And meanwhile, HIV has been a global menace for decades, and there's no vaccine in sight, so what gives?

與此同時，幾十年來，艾滋病毒一直威脅著全球，而目前還沒有疫苗，這又是為什麼呢？

But the COVID-19 mRNA vaccines were a special case.

但 COVID-19 mRNA 疫苗是一個特例。

And it's a fact that stereotypes and discrimination held up funding for HIV research in the early days.

而事實是，陳規定型觀念和歧視在早期阻礙了艾滋病研究的資金投入。

But the honest truth is that lots of people really, really want to make a vaccine for HIV, and the pesky virus makes it really, really, really hard to do.

但老實說，很多人都非常非常想為艾滋病病毒製造疫苗，而討厭的病毒卻讓這一切變得非常、非常、非常困難。

Yet, researchers haven't given up.

然而，研究人員並沒有放棄。

And if anything, the success of COVID vaccines has only injected new hope into their search.

而 COVID 疫苗的成功也為他們的探索注入了新的希望。

By harnessing biology both in your body and in the lab, scientists have all sorts of tricks to try in the search for a vaccine against HIV.

通過利用人體和實驗室中的生物特性，科學家們在尋找艾滋病毒疫苗的過程中可以嘗試各種方法。

[♪ INTRO ♪

[INTRO

Getting diagnosed with HIV used to be a death sentence.

過去，被診斷出感染艾滋病毒就等於被判了死刑。

But it isn't anymore.

但現在不是了。

People with HIV can now live long, full lives, thanks to highly effective treatments in the form of antiretroviral therapy.

由於抗逆轉錄病毒療法的高效治療，艾滋病病毒感染者現在可以活得長久、充實。

We even have reliable prevention in the form of pre-exposure prophylaxis, or PrEP for short.

我們甚至還有可靠的預防措施，即接觸前預防，簡稱 PrEP。

But it's not recommended for everyone, only those at high risk.

但並不建議每個人都這樣做，只建議高危人群這樣做。

But what would be really sweet is if we had a nice little one-and-done jab in the arm for absolutely everybody, so we can put a stop to the over a million new HIV diagnoses worldwide every year.

但是，如果我們能為所有人提供一種一次性的手臂注射，那才是真正的好事，這樣我們就能阻止全世界每年新增超過一百萬的艾滋病毒診斷病例。

But developing an HIV vaccine has not been easy.

但是，研製艾滋病疫苗並非易事。

There have been many clinical trials representing various attempts, with the earliest trial starting all the way back in 1987.

有許多臨床試驗代表了不同的嘗試，最早的試驗始於 1987 年。

But so far, none have shown enough success to be given the FDA stamp of approval.

但到目前為止，還沒有一種藥物取得足夠的成功，從而獲得美國食品及藥物管理局的準許。

It turns out, the biological nature of HIV makes it especially challenging to vaccinate against.

事實證明，艾滋病病毒的生物特性使其疫苗接種尤其具有挑戰性。

In general, when a pathogen enters your body, or when a vaccine introduces a version of it, your immune system makes antibodies to fight it off.

一般來說，當病原體進入人體或疫苗引入病原體時，人體免疫系統會產生抗體來抵禦病原體。

But with HIV, that immune response just doesn't really happen.

但對於艾滋病病毒，這種免疫反應並沒有真正發生。

When HIV enters your body, it disguises itself in a trench coat of sugar molecules, shielding its proteins from being detected by your immune system.

艾滋病病毒進入人體後，會將自己偽裝在糖分子的外衣中，以防止免疫系統檢測到它的蛋白質。

This allows it to slip past your natural defenses without triggering the alarm.

這樣，它就能穿過你的天然防禦系統，而不會觸發警報。

Then, HIV turns the tables and dismantles the cells of your immune system that were supposed to defend against it.

然後，艾滋病病毒會反其道而行之，摧毀你免疫系統中本應抵禦艾滋病病毒的細胞。

And as a second layer of disguise, many of the HIV proteins mimic human immune cell proteins, meaning a vaccine targeting those viral proteins might direct your own immune system at your own cells by mistake.

