December 7, 2022

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Reviewing the 40-year development history of AIDS vaccines

Reviewing the 40-year development history of AIDS vaccines

 


Reviewing the 40-year development history of AIDS vaccines.  When the virologist José Esparza started working with the World Health Organization to fight the AIDS epidemic in the 1980s, he and many of his colleagues believed that vaccines would be a solution, and it would be soon arrival.

Their optimism is based on a solid scientific foundation. Researchers know that people will develop antibodies to the human immunodeficiency virus that causes AIDS. Stimulating the body to produce antibodies has been a common and successful vaccine strategy, which has greatly reduced cases of measles, smallpox and many other diseases. The response to AIDS seems equally feasible.

Espasa said: “We thought it would be a trivial thing,” he was a senior consultant for the Bill and Melinda Gates Foundation, now affiliated with the University of Maryland School of Medicine. “We didn’t know the complexity of HIV.” After more than 30 years, there is still no viable HIV vaccine candidate, even though scientists have produced a variety of effective vaccines for the SARS-CoV-2 virus less than a year after its emergence. Vaccine, the virus caused COVID-19.

Now, recent discoveries are inspiring new hope. At an international AIDS conference in February, researchers from the Scripps Institute and the non-profit vaccine research organization IAVI announced encouraging blood tests in the first phase of human trials of a new HIV vaccine strategy result.

William Schief, an immunologist at Scripps University and executive director of vaccine design at the Neutralization Antibody Center of the International Union of Immunizations, said reality is far more detailed than the hype implies. He said that although the immune response detected by his team was an important proof-of-concept finding, the field is still years away from producing a vaccine that makes people less likely to be infected with HIV. Even so, the final vaccine may include multiple injections, which may be a difficult sale.

“In science, this is a beautiful concept,” Espasa said. “Actually, it is not easy to implement.”

However, after decades of frustration, these results are still gratifying news, and some intriguing links to COVID-19 vaccine work may help accelerate HIV work.

Scheff said: “This is a small step towards making an HIV vaccine, but it is also a huge step,” indicating a viable way forward. “And in fact, in this particular case, it worked amazingly well.”

 

 

Three waves of research

After scientists isolated the virus in 1984 and confirmed that it caused AIDS, the search for an HIV vaccine soon began. Esparza said that since then, scientific exploration has gone through three waves of research, and he published a historical record on the search for an HIV vaccine in 2013.

First Wave:

The first wave of research focused on the most mature ideas: trying to stimulate the human immune system to produce so-called neutralizing antibodies to inactivate specific viruses. This is a strategy used by many other vaccines, including the COVID-19 vaccine. For many years, researchers have worked to determine the antibodies that people produce in response to HIV infection, and then develop vaccines that can induce similar antibodies.

But HIV proved to be an elusive enemy. The target of the antibody is a specific protein on the surface of the virus. However, HIV rapidly mutates into a variant that antibodies cannot recognize, which means that it has been one step ahead of the immune system. Scheff said that in a classic study, researchers repeatedly tested the blood of HIV-infected people and found that their immune system always produced antibodies three to six months later than the virus.

Larry Corey, an expert in virology, immunology, and vaccine development at the Fred Hutchinson Cancer Research Center in Seattle, and a principal investigator of the HIV Vaccine Trial Network, said: “HIV is still a more difficult scientific goal. “It’s more difficult than SARS-CoV-2. “98% of humans recover from SARS-CoV-2, and we have zero in the 78 million self-recoveries of HIV.”

Second Wave:

By the beginning of the 21st century, researchers were seeking a second wave of HIV vaccines, based on the idea of ​​targeting human soldier-like “killer” T cells, rather than trying to stimulate antibodies. Long-term human immunity depends on two main groups of cells. B cells and T cells. Both help produce antibodies, but T cells also seek out and destroy infected cells. The idea of ​​a T-cell vaccine is to stimulate cells that recognize proteins inside the virus.

In 2007, in a double-blind, randomized phase 2 trial called STEP, this idea not only failed to provide protection, it also seemed to increase the risk of HIV infection. “Espalza said: “The test failed miserably.

This is far from the only vaccine attempt that has failed. After decades of human trials, only one trial showed any degree of effectiveness in the real world. The two vaccine combinations completed in Thailand in 2009 adopted the first wave of strategies to induce antibodies and reduced the HIV infection rate by 31%, which was not enough to obtain regulatory approval.

