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Why there is no vaccine against Human Immunodeficiency Virus (HIV)?

Why there is no vaccine against Human Immunodeficiency Virus (HIV)?


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I was informed by my teacher that this retrovirus changes its RNA, so there is not a drug which can recognize the RNA and somehow inactivates it. Are there any other reasons explaining why there isn't a vaccine for the HIV?


One of the reasons we don't have an HIV vaccine yet is we've only been trying to make one for a little over 30 years. It can take a long time to develop a vaccine. Beyond that, there are a number of specific challenges.

One of them is that, yes as your teacher said, the virus is highly variable. Specifically, the parts of the viral proteins involved in binding and infecting a host cell are highly variable. There are a number of other challenges. One important and related challenge is that, unlike with many vaccine preventable diseases (e.g., measles), an successful HIV vaccine will have to entirely prevent infection rather than just control and clear infection without developing disease. Once a reservoir of infected cells is established, the opportunity for clearance is gone. This makes the production and maintenance of high titers of neutralizing antibodies that much more important.

There is a very good review of the challenges and current directions of HIV vaccine development here


World AIDS Vaccine Day 2021: Here's Why We Don’t Have an HIV Vaccine

World AIDS Vaccine Day is celebrated internationally on May 18. A day dedicated to emphasize the ongoing urgent requirement of an HIV vaccine and also acknowledge the insurmountable work done by healthcare professionals, researchers on HIV, all across the globe, World AIDS Vaccine Day is an extremely significant event.

Attempting towards spreading awareness on HIV, AIDS, educating individuals on the preventive measures, causes, the day is also known as HIV Vaccine Awareness Day.

It has been a long time since the world was inflicted with this life-threatening HIV (Human Immunodeficiency Virus). Only a proper vaccine can limit the spread of the disease and help us eliminate it from the root.

Having said that, sadly there has been no vaccine produced yet to counter this epidemic.

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As a matter of fact it is not an easy job to develop a vaccine to battle the disease that has taken away so many lives in all these years.

Wondering why? On this World AIDS Vaccine Day, let’s find out why we don’t have an HIV vaccine:

In 1984 HIV was first identified. Although at that time the U.S. Department of Health and Human Services declared that there will be a vaccine in 2 years, several clinical trials of potential vaccines proved futile.

The following reasons have been deduced after encountering the setbacks of failed vaccine administration:


HIV invasion of immune cells

HIV infects T cells via high-affinity interaction between the virion envelope glycoprotein (gp120) and the CD4 molecule. The infection of T cells is assisted by the T-cell co-receptor called CXCR4 while HIV infects monocytes by interacting with CCR5 co-receptor (Figure 1). As illustrated in Figure 2, after gp120 binds to CD4 on the T cell (1). Nucleocapsids containing viral genome and enzymes enters the target cell (2). Following the release of viral genome and enzymes from the core protein, viral reverse transcriptase catalyses reverse transcription of ssRNA to form RNA-DNA hybrids (3). To yield HIV dsDNA the viral RNA template is partially degraded by ribonuclease H and the second DNA strand is synthesized (4). The viral dsDNA is translocated into the nucleus and integrated into the host genome by the viral integrase enzyme (5). Transcription factors transcribe the proviral DNA into genomic ssRNA (6), which is exported to cytoplasm (7). In the cytoplasm, host-cell ribosomes catalyse synthesis of viral precursor proteins (8). The viral precursor proteins are cleaved into viral proteins by viral proteases (9). HIV ssRNA and proteins assemble beneath the host-cell plasma membrane (10) forming virion buds from it (11). Maturation occurs either in the forming buds or after budding from the host cell (12). During maturation, HIV proteases cleave the poly-proteins into individual functional HIV proteins. The mature virions are able to infect another host cell.

