The Sure Shot: Challenging HIV Vaccinology

Dr. Ignacio Relano-Rodriguez on contributing to a first-in-class HIV vaccine that induces neutralizing responses in fewer injections and features a completely new type of antibody

Dr. Relano-Rodriguez, postdoctoral fellow in the lab of Dr. Amelia Escolano, set off to create an HIV vaccine by removing a single sugar on an HIV protein—in the canon of HIV research, this sugar was seen as fundamental to effectively targeting HIV. This resulted in a scientific breakthrough: inducing a new class of HIV-fighting antibodies that neutralize the virus after just two injections instead of many. This discovery may help make an HIV vaccine available to people worldwide. Dr. Relano-Rodriguez on going against the grain of popular scientific thought.

HIV has been around for decades — why don’t we have a vaccine yet, and what makes designing one so hard?
Ignacio Relano-Rodriguez: HIV is a very difficult virus for two reasons. First, it mutates at very high rates—much more frequently than viruses like the flu. This means there are hundreds of different versions of it and inducing an immune response that can recognize and block all these versions, or strains, is extremely challenging.

Second, the part of the virus we use for designing vaccines is covered by a lot of sugar molecules, and these sugars act like a shield hiding the virus from the immune system.

So not only does the virus change constantly, but it also hides from the immune system, and this combination makes HIV one of the hardest vaccine targets.

What is a broadly neutralizing antibody? Why is it the holy grail for HIV vaccines?
IR-R: A broadly neutralizing antibody is a rare, potent antibody that targets the unchanging parts of the virus allowing them to neutralize many different HIV strains. We know these antibodies can develop naturally after many years in some people living with HIV. One thing that makes them important is given directly in passive immunization (a person is given antibodies to help fight infection), broadly neutralizing antibodies can protect against HIV infection. The goal of any efficacious HIV vaccine is to teach the immune system how to produce these antibodies before being exposed to the virus.

There’s a specific part of the HIV virus called the “V3-glycan epitope” that your vaccine targets. Can you describe what that is in simple terms — and why it’s such an attractive target?
IR-R: The HIV envelope protein (spike protein of HIV) has regions where, even though the virus mutates a lot, remain very similar across many strains. One region is the V3-glycan epitope—conserved among many different strains. Many people living with HIV develop broadly neutralizing antibodies targeting the V3-glycan epitope, thus this region seems to be an easier target for our immune system.

Another advantage of the V3-glycan epitope is that the antibodies that target it are diverse. We want a response that the immune system knows how to make in different ways and that’s why we think targeting the V3-glycan epitope gives us a better chance of success in a diverse global population.

Your new immunogen is called WIN332. What does it do differently from what came before, and what was the key insight that led you to design it this way?IR-R: WIN332 is an envelope-based immunogen and it is named for Wistar Institute 332. The “332” stands for removing a sugar at position 332. For years, the field believed this sugar was essential for activating protective antibodies against the V3-glycan epitope. So, it was dogma that immunogens needed to have this sugar. However, we obtained evidence that there are some antibodies that do not need this sugar for binding to the envelope protein. In our latest Nature Immunology paper, we show that removing the N332 sugar results in much better responses. This challenges a long-standing assumption in the field.

Very recently, another research group found potent, broadly neutralizing antibodies that target the V3-glycan epitope also do not need this N332 sugar, confirming that the immune system can develop these antibodies. This other group published in Nature Immunology at the same time as we did as our stories are complementary. We designed an immunogen to elicit one type of antibody, and they show these antibodies exist in humans.

Your paper talks about removing a sugar molecule called the N332-glycan from the immunogen. That sounds counterintuitive — why would removing something from the virus help train the immune system better?
IR-R: These sugars act like camouflage and hide the viral components from the immune system. By removing this sugar, we are exposing the important viral target that is underneath the sugar, and that makes it easier for the immune system to recognize and respond to it.

Other groups have taken a similar approach removing glycans to induce antibody responses to different epitopes, however, those immunogens elicited a response in which the antibodies could not block the HIV virus. What is remarkable and very exciting about our study is that the antibodies we generate can block HIV when the sugar is there or is not there.

We have established a new category of antibody. V3-glycan antibodies can be divided into “canonical” Type I antibodies that need the N332 sugar, and non-canonical Type II antibodies that do not need the sugar and are elicited by our new WIN332 immunogen. One interesting thing about WIN332 is even though it does not have this specific sugar, it is able to activate both types of antibodies.

You mention that existing vaccine protocols require many shots over a long period of time and still don’t work very well. What’s going wrong with those approaches?
IR-R: The field of HIV vaccinology has been trying to develop new approaches for several years, and some approaches require seven, 10, or even more shots over a very long period, because they are mimicking how this infection occurs in people living with HIV. Getting 10 or even seven shots for a vaccine to be effective is not practical for real world use.

During the COVID pandemic, it was difficult for the public to reliably get two vaccinations. So, we need to improve the approach, and we have learned a lot over the years.

With the very first immunization of our new immunogen WIN332, we showed the first shot can be made much more effectively compared to all the others. And if we can make this first step stronger, we may be able to reduce the total number of shots needed to move closer to something that is realistic for global use.

What’s next for you?
IR-R: We are trying to move WIN332 to clinical trials and I am developing new projects with the goal of becoming an independent PI and start my own lab.

Tell us a bit about you outside of science.
IR-R: I love to dance salsa and Bachata. I love to spend time in nature with my wife and daughter.