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Day after cutting-edge HIV vaccine trial scrapped: ‘It wasn’t a futile effort’

José Molto admits his frustration, but talks about HIV with some optimism. Just a week ago, Jansen announced that he was canceling Mosaic, the most advanced study of a human immunodeficiency virus vaccine in which there were high hopes for a cure that scientists have sought for four decades. “These are not the results we expected, but they allow us to move forward,” explains the attending physician and researcher at the Fundació Lluita contra les Infeccions and one of the coordinators of the study.

The last phase of Mosaico involved 3,800 volunteers from the United States, Europe and Latin America. In Spain, the Trias Hospital of the Germans and in Catalonia Vall d’Hebrón, Reina Sofía, Jimenez Diaz Foundation and San Carlos Clinic in Madrid and General Universitario de Valencia were involved. “It was not a futile effort. The research will allow us to gain a lot of very valuable information for the future,” Molto asserts throughout this interview. The participants don’t forget either. “You have to thank them for their commitment,” he says.

What does it mean to cancel a Mosaico rehearsal?

A bit of a shock and a bit of a disappointment, but it happens a lot in research. I read a lot of headlines these days that talk about research failure or error. I don’t explain it that way. These results, while not what we expected, also allow us to move forward. Now we need to study in depth what happened and why the vaccine did not work. This research will provide valuable information for the development of future vaccines.

How did they work in the hospital?

At our center, we had 50 participants in the study, and all but one were in active follow-up for a year and a half to two years. Only one dropped out early. This is something to be appreciated, they are healthy people who do this altruistically and their commitment was very high.

How was it determined that the vaccine did not provide protection?

Everything is very neat. Before starting the research, a monitoring plan is formed, which includes an external committee, which periodically reviews the data at a predetermined time. Here we discuss the safety data, which is very important to consider in this study, where there were no safety issues, and the efficacy data. Before that, it is already determined what data to review and when. Certain criteria are also established, and if they are not met, the study stops. This was done from time to time, but not publicly or for us. As these stopping criteria were not met, the study continued until the January 2023 review met these minimum criteria. The decision is to stop studying, but it is nothing improvised. Everything was formed for more than two years.

Were the volunteers exposed to the virus or were the samples tested in a laboratory?

No, we are talking about new infections here. There were volunteers in the placebo group and the vaccine group. This is a double-blind study where neither they nor the researchers know the treatment arm. It is this committee that examines the frequency of new cases of infection among participants in the two branches. When they were compared, it was observed that the incidence was the same and that the vaccine did not reduce the incidence. Therefore, it does not provide efficiency.

In September 2021, the Imbokodo study, another branch of the study in South Africa that involved mostly women but had many similarities to mosaic (men who have sex with men and trans people), was cancelled. How were they different?

The same thing happened with Imbokodo. It was a cold water can because there were a lot of similarities, but we also highlighted that there were differences. For example, the type of virus that circulates in South Africa and Europe, the United States and Latin America, where the mosaic was made. And there are differences in the front doors. You may have immunity in one mucosa, such as the rectum, but not in another, such as the vagina. They should not be interchangeable results. In addition, there was a component in the mosaic that was similar to toughening, a protein that covered more than 90% of strains worldwide. At that point, it made all the sense in the world to continue.

What happens the day after this type of study is cancelled?

The press release was issued at 13:00 and the phones started ringing at 14:00. This is what turns everything upside down. The sponsor shared the information with us 24 hours in advance, but only to the principal investigators and as part of the embargo policy. We couldn’t say anything until it became public, so there were people who had invested heavily for two years who suddenly heard from the media. We proactively contacted all participants in the center, providing them with the most basic information and, above all, a message of reassurance that there was no safety issue. Little by little, we’re calling them one by one this week with more personalized information. They’ve already unblinded and we know who got the vaccine and the placebo and we’re asking them what they want to do after the study is over, keep checking, use PREP…

Is it too early to know what they learned thanks to Mosaic?

I think soon. We need to learn why it was not effective and do a lot of analysis in general and specifically on the participants who are infected and how it can be improved for future vaccines. On a personal level, I learned to work with healthy volunteers, which was completely new to me, and to understand the needs of an HIV-free community.