Figure 1. Interaction between HIV and coreceptors of a T cell and a monocyte

Figure 2. Overview of HIV infection of a target cell (e.g. T cell)

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(THE CONVERSATION) Smallpox has been eradicated from the face of the Earth following a highly effective, worldwide vaccination campaign. Paralytic poliomyelitis is no longer a problem in the U.S. because of development and use of effective vaccines against the poliovirus.

In current times, millions of lives have been saved because of rapid deployment of effective vaccines against COVID-19. And yet, it has been 37 years since HIV was discovered as the cause of AIDS, and there is no vaccine. Here I will describe the difficulties facing development of an effective vaccine against HIV/AIDS.

I am a professor of pathology at the University of Miami Miller School of Medicine. My laboratory is credited with the discovery 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.

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 new disease AIDS burst onto the scene in the early 1980s and the virus that caused it was discovered in 1983-84, it was only natural to think that the research community would be able to develop a vaccine for it.

At a now famous press conference in 1984 announcing HIV as the cause of AIDS, then U.S. Secretary of Health and Human Services Margaret Heckler predicted that a vaccine would be available in two years. Well, it is now 37 years later and there is no vaccine. The rapidity of COVID-19 vaccine development and distribution puts the lack of an HIV vaccine in stark contrast. The problem is not failure of government. The problem is not lack of spending. The difficulty lies in 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 cost of over US$100 million. The first three of these failed quite convincingly no protection against acquisition of HIV infection, no lowering of viral loads in those who did become infected. In fact, in the third of these 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 among vaccinated individuals. However, a subsequent statistical analysis reported that there was less than a 78% chance that the protection against acquisition was real.

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

What is the problem? 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 continuous unrelenting virus replication. Once HIV gets its foot in the door, it’s “gotcha.” Many vaccines do not protect absolutely against the acquisition of an infection, but they are able to severely limit the replication of the virus and any illness that might result. 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 evolved an ability to generate and to tolerate many mutations in its genetic information. The consequence of this is an enormous amount of variation among strains of the virus not only from one individual to another but even within a single individual. Let’s use influenza for a comparison. Everyone knows that people need to get revaccinated against influenza virus each season because of season-to-season variability in the influenza strain that is circulating. Well, the variability of HIV within a single infected individual exceeds the entire worldwide sequence variability in the influenza virus during an entire season.

What are we going to put 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 such as coronaviruses and herpes viruses encode a structure on their surface that each virus uses to gain entry into a cell. This structure is called a “glycoprotein,” meaning that it is composed of both sugars and protein. But the HIV envelope glycoprotein is extreme. It is the most heavily sugared protein of all viruses in all 22 families. More than half the weight is sugar. And the virus has figured out a way, meaning the virus has evolved by natural selection, to use these sugars as shields to protect itself from recognition by antibodies that the infected host is trying to make. The host cell adds these sugars and then views them as self.

These properties have important 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 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 elicit antibodies that will neutralize one strain, but not antibodies with an ability to protect against the thousands and thousands of strains circulating in the population. That’s a major problem for vaccine development efforts.

HIV is continually evolving within a single infected individual to stay one step ahead of the immune responses. The host elicits a particular immune response that attacks the virus. This puts selective pressure on the virus, and through natural selection a mutated virus variant appears that is no longer recognized by the individual’s immune system. The result is continuous unrelenting viral replication.

[Understand new developments in science, health and technology, each week. Subscribe to The Conversation’s science newsletter.]

So, should we researchers give up? No, we shouldn’t. One approach researchers are trying in animal models in a couple of laboratories is to use 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 are infected for life. And immune responses persist not just as memory but in a continually active fashion. Success of this approach, however, will still depend on figuring out how to elicit the breadth of immune responses that will allow coverage against the vast complexity of HIV sequences circulating in the population.

Another approach is to go after protective immunity from a different angle. Although the vast 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 figured out 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 administered to muscle, muscle cells become factories that continuously 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 give up.

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HIV/AIDS vaccine: Why don't we have one after 37 years, when we have several for COVID-19 after a few months?

