美國國家衛生院在HIV 疫苗上的失敗:「讓你的HIV 陰性且

 

美國國家衛生院在HIV 疫苗上的失敗:「讓你的HIV 陰性且具高風險病人明天起即接受暴露前預防性投藥 PrEP   

Heather Boerner - 2021 9 2 日, Medscape 

 

去年,當輝瑞 (Pfizer) COVID-19 疫苗有效性為 95% 時,南非開普敦的 HIV 預防研究員凱瑟琳·吉爾 (Katherine Gill) 意識到,她對疫苗研究變得有多麼厭倦。在她從事 HIV 臨床試驗的職業生涯中,她從未見過這樣的情形,即使她所研究過有效的 HIV 預防方法,如含達匹韋林的陰道內環( dapivirine ring ),也只有30%成效。

COVID-19 的成功故事開始軟化她對其正在協助進行的另一項疫苗試驗的看法,這是一項 HIV 疫苗試驗,該試驗使用與強生公司成功的 COVID 19 疫苗相同的平台。

「當 COVID 疫苗如此迅速破解且看似很容易時,我確實開始想,「好吧,也許……也許這對 HIV 有效“」,她告訴 Medscape Medical News

結果證明這是錯誤的希望。本週,美國國家衛生研究院 (NIH) 宣布 Gill 正在協助進行的試驗 HVTN 705 提前停止,因為它沒有讓參與者產生足夠的免疫反應來證明它的繼續是合理的。這是去年第二個失敗的 HIV 疫苗。這也是最近期在試圖發展促進人類免疫系統以免除持續治療來對抗 HIV的一連串失望中的一次。

HVTN 705 中,被稱為 Imbokodo 研究(imbokodo 是祖魯語,是關於女性堅強如磐石的一種說法),研究人員使用了由普通感冒的腺病毒26所組成的平台,向參與者的免疫系統提供由電腦鑲嵌生成的 HIV 抗原。這種抗原鑲嵌體的目的是讓免疫系統在暴露於HIV的情況時識別它。

HIV 進入人體時,它會滲入免疫細胞並在其中進行複製。對於免疫系統的其餘部分,這些細胞仍然只是典型的 T 細胞。免疫系統的其他部分看不到病毒正在通過旨在保護身體免受疾病侵害的細胞進行傳播。再加上包裹病毒的含糖糖蛋白的盔甲,使愛滋病毒幾乎不受疫苗接種的影響。

然後,在所謂的「主要」注射之後是針對糖蛋白 140 的第二次注射,是針對非洲最常見的 HIV 亞型(或進化支)進化支 C。在 Imbokodo 試驗中,共有 2,637 名女性來自五個撒哈拉以南非洲國家,在基準線、3 個月、6 個月和 1 年時接受了注射。然後研究人員在第三次注射後的第 7 個月到兩年內追踪這些女性,測試她們的血液看看他們的免疫系統是否已經產生了疫苗所誘導的免疫反應——以及這種免疫反應是否與較低的 HIV 感染率有關。

當研究人員查看前兩年的數據時,他們了解到該疫苗是安全的。他們總共發現了 114 例新的 HIV 感染病例——其中 51 例在接種疫苗的女性中,63 例在接種安慰劑的女性中。那是 25.2% 的有效率——但在統計上並不顯著。

美國國家過敏和傳染病研究所 (NIAID) 愛滋病科科長 Carl Dieffenbach 博士說,結果令人沮喪。 NIAID 是該研究的資助者之一。

「這個[試驗] 有點令人困惑,因為疫苗和安慰劑之間的統計學差異很小,從第 9 個月左右開始,然後在接下來的 15 個月內一直保持著這種低水平」,他告訴 Medscape醫學新聞。 「這有點令人沮喪。這是否意味著是一種跡象,或者這只是機率關係?因為那正是統計學告訴我們的,不要相信你的最後一個數據點」。

