SALT LAKE CITY — With more than 100 different COVID-19 vaccine candidates in various stages of development — eight already in human trials — experts are “cautiously optimistic” the world will get a vaccine.
They just don’t know when.
It’s possible an emergency vaccine could come by the end of 2020 or early 2021 if — and only if — promising results come from those first human trials, said Barry Bloom, a professor of public health and former dean of the Harvard T.H. Chan School of Public Health, during a recent online Q&A.
But there’s a big difference between identifying a successful COVID-19 vaccine in a lab and having a studied-at-length, licensed vaccine available in every corner pharmacy.
The entire process is laden with potential setbacks — not the least of which is finding enough vials to hold the life-saving serum.
But suppose a vaccine is identified by late 2020.
The next step would be getting emergency use authorization from the FDA, which would allow policymakers to offer the vaccine to health care workers, first responders and essential workers like grocery store clerks and delivery truck drivers.
Yet never before has the U.S. vaccinated millions under emergency use authorization, says Norman Baylor, president and CEO of Biologics Consulting and a former director of FDA’s Office of Vaccines Research and Review.
Although the vaccine’s safety should be solid, how long it protected someone against COVID-19 would still be unknown, Baylor said. Scientists would continue to gather data to answer that question, gain official licensure from the FDA and make the vaccine more available to the general public.
So when will that be? That’s the million-dollar question, says Baylor.
“A lot of people are answering that question, and I don’t think they should be,” he says. “We haven’t seen an ounce of data in humans yet. It’s coming, we’ll see it soon. But to answer that question without even seeing, I think that would be a little careless.”
Speed of science
In nearly every conversation about finding a vaccine for COVID-19, Paul Offit hears the same question: “Why is it taking this long?”
Yet as Offit, a pediatrician and director of the Vaccine Education Center at The Children’s Hospital of Philadelphia, lists off the steps for the typical vaccine timeline, one can almost hear him shaking his head.
Vaccine development is measured in decades — not months, with each step taking years, not weeks.
The vaccine Offit co-developed to protect babies against rotavirus took 26 years.
Dr. Afzal Siddiqui, a professor of internal medicine, immunology and molecular microbiology and director of the Center for Tropical Medicine and Infectious Diseases at Texas Tech University, has been working on a vaccine for the parasitic disease schistosomiasis — also called snail fever — since before his son was born.
Today that son is a physician. And Siddiqui just started clinical trials in humans in the United States and Africa last year.
“The chances of getting every piece of the puzzle in place in 12 to 18 months ...” Siddiqui pauses as he contemplates a COVID-19 vaccine. “If it happens, it will be a miracle.”
Yet everything about this COVID-19 vaccine process is different. Faster. More urgent.
After Chinese scientists identified the new virus wreaking havoc in Wuhan, they alerted the world’s scientific community and shared the viral genome. Within hours, researchers in the U.S. had started to work on a vaccine, said Dr. William Schaffner, a professor of preventive medicine and infectious diseases at Vanderbilt University Medical Center and medical director of the National Foundation for Infectious Diseases.
Thanks to existing research on SARS and MERS, cousins of the novel coronavirus, scientists had some idea of what they were facing, just not how to stop it.
In nonpandemic time frames, this “discovery phase,” and preclinical studying of the enemy virus can span years.
Yet on April 19 — only 110 days after a cluster of COVID-19 cases was identified in Wuhan — researchers from Sinovac Biotech in Bejing reported that their vaccine for COVID-19 had protected eight rhesus macaque monkeys against the virus.
Now, researchers are trying eight different approaches or platforms for a vaccine.
Sinovac and the Wuhan Institute of Biological Products/Sinopharm are two labs injecting weakened or inactivated forms of the virus — like how the polio or measles vaccines work — to promote an immune response.
Labs like Moderna in Massachusetts and a joint collaboration between New York’s Pfizer and Germany’s BioNTech, are working on vaccines that contain bits of mRNA — genetic instructions that cause cells to reproduce the viral protein and hopefully trigger an immune response that way.
CanSino, in China, and the University of Oxford in the UK are both trying the approach of genetically engineering other viruses so they produce coronavirus proteins, prompting an immune response without actually risking an infection for the subject.
And Japan’s National Institute of Infectious Disease, the University of Pittsburgh and Novavax are among the dozens of labs trying to inject coronavirus proteins directly, sending in fragments to generate an immune response — though all protein approaches are still in the preclinical phase.
Each approach has both pros and cons.
Protein-based vaccines require multiple doses to be effective plus an adjuvant — or catalyst — to help the vaccine work more effectively. Inactivated virus vaccines require a lot of virus to begin with, and DNA and mRNA vaccines, while easy to manufacture, have never been licensed for human vaccine use before.
Yet in a pandemic, David Weiner said no rational approach is off-limits and every study showing positive results should be encouraged and funded.
“This is a different circumstance,” says Weiner, executive vice president and director of the Vaccine & Immunotherapy Center at The Wistar Institute, who’s leading a team at work on a COVID-19 DNA vaccine. “This calls for different thinking. Maybe we needed that wakeup.”
Once animal studies are successful, it’s time to test in humans — in three phases and in this case, as quickly as possible.
Phase I is small, usually less than 100 volunteers, and focuses on finding the right dose and watching for safety issues.
Weiner’s group inoculated its first 40 volunteers at the beginning of April and plans to announce more candidates soon. They hope to have data by June, he said.
Pfizer and BioNTech recently announced that they’ve begun a study of four mRNA candidates in a single continuous study, starting with 360 volunteers.