It was the first vaccine to reach Phase III in a decade. Do you think we will have to wait another ten years to get back to this state?

You know we don’t like to pull out the crystal ball… I don’t know if it’s going to be a decade, probably not. I am optimistic, and there are other vaccines in development with a completely different strategy, such as Moderna’s, which uses an RNA platform. The first results in Phase I are pretty good, and if all goes well, I believe it will enter Phase III within ten years.

Why is it so hard to find an HIV vaccine?

It’s much more difficult if you compare it to other infections, like Covid-19, because they’re completely different viruses. If you look at SARS-CoV-2, the parts that the immune system recognizes are super exposed and change very little, so it’s relatively easy to make a vaccine that targets those proteins. In the case of HIV, imagine that these antigens are covered by a layer of blandiblue that covers all these parts and prevents the antibodies from binding together. In addition, they must be constantly changed because the South African virus is not the same as the one circulating in Europe. But even in Barcelona there are many different viruses circulating. It is very dynamic and it is one of the big barriers.

The hospital is also working on AELIX Therapeutics’ therapeutic HTI vaccine. What does this investigation involve and what is its status?

This is a different concept. We want to improve the immune response of people who already have the infection and see if this can help control the virus’s replication. As a rule, we treat a person with HIV with antiretroviral treatment and leave the virus frozen. Patients are asymptomatic and do not transmit the infection, but if they stop taking the medication, more than 90% of the time, the virus reappears within a few weeks and we are back to square one. Some patients can control the virus without medication. They are what we call “elite controllers”, but they make up about 1%. With this immunotherapy, what we’re trying to do is transform the normal response of the 99% so that it’s more like the 1% and, if they stop taking the medication, the virus doesn’t come back. This is a very promising area of ​​research for the coming years.

If a person living with HIV can maintain an undetectable viral load without medication, are we talking about a cure?

This is what we call functional healing. I may have a urinary tract infection, I take an antibiotic to kill the bacteria. It would be eradication, which in the case of HIV has only been achieved in four patients with bone marrow transplants because they had leukemia or lymphoma and very specific characteristics. We have long since abandoned this concept of a radical cure and are now looking at something more realistic, which can be a functional cure. The virus will still be there, but there will be factors that can control it. This already happens with other viruses, for example, chicken pox or herpes. Once we catch them, we know they’re there, we’re not going to eradicate them, but we can control them.

The Ministry of Health has included cabotegravir and rilpivirine injections for HIV treatment in its core portfolio of services. How do these drugs improve the lives of people living with HIV?

They make it better because they allow us to make treatment more individualized. I explain to my patients that they are no more effective than what we already have, which are close to 100% (and in the few cases that fail, it is because they are not taken properly), they are no safer, and they have no fewer side effects. events. What they bring is flexibility. There are patients for whom taking pills every day (conventional treatment) is a reminder that they have a health problem and in the long run it affects their quality of life. Or that they have to take their medication in secret because they live with their family or live in an apartment and don’t want it known because, make no mistake, there is still a stigma attached to HIV. This (six punctures per year, instead of one tablet per day) improves these aspects, but there are other patients who are unaffected by taking a pill a day, who do not have to carry it secretly, and who have good control of their periods. Twice a year in the hospital. Otherwise, they would have to come once in two months, and maybe it interferes more with their personal or work life.

Despite being an infection for which there are effective treatments that reduce mortality and currently provide a life expectancy similar to that of a seronegative person, AIDS will kill 650,000 people in 2021. What are the main difficulties in accessing medicines?

Mostly it happens in hard to reach parts of the world where we are lucky not to be. Where most of these deaths are concentrated in Africa, parts of Asia and Eastern Europe. On the one hand, we have what is most restrictive, which is pure access to medicine. I think the barriers are coming down because there are many international programs that facilitate access. Then there is the very important part of access to care, for example in Africa, where perhaps to access one of these programs, you have to go many kilometers into the city and it takes two days to travel. And above all, there’s the stigma that can come with being in one of these programs because it suggests your orientation or your sexual activity.

Source: El Diario





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