Media headlines often suggest that HIV vaccines and cures are imminent. Not so fast!

Even aside from the news that broke in mid-February that a third-ever person had been potentially cured of HIV thanks to a stem-cell transplant, you’ve perhaps seen headlines like this in your social or news feeds:

Scientists Begin HIV Vaccine Trial That Uses Breakthrough mRNA Technology from Moderna’s COVID Jab

Excision Starts CRISPR Gene-Editing Trial for HIV Patients

Merck’s Cancer Blockbuster Keytruda Might Treat HIV Too

In all three cases, you might be led to believe that an HIV vaccine or cure for all was just around the bend, given how variations on the three headlines (which are all real, by the way—see our “Sources” section below) have proliferated recently.

Let’s be clear: all three do represent exciting and legitimate new lines of exploration into possible HIV vaccines and cures—two things that have eluded researchers for decades, because HIV is a wily virus that resists being apprehended and hides out in the body even though much of it is suppressed by HIV meds. (Each of these stories involve an approach to eliminating HIV that’s very different from the one that put the New York patient into HIV remission.)

But now let’s be really clear: These new lines of inquiry are so much further away from prime time than headlines in mainstream news outlets make them seem. (The same thing goes for a recent announcement from the U.S. National Institutes of Health that they had launched their own first-phase study of three mRNA HIV vaccines.)

I checked in with longtime HIV cure research expert Richard Jeffreys at the New York City-based think tank and advocacy organization Treatment Action Group to break some of these headlines down one by one—and separate the hype from the reality. We’ll say this: these efforts may be embryonic, but they are pretty fascinating.

Moderna’s HIV Vaccine Trial

Tim Murphy: Hi Richard! Thank you so much for being our scientific explainer-in-chief once again. Before we break down the three items in question here, what would be your topline thought about them?

Richard Jefferys: They definitely generate excitement. This is valuable science and it’s welcome to see it moving forward.

Problems arise in terms of people misunderstanding the significance of the launch of these studies. And the worst example is the Moderna HIV vaccine Phase 1 trial, which has been misinterpreted on social media as signaling that an HIV vaccine is imminent.

Murphy: Right, OK. So let’s start with that. Many headlines have reported that Moderna and the nonprofit IAVI have launched Phase 1 trials for an HIV vaccine using the same mRNA technology that Moderna—and other companies—successfully used for COVID vaccines. What’s the full story here?

Jefferys: It’s a Phase 1 study. It’s exploratory—about whether this mRNA technology [which teaches our cells how to make a protein that will trigger an immune response inside our bodies] can prepare the immune system to generate an antibody response in the future, when additional vaccines are designed. They’re testing whether this approach can expand the number of B cells in the body that might in turn produce antibodies capable of fighting HIV.

Murphy: Many HIV vaccine studies that went all the way into Phase 3 have failed over the years. What is different about this approach?

Jefferys: The No. 1 thing to know is that what is being tested in this trial will never be evaluated for efficacy—it’s not anticipated to induce an immune response against HIV. Again, it’s taking advantage of mRNA technology to study whether delivering certain proteins in the body can create a larger group of B cells that can make antibodies capable of blocking HIV. Usually, a vaccine is sending in an actual pathogen, like a dead virus or a piece of that virus, to try to improve the ability of the immune system to respond to the real thing. So this mRNA experiment is trying to address the fact that most people don’t have enough of the antibodies that block HIV effectively in the first place.

Murphy: Ah, I see; so it’s trying to spark the step before a traditional vaccine comes into the picture. What is the likelihood it will succeed?

Jefferys: They’ve once done a trial protein on its own like this, but didn’t use mRNA to deliver it. It was a small study, but by the end, almost everyone could detect more of these B cells, which was encouraging. Now, with the mRNA approach, they have an additional protein, so they can take another step toward creating more B cells. mRNA tech is ideal because it’s like plug-and-play—it’s quite straightforward to plug in the genetic code for different types of proteins.

Murphy: So, assuming the mRNA approach can make more B cells, how certain are we that’ll block HIV?

Jefferys: B cells are like trainees the experiment hopes to educate to make good antibodies, or what’s called broadly neutralizing antibodies, or bNAbs. We know that bNAbs exist in some rare people that can generate antibodies, but we don’t know whether it’s possible to reproduce that with vaccination. They have an idea that it’s possible from looking at how the genetic code in the B cells changes over time.