Credit: Pixabay/CC0 Public Domain

Smallpox has been eradicated from the face of the Earth following a highly effective, worldwide vaccination campaign. Paralytic poliomyelitis is no longer a problem in the U.S. because of development and use of effective vaccines against the poliovirus. In current times, millions of lives have been saved because of rapid deployment of effective vaccines against COVID-19. And yet, it has been 37 years since HIV was discovered as the cause of AIDS, and there is no vaccine. Here I will describe the difficulties facing development of an effective vaccine against HIV/AIDS.

I am a professor of pathology at the University of Miami Miller School of Medicine. My laboratory is credited with the discovery 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.

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 new disease AIDS burst onto the scene in the early 1980s and the virus that caused it was discovered in 1983-84, it was only natural to think that the research community would be able to develop a vaccine for it.

At a now famous press conference in 1984 announcing HIV as the cause of AIDS, then U.S. Secretary of Health and Human Services Margaret Heckler predicted that a vaccine would be available in two years. Well, it is now 37 years later and there is no vaccine. The rapidity of COVID-19 vaccine development and distribution puts the lack of an HIV vaccine in stark contrast. The problem is not failure of government. The problem is not lack of spending. The difficulty lies in 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 cost of over US$100 million. The first three of these failed quite convincingly no protection against acquisition of HIV infection, no lowering of viral loads in those who did become infected. In fact, in the third of these 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 among vaccinated individuals. However, a subsequent statistical analysis reported that there was less than a 78% chance that the protection against acquisition was real.

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

The complexity of HIV

What is the problem? 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 continuous unrelenting virus replication. Once HIV gets its foot in the door, it's "gotcha." Many vaccines do not protect absolutely against the acquisition of an infection, but they are able to severely limit the replication of the virus and any illness that might result. 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 evolved an ability to generate and to tolerate many mutations in its genetic information. The consequence of this is an enormous amount of variation among strains of the virus not only from one individual to another but even within a single individual. Let's use influenza for a comparison. Everyone knows that people need to get revaccinated against influenza virus each season because of season-to-season variability in the influenza strain that is circulating. Well, the variability of HIV within a single infected individual exceeds the entire worldwide sequence variability in the influenza virus during an entire season.

What are we going to put 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 such as coronaviruses and herpes viruses encode a structure on their surface that each virus uses to gain entry into a cell. This structure is called a "glycoprotein," meaning that it is composed of both sugars and protein. But the HIV envelope glycoprotein is extreme. It is the most heavily sugared protein of all viruses in all 22 families. More than half the weight is sugar. And the virus has figured out a way, meaning the virus has evolved by natural selection, to use these sugars as shields to protect itself from recognition by antibodies that the infected host is trying to make. The host cell adds these sugars and then views them as self.

These properties have important 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 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 elicit antibodies that will neutralize one strain, but not antibodies with an ability to protect against the thousands and thousands of strains circulating in the population. That's a major problem for vaccine development efforts.

HIV is continually evolving within a single infected individual to stay one step ahead of the immune responses. The host elicits a particular immune response that attacks the virus. This puts selective pressure on the virus, and through natural selection a mutated virus variant appears that is no longer recognized by the individual's immune system. The result is continuous unrelenting viral replication.

So, should we researchers give up? No, we shouldn't. One approach researchers are trying in animal models in a couple of laboratories is to use 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 are infected for life. And immune responses persist not just as memory but in a continually active fashion. Success of this approach, however, will still depend on figuring out how to elicit the breadth of immune responses that will allow coverage against the vast complexity of HIV sequences circulating in the population.

Another approach is to go after protective immunity from a different angle. Although the vast 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 figured out 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 administered to muscle, muscle cells become factories that continuously 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 give up.

This article is republished from The Conversation under a Creative Commons license. Read the original article.


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 new disease AIDS burst onto the scene in the early 1980s and the virus that caused it was discovered in 1983-84, it was only natural to think that the research community would be able to develop a vaccine for it.

