox work it does to replicate in there and bust back out to infect more human cells. “And HIV’s internal components are less prone to mutation than the envelope on the outside of the virus,” which an effective vaccine would have to breach, he added.
As for PrEP, it effectively stops the HIV process called “reverse transcriptase”—converting its RNA into DNA—which the virus must do to really take hold in the body. “Once that happens,” said Jefferys, “you have a lifelong HIV factory in the body that is impossible to get rid of,” but PrEP stops that from happening.
So Where Are We Now? And Is It Worth It?
If an effective HIV vaccine is that hard to create, will we ever get there? “That’s a really tough question,” said Jefferys. “In science, there can always be surprises, good and bad. It’s possible that Janssen’s will have protective power.”
He’s referring to a vaccine from Janssen, a Johnson & Johnson subsidiary, that has recently been in a phase 3 (largest and final) trial among cisgender men who have sex with men and transgender people in Latin America, Europe, and the U.S., alongside a phase 2b trial among cisgender women at high risk for HIV in several African countries—and that was due to be analyzing results in July. It’s not an mRNA vaccine, but a so-called “vector” vaccine, which uses a modified version of a different virus (in this case, an adenovirus) to deliver important info to human cells on fighting off HIV. The vaccine isn’t able to induce broadly neutralizing antibody responses, but rather creates other kinds of immune responses that researchers think may have a chance of preventing HIV infection.
If the Janssen results are negative, Feinberg cautioned, that may be the last attempt to create a vaccine that sparks these types of immune responses. Future trials, he said, would only have the B-cell wing of the immune system left to concentrate on. But, cautioned Feinberg, “broadly neutralizing antibodies have to go through multiple steps of evolution to get to the structure that can bind to HIV,” meaning that creating such a vaccine will itself be a slow, multi-step process.
If These mRNA Vaccines Are So Great, Why Don’t We Have One for HIV Yet?
https://www.thebody.com/article/mrna-hiv-vaccine-development-challenges?utm_source=hiv+update-english&utm_medium=email&utm_campaign… 3/3 He added that his group, IAVI, is also working with biotech Moderna and Scripps Research on a vaccine that may have the potential to guide B cells toward producing broadly neutralizing antibodies.
For all the challenges, though, Feinberg pushes back on those who say that making an effective HIV vaccine is too challenging to be worth it, especially when we now have increasingly globally available prevention and treatment options that are evolving from a daily pill to a shot you get monthly—or perhaps soon just once or twice yearly.
“Even those advances would just be temporary measures,” said Feinberg. “You still need to get those things to everyone who needs them every year instead of just once. The only way we’re going to end the global AIDS pandemic is if we have a vaccine.” (For the record, 1.5 million people globally contracted HIV in 2020 alone, according to the Joint United Nations Programme on HIV/AIDS, or UNAIDS.)
Feinberg also reminds us, “The pursuit of an HIV vaccine has taught us more about how to develop new-generation vaccines than any other scientific enterprise. Only because of that did we develop COVID vaccines as quickly, and it’s given us the foundation to go after a more effective flu vaccine. HIV vaccine research has raised the level of sophistication overall. So anyone who says that progress has not been made is wrong.”
Tim Murphy
@TimMurphyNYC
Tim Murphy, based in Brooklyn, has been writing about HIV/AIDS for 25 years, for publications and organizations including TheBody, TheBodyPro, POZ, New York Magazine, The Nation, Housing Works, and Lambda Legal.