Vaccine Tech 30 Years in the Making Is Getting Put to the Ultimate Test

The coronavirus pandemic could change the way we make vaccines

Photo: SOPA Images/Getty Images

In September 1992, Deborah Fuller traveled from Wisconsin to New York for a scientific conference at the nonprofit Cold Spring Harbor Laboratory, brimming with anticipation. She was there to present early but promising research on a completely new vaccine approach that she had been working on.

It turned out to be a fortuitous meeting. “I go there thinking I’m going to be the only one with this new idea, and there were half a dozen other people all presenting this concept,” says Fuller, PhD, now a professor of microbiology at the University of Washington School of Medicine in Seattle who’s working on a coronavirus vaccine. If other labs were getting the same results, it meant her research wasn’t just a fluke.

The conference organizers were riveted by the new idea. They reshuffled the meeting schedule so that Fuller and the others could present their research during the same session, on the last day of the meeting. Scientists who planned to leave the conference early scrambled to reschedule their flights home so they could stick around to hear about it.

The idea was elegant: Deliver a set of instructions that tells the body’s own cells to make a vaccine.

It was a complete departure from the way vaccines were being made — and largely still are — which involves a complex and costly process. This new approach, by contrast, could be quickly adapted to virtually any infectious pathogen and promised to drastically shorten the timeline it took to bring a vaccine to market. “It was a revolution in the sense of vaccines at the time,” Fuller says. “We immediately recognized its potential for fighting against future pandemics.”

Now, 30 years later, none of these so-called genetic vaccines have ever been approved for human diseases. But a handful of labs and companies have kept at it, steadily improving the technology. And the coronavirus pandemic has presented itself as an opportunity to put the experimental technology to the ultimate test. Now, several genetic vaccines for Covid-19 are advancing through clinical trials and have emerged as front-runners. Moderna, Inovio Pharmaceuticals, and Pfizer are all pursuing genetic vaccines.

Critics point out that neither Moderna nor Inovio has ever brought a drug or vaccine to market before. And before the coronavirus, genetic vaccines hadn’t been tested in large-scale clinical trials for infectious diseases.

If the technology works for Covid-19, it could pave the way for more of these vaccines for other diseases, including new pathogens that emerge in the future. When the next infectious disease outbreak comes, governments could be better prepared with a safe and effective vaccine technology to quickly test, manufacture, and scale-up.

“It may actually change how other vaccines are produced,” Rahul Gupta, MD, senior vice president and chief medical and health officer at the March of Dimes, told reporters during a National Press Foundation briefing on August 7. “We may be at the cusp of very much a new technology.”

But if it fails, it could be a major setback for stemming the tide of the deadly coronavirus.

All vaccines work by essentially tricking the body into thinking it’s been infected. The immune system kicks into gear and registers the invader’s characteristics, so that if it ever encounters the real version, later on, it’s primed to attack.

Traditional vaccines spur this immune response by injecting either a weakened or killed version of the pathogen into the body. Many of the vaccines we currently use are made this way, including those for chickenpox, polio, flu, rabies, and measles, mumps, and rubella.

Weakened, or attenuated, vaccines elicit a strong and long-lasting immune response because they’re so similar to the natural infection. But because of this, people who are immunocompromised are vulnerable to get sick from an attenuated vaccine, and can’t use them. Killed or inactivated vaccines, on the other hand, don’t produce as strong of an immune response and sometimes require a booster shot.

The tried-and-true method of making vaccines involves growing a pathogen in chicken eggs or animal cells, then extracting it so that it can be killed or weakened. Finally, the vaccine is purified and undergoes several safety tests. The process is laborious. The flu vaccine, for instance, requires millions of eggs every year and can take six months to make. Other vaccines can take years to make and test for safety. Genetic vaccines promise to be faster and simpler.

“Most of our vaccine development is really mired in the past,” says William Klimstra, PhD, a professor of immunology at the University of Pittsburgh. “Our ways of generating vaccines go back to the 1930s.”

