Smallpox has been eradicated from the face of the Earth following a highly effective, worldwide vaccination campaign. Paralytic poliomyelitis is not any longer an issue within the U.S. due to development and use of effective vaccines against the poliovirus. In current times, hundreds of thousands of lives have been saved due to rapid deployment of effective vaccines against COVID-19. And yet, it has been 37 years since HIV was discovered because the reason for AIDS, and there is no such thing as a vaccine. Here I’ll describe the difficulties facing development of an efficient vaccine against HIV/AIDS.

I’m a professor of pathology on the University of Miami Miller School of Medicine. My laboratory is credited with the invention of the monkey virus called SIV, or simian immunodeficiency virus. SIV is the close monkey relative of the virus that causes AIDS in humans – HIV, or human immunodeficiency virus. My research has contributed importantly to the understanding of the mechanisms by which HIV causes disease and to vaccine development efforts.

Dr. Anthony Fauci discusses the problem of finding a vaccine for HIV/AIDS in 2017.

HIV vaccine development efforts have come up short

Vaccines have unquestionably been society’s most potent weapon against viral diseases of medical importance. When the brand new disease AIDS burst onto the scene within the early Eighties and the virus that caused it was discovered in 1983-84, it was only natural to think that the research community would have the opportunity to develop a vaccine for it.

At a now famous press conference in 1984 announcing HIV because the reason for AIDS, then U.S. Secretary of Health and Human Services Margaret Heckler predicted that a vaccine could be available in two years. Well, it’s now 37 years later and there is no such thing as a vaccine. The rapidity of COVID-19 vaccine development and distribution puts the shortage of an HIV vaccine in stark contrast. The problem just isn’t failure of presidency. The problem just isn’t lack of spending. The difficulty lies within the HIV virus itself. In particular, this includes the remarkable HIV strain diversity and the immune evasion strategies of the virus.

So far there have been five large-scale Phase 3 vaccine efficacy trials against HIV, each at a price of over US$100 million. The first three of those failed quite convincingly; no protection against acquisition of HIV infection, no lowering of viral loads in those that did develop into infected. In fact, within the third of those trials, the STEP trial, there was a statistically significant higher frequency of infection in individuals who had been vaccinated.

The fourth trial, the controversial Thai RV144 trial, initially reported a marginal degree of successful protection against the acquisition of HIV infection amongst vaccinated individuals. However, a subsequent statistical evaluation reported that there was lower than a 78% probability that the protection against acquisition was real.

A fifth vaccine trial, the HVTN 702 trial, was ordered to substantiate and extend the outcomes of the RV144 trial. The HVTN702 trial was halted early due to futility. No protection against acquisition. No lowering of viral load. Ouch.

The complexity of HIV

What is the issue? The biological properties that HIV has evolved make development of a successful vaccine very, very difficult. What are those properties?

First and foremost is the continual unrelenting virus replication. Once HIV gets its foot within the door, it’s “gotcha.” Many vaccines don’t protect absolutely against the acquisition of an infection, but they’re able to severely limit the replication of the virus and any illness that may result. For a vaccine to be effective against HIV, it should likely need to supply an absolute sterilizing barrier and not only limit viral replication.

HIV has evolved a capability to generate and to tolerate many mutations in its genetic information. The consequence of that is an unlimited amount of variation amongst strains of the virus not only from one individual to a different but even inside a single individual. Let’s use influenza for a comparison. Everyone knows that folks must get revaccinated against influenza virus each season due to season-to-season variability within the influenza strain that’s circulating. Well, the variability of HIV inside a single infected individual exceeds the whole worldwide sequence variability within the influenza virus during a complete season.

What are we going to place right into a vaccine to cover this extent of strain variability?

HIV has also evolved an incredible ability to shield itself from recognition by antibodies. Enveloped viruses corresponding to coronaviruses and herpes viruses encode a structure on their surface that every virus uses to realize entry right into a cell. This structure is known as a “glycoprotein,” meaning that it consists of each sugars and protein. But the HIV envelope glycoprotein is extreme. It is essentially the most heavily sugared protein of all viruses in all 22 families. More than half the burden is sugar. And the virus has found out a way, meaning the virus has evolved by natural selection, to make use of these sugars as shields to guard itself from recognition by antibodies that the infected host is attempting to make. The host cell adds these sugars after which views them as self.

These properties have essential consequences relevant for vaccine development efforts. The antibodies that an HIV-infected person makes typically have only very weak neutralizing activity against the virus. Furthermore, these antibodies are very strain-specific; they may neutralize the strain with which the person is infected but not the hundreds and hundreds of other strains circulating within the population. Researchers know methods to elicit antibodies that may neutralize one strain, but not antibodies with a capability to guard against the hundreds and hundreds of strains circulating within the population. That’s a significant problem for vaccine development efforts.

HIV is continually evolving inside a single infected individual to remain one step ahead of the immune responses. The host elicits a specific immune response that attacks the virus. This puts selective pressure on the virus, and thru natural selection a mutated virus variant appears that is not any longer recognized by the person’s immune system. The result’s continuous unrelenting viral replication.

So, should we researchers surrender? No, we shouldn’t. One approach researchers are attempting in animal models in a few laboratories is to make use of herpes viruses as vectors to deliver the AIDS virus proteins. The herpes virus family is of the “persistent” category. Once infected with a herpes virus, you might be infected for all times. And immune responses persist not only as memory but in a continually energetic fashion. Success of this approach, nonetheless, will still rely on determining methods to elicit the breadth of immune responses that may allow coverage against the vast complexity of HIV sequences circulating within the population.

Another approach is to go after protective immunity from a unique angle. Although the overwhelming majority of HIV-infected individuals make antibodies with weak, strain-specific neutralizing activity, some rare individuals do make antibodies with potent neutralizing activity against a broad range of HIV isolates. These antibodies are rare and highly unusual, but we scientists do have them in our possession.

Also, scientists have recently found out a strategy to achieve protective levels of those antibodies for all times from a single administration. For life! This delivery is dependent upon a viral vector, a vector called adeno-associated virus. When the vector is run to muscle, muscle cells develop into factories that constantly produce the potent broadly neutralizing antibodies. Researchers have recently documented continuous production for six and a half years in a monkey.

We are making progress. We must not surrender.

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