作為第二層偽裝，許多艾滋病病毒蛋白質都會模擬人類免疫細胞的蛋白質，這意味著針對這些病毒蛋白質的疫苗可能會誤導你自己的免疫系統攻擊你自己的細胞。

As if all of that wasn't challenging enough, HIV is also a notorious shapeshifter.

如果這一切還不夠具有挑戰性，那麼艾滋病毒還是一個臭名昭著的變形者。

It mutates quickly, even within the same person, which means that any antibodies that you might have created against one version may no longer work after a few mutations.

它的變異速度很快，即使在同一個人體內也是如此，這就意味著你針對一種變異產生的抗體在經過幾次變異後可能就不再起作用了。

That is, almost any antibodies.

也就是說，幾乎所有的抗體。

Since the early 2000s, much of the focus for an HIV vaccine has been on a class of antibodies called broadly neutralizing antibodies, or BNABs for short.

自 21 世紀初以來，HIV 疫苗的研究重點主要集中在一類被稱為廣譜中和抗體（簡稱 BNAB）的抗體上。

The B-cells of your immune system are the ones in charge of making all of your antibodies, with each B-cell specializing in one specific antibody.

免疫系統中的 B 細胞負責製造所有抗體，每個 B 細胞專門製造一種特定的抗體。

But new B-cells are pretty much randomly mixing and matching antibody genes.

但新的 B 細胞幾乎是隨機混合和匹配抗體基因。

Your immune system's not waiting around for a pathogen to show up and design it a perfectly custom antibody.

你的免疫系統不會坐等病原體出現，併為它設計出完美的定製抗體。

There is a method to this madness.

這種瘋狂是有方法的。

Randomly generating as many different B-cells as possible maximizes the chance of at least one of those guys getting a match that's close enough to grab onto the pathogen.

隨機生成儘可能多的不同 B 細胞，可以最大限度地提高其中至少有一個人獲得足夠接近的匹配以抓住病原體的機會。

And once a B-cell matches with a pathogen, it will begin spitting out a bunch of antibodies.

一旦 B 細胞與病原體相匹配，它就會開始吐出大量抗體。

Since the initial fit might not have been perfect, those antibodies will get mutated further to try and improve the match.

由於最初的匹配可能並不完美，這些抗體會進一步變異，以嘗試改善匹配。

Even then, those changes are still random.

即便如此，這些變化仍然是隨機的。

So your B-cells make a lot of duds in order to find the antibodies that are actually better.

是以，你的 B 細胞會製造大量啞彈，以便找到真正更好的抗體。

So HIV B-NABs happen when your immune system hits the jackpot and manages to make antibodies against a less variable part of the virus, so they can bypass its shape-shifting and work against more versions of HIV.

是以，當你的免疫系統中了頭獎，成功製造出針對病毒中變化較少部分的抗體時，就會出現 HIV B-NAB，這樣它們就能繞過病毒的變形，對更多版本的 HIV 起作用。

And B-NABs are produced naturally in 10 to 25% of people living with HIV, but they aren't perfect.

10%到25%的艾滋病病毒感染者體內會自然產生B-NAB，但它們並不完美。

Even if you do have them, there aren't usually enough B-NABs in your body to neutralize all of the virus on their own.

即使您體內有，通常也沒有足夠的 B-NAB 來中和所有病毒。

There may be a good reason why we don't usually have too many of them at the ready.

我們通常不會準備太多，這可能是有原因的。

B-NABs are known to show some auto-reactivity, meaning that they may be primed to target some of your body's own cells.

眾所周知，B-NABs 具有一定的自身反應性，這意味著它們可能會以人體自身的某些細胞為目標。

In general, that's seen as a bad thing for antibodies, because you don't want your immune system to attack you.

一般來說，這對抗體來說是件壞事，因為你不希望你的免疫系統攻擊你。

So your body has checks in place to destroy auto-reactive B-cells before they can fully develop.

是以，在自身反應性 B 細胞完全發育之前，您的身體就已經有了消滅它們的檢查機制。

But some of the B-NABs that are the best at neutralizing HIV also tend to have more auto-reactivity.