Some vaccines are now made with just a piece of a pathogen — a protein or two — that best stimulates the immune system, instead of the whole germ. The hepatitis B and human papillomavirus vaccines are made with this approach. These vaccines can be safer since they only contain part of a pathogen but often have to be combined with adjuvants, substances that boost the immune response. Sometimes a second dose is needed. Starting in the late 1980s to 1990s, vaccine developers started to use genetic engineering to make synthetic versions of these proteins instead of using the real thing.

That’s when genetic vaccines entered the scene.

“We were starting to think about a simpler way to go about making vaccines,” says David Weiner, PhD, executive vice president of the Wistar Institute, a nonprofit biomedical research institute in Philadelphia and founder of Inovio, where he is still on the scientific advisory board. The institute is collaborating with Inovio on its DNA vaccine for Covid-19. “What if we didn’t have to depend on all this complicated machinery?”

Weiner was among the handful of scientists who pioneered the idea of genetic vaccines at the Cold Spring Harbor meeting back in 1992.

Genetic vaccines don’t contain any part of the actual pathogen. Instead, they use a small piece of genetic material — either DNA or RNA — that temporarily instructs a person’s own cells to make a piece of a pathogen.

“They encode information,” Weiner explains. “What we’re delivering is information that encodes something that, in this case, looks like a viral protein.”

For SARS-CoV-2, the virus that causes Covid-19, scientists have zeroed in on the “spike” protein, which is found on the virus’s surface and gives it a crown-like appearance. The virus uses the spike protein to attach to and get inside human cells. Genetic vaccines for Covid-19 carry a code that tells cells to make this protein. The hope is that the body will recognize it as foreign and mount an immune response against it.

The allure of DNA and RNA vaccines — and what captured the imaginations of scientists at that 1992 meeting — is their adaptability. The piece of genetic code can be easily swapped out depending on the disease you want to make a vaccine for. You don’t need the actual pathogen; you just need to know its genetic code.

“I kind of liken it to, once you discover the recipe for ice cream, you can make different flavors of ice cream very easily,” says Margaret Liu, MD, chairman of the board of the International Society of Vaccines, who presented early work on genetic vaccines at the 1992 meeting and helped establish the field.

Another potential advantage is that DNA and RNA can be manufactured more quickly than traditional vaccines, and a smaller amount of genetic material is needed for each dose.

“Production is certainly faster with genetic vaccines,” says Roxana Rustomjee, PhD, senior vice president of research and development at the nonprofit Sabin Vaccine Institute in Washington, D.C. “But scientifically, I would say the advantages are still unclear. We’re still on the fence as to whether the immune response that will develop is going to be significant enough to offer protection.”

The idea behind genetic vaccines seemed straightforward, but getting them to work in people was another thing.

Once Fuller, Weiner, and the others got home from that 1992 meeting, they raced to file patents on their technology and publish their work. But getting those early papers accepted to scientific journals wasn’t easy, Weiner says. When he tried to submit his findings, reviewers were doubtful that the approach would work. But eventually, he and others were able to get their papers published.

In animals, genetic vaccines seemed to work perfectly. In 1997, Weiner and his colleagues at the University of Pennsylvania reported that a DNA vaccine they made successfully protected two chimpanzees from HIV. But the first human trials of genetic vaccines were a flop. People didn’t mount the immune response needed to protect them against disease.

“It was a complete and utter failure,” Fuller says. It’s a common problem in biomedical research. Often, a drug or vaccine works in animals but isn’t effective in people.

A key problem to overcome was figuring out how to get the DNA or RNA into cells. Both presented their own challenges that took years to work out. By then, much of the initial excitement for genetic vaccines had fizzled out, and many companies that had gotten into the field left after early trial failures.

Fuller, Weiner, and some others kept at it, focusing first on DNA. They knew that DNA is more stable than RNA, which helps preserve genetic information. But cells don’t take up DNA readily, so scientists needed to devise gadgets to deliver DNA vaccine particles. One of those, created by John Sanford at Cornell University, is called a gene gun. Originally made for experiments on plants, the gun uses helium and gold particles to propel genetic material through cell walls.