Oxford University has already made headlines for prior research that has allowed it to speed forward with a blended phase I and II trial involving around 1,100 subjects. Positive results could lead to a possible vaccine by September.
In phase II trials, researchers recruit a larger subject pool to again look for safety issues, as well as signs that the vaccine is promoting the right antibody response.
No one wants a vaccine that encourages the body to produce antibodies that actually make the problem worse — as happened just a few years ago with the dengue fever vaccine in the Philippines.
Moderna recently announced it received FDA permission to begin phase II of its mRNA vaccine “shortly.”
Not many vaccine candidates ever make it to phase III — the largest human trials where researchers review safety and look for large-scale side effects, but also ask, is this vaccine better than nothing? And how long will protection last?
For these massive studies, often in the tens of thousands, subjects are divided. Half receive the vaccine and half receive a placebo — but distribution is coded so neither subjects nor doctors know which is which.
When doctors compare sickness rates, they can identify if their vaccine is working — and if there’s anything they can say about its effectiveness for subgroups, like elderly versus young people. Most of the clinical trials going on right now for COVID-19 involve healthy people ages 18-55, says Baylor, so more studies looking at the elderly and children will be needed.
Americans already accept a range of effectiveness for vaccines, with tetanus and measles being nearly 100% effective for those who get the shot, whereas the flu vaccine is only around 50% effective, Offit said.
Yet, because the flu kills nearly 50,000 people a year, protection is sought in favor of nothing.
At this point, experts have no idea how effective a COVID-19 vaccine would be, nor if it would be a one-time shot or a seasonal necessity. They also don’t know if it would require an initial shot, then a booster in a few months or a year — all of which would exponentially increase the production order.
Whatever is developed, the goal is to at least prevent moderate to severe cases, said Offit, keeping people out of the hospital and off a ventilator.
What could go wrong
Baylor, formerly with the FDA, is hopeful a successful vaccine will emerge, but he’s also aware that even when scientists are not in a pandemic-rush, there are still “so many things that could go wrong,” he said.
That’s why slowing down, and being extra cautious — despite the desperate demands for a solution — is critical.
“Any misstep here could have the potential of damaging our whole immunization program in the U.S. and the world,” he said. “The key to an immunization program is acceptance by the public. If you damage that acceptance, you have just crippled your public health response.”
Safety is the No. 1 concern for anyone involved with vaccines, says Schaffner.
“Remember, you give vaccines to people who are healthy,” he says. “Therefore the standards for safety are very, very high.”
After a vaccine is out, safety in the U.S. is monitored through the Vaccine Adverse Event Reporting System, which keeps track of every negative event associated with receiving a licensed vaccine, and studying whether it was coincidental or potentially caused by the vaccine.
One example of the reporting system’s effectiveness was the response to the first rotavirus vaccine, made by Wyeth and licensed by the FDA in 1998.
Despite proving safe in the lab and initial clinical studies of nearly 12,000 children, when the vaccine was released nationally, after a few weeks there were 15 reports of serious problems in vaccinated infants.
Distribution of the vaccine was paused, studied and eventually pulled in 1999.
Because of that, stakes were even higher for Offit and his team, who had to test 70,000 babies in 11 countries before their rotavirus vaccine was licensed.
That testing alone took them four years.
Offit isn’t convinced that such strenuous testing would happen for a quickly developed COVID-19 vaccine.
“When you talk about doing something in 12 to 18 months, you can assume correctly that things are being skipped,” he said. “I think it’s going to be offered to the general public before you’ve had the kind of large study that I just talked about — which takes time doing.”
An emergency use vaccine may have been through a smaller phase III trial, or perhaps just a really large phase II trial, but even after it’s rolled out — the clinical trials won’t stop, says Baylor.
At that point, it will be almost like two parallel tracks: scientists studying in real-time those who have already been inoculated, offering supportive data to the ongoing large-scale phase III studies to determine how long protection lasts and if there are any side effects not seen at smaller levels.
The ultimate goal is still official licensure from the FDA — which requires all the proper data.
It’s also possible that there will be multiple emergency vaccines available — both in the U.S. and globally. If so, scientists will carefully monitor results and if one vaccine is clearly superior, it will become the new favorite.
Once countries have a licensed vaccine, they’ll most likely vaccinate their own people first before turning to help others, Schaffner said. Companies will likely be willing to sell successful vaccine technology to those who are capable of trying to make it on their own — a very difficult, but potentially possible solution.
Yet, no matter what vaccine is licensed, it does little good if no one will take it because they don’t trust it.
Some are even rallying to protest what they see as infringement of personal rights and individual autonomy. Others may just be worried about getting something that was developed at an unprecedented pace.
“We’re not the same people who made vaccines in the ’60s, ’70s,” says Weiner. “We are quite comfortable that Amazon can deliver a package to anyone in the world from anyone in the world in just a few days, yet we suspect that all these unusual, uncharted things are happening with our vaccines, and they’re not. They’re monitored just like (packages) with similar computer models and systems.”
Hesitancy toward vaccines is likely the result of them becoming victims of their own success, says Dr. Walter Orenstein, associate director of the Emory Vaccine Center, and former director of the United States Immunization Program. They’ve completely eradicated some diseases, such that people have never seen what polio or scarlet fever can do.
“That’s not the case here,” Orenstein said. “People recognize that this is a bad disease and so hopefully that will overcome some of the hesitancy.”
He’d also like to believe that the increased attention on the vaccine process will help people see just how difficult and time-consuming it is, and how carefully each step is monitored: “It’s not in the lab today, in the arm tomorrow.”