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

At a now famous press conference in 1984 announcing HIV as the cause of AIDS, then U.S. Secretary of Health and Human Services Margaret Heckler predicted that a vaccine would be available in two years. Well, it is now 37 years later and there is no vaccine. The rapidity of COVID-19 vaccine development and distribution puts the lack of an HIV vaccine in stark contrast. The problem is not failure of government. The problem is not lack of spending. The difficulty lies in 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 cost of over US$100 million. The first three of these failed quite convincingly no protection against acquisition of HIV infection, no lowering of viral loads in those who did become infected. In fact, in the third of these 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 among vaccinated individuals. However, a subsequent statistical analysis reported that there was less than a 78% chance that the protection against acquisition was real.

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


Why Anti-HIV Antibodies Are Ineffective At Blocking Infection

Some 25 years after the AIDS epidemic spawned a worldwide search for an effective vaccine against the human immunodeficiency virus (HIV), progress in the field seems to have effectively become stalled. The reason? According to new findings from a team of researchers from the California Institute of Technology (Caltech), it's at least partly due to the fact that our body's natural HIV antibodies simply don't have a long enough reach to effectively neutralize the viruses they are meant to target.

"This study helps to clarify the obstacles that antibodies face in blocking infection," says Pamela Bjorkman, the Max Delbrück Professor of Biology at Caltech and a Howard Hughes Medical Institute Investigator, "and will hopefully shed more light on why developing an effective vaccine for HIV has proven so elusive."

Y-shaped antibodies are best at neutralizing viruses--i.e., blocking their entry into cells and preventing infection--when both arms of the Y are able to reach out and bind to their target proteins at more or less the same time. In the case of HIV, antibodies that can block infection target the proteins that stud the surface of the virus, which stick out like spikes from the viral membrane. But an antibody can only bind to two spikes at the same time if those spikes fall within its span--the distance the antibody's structure allows it to stretch its two arms.

"When both arms of an antibody are able to bind to a virus at the same time," says Joshua Klein, a Caltech graduate student in biochemistry and molecular biophysics and the PNAS paper's first author, "there can be a hundred- to thousandfold increase in the strength of the interaction, which can sometimes translate into an equally dramatic increase in its ability to neutralize a virus. Having antibodies with two arms is nature's way of ensuring a strong binding interaction."

As it turns out, this sort of double-armed binding is easier said than done--at least in the case of HIV.

In their PNAS paper, Bjorkman and Klein looked at the neutralization capabilities of two different monoclonal antibodies isolated from HIV-infected individuals. One, called b12, binds a protein known as gp120, which forms the upper portion of an HIV's protein spike. The other, 4E10, binds to gp41, which is found on a lower portion of the spike known as the stalk.

The researchers broke each of the antibodies down into their component parts and compared their abilities to bind and neutralize the virus. They found, as expected, that one-armed versions of the b12 antibody were less effective at neutralizing HIV than two-armed versions. When they looked at the 4E10 antibody, by comparison, they found that having two arms conferred almost no advantage over having only one arm. In addition, they found that larger versions of 4E10 were less effective than smaller ones. These results highlight potential obstacles that vaccines designed to elicit antibodies similar to 4E10 might face.

But b12 has its own obstacles to overcome as well. In fact, when the researchers looked more closely at their data, they realized that the benefits of having two arms--even for b12--were much smaller than those seen for antibodies against viruses like influenza. In other words, the body's natural anti-HIV antibodies are much less effective at neutralizing HIV than they should be.

"The story really starts to get interesting when we think about what the human immunodeficiency virus actually looks like," says Klein. Whereas a single influenza virus's surface is studded with approximately 450 spikes, he explains, the similarly sized HIV may have fewer than 15 spikes.

With spikes so few and far between, finding two that both fall within the reach of a b12 or 4E10 antibody--the spans of which generally measure between 12 and 15 nanometers--becomes much more of a challenge.

