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First COVID, now HIV — Moderna and La Jolla researchers race to make a vaccine

Jenny Hu, a senior staff scientist, prepares proteins at Scripps Research in La Jolla.
Jenny Hu, a senior staff scientist, prepares proteins at Scripps Research in La Jolla. Scripps scientists have teamed with Moderna to develop and test an HIV vaccine that will use the same RNA technology employed against COVID-19.
(K.C. Alfred / The San Diego Union-Tribune)

Researchers plan to use a series of shots to teach people’s immune systems to produce powerful antibody responses against the virus.

After developing a COVID-19 vaccine in record time, Moderna is teaming with scientists at Scripps Research in La Jolla to use the biotech’s technology to make shots against HIV, the virus that causes AIDS.

A Scripps team is working with Moderna to test an HIV vaccine engineered to teach the immune system to make antibodies powerful enough to stop the virus. Researchers are using the same RNA vaccine technology that proved safe and effective against the COVID-19 coronavirus, with an initial clinical trial set to begin in November.

The effort is made possible in part by years of work by San Diego scientists, who have played a leading role in deciphering how the immune system responds to HIV — one of the world’s most complex and crafty viruses — and why, most of the time, those responses are weak and limited.

Though antivirals are widely available in wealthier countries, there’s clear need for a vaccine, researchers and advocates say. About one-third of infected people are not on any kind of treatment, according to the World Health Organization, often because of limited access to medication in lower-income nations. Last year, 700,000 people died of AIDS-related illnesses.

Every other HIV vaccine strategy in the past 40 years has failed or produced lackluster results. But observers say there’s cause for genuine, albeit cautious, optimism this time.

“I don’t know if Scripps has figured it out,” said Mitchell Warren, executive director of the nonprofit AIDS Vaccine Advocacy Coalition. “But we definitely want to follow the science, and the science looks exciting right now.”

A problem gone viral

If scientists ever develop an HIV vaccine, they’ll have to overcome decades of disappointment.

Vaccine efforts have flopped for a few reasons. One is that HIV covers up its most vulnerable spots. Just like the coronavirus, HIV looks a bit like a spiky ball, and the spikes allow the virus to grab onto cells and slip inside them. But HIV’s spikes are mostly hidden beneath a thicket of sugar molecules.

Another issue is that the virus mutates its genetic code with mind-boggling speed, dwarfing the mutation rate of the coronavirus. The immune system tends to recognize the areas on the virus that change the most, making the responses weak and short-lived. Any would-be vaccine must do much better, according to Dennis Burton, an immunologist at Scripps Research.

“That’s one of the great problems with HIV,” he said. “It’s literally hundreds of thousands of different strains, and you don’t know which one you’re going to be exposed to. So you need to be protected against them all.”

‘A long and winding road’

Dennis Burton is chairman of the department of immunology and microbiology at Scripps Research.
Dennis Burton, chairman of the department of immunology and microbiology at Scripps Research, and his team have spent years understanding how the immune system naturally responds to HIV — and why those responses are often too little, too late.
(K.C. Alfred / The San Diego Union-Tribune)

Burton’s team has taken an unorthodox approach to hunting for a vaccine. Rather than test a slew of candidates and hope one produces the right kind of immunity, the researchers are taking cues from patients. Their goal is to find people whose immune systems produce unusually powerful counterattacks to the virus, then design vaccines that do the same in those who have yet to be infected.

Anyone carrying the virus produces antibodies against it; in fact, HIV is usually diagnosed with an antibody test. But Burton’s team has found that only 10 percent to 20 percent of patients produce so-called broadly neutralizing antibodies. These Y-shaped immune proteins latch onto the virus tightly enough and at the right spots to stop most strains from infecting. To do so, the antibodies grip some of the few regions on HIV’s surface that don’t change because mutations there would cripple the virus’s ability to infect and spread.

Animal studies and a recent clinical trial have shown that infusing someone with high levels of broadly neutralizing antibodies could help them fight off the virus. That’s the same idea behind the convalescent plasma and monoclonal antibody therapies now in use against COVID-19.

A tale of two vaccines, HIV and COVID-19

It’s a temporary and expensive way to protect people, however, as antibody treatments must be regularly administered intravenously. A much cheaper and longer-lasting solution would be to teach the body to make the antibodies.

But researchers now understand why that seldom happens naturally.

