Scientists at Fred Hutchinson Cancer Research Center in Seattle have developed a new strategy to counter the frustrating ability of HIV to sidestep vaccines designed to block it.
It is a scheme that relies on one of the oldest tricks in the book for a fisherman: Use the right bait.
“The kind of vaccine strategy that we are talking about is very different than all other vaccines that are on the market,” said Hutch immunologist Dr. Justin Taylor, who, along with colleagues Drs. Andrew McGuire and Leo Stamatatos, led the development effort.
In a pair of papers recently published in the Journal of Experimental Medicine, the Hutch vaccine researchers explain how they were able to use a tiny chunk of protein as bait to fish for extremely rare white blood cells hidden within ordinary blood.
When these rare B cells bind with the bait, they multiply and are not so rare anymore.
That’s important, because these B cells are just a few evolutionary steps away from generating — with some nudging from a series of additional injections — the kind of long-lasting immune responses needed for an effective HIV vaccine.
And if this new multistep approach to making a vaccine works, it could open the way to developing more effective vaccines against other viruses, such as influenza, that mutate so rapidly they can render immunizations ineffective in less than a year.
The strategy is based on the understanding that standard-issue antibodies — like the tiny immune proteins that neutralize measles or polio — are not up to the task against a shape-shifting bug like HIV. The fierce mutations on the surface of the AIDS virus require much stronger antibodies, and the Hutch work focuses on developing a process to coax the body into creating them.
Researchers have identified more than 20 varieties of these so-called “broadly neutralizing antibodies.” They retain their effectiveness across changing strains of HIV because to slip free of these immune proteins the virus would have to undergo extreme mutations of its surface structures, making it no longer able to infect or replicate.
It is possible to grow these complex structures in a test tube. But researchers have not found the ingredients for a vaccine that can prompt B cells — our antibody-making factories — to churn out lots of these oddball proteins after a shot in the arm. So scientists have yet to bring the world an HIV vaccine that reliably stimulates the body’s immune system to make these potential epidemic-busting proteins.
To find the right bait for catching rare precursor B cells, Hutch researchers turned to a technology that even most scientists would agree is a mouthful: anti-idiotypic antibodies. These are small Y-shaped immune proteins — antibodies — that can latch onto other antibodies. Discovered in the 1960s, they have intrigued biologists for decades. The Hutch researchers generated “anti-ids” that could latch onto known HIV-blocking antibodies like VRC01. Then, they took a tiny piece of protein from the anti-id where it sticks to the target antibody. That piece serves as the bait in these experiments. Injected into the body, it snares and activates the rare precursor B cells that scientist hope can evolve the capacity to make antibodies that HIV cannot evade.
The reason is that such antibodies are definitely not standard issue — they are often oddly shaped and found in few patients. They are freakish versions of more common antibody structures, and the B cells that produce them are just as unusual, loaded with gene mutations acquired as they evolve from one generation to the next.
“It takes multiple rounds of B-cell maturation to produce a broadly neutralizing antibody,” said McGuire. “And that’s a selective process. It just takes time.”
It is estimated that one of those super antibodies, known as VRC01, took as long as three years to evolve naturally in the HIV-positive patient in whom it was first found. The genes of the B cells that make them may differ as much as 40 percent from those of the “precursor B cells” from which that lineage began.
The work of the Hutch team is to recreate — and speed up — that process of evolving these protective antibodies inside a person’s bloodstream. And the route they have chosen to do so starts with finding the rare precursor B cells. These cells cannot make broadly neutralizing antibodies on their own, but evolutionarily speaking, they are on their way to doing so.
Much of the research described in the two papers shows how they were able to locate hard-to-find precursors by using as “bait” a vanishingly small protein that recognizes only these precursor cells. Out of trillions of blood cells, the sensitive protein can home in on the rare ones, and when it attaches these cells begin to reproduce. The process can increase their numbers more than a hundredfold, creating raw material for additional changes.
McGuire and Stamatatos are senior authors on a paper describing how this fishing process produced a robust supply of precursor B cells that can evolve into the VRC01 antibody; while Taylor joins them as a senior author of the companion paper describing how the process worked on precursor cells for another broadly neutralizing antibody known as b12.
— Dr. Leo Stamatatos
“What’s great about having the two papers come out at the same time is that it immediately says this is not some one-off thing. It can be done with different lineages of B cells, and it should be possible for other viruses with difficult-to-make vaccines, such as dengue virus,” Taylor said.
Having proven it is possible to find the right precursor cells and expand their numbers exponentially, the researchers are focused on developing the next series of shots, which are designed to drive the evolution of the precursor B cells to produce the desired super antibody.
“Let’s call it a five-step process. Step one is activating these precursor cells that have potential, then steps two through five are making them change to get them there,” Taylor said.
After activating the precursor cells, each shot in the proposed series will contain a different protein; each protein will be designed to stimulate the prior generation of B cells to produce a new crop with genetic changes that make antibodies looking more and more like VRC01 or another desired super antibody.
“As they accumulate mutations, they become better and better at neutralizing HIV,” Stamatatos said.
The first shot in the series would contain the tiny protein “bait” to generate a large population of precursor B cells. Hutch researchers have already designed a series of immune proteins for subsequent shots meant to guide the evolution of B cells toward production of HIV-blocking broadly neutralizing antibodies. They are now in the process of testing them in mice. “Those mice studies are happening now, and we expect results in the next six to 12 months,” Stamatatos said.
The result, if these studies succeed, would be a candidate vaccine that might consist of four to five different shots, each with different ingredients which, in sequence, lead to the production of broadly neutralizing antibodies — a vaccine that could eventually be tested in humans.
Sabin Russell is a former staff writer at Fred Hutchinson Cancer Center. For two decades he covered medical science, global health and health care economics for the San Francisco Chronicle, and he wrote extensively about infectious diseases, including HIV/AIDS. He was a Knight Science Journalism Fellow at MIT and a freelance writer for the New York Times and Health Affairs.
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