Meanwhile, Weiner and Inovio developed an electrical device that zaps the skin and opens up cells so that the DNA vaccine particles can be taken up. Inovio’s Covid-19 vaccine uses the device to deliver the vaccine to a person’s skin. Talking to the New York Times, a volunteer in Inovio’s trial said getting zapped didn’t hurt, but “it just feels strange.” The small, hand-held device will be scaled up using $71 million from the U.S. Department of Defense.

Inovio’s handheld gadget, which uses electrical pulses to deliver a DNA vaccine into a person’s cells. Image: Inovio

The difficulty with RNA is that it breaks rapidly once it’s injected into the body. Scientists couldn’t get RNA vaccines to work until immunologist Drew Weissman, MD, PhD, at the University of Pennsylvania, figured out how to stabilize RNA by packaging it into tiny fatty nanoparticles. Weissman’s technology was so intriguing that a Cambridge, Massachusetts-based biotech company called Moderna ended up licensing it.

Though no DNA or RNA vaccines are on the market yet for human use, a veterinary DNA vaccine to protect horses from West Nile virus was approved in 2005. Liu says it’s proof that the approach can work beyond just lab animals.

In mid-January, shortly after a mysterious respiratory virus emerged in Wuhan, China, in December 2019, Chinese researchers posted the draft genome of the virus online. Companies like Moderna and Inovio were able to start making a genetic vaccine once they had this blueprint.

Scientists immediately realized that the novel virus looked a lot like two they’d seen before: the ones that cause SARS and MERS, which both have a similar spike protein. They knew that people who recovered from being infected with those viruses made antibodies to the spike protein. They reasoned that a vaccine that targets the spike protein could induce an immune response strong enough to protect against disease.

Inovio, Moderna, and German firm BioNTech, the latter of which partnered with pharma giant Pfizer, were already working on medicines that involve DNA and RNA, so they were able to change gears quickly.

In just six weeks, Moderna designed, manufactured, and shipped a vaccine to the U.S. National Institutes of Health for an initial human safety trial, which began in mid-March. Inovio and German firm BioNTech, which partnered with Pfizer, rapidly designed their own genetic vaccines and started testing them in people in April. Now, Moderna and Pfizer are beginning large-scale trials to test vaccine efficacy. To get approved for use, a vaccine for the coronavirus will need to be at least 50% effective, according to the Food and Drug Administration. Early results show that these vaccines look safe and produce an immune response, but there’s reason to be skeptical.

Moderna, historically a secretive startup, doesn’t have a track record of commercializing drugs. And over the years, Inovio has made rosy announcements about many of its vaccines, from Zika to cancer, but the company has yet to get one approved and on the market. Weiner defends the company he created, saying vaccine development just takes a long time. And that’s true; the typical timeline is a decade or more.

Despite the skepticism, all eyes are on the Covid-19 vaccine race. If genetic vaccines fail to work now, they’ll fail in a big way on the world stage.

As much as people like Weiner and Liu are hopeful about the vaccine technology they helped spearhead, they’re also realistic about the fact that this first round of genetic vaccines might not be the most effective ones against the coronavirus.

“I’m not sure that the fastest one out of the gate will make it or that it will be the best vaccine, and maybe that’s okay,” Liu says. “A first vaccine can still make an impact and then later ones can be better.” For instance, the first vaccine for shingles, approved in 2006, reduced the risk of infection by about 51%. But a better vaccine came on the market in 2017 that’s more than 90% effective.

Different vaccines might be better suited to different populations, too. Weiner points to the example of polio to illustrate one potential future for a Covid-19 vaccine landscape. Jonas Salk is known for developing the first effective polio vaccine, which uses a killed or inactivated virus, in 1952. Salk’s rival, Albert Sabin, went on to develop an oral polio vaccine, which uses a weakened or attenuated form of the virus and became available in 1961.

While the Salk vaccine is one of the safest vaccines used today — and is arguably more famous — Sabin’s oral vaccine is widely used in developing countries because it’s easier to give to children than the inactivated injectable vaccine. Together, though, they are both used to keep polio at bay.

“I think that’s a very important lesson,” Weiner says. “Having more vaccine options will benefit all of us.”

Former staff writer at Medium, where I covered biotech, genetics, and Covid-19 for OneZero, Future Human, Elemental, and the Coronavirus Blog.

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