這對疫苗研究的未來方向意味著什麼尚不清楚。 Imbokodo 的姊妹研究 Mosaico 於本週完成了參與者的招募。 Mosaico 使用相同的腺病毒 26 平台,但它裝載了不同的抗原,針對不同的 HIV 亞型針對不同的糖蛋白。如果該試驗顯示成功,則可能意味著該平台是正確的,但 Imbokodo 疫苗中的目標是錯誤的。

迪芬巴赫說,在 NIAID 決定如何處理 Mosaico 之前,他們已經要求研究人員分析有反應者的數據,看看這些人是否感染某種特定的 HIV 病毒株或一些其他生物標記,可用於形成複製下一次HIV 候選疫苗。只有在那之後,他們才會對 Mosaico 做出決定。

但他補充說,這確實讓他想知道,像這種依賴非中和抗體之疫苗方法其有效性上限是否太低,無法改變流行病的進程。

「我認為我們已經發現 [這些非中和方法] 沒有底線,但可能有一個上限」,他說。 25% 29% 的有效性的那些方法,「我不知道我們是否會變得更好」。

Imbokodo 的調查結果,提醒了全球愛滋病預防非營利組織 AVAC 的執行董事米切爾沃倫 (Mitchell Warren) 想起了 1 月份發布的抗體介導預防 (AMP) 之試驗數據。那次試驗將對抗HIV的廣泛中和抗體 (bNAb) VCR01進行了對比——而且在大多數情況下,它失敗了。

VCR01 僅對 30% 的參與者所擁有的 HIV 病毒株起作用。但在這些 30% 的人當中,它在預防愛滋病毒方面的有效性為 75%。現在你有了 Imbokodo,它對抗 HIV 的潛在活性為 25%,這也可能僅是僥倖。對沃倫來說,這需要重新思考整個 HIV 疫苗事業,當我們對已知有效的 HIV 預防方法(例如暴露前預防,PrEP)有二倍、三倍、四倍下降時。

迪芬巴赫同意了。對於臨床醫生而言,迪芬巴赫​​說,這項 HIV 疫苗試驗散發的信息非常緊迫:「明天起讓您的 HIV 陰性具高危人群接受 PrEP吧」。

現在有兩種藥丸被批准用於預防愛滋病毒,均已發現在持續服用時有高達 99% 的有效性。第三種選擇,注射型 cabotegravir (Vocabria),已提交給美國食品與藥物管理局評估是否批准。聯邦政府已備妥並設定 PrEP 計劃向符合條件的人免費提供藥物,最近拜登政府重申,根據《平價醫療法案》規定,保險公司應承擔與 PrEP 相關的所有費用,包括檢驗回診和實驗室工作。

但對於遠在南非西南端 Masiphumelele Gill的實驗現場參加試驗的 157 名婦女來說,試驗是有關個人的,Desmond 的社區聯絡官 Jason Naidoo 說道。Tutu HIV 基金會,該基金會進行了部分的研究。他說,這些女性的父母、兄弟姐妹或孩子都感染了愛滋病毒,或者死於愛滋病定義的疾病。他們的生活是亂紛紛的,在接到通知片刻立即啟程前往東開普省的家鄉,車程 11 小時——搭乘公共汽車則更久——去參加傳統的祈禱、葬禮和其他重要活動。Naidoo 記得為婦女安排巴士返回預定的門診回診,於下午離開東開普省,在清晨到達 Masiphumelele,只是為了維持預約的回診。然後,他們會掉頭向東返回。

Naidoo 說,他們這樣做了 3 年。他說:「事實上,這些參與者堅持這一點,並在所有混亂中堅持獻身於他們對實際擁有愛滋病毒疫苗的承諾」。「身為南非的年輕黑人女性他們知道自己的風險狀況,她們理解為子孫後代進行預防介入的必要性」。”

「所以你可以理解那種情緒和悲傷、失望——難以置信的[]相信這種[疫苗的失敗]可能會發生,因為期望是如此的高」。

對於在 Masiphumelele 擔任 Imbokodo 首席研究員的 Gill 來說,對疫苗的厭倦又回來了。另一項針對 HIV 疫苗的試驗也在進行中,該試驗使用另一個在 COVID-19 中取得成功的平台——使用信使 RNA (mRNA),就像輝瑞 (Pfizer) Moderna COVID-19 疫苗所做的那樣。

