Per reporter: Li Menglin
This year, more than 40 years have passed since the world first reported the detection of AIDS cases. But to this day, AIDS remains an incurable disease.
After more than 30 years of exploration and research, the world has still not been able to develop an effective AIDS vaccine. "The challenges that HIV (human immunodeficiency virus, also known as HIV) pose to vaccine development is a completely different level, as it is a true 'master' in mutating, stealth and evading immune control." Paolo Lusso, head of research on the pathogenesis of viruses at the National Institute of Allergy and Infectious Diseases (NIAID), explained to the Daily Economic News.
According to Dagna Laufer, vice president of the International Aids Vaccine Initiative (IAVI), "HIV is not one virus, but millions of different viruses, which poses a huge challenge for vaccine development." ”
However, the widespread use of COVID-19 vaccines based on mRNA (messenger ribonucleic acid) technology has brought new light to the field of HIV vaccine research and development.
"The rapid development and successful vaccination of the mRNA covid-19 vaccine has proved the efficiency and practicality of the mRNA vaccine, and I think these characteristics are also true in the development of HIV vaccines," Luso told reporters.
In August 2021, with funding from the Gates Foundation, IAVI and Modena collaborated to officially launch the world's first clinical trial of an HIV vaccine based on mRNA technology, and the results of the trial are expected to be released in 2023. The mRNA AIDS vaccine, co-led by NIAID Director Anthony Fauci and Luso, is also expected to begin Phase I clinical trials in the fourth quarter of 2022.
Can the mRNA technology tested in the COVID-19 pandemic once again bring about a new breakthrough? Each reporter interviewed the main person in charge of the two mRNA HIV vaccine trials to analyze the unique advantages of deconstructing this vaccine and the challenges that may be faced in the development of the road ahead.
Why is the AIDS vaccine "difficult to give birth"?
2021 marks the fortieth anniversary of the first human report of AN AIDS cases.
Currently, AIDS has been controlled as a chronic disease through highly effective antiretroviral therapy (cocktail therapy), and pre-exposure prophylaxis (PrEP) has significantly reduced the risk of contracting the virus in high-risk groups. However, as the most effective weapon to end the AIDS epidemic, vaccines have not yet arrived.
Why is HIV vaccine development so difficult?
Luso told the Daily Economic News that the development of HIV vaccines has been slow due to the greater challenges in mutation, stealth and evasion of immune control.
Scientific studies have shown that the proteins on the surface of the HIV virus are wrapped in a layer of sugar molecules, as if wearing a coat, causing the immune system to have difficulty recognizing HIV and thus unable to produce antibodies to fight infection.
In addition, in the process of virus replication and progeny, HIV's genetic material will be highly changed, resulting in its mutation rate is extremely fast, and the body's immune system can not keep up at all. Studies have pointed out that the virus changes in a single HIV-infected person than the influenza virus mutation that accumulates in a flu season around the world.
HIV is also divided into two main types, each of which has a number of different subtypes, and different subtypes are constantly reorganized to form new subtypes during the epidemic process. Lowe, vice president of the International Association for AIDS Vaccine Initiatives (IAVI), told reporters that the challenge that HIV poses to vaccine development is that it can almost be said not to be a virus, but to millions of different viruses.
IAVI is a non-profit international organization that accelerates the development of HIV vaccines by coordinating resources from both the public and private sectors, including academia, industry, and government. Dagena Laufer oversees clinical trials of HIV vaccine candidates sponsored by the organization.
In fact, from the development of AIDS vaccines in the past few decades, we can also get a glimpse of the difficulties.
In 1984, then-U.S. Health Secretary Margaret Heikoler announced at a news conference that HIV was the cause of AIDS and optimistically predicted that a vaccine would be available within two years. However, in the following thirty-seven years, from the beginning of the traditional means of inactivated vaccines, live attenuated vaccines, and then to new ideas such as protein subunit vaccines, viral vector vaccines, and DNA vaccines, scientists have tried a variety of routes, as well as "combination vaccines" combined with different routes, but have not been successful.