但是，一些中和艾滋病毒能力最強的 B-NAB 也往往具有更強的自身反應性。

In fact, some research suggests that the development of anti-HIV powers comes at the inherent cost of picking up some auto-reactive mutations.

事實上，一些研究表明，開發抗艾滋病毒能力的固有代價是獲得一些自身反應突變。

And this creates a bit of a catch-22.

這就產生了一個問題。

The better the B-NABs, the more auto-reactivity.

B-NAB 越好，自動反應能力就越強。

But that means that any B-NAB-producing B-cells you have might get nuked by your body before they ever mature.

但這意味著，你體內任何產生 B-NAB 的 B 細胞都可能在成熟之前就被身體 "核彈 "消滅。

And that includes B-cells developing in response to a vaccine.

這包括對疫苗產生反應的 B 細胞。

This has made it really difficult for vaccines to drum up enough B-NAB activity to tackle HIV.

這使得疫苗很難獲得足夠的 B-NAB 活動來應對艾滋病毒。

Some researchers have found some success in stimulating the natural precursors that create B-NABs, rather than trying to get to the B-NABs directly.

一些研究人員在刺激產生 B-NAB 的天然前體方面取得了一些成功，而不是試圖直接獲取 B-NAB。

Scientists wanted to see if they could get a vaccine to switch on the specific B-cells that go on to make B-NABs against HIV.

科學家們想知道，他們是否能研製出一種疫苗，開啟特定的 B 細胞，使其產生 B-NAB 來抵禦艾滋病毒。

A Phase 1 clinical trial published in 2022 provided a proof-of-concept that stimulating more B-NAB precursors with a vaccine might be feasible in humans.

2022 年公佈的一項一期臨床試驗提供了一個概念證明，即用疫苗刺激更多的 B-NAB 前體在人體中是可行的。

This study only looked at people not living with HIV, but the vaccine did successfully stimulate a type of B-cell that makes B-NABs.

這項研究只調查了非艾滋病毒感染者，但疫苗確實成功刺激了一種製造 B-NAB 的 B 細胞。

However, there are some challenges to overcome before we can develop this strategy further.

然而，在進一步發展這一戰略之前，我們還需要克服一些挑戰。

Basically, the strategy wasn't specific enough to turn on only the kinds of B-cells that make B-NABs.

從根本上說，這種策略不夠具體，無法只開啟製造 B-NAB 的 B 細胞。

It might also switch on other B-cells willy-nilly.

它還可能隨意開啟其他 B 細胞。

But while scientists tinker away at optimizing B-NAB technology, there's another angle that people are looking at for an HIV vaccine.

不過，在科學家們努力優化 B-NAB 技術的同時，人們也在從另一個角度研究艾滋病疫苗。

The COVID-19 pandemic granted fame and glory to the mRNA vaccine.

COVID-19 大流行為 mRNA 疫苗帶來了聲譽和榮耀。

And it's inspired high hopes that we might be able to use that same technology and apply it to different diseases, including HIV.

這也激發了我們的殷切希望，我們或許可以利用同樣的技術，將其應用於不同的疾病，包括艾滋病。

mRNA refers to the little pieces of genetic information that tells your cells how to make a protein.

mRNA 指的是告訴細胞如何製造蛋白質的少量遺傳信息。

Unlike traditional vaccines that deliver viral proteins directly to your body, mRNA vaccines deliver the instructions to make viral proteins.

傳統疫苗將病毒蛋白直接輸送到您的體內，而 mRNA 疫苗則不同，它將病毒蛋白的製造指令輸送到您的體內。

Once the mRNA gets in, it marches right into your cell's protein-making factories, and the viral protein gets translated along with all the others.

一旦 mRNA 進入，它就會直接進入細胞的蛋白質製造工廠，病毒蛋白質就會和其他蛋白質一起被翻譯出來。

Then, once the viral protein is made, it can be presented to your immune system to trigger antibody production.

然後，一旦病毒蛋白被製造出來，它就可以呈現給免疫系統，從而觸發抗體的產生。

Since your body is much better at making proteins naturally than we can in a lab, this is a great tool to leverage against the diverse and complicated proteins of HIV.