"HIV may have evolved a way to escape one of the main strategies our immune system uses to defeat infections," says Klein. "Based on these data, it seems that the virus is circumventing the bivalent effect that is so key to the potency of antibodies."

"I consider this a very important paper because it changes the focus of the discussion about why anti-HIV antibodies are so poor," adds virologist David Baltimore, the Robert Andrews Millikan Professor of Biology and a Nobel Prize winner. "It brings attention to a long-recognized but often forgotten aspect of antibody attack--that they attack with two heads. What this paper shows is that anti-HIV antibodies are restricted to using one head at a time and that makes them bind much less well. Responding to this newly recognized challenge will be difficult because it identifies an intrinsic limitation on the effectiveness of almost any natural anti-HIV antibodies."

The work described in the paper was supported by a Bill and Melinda Gates Foundation Grant through the Grand Challenges in Global Health Initiative and the Collaboration for AIDS Vaccine Discovery.


A Bad Memory

The secret to why HIV is so hard to cure lies in a quirk of the type of cell it infects. Our immune system is designed to store information about infections we have had in the past this property is called “immunologic memory.” That’s why you’re unlikely to be infected with chickenpox a second time or catch a disease you were vaccinated against. When an infection grows in the body, the white blood cells that are best able to fight it multiply repeatedly, perfecting their infection-fighting properties with each new generation. After the infection is cleared, most of these cells will die off, since they are no longer needed. However, to speed the counter-attack if the same infection returns, some white blood cells will transition to a hibernation state. They don’t do much in this state but can live for an extremely long time, thereby storing the “memory” of past infections. If provoked by a recurrence, these dormant cells will reactivate quickly.

This near-immortal, sleep-like state allows HIV to persist in white blood cells in a patient’s body for decades. White blood cells infected with HIV will occasionally transition to the dormant state before the virus kills them. In the process, the virus also goes temporarily inactive. By the time drugs are started, a typical infected person contains millions of these cells with this “latent” HIV in them. Drug cocktails can prevent the virus from replicating, but they do nothing to the latent virus. Every day, some of the dormant white blood cells wake up. If drug treatment is halted, the latent virus particles can restart the infection.

Latent HIV’s near-immortal, sleep-like state allows it to persist in white blood cells in a patient’s body for decades.

HIV researchers call this huge pool of latent virus the “barrier to a cure.” Everyone’s looking for ways to get rid of it. It’s a daunting task, because although a million HIV-infected cells may seem like a lot, there are around a million times that many dormant white blood cells in the whole body. Finding the ones that contain HIV is a true needle-in-a-haystack problem. All that remains of a latent virus is its DNA, which is extremely tiny compared to the entire human genome inside every cell (about 0.001% of the size).


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 new disease AIDS burst onto the scene in the early 1980s and the virus that caused it was discovered in 1983-84, it was only natural to think that the research community would be able to develop a vaccine for it.

At a now famous press conference in 1984 announcing HIV as the cause of AIDS, then U.S. Secretary of Health and Human Services Margaret Heckler predicted that a vaccine would be available in two years. Well, it is now 37 years later and there is no vaccine. The rapidity of COVID-19 vaccine development and distribution puts the lack of an HIV vaccine in stark contrast. The problem is not failure of government. The problem is not lack of spending. The difficulty lies in 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 cost of over US$100 million. The first three of these failed quite convincingly no protection against acquisition of HIV infection, no lowering of viral loads in those who did become infected. In fact, in the third of these 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 among vaccinated individuals. However, a subsequent statistical analysis reported that there was less than a 78% chance that the protection against acquisition was real.

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


HIV/AIDS vaccine: Why don’t we have one after 37 years, when we have several for COVID-19 after a few months?

