Two centuries isn’t a bad run for a medical technology. But while vaccination has prevented hundreds of millions of deaths since 1796, when Edward Jenner inoculated a boy with cowpox to prevent smallpox, there’s clearly room for improvement: Vaccines are risky or ineffective in people with compromised immune systems, they don’t even exist for several viral diseases, and flu vaccines, in particular, often fail in the elderly.
All of which gave scientists in half a dozen labs the same idea: Rescue one of the oldest biotechnologies with one of the newest — CRISPR.
In one study published last month, another posted to the preprint site bioRxiv, and nearly half a dozen that are planned or underway, researchers are using this genome-editing tool to skip a step in antibody production, in the hopes of turning the immune system against viruses for which there are no vaccines.
Vaccines work by inducing the immune system’s B cells to manufacture antibodies against specific molecules — called antigens — that poke out of a particular virus. The cells are able to do that because their DNA constantly and randomly produces the three basic components of antibodies. But in nature’s version of just-in-time manufacturing, the B cell holds off on assembling the components until the arrival of viruses (or pieces of viruses) from a vaccine or a natural infection. At that point it swings into action, producing and secreting the precise, virus-matching antibodies needed to destroy the invader, out of billions of possibilities its DNA is capable of making.
Despite decades of trying, there are still no vaccines against viruses that kill tens of millions of people and cause untold suffering every year: HIV, respiratory syncytial virus, and the cancer-causing Epstein-Barr virus. There are many reasons why, including how hard it is to identify the exact piece of an antigen that will trigger production of an effective antibody. And even when vaccines exist, they fail when B cells don’t rearrange their DNA segments in a way necessary to manufacture the needed antibodies.
That gave immunologist Justin Taylor of Fred Hutchinson Cancer Research Center an idea — skip the vaccine.
Injecting antibodies directly has been shown to protect premature babies against respiratory syncytial virus, for instance. Antibodies against a number of HIV strains (“broadly neutralizing antibodies) control viral load in people with HIV, said Trevor Mundel, president of global health at the Bill and Melinda Gates Foundation. But the antibodies generally last only 21 days or so, and therefore have to be given again and again. So why not create a one-and-done therapy: use CRISPR-Cas9 to genetically reprogram B cells to produce, and keep producing, whatever antibody someone needs?
“I think engineering B cells is an attractive option that has great promise,” said immunologist Dr. Arturo Casadevall of Johns Hopkins University, who is not involved in such research. It might be difficult to make the approach work against viruses that evolve resistance to antibodies (HIV is infamous for that), but CRISPR’ing B cells “could work” where that “is less of an issue,” he said.
If so, it would be a novel use of the genome-editing technology, whose potential medical applications mostly focus on turning disease-causing genes into healthy ones. In this case, B cells’ genes are just fine. They simply need a nudge to produce the right antibodies, Taylor said.
To do that, he and his colleagues used CRISPR-Cas9 for two tasks. First, they gave B cells growing in lab dishes a little electrical zap, opening portals through which CRISPR slipped in and cut the cells’ DNA at a precise spot. They then used a harmless virus called AAV to carry in DNA for antibodies against respiratory syncytial virus, in the case of mouse B cells, and, in human B cells, DNA for antibodies against HIV, flu, or Epstein-Barr. The goal was for the B cell to repair the cut with the introduced DNA.
That worked in about 15 percent of mouse cells and 5 percent to 59 percent of the human cells, depending on the virus. And when the scientists took mouse B cells that had been CRISPR’d to synthesize antibodies against respiratory syncytial virus and injected them into immune-compromised mice, the recipients soon had anti-RSV antibodies in their blood: When they were infected with RSV, the virus was undetectable in their lungs. The transplanted, CRISPR’d B cells had given them immunity to it, just as a successful vaccine does.
Using CRISPR to edit B cells could produce “immunity against pathogens for which traditional vaccination has failed,” Taylor and his colleagues wrote in their preprint, which they’ve submitted to a journal for peer review.
A competing team got promising results, too. In B cells from three donors, James Voss of Scripps Research Institute and his colleagues edited the genome so it produced an antibody against HIV, they reported last month in the journal eLife. The antibody attached itself to one of HIV’s antigens, the first step toward triggering the immune system to kill the virus.
There’s a long way to go before CRISPR’d B cells give anyone immunity to anything. For starters, the approach won’t replace traditional vaccines, if only for economic reasons. B cells would have to be CRISPR’d individually, patient by patient (donor B cells, CRISPR’d or otherwise, are rejected by the immune system). Vaccines, by comparison, are cheap. Taylor’s team has ideas about how to make universal-donor B cells, and Dan Wattendorf, director of Innovative Technology Solutions at the Gates Foundation, said “there are scientific opportunities” to tweak B cells so they’d be universal donors.
If genetically altered B cells kept churning out antibodies, “it would be a one-shot” preventive or treatment, said the Gates Foundation’s Mundel.
The biggest hurdle would be keeping viruses from outsmarting antibodies produced by CRISPR just as they do antibodies produced by vaccines, by tweaking their antigens just enough for the antibodies not to fit them anymore. But Taylor believes it’s possible to engineer B cells to defeat that antigenic drift, “even if you need five antibodies to cover that,” he said, something that is well within the capabilities of CRISPR.
“We can see gene editing [to protect against viruses] becoming feasible,” said Wattendorf. “It’s a very interesting time.”