由於人體自然製造蛋白質的能力比我們在實驗室中製造蛋白質的能力要強得多，是以這是一種很好的工具，可以用來對付種類繁多、結構複雜的艾滋病病毒蛋白質。

It's also much faster, safer, and more cost-effective than traditional vaccine types.

與傳統疫苗類型相比，它還更快、更安全、更經濟。

Part of the reason why mRNA vaccines were such a breakthrough for HIV is that our traditional vaccine options really are not options.

mRNA 疫苗之所以能在艾滋病防治方面取得突破性進展，部分原因在於我們的傳統疫苗確實沒有選擇餘地。

Vaccines with a weakened form of the virus have a tiny chance of accidentally causing the disease.

含有弱化病毒的疫苗有極小的機率意外導致疾病。

And since HIV is a chronic disease that has no cure yet, even that tiny chance is considered way too unsafe.

由於艾滋病毒是一種慢性疾病，目前還無法治癒，即使是這種微小的機會也被認為是太不安全了。

And vaccines that packed a completely killed version of HIV didn't generate enough of an immune response to work.

而含有完全被殺死的艾滋病毒的疫苗並不能產生足夠的免疫反應。

So enter mRNA vaccines.

是以，mRNA 疫苗應運而生。

Since they don't contain any actual virus, there's no way to accidentally cause the disease.

由於它們不含任何真正的病毒，是以不會意外致病。

And since mRNA molecules are easy to pack, you can put the instructions for a bunch of different proteins all into one vaccine way more easily than you can with traditional approaches.

由於 mRNA 分子易於包裝，是以與傳統方法相比，您可以更容易地將多種不同蛋白質的指令全部放入一種疫苗中。

And this is important because targeting just one HIV protein doesn't produce a strong enough immune response.

這一點非常重要，因為只針對一種 HIV 蛋白並不能產生足夠強的免疫反應。

So, once again, mRNA vaccines are awesome for producing a robust immune response against all the various proteins that are on the surface of HIV.

是以，mRNA 疫苗能再次產生強大的免疫反應，抵禦 HIV 表面的各種蛋白質。

In theory. In practice, it's again proving trickier.

理論上是這樣。在實踐中，它又被證明更加棘手。

A group of researchers across North America conducted an initial test of an HIV mRNA vaccine in rhesus macaques and mice.

北美的一組研究人員在獼猴和小鼠身上對艾滋病毒 mRNA 疫苗進行了初步測試。

They found that packaging the mRNA for two different proteins into one dose got a significantly better immune response than either of the proteins alone.

他們發現，將兩種不同蛋白質的 mRNA 包裝成一個劑量所產生的免疫反應明顯優於單獨使用其中一種蛋白質所產生的免疫反應。

This vaccine was able to induce BNAB production in the rhesus macaques, and the monkeys successfully made new immune cells in response to HIV exposure.

這種疫苗能夠誘導獼猴產生 BNAB，而且獼猴成功地製造出了新的免疫細胞來應對艾滋病病毒暴露。

Unfortunately, this doesn't mean it's ready to go into human arms just yet.

遺憾的是，這並不意味著它可以投入人類的懷抱。

While the vaccine did get an immune response, the level of response wasn't high enough to count as fully protective.

雖然疫苗確實產生了免疫反應，但反應水準還不夠高，不足以算作完全保護。

Plus, this protocol included more than seven injections in total, which is just way too many to be practical.

此外，該方案總共包括七次以上的注射，注射次數太多，不切實際。

And even though HIV mRNA vaccines have shown promise in animal models, they seem to lose momentum when translating to human participants.

儘管 HIV mRNA 疫苗在動物模型中表現出了良好的前景，但在轉化為人類參與者時似乎失去了動力。

In 2022, three clinical trials were launched to test an mRNA vaccine to protect against HIV.

2022 年，啟動了三項臨床試驗，以測試預防艾滋病毒的 mRNA 疫苗。

And while the results of these Phase 1 trials are not yet published, as of writing this episode, there have been some initial concerns over some participants experiencing itchiness and hives after receiving the vaccine.