Smallpox has been eradicated from the face of the Earth following a highly effective, worldwide vaccination campaign. Paralytic poliomyelitis is no longer a problem in the U.S. because of development and use of effective vaccines against the poliovirus. In current times, millions of lives have been saved because of rapid deployment of effective vaccines against COVID-19. And yet, it has been 37 years since HIV was discovered as the cause of AIDS, and there is no vaccine. Here I will describe the difficulties facing development of an effective vaccine against HIV/AIDS.

I am a professor of pathology at the University of Miami Miller School of Medicine. My laboratory is credited with the discovery 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 difficulty 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 new disease AIDS burst onto the scene in the early 1980s and the virus that caused it was discovered in 1983-84, it was only natural to think that the research community would be able to develop a vaccine for it.

At a now famous press conference in 1984 announcing HIV as the cause of AIDS, then U.S. Secretary of Health and Human Services Margaret Heckler predicted that a vaccine would be available in two years. Well, it is now 37 years later and there is no vaccine. The rapidity of COVID-19 vaccine development and distribution puts the lack of an HIV vaccine in stark contrast. The problem is not failure of government. The problem is not lack of spending. The difficulty lies in 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 cost of over US$100 million. The first three of these failed quite convincingly no protection against acquisition of HIV infection, no lowering of viral loads in those who did become infected. In fact, in the third of these 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 among vaccinated individuals. However, a subsequent statistical analysis reported that there was less than a 78% chance that the protection against acquisition was real.

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

The complexity of HIV

What is the problem? 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 continuous unrelenting virus replication. Once HIV gets its foot in the door, it’s “gotcha.” Many vaccines do not protect absolutely against the acquisition of an infection, but they are able to severely limit the replication of the virus and any illness that might result. 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 evolved an ability to generate and to tolerate many mutations in its genetic information. The consequence of this is an enormous amount of variation among strains of the virus not only from one individual to another but even within a single individual. Let’s use influenza for a comparison. Everyone knows that people need to get revaccinated against influenza virus each season because of season-to-season variability in the influenza strain that is circulating. Well, the variability of HIV within a single infected individual exceeds the entire worldwide sequence variability in the influenza virus during an entire season.

What are we going to put 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 such as coronaviruses and herpes viruses encode a structure on their surface that each virus uses to gain entry into a cell. This structure is called a “glycoprotein,” meaning that it is composed of both sugars and protein. But the HIV envelope glycoprotein is extreme. It is the most heavily sugared protein of all viruses in all 22 families. More than half the weight is sugar. And the virus has figured out a way, meaning the virus has evolved by natural selection, to use these sugars as shields to protect itself from recognition by antibodies that the infected host is trying to make. The host cell adds these sugars and then views them as self.

These properties have important 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 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 elicit antibodies that will neutralize one strain, but not antibodies with an ability to protect against the thousands and thousands of strains circulating in the population. That’s a major problem for vaccine development efforts.

HIV is continually evolving within a single infected individual to stay one step ahead of the immune responses. The host elicits a particular immune response that attacks the virus. This puts selective pressure on the virus, and through natural selection a mutated virus variant appears that is no longer recognized by the individual’s immune system. The result is continuous unrelenting viral replication.

So, should we researchers give up? No, we shouldn’t. One approach researchers are trying in animal models in a couple of laboratories is to use 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 are infected for life. And immune responses persist not just as memory but in a continually active fashion. Success of this approach, however, will still depend on figuring out how to elicit the breadth of immune responses that will allow coverage against the vast complexity of HIV sequences circulating in the population.

Another approach is to go after protective immunity from a different angle. Although the vast 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 figured out 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 administered to muscle, muscle cells become factories that continuously 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 give up.

Ronald C. Desrosiers, Professor of Pathology, Vice-chair for Research, University of Miami

This article is republished from The Conversation under a Creative Commons license. Read the original article.



Comments:

  1. Lach

    It doesn't make sense

  2. Dominik

    Many thanks for the help in this question, now I will know.

  3. Tygojas

    It doesn't make sense

  4. Simao

    It seems to me, what is it already was discussed, use search in a forum.



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