「認為 mRNA 疫苗會破解它」,「我認為我們需要小心」,她說。

該研究由強生公司( Janssen )與美國國家過敏和傳染病研究所 ( NIAID ) 和比爾和梅琳達·蓋茨基金會共同資助,DieffenbachGill Naidoo揭露與其沒有財務上的關聯。

Heather Boerner 是匹茲堡的一名科學記者。她的書《正向地維持陰性:愛、懷孕和科學在對抗愛滋病毒的驚人勝利》於 2014 年出版。

 

 

NIH on HIV Vaccine Failure: ‘Get Your HIV-Negative, At-Risk Patients on PrEP Tomorrow’

Heather Boerner September 02, 2021

Last year, Katherine Gill, MBChB, an HIV prevention researcher in Cape Town, South Africa, realized how jaded she'd become to vaccine research when the Pfizer COVID-19 vaccine came back as 95% effective. In her career conducting HIV clinical trials, she'd never seen anything like it. Even HIV prevention methods she had studied that had worked, like the dapivirine ring, only had an overall efficacy of 30%.

The COVID-19 success story started to soften her views toward another vaccine trial she was helping to conduct, a vaccine trial in HIV that used the same platform as Johnson & Johnson's successful COVID19 vaccine.

"When the COVID vaccine was cracked so quickly and seemingly quite easily, I did start to think, 'Well, maybe…maybe this will work for HIV,' " she told Medscape Medical News.

That turned out to be false hope. This week, the National Institutes of Health (NIH) announced that the trial Gill was helping to conduct, HVTN 705, was stopping early because it hadn't generated enough of an immune response in participants to justify continuing. It was the second HIV vaccine to fail in the last year. It's also the latest in what has been a litany of disappointments in the attempt to boost the human immune system to fight HIV without the need for ongoing HIV treatment.

In HVTN 705, known as the Imbokodo study (imbokodo is a Zulu word that's part of a saying about women being strong as rocks), researchers used the platform made up of a common cold virus, adenovirus 26, to deliver a computer-generated mosaic of HIV antigens to participants' immune systems. That mosaic of antigens is meant to goose the immune system into recognizing HIV if it were exposed to it.

When HIV enters the body, it infiltrates immune cells and replicates within them. To the rest of the immune system, those cells still register as just typical T-cells. The rest of the immune system can't see that the virus is spreading through the very cells meant to protect the body from illness. That, plus the armor of sugary glycoproteins encasing the virus, has made HIV nearly impervious to vaccination.

Then, those so-called "prime" shots were followed by a second shot that targets glycoprotein 140, on the most common HIV subtype (or clade) in Africa, clade C. In the Imbokodo trial, a total of 2637 women from five sub-Saharan African countries received shots at baseline, 3 months, 6 months and 1 year. Then researchers followed the women from month 7 to two years after their third dose, testing their blood to see if their immune systems had generated the immune response the vaccine was meant to induce — and whether such immune response was associated with lower rates of HIV.

When researchers looked at the first 2 years of data, they learned that the vaccine was safe. And they found a total of 114 new cases of HIV — 51 among women who received the vaccine and 63 among those who received a placebo. That's a 25.2% efficacy rate — but it wasn't statistically significant.

The results are frustrating, said Carl Dieffenbach, PhD, director of the Division of AIDS at the National Institute of Allergy and Infectious Diseases (NIAID). NIAID is one of the funders of the study.

"This [trial] is a little more confounding, in that there is this low level of statistically insignificant difference between vaccine and placebo that starts somewhere around month 9 and then just kind of indolently is maintained over the next 15 months," he told Medscape Medical News. "That's kind of frustrating. Does it mean there's a signal or is this just chance? Because that's what statistics tell us, not to believe your last data point.

" What this means for the future direction of vaccine research is unclear. A sister study to Imbokodo, called Mosaico, finished enrolling participants this week. Mosaico uses the same adenovirus 26 platform, but it's loaded with different antigens and targets a different glycoprotein for a different HIV subtype. If that trial shows success, it could mean that the platform is right, but the targets in the Imbokodo vaccine were wrong.