雖然這些第一階段試驗的結果尚未公佈，但在撰寫本期節目時，一些參與者在接種疫苗後出現瘙癢和蕁麻疹的情況已經引起了初步關注。

So there's a bit of a slowdown while the researchers try to figure out what's up.

是以，在研究人員試圖找出問題所在的過程中，工作進展有些緩慢。

Even though itchiness may not be the worst side effect that could possibly happen,

儘管瘙癢可能不是最糟糕的副作用、

Phase 1 trials are all about establishing safety.

第一階段試驗的目的是確定安全性。

The researchers want to make sure that they understand as much as they can about why these skin effects are happening before moving on.

研究人員希望在繼續研究之前，儘可能多地瞭解這些皮膚效應發生的原因。

So far, all of these vaccines that we've discussed have been preventative.

到目前為止，我們討論過的所有疫苗都是預防性的。

But what about people who are already living with HIV?

但是，已經感染艾滋病毒的人怎麼辦？

Well, therapeutic vaccines are also in the works, with the goal of stimulating antibodies after having already acquired HIV.

此外，治療性疫苗也在研發之中，目的是在感染艾滋病毒後激發抗體。

The hope is that the body can retroactively develop the immune cells to destroy any of the virus that's hanging around.

我們希望人體能夠追溯性地發育出免疫細胞，以消滅殘留的病毒。

While none of the tested therapeutic vaccines have worked perfectly yet, there's been a few promising findings.

雖然經過測試的治療性疫苗都還沒有達到完美的效果，但已經有了一些很有希望的發現。

One research group in Europe tested out a therapeutic vaccine on 45 participants with HIV, in a double-blind, placebo-controlled study.

歐洲的一個研究小組在一項雙盲安慰劑對照研究中，對 45 名艾滋病毒感染者進行了治療性疫苗測試。

After vaccinating the participants, they put it to the ultimate test by having the participants stop taking their HIV medication for up to six months, and see how well their bodies could keep the HIV at bay.

給參與者接種疫苗後，他們讓參與者停止服用艾滋病藥物長達 6 個月，以此進行終極測試，看看他們的身體能在多大程度上控制住艾滋病病毒。

And unfortunately, it didn't seem to work.

遺憾的是，這似乎並不奏效。

Well, let's not be too pessimistic. It didn't work well enough. Yet.

我們不要太悲觀。效果還不夠好。還沒有

None of the participants were able to keep their HIV levels down after pausing their medication.

在暫停服藥後，沒有一個參與者能夠將艾滋病毒水準控制在較低水平。

But the vaccine was able to get some immune cell activity going, and it didn't cause any major negative effects.

但疫苗能夠讓一些免疫細胞活躍起來，而且不會造成任何重大的負面影響。

So the researchers think it's still worth tinkering with this vaccine to see if they can boost that response to be more effective.

是以，研究人員認為仍值得對這種疫苗進行修補，看看能否增強這種反應，使其更加有效。

The journey to finding a vaccine for HIV has been long.

尋找艾滋病疫苗的過程是漫長的。

The sneaky virus has a lot of tricks up its tiny little sleeves to try to stay one step ahead of our immune systems.

鬼鬼祟祟的病毒有很多小把戲，試圖領先我們的免疫系統一步。

But scientists aren't closing the gap every day.

但科學家們並不是每天都在縮小差距。

With our ever-improving knowledge on BNABs, we're working on a solution that can handle all of the strains of HIV.

隨著我們對 BNAB 的瞭解不斷加深，我們正在開發一種能夠處理所有艾滋病毒菌株的解決方案。

And the promising track record of mRNA vaccines provides an exciting alternative to traditional technology.

而 mRNA 疫苗的良好記錄為傳統技術提供了令人興奮的替代方案。

So we're tackling this disease from multiple angles.

是以，我們正在從多個角度應對這一疾病。

And with more testing and a few more hurdles to overcome, we might soon be able to prevent and treat the transmission of HIV for everyone.

只要進行更多的檢測，再克服一些障礙，我們也許很快就能為所有人預防和治療艾滋病毒的傳播。

[♪ OUTRO ♪)]

[♪ OUTRO ♪)]