An HIV vaccine trigger tested in a mouse model successfully readied the immune system to repel the virus, according to studies published Thursday. A human test of a vaccine based on this molecule could begin in about two years, according to scientists from The Scripps Research Institute involved in the studies.

HIV researchers David Nemazee, left, William Schief, center, and Dennis Burton, all of the Scripps Research Institute. They played key ...
HIV researchers David Nemazee, left, William Schief, center, and Dennis Burton, all of the Scripps Research Institute. They played key roles in three HIV studies about developing a preventive vaccine. — Howard Lipin

The scientists envision a series of sequential vaccinations, the first to produce immune cells capable of maturing into cells that make antibodies that neutralize a broad spectrum of strains of HIV. The following ones would guide these cells further in the direction of making the desired antibodies.

This sequential immunization trains the immune system to make the desired antibodies with increasingly greater potency, according to the researchers. So when the body is confronted with HIV, it can repel the infection.

All previous HIV vaccines have failed, because they didn’t reliably cause production of these broadly neutralizing antibodies. So the researchers and those following the work caution against over-optimism.

Three studies representing aspects of the research were released; two in the journal Science and the third in Cell. These tackle different parts of the vaccine problem. Together, they appear to provide the missing pieces that can be assembled into a complete vaccine.

One study in Science indicates it is possible to trigger the antibody system, using an engineered molecule that mimics a vulnerable region of HIV, to make early versions of broadly neutralizing antibodies. The scientists say the primed immune system can then be successively exposed to substances that mimic aspects of HIV, to make more mature versions of these antibodies.

A separate study in Cell showed how the use of a different engineered molecule could complete the final stage of the maturation process to protective antibodies. Finally, a third study also in Science showed that the latter engineered molecule behaved well in vaccination of rabbits.

The research’s leaders include TSRI colleagues Dennis Burton, David Nemazee and William Schief.

Burton has been collecting broadly neutralizing antibodies from infected individuals for decades, Nemazee developed a partially humanized mouse used in the study, and Schief does protein engineering to create the right immunogens.

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Conceptual steps for developing an HIV vaccine, starting with broadly neutralizing antibodies from an infected person. — Dennis Burton

“It works much better than we expected,” Nemazee said. “So we’re quite positive now about trying something more complicated, like a human.”

While the results are strong enough to warrant human testing, many more hurdles lie ahead, said Anthony S. Fauci, director of the National Institute of Allergy and Infectious Diseases.

“Whenever you get a result that is encouraging, the next step is to see if we can duplicate that in a very gradual, safe, gingerly way in humans in a Phase 1 trial,” Fauci said.

HIV is uniquely difficult because it’s so well shielded against the immune system, Fauci said.

“That’s why you’ve got to make the body go through all these contortions that are being described in these three very elegant papers,” Fauci said.

Death Star portal

These contortions can be compared to those used in Star Wars to destroy the Death Star, Nemazee said. Most of HIV is covered with shielding proteins, highly visible to the immune system. Consequently, most antibodies go for these nonessential targets. But in a minority of those infected, the immune system learns how to make broadly neutralizing antibodies.

In some cases, these antibodies can keep the virus in check. But in most cases, the broadly neutralizing antibodies aren’t powerful enough to stop HIV, which is already too entrenched. In lab experiments, these antibodies can prevent infection.

Like the Death Star’s thermal exhaust port, HIV’s most vulnerable part is well-shielded, a protein that latches onto the surface of immune cells so it can release its genetic material inside the cells. That’s when infection begins. If the immune cells that make antibodies could be guided to make antibodies to this vulnerable region, that would defend the body against infection.

The vaccine strategy is to target a subset of the antibody-making B cells that are capable of producing the right antibodies, cause them to proliferate, then subject them to antigens that progressively guide these cells into making the broadly neutralizing antibodies.

Schief’s team got the attention of the desired B cells by making a protein and nanoparticle that stimulated production of precursor antibodies.

The particular class of broadly neutralizing antibodies the vaccine is designed to elicit mimic the main receptor on human immune cells that HIV uses for infection, Schief said.

“So they bind to the same place in HIV that HIV uses to contact our cells and infect them,” Schief said.

Because HIV exploits immune system vulnerabilities other pathogens don’t use, HIV research had required extensive probing into how the immune system works.

Most attention has been focused on making antibodies, made by what’s called the adaptive immune system. This part of the immune system produces customized responses to pathogens. But the other part of the immune system, the innate immune system, has also proven to be significant. The innate immune system produces a more generalized response, and is the first part of the immune system to kick in.

These two arms of the immune system are linked, and the implication is that goosing the innate immune response could also stimulate the adaptive immune response. That’s what Sanford-Burnham Medical Research Institute scientists reported earlier this month.

Source: UT San Diego

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