Dieffenbach said that before NIAID decides what to do with Mosaico they've asked researchers to analyze the data on the people who did respond, to see if those people have some specific variant of HIV or some other biomarker that could be used to form the next iteration of an HIV vaccine candidate. Only after that will they make a decision about Mosaico.

But he added that it does make him wonder if vaccine approaches that rely on non-neutralizing antibodies like this one have a ceiling of effectiveness that's just too low to alter the course of the epidemic.

"I think we've discovered that there's not a floor to [these non-neutralizing approaches], but there probably is a ceiling," he said. "I don't know if we're going to get better than" a 25% to 29% efficacy rate with those approaches.

The Imbokodo findings reminded Mitchell Warren, executive director of the global HIV prevention nonprofit, AVAC, of the data released in January from the Antibody Mediated Prevention (AMP) trial. That trial pitted the broadly neutralizing antibody (bNAb) VCR01 against HIV — and mostly, it lost.

VCR01 only worked on HIV variants that 30% of participants had. But in those 30%, it was 75% effective at preventing HIV. Now you have Imbokodo, with its potential 25% activity against HIV, something that may have been a fluke. This, to Warren, requires a rethinking of the whole HIV vaccine enterprise while "doubling, tripling, quadrupling down" on the HIV prevention methods we know work, like pre-exposure prophylaxis (PrEP).

Dieffenbach agreed. To clinicians, Dieffenbach said the message of this HIV vaccine trial is flush with urgency: "Get your HIV-negative, at-risk people on PrEP tomorrow.

" There are now two pills approved for HIV prevention, both of which have been found to be up to 99% effective when taken consistently. A third option, injectable cabotegravir (Vocabria), has been submitted to the US Food and Drug Administration for approval. The federal Ready, Set, PrEP program makes the pill available for free for those who qualify, and recently the Biden administration reaffirmed that, under the Affordable Care Act, insurance companies should cover all costs associated with PrEP, including lab work and exam visits.

But for the 157 women who participated in the trial at Gill's site in Masiphumelele, on the southwestern tip of South Africa, the trial was personal, said Jason Naidoo, community liaison officer at the Desmond Tutu HIV Foundation, which conducted a portion of the study. These were women whose parents, siblings, or children were living with HIV or had died from AIDS-defining illnesses, he said. Their lives were chaotic, traveling at a moment's notice to hometowns on the Eastern Cape, an 11-hour car ride away — longer by bus — for traditional prayers, funerals, and other important events.

Naidoo remembers arranging buses for the women to return for scheduled clinic visits, leaving the Eastern Cape in the afternoon and arriving in Masiphumelele in the early morning hours, just to keep the clinic appointment. Then, they'd turn around and return east.

They did this for 3 years, Naidoo said.

"The fact that these participants have stuck to this and been dedicated amidst all of the chaos talks about their commitment to actually having a vaccine for HIV," he said. "They know their own risk profile as young Black women in South Africa, and they understand the need for an intervention for the future generations." "So you can understand the emotion and the sense of sadness, the disappointment —the incredible [dis]belief that this [the failure of the vaccine] could have happened, because the expectations are so, so high.

" For Gill, who is lead investigator for Imbokodo in Masiphumelele, the weariness toward vaccines is back. Another trial is also underway for an HIV vaccine with another platform that was successful in COVID19 — using messenger RNA (mRNA), like the Pfizer and Moderna COVID-19 vaccines did.

"I think we need to be careful," she said, "thinking that the mRNA vaccines are going to crack it.

" Dieffenbach, Gill, and Naidoo have disclosed no relevant financial relationships. The study was funded by Janssen, a Johnson & Johnson company, with NIAID and the Bill and Melinda Gates Foundation.

Heather Boerner is a science journalist based in Pittsburgh. Her book, Positively Negative: Love, Pregnancy, and Science's Surprising Victory Over HIV, came out in 2014.

Medscape - Sep 02, 2021.