People with broadly neutralizing antibodies have usually been infected for about two years, which is too late. That’s because HIV slips its genetic code inside our own within days of infection. This reservoir of viral DNA lies dormant but can be reactivated at any time, triggering infected cells to churn out new viral copies. That’s why HIV-positive people must take antiviral medications throughout their lives.

Part of the issue is that the most powerful anti-HIV antibodies are only forged after a drawn-out process of cellular evolution. When an antibody-producing cell, known as a B cell, first recognizes a virus, it divides over and over. Most cells in the body split into identical copies, but newly activated B cells mutate their antibody-coding genes, producing cells with different versions of the original antibody — a bit like musical variations on a common theme.

Some versions grab onto a virus better than others. The ones that latch on best survive, while those that don’t die. It’s survival of the fittest, on a microscopic scale.

This is a normal part of any immune response, but broadly neutralizing HIV antibodies rely on it much more than usual.

“The fact that such antibodies exist shows that a vaccine is in principle possible,” Burton said. “[But] it’s a long and winding road to get to broadly neutralizing antibodies. And we have to shorten that road into, effectively, three or four shots.”

A new shot at immunity

Bill Schief is a protein design expert at Scripps Research.
Bill Schief, a protein design expert at Scripps Research, has spent a decade trying to reverse-engineer an HIV vaccine. He and colleagues think any HIV vaccine must consist of multiple shots that guide the development of antibody-producing immune cells.
(K.C. Alfred / The San Diego Union-Tribune)

Figuring out what goes into those shots is where protein design expert Bill Schief comes in.

Schief, a trained physicist who left the University of Washington to join Scripps Research in 2011, is trying to reverse-engineer a vaccine from the antibodies Burton and others have discovered.

His team takes everything researchers have learned about the antibodies — such as where they latch onto the virus and their 3D shape — and uses algorithms to reconstruct what those antibodies looked like before they evolved into powerful weapons against HIV.

It turns out that the initial “baby” versions of the antibodies don’t attach to HIV very well. So simply injecting someone with a piece of the virus as is won’t work. Instead, Schief said, researchers need to inject a series of modified HIV proteins to guide the baby B cells as they mature into full-fledged virus blockers.

Scientists tested the first step of this process in a trial of 48 participants, 12 of whom got a placebo injection while the 36 others were inoculated with a protein meant to activate B cells with broad HIV-neutralizing potential. These cells are few and far between, Schief said, perhaps as rare as one of every million baby B cells. But researchers announced in February that 35 of the 36 vaccinated volunteers responded to the vaccine.

“My first reaction was, ‘OK, it can’t be this good. Something must be wrong in our analysis pipeline. We need to double-check this before we get too excited,’” Schief said. “It wasn’t just a wimpy little small response that might or might not help later in a real vaccine. It was a big response.”

The results have not yet been published in a scientific journal. But the Scripps team, working with the International AIDS Vaccine Initiative, a global nonprofit, has already partnered with Moderna to test whether an RNA version of the vaccine can produce the same results.

Despite the success of COVID-19 vaccines, using RNA won’t guarantee the HIV vaccine works. But researchers say it’s a faster, cheaper and more efficient approach. Rather than manufacture vaccine proteins in a factory, scientists will deliver genetic instructions to the billions of tiny protein-producing factories inside your body: your cells.

“It’s actually, we think, totally transformational in terms of our ability to learn how to develop an HIV vaccine through human clinical testing in a reasonable amount of time,” Schief said.

Moderna’s trial, which likely will begin in November, will recruit 56 volunteers across Georgia, Texas, Washington, D.C., and Washington state to test whether the results Scripps scientists reported earlier this year can be reproduced with an RNA version of the vaccine. Researchers also will give some participants a second shot eight weeks later meant to guide newly activated B cells toward the next step in producing broadly neutralizing antibodies.

“We know we can start,” Burton said. “We now need to know that we can do the middle bit and that we can finish.”

He thinks it could take about five years to know whether this sequential strategy produces broadly neutralizing antibodies in people, and longer to know whether those antibody responses prevent infection, the ultimate goal. But using RNA makes the timeline years faster than it would be otherwise.

Advocates say the need for an HIV vaccine won’t go away, regardless of how long it takes to get one.

“We need an HIV vaccine as desperately today as we’ve ever needed in 40 years of the pandemic,” Warren said. “COVID hasn’t changed that.” ◆