For decades, scientists have struggled to develop vaccines to stop the spread of HIV. And for decades, the vaccines have failed. HIV mutates at a ferocious pace, outrunning the immune system’s antibodies.
Studies published Thursday demonstrate that the immune system can be accelerated so it’s primed and ready to block HIV infection.
The studies describe a multi-pronged approach to an HIV vaccine, each one demonstrating a component of the process. Assembling all these components into a vaccine for humans is the final step. Testing could take place in about two years, the scientists say.
The scientists, from The Scripps Research Institute, Harvard, MIT and other institutions have mapped out each step and shown in animal models that they work.
Three studies representing aspects of the research were released; two in the journal Science and the third in Cell.
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. The scientists say they’re excited about the results.
“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,” said Fauci, who has been researching HIV since the early years of the AIDS epidemic.
Learning from nature
The scientists envision a series of sequential vaccinations. The first one is intended 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.
The strategy is based on reverse-engineering how the immune system naturally responds to HIV exposure.
In the natural course of HIV infection, most people eventually become immune-deficient due to the relentless attacks of the virus, which keeps mutating around antibody attacks. If untreated, these people develop AIDS.
But in a minority of those infected, the immune system learns how to make broadly neutralizing antibodies. In a very few individuals, these antibodies are made soon enough and are powerful enough to keep HIV under control, even without medications. They don’t progress to AIDS.
Most often, though, these broadly neutralizing antibodies arise too late to suppress HIV, so these patients require medication. However, in lab experiments, the broadly neutralizing antibodies have been shown to prevent infections.
So the expectation is that if a vaccine induces these broadly neutralizing antibodies, uninfected people will be protected and remain HIV-free even if they come in contact with the virus.
The three Scripps Research scientists play complementary roles in this work.
Burton has been collecting broadly neutralizing antibodies from infected individuals for decades. He studies them for clues as to how they work. Nemazee developed a partially humanized mouse used in the study. Schief uses information from Burton to create the right molecules to elicit the desired response, a process called protein engineering.
The vaccination procedure envisioned for humans would require several injections over a period of weeks or perhaps months.
The first step is to cause the immune system to make more of a subtype of B cells that can produce the broadly neutralizing antibodies. This cell is a subtype of antibody-making B cells. Only a fraction of B cells are capable of maturing into cells that make these antibodies. So the population of these cells must be goaded into multiplying, priming the immune system.
But these B cells aren’t yet ready to make the broadly neutralizing antibodies. So people would then be injected with engineered molecules evoking specific characteristics of the virus structure.
This would mimic the immune system’s response to infection over time, but at a much faster pace, and without the debilitating consequences of actual infection.
At the end of the process, the primed and matured B cells would make the powerful broadly neutralizing antibodies, enabling uninfected people to repel HIV when exposed to it.
This is a lot of work, compared to the relatively straightforward process used to develop such well-known vaccines as those against smallpox or polio. For smallpox, the vaccine contains a living relative of the virus that stimulates an immune reaction. For polio, either killed virus or weakened live virus is used in vaccines.
HIV is different, 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 port
These contortions can be analogized with those used by the rebels in “Star Wars” to destroy the Death Star, Nemazee said. It required Luke Skywalker to maneuver to a location where he could send proton torpedoes down a narrow pipe to the vulnerable core. No other attack would have worked.
“The Death Star is covered with stuff that is irrelevant,” Nemazee said. “You could attack it and nothing would happen.”
Likewise, most of HIV is covered with shielding proteins, highly visible to the immune system. Consequently, most antibodies go for these decoys and viral replication continues unhindered.
If the immune cells 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 precursors to these broadly neutralizing antibodies.
The particular class of broadly neutralizing antibodies the vaccine is designed to elicit mimics 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.
Immune system education
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.
Production of broadly neutralizing antibodies is associated with higher levels of certain “helper” immune cells, according to a 2013 study led by Shane Crotty, a vaccine researcher at the La Jolla Institute for Allergy & Immunology.
These and other studies have illuminated previously unknown levels of complexity in the immune system. Since HIV takes such efficient advantages of immune weaknesses, it’s logical that designing an HIV vaccine is harder than other vaccines, said Fauci, of NIAID.
“It’s much more complicated than with plain ol’ vaccinology, where you walk away with your flu shot and you’re done,” Fauci said. “Once you get the right antigen, you’re good to go with those others. That’s the reason we’re testing an Ebola vaccine right now. It’s a pretty uncomplicated vaccine.”