Move over, Pfizer and Moderna. You won’t be the only games in town too much longer.
COVID-19 has existed for barely more than a year, but 64 vaccines are in clinical development and another 173 in preclinical development worldwide nonetheless, according to the World Health Organization. Dozens of hopefuls are in clinical trials in the U.S., including several by California researchers.
But the two inching closest to the finish line here — by Oxford-AstraZeneca and Johnson & Johnson — could win emergency use authorization from the U.S. Food and Drug Administration as soon as this spring, which would instantly increase supply and deliver a much-needed jolt to the nation’s maddeningly sluggish mass vaccination campaign.
“In science, we often say we’re on the cusp of great things — but now, really, we’re on the cusp of great things,” said Bali Pulendran, professor of microbiology and immunology at Stanford University.
“There’s a bubbling cauldron of vaccine ideas out there. It’s unprecedented. When have we ever seen so many candidates developed in such a short amount of time?” Pulendran said. “This virus has energized every dimension of vaccinology, and we should parlay some of that energy into transforming the field as we know it. We should talk not only about targeting cancer, HIV and influenza, but a whole host of other diseases for which we don’t yet have effective vaccines.”
The breakneck pace of scientific advancement over the past year — fueled by extraordinary cooperation between researchers worldwide, unprecedented financial investment from governments, and technology that harnesses the body’s own cellular factories to produce viral proteins, rather than manufacturing them in brick-and-mortar factories — promises an end to a deadly pandemic that has infected nearly 100 million people, killed more than 2 million and paralyzed much of the world.
On the near horizon: a COVID vaccine that can protect after just one shot, rather than two. Vaccines that can be stored in regular refrigerators rather than in expensive, ultra-cold freezers. Vaccines that employ a sci-fi smorgasbord of advanced technologies to do their work.
The efficacy of these up-and-comers, however, remains to be seen — will they be as good as Moderna and Pfizer, at a stunning 95% after two shots? It seems clear that many will eclipse the low 50% bar originally set by the FDA for emergency use authorization. A more serious threat, perhaps, is the mutating virus itself: Will it evolve to evade the snares these flotillas have laid to catch it?
Time will tell. Still, more vaccines mean less disease, and less disease means fewer deaths.
The near horizon
Essentially, all vaccines work the same way, by triggering the body’s immune system so it can recognize and fight the invading disease if and when it arrives. How that’s accomplished, though, differs from vaccine to vaccine.
While the Moderna and Pfizer vaccines use a single strand of delicate messenger RNA, wrapped in a fatty package, to deliver instructions to human cells on how to manufacture the virus’ spike protein, both Johnson & Johnson and AstraZeneca use adenoviruses, of the sort that cause runny noses and common colds, to deliver more rugged, double-stranded bits of coronavirus DNA to the same end.
Johnson & Johnson uses an adenovirus that’s been modified so it can enter cells, but can’t reproduce or cause illness. Some scientists worry that this might be less effective in people who’ve been exposed to similar adenoviruses, meaning the immune system would attack before the vaccine gets to do its work. AstraZeneca tries to work around this by using a modified adenovirus from chimpanzees, which the human immune system won’t recognize.
Both of these candidates are “non-replicating viral vector vaccines,” and there are 10 using this technology in trials worldwide, according to the WHO.
The single-dose COVID-19 vaccine being developed by the Janssen Pharmaceutical Cos., the Belgium-based branch of behemoth Johnson & Johnson, is expected to release critical data from late-stage trials in the next week or two, with emergency use authorization coming as soon as March. Vastly simpler than the two-dose regimens, the candidate appears to work.
Epidemiologist and population health scientist Andrew Noymer at UC Irvine says the single-dose feature is “huge, absolutely huge.” He’s been watching with consternation as people who have received their first Pfizer and Moderna shots struggle to get appointments for the required second doses. “Two shots is more than twice as complicated as one,” he said.
Storage is vastly simpler as well. Rather than having to be frozen at very low or sub-arctic temperatures, Johnson & Johnson’s vaccine can be kept in refrigerators for months. And the company’s sheer size could go a long way toward easing supply strangleholds: Johnson & Johnson has said it hopes to manufacture a billion doses by the end of the year.
AstraZeneca’s version, meanwhile, is more cumbersome, requiring two shots spaced four weeks apart. But storage is similarly simple, requiring just refrigeration rather than freezing. And while it already has emergency approval in the United Kingdom — and has been injected into arms for weeks — its path forward in the U.S. is a bit more fraught.
