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Scripps HIV vaccine candidate shows promise in mice study: precision vaccinations



A new vaccine candidate against HIV overcomes the technical obstacles that hampered previous vaccine efforts and stimulates a potent antibody response against HIV in animal tests, Scripps Research reported.

"This is the first time that a candidate HIV vaccine induces this desired type of antibody response in mice," said Scripps researchers in a press release.

This is important news because, despite the years and tens of millions of dollars of experimentation, HIV vaccine researchers have not been able to find a widely applicable method to stabilize Env receptors in the desired way before the infection.

This new vaccine strategy, described in an article published on November 23 in Scientific advances, is based on the HIV envelope protein, Env.

This complex molecule that changes shape has been notoriously difficult to produce in vaccines in a way that induces a useful immunity to HIV.

However, scientists at Scripps Research found a simple and elegant method to stabilize Env proteins in the desired form even for various strains of HIV.

Mounted on virus-like particles to mimic a whole virus, stabilized Env proteins elicited robust anti-HIV antibody responses in mice and rabbits.

The candidate vaccines based on this strategy are now being tested in monkeys.

"We see this new approach as a general solution to the long-standing problems of designing the HIV vaccine," said lead researcher Jiang Zhu, an associate professor in the Department of Structural Biology and Integrative Computing at Scripps Research.

Copies of Env stud the surface of HIV; Its main function is to grab the host cells and penetrate them to start the infection.

Given that Env plays this crucial role in the infection and it is the viral structure with the highest exposure to the immune system of an infected host, it has been the main target of HIV vaccination efforts.

The idea has been to inoculate people with all the Env protein or its subunits to stimulate the production of antibodies that bind to Env, in the hope that these antibodies prevent HIV from infecting host cells in future exposures to the virus.

Many researchers believe that an HIV vaccine can work if it presents Env proteins to the immune system in a way that closely resembles the form of Env in a real virus before it has infected a cell.

But presenting Env correctly has been a great challenge.

In an HIV virus, Env protrudes from the viral membrane in tight clusters of three, called trimers, and these complex structures take radically different forms before and after infecting the cells.

"The trimer stabilization solutions that have been reported so far have worked for some strains of HIV but they have not been generalized," says Zhu.

"The" metastability "of trimeros, as we call it, has really been a central problem for the design of HIV vaccines based on trimers."

Zhu reported that modifying a short and elastic section of Env called HR1 could do the trick, which allowed Env to remain in the "closed" form of preinfection.

In the new study, he and his team showed that this strategy does work for Env parasites of various strains of HIV circulating in different parts of the world.

This "unscrambled pre-perfusion optimized" (UFO) approach, as they call it, produces Env trimers that stabilize in the closed form and can be produced efficiently, with a surprisingly small purification need, in the cell types that they are normally used in the manufacture of biotechnology.

"At this time, in my laboratory, we have made this modification to Envs from 30 to 40 different strains of HIV, and in most cases it has worked like a charm," says Zhu.

He and his colleagues further optimized their vaccination strategy by genetically linking their stabilized Env trimers, up to 60 at a time, to individual nanoparticles that mimic the globular shape of a complete virus.

In this way, the vaccine molecule, although it is artificial and lacks the genetic material for viral replication, it seems that the immune system closely resembles a real invasive virus and stimulates a stronger reaction.

In mice, Zhu and his team found, a sample of the Env-on-nanoparticles vaccine, in just eight weeks, elicited antibodies that in laboratory tests successfully neutralized a naturally circulating HIV strain, of a type against which Previous candidate vaccines have generally failed.

"This is the first time that a vaccine candidate against HIV induces this desired type of antibody response in mice," says Zhu.

Similarly, unprecedented results were obtained in rabbits, demonstrating that the nanoparticle-based approach is clearly superior to the use of isolated Env proteins: it elicits a significantly stronger response and does so much more rapidly.

More tests are being conducted on 24 monkeys at the National Southwest Primate Center sponsored by the National Institutes of Health in San Antonio, Texas.

"We are now testing two candidate vaccines based on Env trimers from different strains of HIV, in addition to a third candidate vaccine that is a cocktail of three Env-based vaccines," says Ji Li, CEO of Ufovax.

"We believe that this new approach represents a real breakthrough after 30 years of research on the HIV vaccine."

These investigators did not reveal any conflict of interests. Funding was provided by the National Institutes of Health (AI129698, AI125078-01A1, and AI084817), by the International AIDS Vaccine Initiative, the Bill and Melinda Gates Foundation (OPP1084519 and OPP1115782), and by the Center for Vaccine Immunology and Immunology against HIV / AIDS. Discovery (CHAVI-ID UM1 AI100663).


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