 

 

Targeting naive B cells

 

Third Wave:

The third and current HIV vaccine research began in the late 2000s, when researchers discovered that a small number of people infected with HIV produced particularly effective antibodies that can neutralize multiple HIV strains at the same time. So far, scientists have identified dozens of such broad-spectrum neutralizing antibodies, which target certain parts of the virus surface (much like the spike protein on SARS-CoV-2), which are involved in different viruses. The strains are consistent.

Sheff said that the people who make these proteins still cannot resist HIV because their bodies only make these antibodies after the virus is infected, and the virus continues to mutate during this period. But this discovery sparked a new idea. Perhaps an effective vaccine can be one step ahead of the virus by targeting so-called naive B cells (also known as precursor cells), which circulate in our blood. If a vaccine can mutate naive B cells and turn them into cells that produce broadly neutralizing antibodies before being infected with HIV, the body may be able to fight back the virus when it first encounters it.

In 2010, Schiff’s group began to study a class of broad-spectrum neutralizing antibodies called VRC01, which was the first antibody discovered by the National Institutes of Health Vaccine Research Center. First, they developed a designed protein nanoparticle, which they reported, can bind to naive B cells in human blood samples. In mouse studies, the nanoparticles can activate these cells, allowing them to multiply and mutate, and produce antibodies similar to VRC01. This new study aims to find out whether the same situation can happen to people.

This is a big “hypothesis”. Scheff said that only one in every 300,000 naive B cells is likely to develop into a VRC01 antibody-producing cell. But in a complex analysis of blood, the research team found that of the 36 people who received the vaccine (a type of “engineered protein nanoparticle”), 35 had the expected B cell response.

Scheff said that these findings are still being analyzed and have not yet been submitted for publication. They are still a long way from showing any type of HIV protection, even though a large number of elated social media users say it as if the HIV vaccine is suddenly in sight. .

He said: “Someone sent a tweet a week ago saying that our trial is eliciting a response and can protect 97% of vaccine recipients from HIV. This is completely untrue.”

Sheff said that eventually, people may get injections continuously for weeks to years, starting with what the new experiment does: interacting with the right naive B cells to start the process. Subsequent injections will guide B cells to produce fully mature broadly neutralizing antibodies.

Scheff said: “We are trying to occupy the driver’s seat of the immune system and educate it step by step with vaccines. The same idea may one day develop vaccines for Zika, hepatitis C, malaria and other diseases, including universal flu vaccines. And the future coronavirus.

Corey said this work is also an important sign that scientists are on the right path. He added that a recent study found that providing people with high levels of broad-spectrum neutralizing antibodies can prevent HIV. .

“The main breakthrough of Scripps research is that we can give an antigen that makes these precursors more common in people, and they will not be eliminated like antibodies,” Corey said. “We have made a breakthrough here and taken the first step.”

 

 


Utilize COVID-19 vaccine infrastructure

In addition to scientific challenges, HIV vaccine research has long been hindered by a lack of urgency. Although public and political will and major industry investments have pushed COVID-19 work forward at a record rate, Esparza says that HIV is a disease that disproportionately affects marginalized groups, and that pharmaceutical companies Unwilling to invest in expensive HIV trials before scientists build more basic science.

Espasa said: “If society really values ​​HIV vaccines, we will conduct several efficacy trials at the same time like COVID. The trials are expensive? Yes. But the cost of the HIV epidemic is huge.”

According to a study, from 2000 to 2015, the total health expenditure on HIV/AIDS in 188 countries exceeded US$562 billion.

Therefore, when the world watches the COVID-19 vaccine arrive at an unprecedented rate, one hope is that this enthusiasm will power various long-term vaccine development efforts, which will be the key to the fight against HIV.

There is already a connection between the two. Corey said that COVID-19 vaccine work relied on the clinical, laboratory, and biostatistics infrastructure created by the HIV Vaccine Trial Network. Scheff added that for many years, his team has worked with Moderna to test the mRNA delivery of its proteins in animal models. They plan to work together to quickly create HIV vaccine candidates for use in human clinical trials.

Given the enthusiasm for the COVID-19 vaccine and the new mRNA technology that can quickly produce vaccine variants, this may be the time to arouse people’s new interest in finding HIV vaccines, which also requires cooperation.

“If we come up with an HIV vaccine,” Schiff said, “I think the global experience of the COVID vaccine might make it easier for us to deploy it.”

 

 

 

 

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