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

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

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

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.

Yet, researchers haven't given up.

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

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.

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Getting diagnosed with HIV used to be a death sentence.

But it isn't anymore.

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

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

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

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.

But developing an HIV vaccine has not been easy.

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

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

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

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.

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

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.

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

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

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.

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

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.

That is, almost any antibodies.

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.

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.

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

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

There is a method to this madness.

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.

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

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

Even then, those changes are still random.

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

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.

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

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.

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

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

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

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

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

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

And this creates a bit of a catch-22.

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

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

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

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

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.

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.

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.

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.

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

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

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

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

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

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

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

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

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.

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

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.

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

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

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

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

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

So enter mRNA vaccines.

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

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.

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

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.

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

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

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.

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.

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

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

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

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

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

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.

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

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

Phase 1 trials are all about establishing safety.

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

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

But what about people who are already living with HIV?

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

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

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

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

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.

And unfortunately, it didn't seem to work.

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

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

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

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

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

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

But scientists aren't closing the gap every day.

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

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

So we're tackling this disease from multiple angles.

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.

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