There were errors in AstraZeneca’s late-stage trials that the FDA frowns upon. Researchers mistakenly gave some participants just a half-dose for the first shot, and this mistake actually turned out to provide far more protection than did two full doses. The error — a half-dose, followed by a full dose — proved 90 percent effective at preventing COVID-19, while two full doses were just 62 percent effective.
The FDA wants more data before considering emergency use authorization for its use here, but that could happen as soon as April. The company hopes to produce up to 3 billion doses globally this year.
The farther horizon
Los Angeles billionaire Patrick Soon-Shiong is in the early phases of testing a nonreplicating viral vector vaccine, developed by his NantKwest Inc./ImmunityBio companies, at Hoag Hospital in Newport Beach.
Another California candidate, by City of Hope in Duarte, is moving out of first phase trials as well. Arcturus Therapeutics of San Diego is in second phase trials with its RNA-based vaccine. Novavax, based in Maryland, is in late-stage clinical trials and well, and dozens of other vaccine candidates are moving forward in China, Russia, Italy, Germany, Japan, the U.K., Israel and several other nations.
“My personal favorite candidate is the Indian vaccine Covaxin, which is still being tested and may be co-developed in the USA with the biotech company Ocugen,” said Egest J. Pone, project scientist in UC Irvine’s Vaccine Research & Development Center. It’s a traditional, whole, inactivated coronavirus, supplemented with common immune-response boosters.
“The reasons a lot of researchers like the whole inactivated virus are that: 1) it includes all the viral proteins and not just the main spike (or viral ‘handle’) as in the RNA vaccines by Pfizer and Moderna; 2) the viral proteins are represented on the actual spherical virus so their orientation may yield antibodies to the main part of the virus that attaches to the lung cells of the host; and 3) since the viral antigens are repeated on the whole inactivated virus (i.e. there are dozens of copies of the virus protein), this stimulates a stronger immune response compared to the RNA vaccines,” he said by email.
Scientists are poring over vital variables to understand how the different vaccines perform: What is the strength of the antibody response after the first vaccine? After the second? Is a boost necessary for some and not others? Does response wane over time? Which vaccines are more durable? If a person was already exposed to the novel coronavirus, does it impact a vaccine’s efficacy, durability or side effects?
“We’re starting to collect data of that kind now,” said Philip L. Felgner, director of UC Irvine’s Vaccine Research and Development Center and Protein Microarray Laboratory and Training Facility.
At UC Irvine’s Laboratory of Cellular and Molecular Immunology, director Lbachir BenMohamed is pushing the next frontier — a preemptive, “pan-coronavirus” vaccine designed to squash everything from COVID-19 to the common cold. It’s being tested in mice, with hopes of starting clinical trials in people this year.
“In the past 20 years, there have been several deadly coronaviruses, and there’s no reason to think there won’t be another in the coming years — 2025? 2028? 2030?” BenMohamed said. “The only unknown is how bad it will be. We must learn lessons from what’s happened in 2020.”
By mapping the proteins common to a variety of human and animal coronaviruses — and designing a vaccine to combat them — a pandemic could be stopped before it even starts. His lab targets the virus’ spike protein as well as about 10 others.
At Stanford, Pulendran is working on novel ways to take the guesswork out of vaccine trials altogether.
“It can take years to develop a vaccine, and most of that time is spent on testing in humans to see if it induces immunity,” he said. “What if there was some way you could tell very quickly — in smaller phase 1 trials of 50 or 100 people — whether it’s likely to work or not? You wouldn’t have to wait a year to know the likelihood of long-term responses. You could predict it in a few days.”
Pulendran’s lab is using immune-monitoring methods to do just that. By taking blood from vaccine trial volunteers, peering deeply at the genetic changes that occur — or don’t occur — in their cells, it’s possible to use computational analysis to predict how they’ll respond over time. “I feel that sort of thing is going to play an increasingly important role in testing vaccines in humans,” he said.
Again, all this means more vaccines, and more vaccines mean less disease, and less disease means less death. But that’s just part of the bigger picture, said Richard Carpiano, a public health scientist and medical sociologist at UC Riverside.
“We will still need to address supply chain and coordination issues that exist, from manufacturers all the way to the local level where the vaccines are being administered,” he said. “New vaccines will be an important asset for achieving vaccination goals, but will not be an automatic fix to the problems we have been currently experiencing with rollout.”