During this period, only five vaccines reached the stage of large-scale phase III clinical trials, and only one of them was shown to be effective in preventing infection, but only 31.2% effective, failing to meet the threshold of large-scale application, and this data was not reproduced in subsequent trials.
The successful use of mRNA technology in the new crown vaccine has ignited new hopes for the scientific community to overcome the HIV virus. In the year or so since the outbreak of the new crown epidemic, several new crown vaccines have completed the process from research and development, clinical trials to emergency approval, which is a miracle in the history of medicine.
mRNA: more likely to trigger an immune response
Image source: Visual China
The Chinese of mRNA translates to messenger ribonucleic acid, and as the name suggests, its function is to send signals to the body that direct cells to produce virus-specific proteins that stimulate an immune response in the body.
In the application of the new crown vaccine, after the mRNA enters the human body, it will instruct the cells to produce fragments of the new crown virus spike protein that are not infective, and after the immune system recognizes this foreign protein, it will produce antibodies and activate other immune cells to attack. Because spike protein is the component that the new crown virus uses to unlock the infected body, after the vaccine is injected, the body can learn how to recognize and resist the new crown virus.
In experimental HIV vaccines, mRNA instructs cells to produce HIV envelope proteins, the only HIV component that induces protective neutralizing antibodies, and plays a role in vaccine design similar to the spike proteins of the new coronavirus.
Paul Luso (left) Virologist Robert M. Chinnock (right)
Image source: Courtesy of the interviewee
Luso pointed out that the most unique advantage of mRNA compared to the traditional vaccine route is that it makes the body itself a "vaccine factory": the envelope glycoprotein synthesized by mRNA using human cells is "extremely similar" to the envelope glycoprotein after the HIV virus actually invades the human body.
He explains that the structure of envelope glycoproteins is extremely complex, and the cells that produce this protein bring it a variety of "modifications", such as covering its surface with a layer of sugar molecules (glycosylated modifications), which makes it look more like the body's own proteins, thus escaping recognition by the immune system.
Therefore, the more similar the vaccine-induced protein is to the HIV protein, the easier it is for the immune system to recognize the latter, "if the envelope glycoprotein is synthesized in a laboratory or on an engineered cell line, the modifications that occur will be inconsistent with the virus itself, and the immune system may not be able to respond."
The advantages of mRNA don't stop there. Zhang Peng, a Chinese scientist and researcher in charge of vaccine design in Luso's team, told the Daily Economic News that the expression of envelope glycoproteins produced by optimized mRNA technology is very high on cells, and the expression range is very wide, "The previous carrier protein technology can only target one cell, and after mRNA enters the human body, envelope glycoprotein can be diversified on muscle, epithelium, liver and other cells."
Zhang Peng hopes that in the future, this diversified expression ability of mRNA can be realized on lymphocytes, because lymphocytes in the immune system are target cells for HIV infection and attack.
In addition, the sequence design of mRNA vaccines is relatively simple and easier to achieve large-scale production, which has been fully demonstrated in the new crown vaccine.
The world's first mRNA AIDS vaccine enters clinical trials
In fact, before the new crown epidemic, the scientific community had been developing mRNA vaccine technology for many years, but there had never been a large-scale effectiveness trial.
"The rapid development and successful vaccination of the mRNA covid-19 vaccine has proved the efficiency and practicality of the mRNA vaccine, and I think these characteristics are also true in the development of HIV vaccines." Luso told the "Daily Economic News" reporter.
On August 19, 2021, with funding from the Gates Foundation, IAVI and Modena collaborated to officially launch the world's first clinical trial of an HIV vaccine based on mRNA technology.
The test used mRNA technology to deliver two HIV viral antigens, first with an antigen called eOD-GT8 60mer (an envelope glycoprotein) for initial immunity, and then with an antigen called Core-g28v2 60mer for enhanced immunity, hoping that this combination would activate specific cell populations and guide them to produce broad-spectrum neutralizing antibodies against HIV.
The effectiveness of the eOD-GT8 60mer has been preliminarily proven. In February of the same year, IAVI and the Scripps Institute, which developed the antigen, jointly published the results of a Phase I clinical trial conducted with non-mRNA techniques, and 97% of the subjects produced the B-cell responses needed to promote broad-spectrum neutralizing antibody secretion. Subsequently, Modena joined the trial to deliver both antigens using its own mRNA platform.
