When we give a talk about the AIDS vaccine, the most frequent question is: how has it been possible to manufacture a vaccine against COVID-19 in less than a year and that after four decades we still do not have one for HIV? In addition to feeling a little awkward, we try to explain that the two viruses cannot be compared. That HIV represents a completely new challenge in the field of vaccines.
First of all, let’s make clear what a vaccine is: we are talking about a biological simulation in which we confront our immune system with a false attack by a microbe. Thanks to this simulation, our system is activated and stores in its memory the germ with which we have vaccinated. When we later face the actual infection, the already trained system rememberrecognizes and eliminates the microbe.
The AIDS vaccine: a succession of failures
In the case of vaccines that have been developed against AIDS, we can distinguish three stages.
Initially, prototypes similar to those of classical vaccines against other viruses such as polio and hepatitis B were used. These immunizations induce antibodies, biological missiles that block viruses before they enter our cells. Given its failure, in a second stage we sought to induce responses called cellular, the infantry It destroys infected cells. Also these prototypes failed.
We can say that HIV has left the history of vaccines strewn with corpses with names of clinical trials. Recently suspended due to its lack of efficacy, the Janssen company’s Mosaic study was the last. There are no further phase III trials planned.
Why have we failed?
The biggest limitation to getting the vaccine is that our immune system is not prepared to deal with HIV. It is easy to understand with an example. What happens when we get infected with covid? If we are not among the 1% of deceased, 99% of those affected will be cured because our immune system eliminates the virus in a few days. In contrast, out of 100 people infected with HIV, none is capable of eliminating the virus. In the absence of treatment, 99 of those 100 will die of AIDS.
We are therefore facing a new challenge: teaching the immune system to do something that it does not know how to do naturally. It’s not enough wake up the response as traditional vaccines do, because that reaction doesn’t work. One has to instruct the immune system to do something new that works.
What makes HIV so resistant to the immune response?
Evolution has provided HIV with an envelope, or devilish envelope. Coat proteins are found on the surface of viruses and allow them to infect cells by binding to cell receptors. A vaccine is effective only if it induces antibodies that block these proteins, preventing the entry of the virus. They are called neutralizing antibodies. The HIV envelope evades these antibodies by four mechanisms.
- It forms an inaccessible closed structure. Imagine that the antibodies are directed at the fingers of one hand. The envelope of SARS-CoV-2 is an open hand whose fingers are easy to reach, while that of HIV is a clenched fist that only opens when it touches the cell membrane. Too late for the antibodies to reach their target.
- Like the shield of the star wars ships, HIV covers its coating with sugars that block the arrival of antibodies to its surface. It’s like a lollipop that protects the chocolate core inside.
- In the outer areas, accessible to antibodies, the highly variable envelope protein mutates and escapes attack.
- Added to these limitations is the fact that our immune system is slow against HIV. It takes two years to generate potent antibodies, and in that time the virus generates resistant variants. In the race between the antibodies and the envelope, HIV runs much faster.
The real-life difficulties of testing vaccines
Added to the technical difficulty of obtaining a vaccine prototype with the possibility of success is the difficulty of investigating the efficacy of these prototypes in clinical practice. This is basically due to three reasons:
- The attack rate (new infections) is low, which is why cohorts of thousands of patients are required, which must be followed up for years to find significant differences between the vaccinated group and the placebo.
- Vaccines should be evaluated in populations with a higher possibility of infection, such as those in sub-Saharan Africa, places with fragile health structures.
- From an ethical point of view, participants must be offered and reminded that they have to use protection measures, condoms… This reduces the number of infections and makes it more difficult to obtain differences between groups.
Is there any good news or should we just give up?
Although it may seem hard to believe, there is good news. First of all, despite its secrecy, we have found small cracks in the HIV envelope for a vaccine. Some very special antibodies, which we call “broadly neutralizing,” can reach those Achilles heels from the virus and block it.
Although very rare, these antibodies exist and are produced by some patients. Since we know the precise area of the HIV envelope they are aimed at, we can modify it and tune it up to generate vaccines that induce these antibodies.
The ultimate challenge is producing those antibodies quickly. This can be done by sequential immunization with different variants of the envelope protein. Through this strategy we accelerate the maturation of the antibodies produced by the immune system.
Mission Impossible?
We need vaccines capable of activating the few cells that produce those exceptional antibodies capable of crossing the barriers of the virus and reaching its Achilles heels. Powerful antibodies, capable of neutralizing hundreds of variants and that must be produced in weeks instead of taking years to generate. They are completely new vaccines against a new problem, of high technological design. The SARS-CoV-2 vaccine is a walk compared to HIV, a summit of enormous difficulty.
In 2020, 1.5 million people became infected with HIV and 680,000 died of AIDS. The virus is there, and it continues to kill. Developing a vaccine is the only way to kill it. As difficult as it is, we have to keep trying. in his book The Art of War, Yun-Tzu says: “If you know your enemy and you know yourself, you should not fear the result of a thousand battles. If you don’t know either the enemy or yourself, you will lose every battle.”
Now, thanks to our failures, we know our weaknesses and the enemy’s strengths. Perhaps for the first time we have a chance to win with the new generations of designer vaccines that we are working on.