But it’ll take time to know if this works. The study has 56 participants and estimates completion by April 2023, but they may be able to see results sooner—like the end of this year.

Excision’s HIV CRISPR Gene-Editing Study

Murphy: OK, very cool, thanks. Now on to Big Headline No. 2, which is that Excision’s gene-editing CRISPR technology is heading into trials in folks with HIV to see if, basically, it can lead to a cure.

Jefferys: Right: This is the first human study of what’s called CRISPR gene editing, which is a very attractive idea in theory. It’s to use this technology derived from bacteria to identify the HIV genetic code in infected human cells and snip them out—like a genetic surgery.

Murphy: You’re talking about the cells in the body where so-called “latent” HIV—the stuff that HIV meds can’t get to—hides out? Getting that stuff would deplete the hidden HIV reservoir in the body and pave the way for eradication, or cure, yes?

Jefferys: They’re using a technology called adeno-associated virus vector. What is the reach of this vector in terms of detecting hidden HIV? They have some data from macaques [monkeys] suggesting that the snipping technology does get distributed well in the body. But a big concern is whether it could have off-target effects, which might be damaging to the cell or carry a risk of cancer.

Murphy: Wow—might that not be too much risk for the study subjects?

Jefferys: The initial study is limited to nine men. The FDA [U.S. Food and Drug Administration], in approving this, had concerns that there wasn’t enough information about reproductive toxicity in women. But because they saw no off-target effects in the macaques, they showed the FDA that this was an acceptable risk. And in other diseases, studies have shown that CRISPR editing has worked.

The estimated end date of the trial is December 2024, but we may have results before then, and if they’re good, they’ll expand the trial.

Murphy: What are the end goals?

Jefferys: To see whether they can measure a decline in the body’s HIV reservoir, and then hence if the study participants are eligible to do an HIV treatment interruption. They’ll look at a large number of blood samples, but also will probably sample tissue from the lymph nodes.

Murphy: Won’t it be difficult to find HIV given that people in the study are currently on HIV meds and presumably undetectable?

Jefferys: You can usually detect the reservoir still—it’s looking for the HIV DNA instead of the RNA, which is what a typical viral load test looks for. And these folks will be followed up for 15 years to make sure their genetic code hasn’t been messed with.

Overall, this is a very appealing approach—you just find the HIV and snip it out rather than finding some way of “shocking” or “flushing” it out of hiding before killing it. It’s just about making sure it’s safe. Because the approach is derived from bacteria, people might make an immune response with adverse effects.

Can a Cancer Drug “Flush” HIV Out of Reservoirs in the Body?

Murphy: OK, great. And finally, we have the much-reported finding that the very successful cancer drug Keytruda may be able to flush out the very hidden HIV we were just talking about.

Jefferys: Yes, this is based on using Keytruda in people with HIV who had cancer, and they were looking at the HIV reservoir in them post-Keytruda secondarily. Keytruda inhibits the PD-1 protein, and because HIV reservoir cells often express this particular protein, there was evidence that the drug was waking up the virus and reactivating the latent HIV reservoir. In other words, doing the “shock” or “flush” part of the shock/flush-and-kill theory of curing HIV.

The big issue here is that we don’t know how much of the HIV reservoir the drug targeted—it could be only 1%. And we don’t know if such drugs can be safely used in people who don’t have cancers, because of side effects. There’ve been two studies so far in people with HIV without cancer, and in both there was evidence of immune toxicities like hyperthyroidism. But studies at the NIH and in Australia are looking at low-dose or single-dose versions of this approach with this drug.

Murphy: Wow, OK; some deep science on all three counts. What’s the current take-away for the average reader, living with HIV or not?

Jefferys: It doesn’t matter what the headlines say today—you have to keep an eye out for these results over the next year or two. That’s the only way to know if something comes of this. We can’t say for sure they’ll represent progress, but there’s good reason to hope they might.

And the other take-away is that we should take a moment to appreciate the folks with HIV who are making themselves available for these studies.

Murphy: Indeed, that’s very cool of them—and I’d like to do the same at some date in the near future. Richard, thank you so much for breaking things down with us!

By Tim Murphy