Smallpox has been eradicated from the face of the Earth following a highly successful global vaccination campaign. Paralytic polio is no longer a problem in the United States due to the development and use of effective poliovirus vaccines. Currently, millions of lives have been saved thanks to the rapid deployment of effective COVID-19 vaccines. And yet it has been 37 years since HIV was discovered to be the cause of AIDS, and there is no vaccine.
Here I will describe the challenges in developing an effective vaccine against HIV / AIDS.
I am a pathology professor at the Miller School of Medicine at the University of Miami. My lab is credited with the discovery of the monkey virus called SIV or simian immunodeficiency virus. SIV is the monkey closely related to the virus that causes AIDS in humans – HIV or the human immunodeficiency virus. My research has contributed significantly to understanding the mechanisms by which HIV causes disease and to vaccine development efforts.
HIV vaccine development efforts have failed
Vaccines are arguably society’s most powerful weapon against medically important viral diseases. When the new disease, AIDS first appeared in the early 1980s and virus that caused it was discovered in 1983-84, it was natural to think that the research community would be able to develop a vaccine against it.
At a now famous 1984 press conference announcing HIV as the cause of AIDS, then US Secretary of Health and Human Services Margaret Heckler predicted that a vaccine would be available in two years. Well, it’s now 37 years later and there’s no vaccine. The speed of development and distribution of the COVID-19 vaccine puts the lack of an HIV vaccine in stark contrast. The problem is not government failure. The problem is not the lack of spending. The difficulty lies in the HIV virus itself. In particular, this includes the remarkable diversity of HIV strains and the virus’ immune evasion strategies.
So far there has been large-scale efficacy of five phase 3 vaccines HIV trials, each costing over $ 100 million. The first three failed convincingly enough; no protection against acquiring HIV infection, no decrease in viral load in those who have been infected. In fact, in the third of these trials, the STEP trial, there was a statistically significant higher frequency of infection in people who had been vaccinated.
The fourth trial, the controversial Thai test RV144, initially reported a marginal degree of effective protection against acquisition of HIV infection in those vaccinated. However, subsequent statistical analysis found that there was less than a 78% chance that the acquisition protection was real.
A fifth vaccine trial, the HVTN 702 trial, was ordered to confirm and extend the results of the RV144 trial. the HVTN702 test was aborted early because of futility. No acquisition protection. No lowering of the viral load. Ouch.
The complexity of HIV
What is the problem? The biological properties of HIV have made the development of an effective vaccine very, very difficult. What are these properties?
First and foremost is the continued and relentless replication of the virus. Once HIV sets foot in the door, it is “gotcha”. Many vaccines do not absolutely protect against acquiring infection, but they are able to severely limit the replication of the virus and any illness that could result from it. For a vaccine to be effective against HIV, it will likely need to provide an absolute sterilizing barrier and not just limit viral replication.
HIV has developed the ability to generate and tolerate many mutations in its genetic information. The consequence is a huge variation between strains of the virus not only from one individual to another but even within a single individual. Let’s use the flu for a comparison. Everyone knows that people need to be revaccinated against the flu virus every season because of the seasonal variability in the flu strain that circulates. Well, the variability of HIV in a single infected individual exceeds all global variability in influenza virus sequences for a whole season.
What are we going to put in a vaccine to cover this extent of strain variability?
HIV has also developed an incredible ability to protect itself from recognition by antibodies. Enveloped viruses such as coronaviruses and herpes viruses encode a structure on their surface that each virus uses to enter a cell. This structure is called a “glycoproteinWhich means that it is made up of both sugars and protein. But the HIV envelope glycoprotein is extreme. It is the sweetest protein of all the viruses in the 22 families. More than half of the weight is sugar. And the virus has found a way, which means the virus evolved by natural selection, to use these sugars as shields to protect itself from recognition by the antibodies that the infected host is trying to make. The host cell adds these sugars and then considers them to be themselves.
These properties have important consequences relevant to vaccine development efforts. Antibodies produced by a person infected with HIV usually have very little neutralizing activity against the virus. In addition, these antibodies are very specific for the strain; they will neutralize the strain with which the individual is infected but not the thousands and thousands of other strains circulating in the population. Researchers know how to get antibodies that will neutralize a strain, but not antibodies that can protect against the thousands and thousands of strains circulating in the population. This is a major problem for vaccine development efforts.
HIV evolves continuously in a single infected individual to stay one step ahead of immune responses. The host triggers a special immune response that attacks the virus. This exerts a selective pressure on the virus and, thanks to natural selection, a mutated viral variant appears which is no longer recognized by the individual’s immune system. The result is continuous and relentless viral replication.
So should we researchers give up? No, we shouldn’t. One approach that researchers are trying in animal models in a few labs is to use herpes virus as vectors to deliver the proteins of the AIDS virus. The herpes virus family is in the “persistent” category. Once infected with a herpes virus, you are infected for life. And immune responses persist not only in memory, but in a continually active way. The success of this approach, however, will always depend on determining how to achieve the magnitude of immune responses that will cover the vast complexity of HIV sequences circulating in the population.
Another approach is to look for protective immunity from a different angle. Although the vast majority of people infected with HIV produce antibodies with low strain-specific neutralizing activity, some rare individuals produce antibody with strong neutralizing activity against a wide range of HIV isolates. These antibodies are rare and very unusual, but we scientists have them.
In addition, scientists recently found a way to achieve protective levels of these antibodies for life from a single administration. For life! This delivery depends on a viral vector, a vector called adeno-associated virus. When the vector is delivered to the muscle, the muscle cells become factories that continuously produce the powerful, largely neutralizing antibodies. Researchers recently documented continuous production for six and a half years in a monkey.