Laufer told every reporter that the results of the Phase I clinical trial of the HIV vaccine based on mRNA technology will be released in 2023. If the results are satisfactory, Phase II and III clinical trials will follow.
On December 9, 2021, the mRNA HIV vaccine project, co-led by NIAID Director Anthony Fauci and Luso, published the results of animal tests in the journal Nature Medicine. The vaccine is provided by mRNA with coding instructions for the manufacture of HIV envelope glycoprotein "Env" and structural protein "Gag", which are assembled by the muscle cells of the subject animal to produce HIV-like but disease-causing virus-like particles (VLPs), thereby stimulating immune responses such as broad-spectrum neutralizing antibodies in the animals.
Broad-spectrum neutralizing antibodies are able to identify areas shared by HIV strains that are not easily changed, providing the ability to capture multiple HIV strains. Due to the extremely fast mutation rate of HIV, how to quickly produce broad-spectrum neutralizing antibodies when the human body encounters HIV is one of the ultimate goals pursued by vaccine research and development.
Trials showed that rhesus monkeys who received multiple booster vaccinations after initial vaccination had a 79% lower risk of infection with monkey/human immunodeficiency chimeric virus (SHIV) compared with unvaccinated rhesus monkeys. (Note: Because animals cannot be infected with HIV, the scientific community often uses SHIV, a recombinant virus synthesized from humans, to test the effectiveness of vaccines in animals.) ）
Luso said the team is preparing for a Phase I clinical trial, which could begin as early as the fourth quarter of 2022. If successfully implemented, it will be the second mRNA HIV vaccine to open clinical trials.
Effectively combating multiple HIV strains is a difficult one
Image source: Photo by reporter Zhang Jian
Laufer said that the success of the new crown vaccine proves that mRNA is safe, the human body has a good tolerance to it, the design of mRNA-based vaccines can be modified quickly, and large-scale production is relatively easy, and these characteristics are expected to continue in HIV vaccine development.
"However, the development of HIV vaccines has its own special challenges, and we do not expect mRNA technology to solve these inherent problems, which require progress in HIV immunology and vaccinology research to solve," Love told reporters.
Both Laufer and Luso believe that the biggest challenge is how to make vaccines widely applicable to major HIV strains circulating around the world.
This means that vaccines need to use mRNA to deliver multiple envelope glycoproteins, Luso said, because the immune system needs to see different strains before it can produce a focused immune response to the "shared region" of envelope glycoproteins, which induces the production of broad-spectrum neutralizing antibodies.
This process takes a long time. Laufer pointed out that the combination of antigens used in the phase I clinical trial of the world's first HIV vaccine based on mRNA technology can only induce b-cell response, which is only the first step in producing a broad-spectrum neutralizing antibody, and further vaccine injections are needed in the future.
Luso's team vaccinated the monkeys for two years, and it took at least six booster injections to see the broad-spectrum neutralizing antibody appear, and its titers were still very low, "and our trial results were a big breakthrough, but it was far from the finish line."
Luso estimated that the same number of booster needles may be needed on the human body to achieve a comparable effect. Citing research, he pointed out that some HIV-infected people known as "elite controllers" are able to produce broad-spectrum neutralizing antibodies on their own and do not need to take drugs, but antibodies are usually produced after months or even years of persistent infection.
"Is it feasible to give people six or more booster shots?" Of course not! Luso said. The next step is to focus on making the vaccine more efficient, hoping to reduce the number of booster injections to about four.
As the main person in charge of vaccine design, Zhang Peng said that the second animal trial is in the final stages, hoping that by optimizing the vaccine's antigen sequence, formula, dose and immunization time, the new protocol can show higher efficacy, thereby helping to optimize the design of clinical trials. He predicts that it will take at least three years from the start of the Phase I trial to the end of the Phase III trial.
Reporter: Li Menglin
Editor: Lan Suying
Vision: Liu Yang
Typography: Lan Suying Ma Yuan
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