Editor’s Note: After this article appeared, the U.S. authorized several COVID-19 vaccines that were vetted by medical experts through an extensive federal review process. These vaccines have met rigorous scientific standards for safety, and have proven highly effective at preventing illness, hospitalizations, and death from the disease. Read how the first COVID-19 vaccines were developed, and find safety information from independent scientists and in this AAMCNews article.
A viral disease spreads across the globe, causing debilitating illness and death in numbers that mount by the day. Scientists race to develop a vaccine as panic grows, and within a year, millions of Americans get inoculated. The scourge recedes.
Except for those who get one of the 120,000 doses that accidentally contain the live virus. Some 40,000 inoculated children contract a mild form of the disease. Dozens more children get stricken by the paralysis that the vaccine was designed to prevent, as do over 100 other people who pick up the virus from the inoculated children. Ten of them die.
Such tragic errors from inoculations against disease — this one from the polio vaccine developed by Jonas Salk, MD, in the 1950s, one of the most successful immunizations in history — help to explain why an anxious world must wait up to two years for a vaccination to shield people from the potentially fatal novel coronavirus.
“We are moving as fast as humanly possible,” says research scientist Brooke Fiala during a break from working on a vaccine at the University of Washington’s (UW) Institute for Protein Design.
Yet bringing a vaccine from lab to public deployment proceeds at a glacial pace, and it’s a costly expedition. “From the creation of the idea to having a marketable vaccine is usually seven to 10 years or more, and about 1 billion U.S. dollars,” says Gregory A. Poland, MD, director of the Mayo Vaccine Research Group.
That’s by design: the design of human biology and procedures built to minimize harm.
“The basic history lesson when it comes to vaccines and immunization is that there always has been a risk and there always will be a risk,” says David S. Jones, PhD, the A. Bernard Ackerman professor of the culture of medicine at Harvard University.
Looking at the risks and the steps to mitigate them sheds light on some of the factors behind the long, expensive process.
Labs at academic research institutions were well-positioned to search for a vaccine soon after the novel coronavirus was first reported in China in January. Many of those labs have been conducting research into viruses and vaccine development for years, including forms of coronavirus. Researchers at UW, Mayo Clinic, Duke University School of Medicine, and Baylor College of Medicine, among others, tapped into past and ongoing projects to focus on stopping the virus that causes COVID-19.
At Mayo, Poland echoes the thinking of other lab leaders when he says, “We have technology and expertise. We’ve developed patents. Let’s jump in.”
For academic medical labs with the foundational research, scientific tools, and human expertise, producing a vaccine to test can take just months. Several reported in late March that they were preparing to test vaccines on animals or humans. That’s where the process slows to a degree that surprises outsiders.
“We are moving as fast as humanly possible.”
University of Washington Institute for Protein Design
“What we have control over is the development side. We’re moving at lightning speed through that now,” says Fiala at UW. “What we can’t control is the animal studies and clinical trials.”
Those steps are dictated by federal regulations that address the inherent risk of vaccines: Unlike treatments for disease victims, vaccines are administered to healthy people to stave off illness if they get exposed to the virus. Vaccines typically provide that protection by giving people a bit of the virus to trigger an immune response.
Two of the most common types of vaccines that labs are working on, as defined by the Centers for Disease Control and Prevention (CDC), are “attenuated,” which use a weakened form of the virus, and “inactivated,” which use a killed version of the virus. However, some of the efforts rely on infusing messenger RNA molecules to produce a protein that sets off a cellular process that activates an immune response.
Salks’ polio vaccine used an inactivated virus and was licensed for public use hours after clinical trial results were announced in 1955. Some lots from one of the production labs, Cutter Laboratories, contained the live virus, leading to tragic results. The Cutter batches were pulled from the market, while vaccines from other labs continued to be safely administered.
The so-called Cutter Incident involved a production error. When inactivated vaccines are produced correctly, the risks lie in the countless variables that affect a body’s reaction, including the person’s immune system (which are not fully developed in young children, and often weakened in the elderly); physical condition (are they pregnant or ill?); and environment (including exposure to other forms of the virus).
“The risks of vaccines are lower now than in the past because production is much better than it used to be.”
David S. Jones, PhD
Here are some examples of unexpected adverse effects:
Measles: This widespread, highly effective vaccination against the childhood disease started with some severe consequences. Thousands of children who received a particular inactivated vaccine in the early 1960s and were then exposed to the actual measles virus developed atypical measles — characterized by high fever, severe abdominal pain, and inflammation of lung issue — and often required hospitalization. That vaccine was withdrawn, and later versions of attenuated virus vaccines proved safe and effective. The World Health Organization reports that measles cases worldwide are a small fraction of what they were decades ago, although they remain common in many developing countries.
Respiratory syncytial virus (RSV): This pervasive respiratory virus has proven resistant to vaccination. Children treated with one vaccine in the 1960s developed an enhanced form of the disease, suffering high fever, bronchopneumonia, and wheezing. Many were hospitalized and two died.
“That set the field back years,” Poland said, as researchers and manufacturers “were afraid” to try again.
Researchers have since tried but still not developed an RSV vaccine for public use, according to the CDC. Babies at particularly high risk for RSV are sometimes injected with an antibody to help fight off infection.
Dengue fever: The Philippines halted a school-based vaccination program in 2017 after reports of complications and several deaths linked to the product, Dengvaxia. The French manufacturer, Sanofi Pasteur, later said the vaccine posed a risk to people without prior infection from one of the disease’s four stereotypes, actually increasing the risk that the child would contract a more severe form of the disease. The U.S. Food and Drug Administration (FDA) approved the vaccine last year for limited use: for children of certain ages, living in endemic areas, and previously infected with a form of the virus.
Despite those and other reports of harmful effects, the CDC estimates that since 2011, vaccines have averted 23.3 million deaths from disease worldwide. “Smallpox is gone,” Jones notes. Polio, once blamed for paralyzing an average of 35,000 people a year in the United States, was declared eradicated in the country in 1979.
Now as researchers dream of doing the same to COVID-19, the testing and revising phases apply the brakes.
Vaccine testing proceeds slowly because the human body responds slowly: It takes weeks to produce the antibodies that provide immunity, and it can take longer to show harmful side effects.
“The regulatory pathway is meant to be slow, deliberate, reflective,” Poland says. “Data-rich, data-informed, and peer reviewed. Where you shortcut that, you can run into problems.”
With federal oversight, the process typically works through these phases:
Animal trials: A lab tests the vaccine on small animals (usually mice) to see if it triggers an immune response and side effects.
Clinical trials: If those tests show that the vaccine safely produces the intended immune responses, the product moves to human clinical trials, as explained by the CDC and the FDA:
- Phase I, involving a small group (typically several dozen) of volunteers to test the safety of various doses and see if they produce immune responses.
- Phase II, expanding to more people (typically hundreds) “who have characteristics (such as age and physical health) similar to those for whom the new vaccine is intended.” The objective is to determine safety and immune response in a more diverse set of subjects.
- Phase III, giving the vaccine to thousands of people to provide data about safety and effectiveness (measured, for example, by how many contract the disease in an area where the virus exists).
Through these processes, researchers use control groups that do not receive the vaccine, and they make adjustments in delivery method, dose, and frequency based on the results. At each stage, the FDA says, “if data raise significant concerns about either safety or effectiveness,” the agency might request more information or another round of studies — or halt the studies.
“If we aren’t deliberate and careful, we could harm people. We have to remember that.”
Gregory A. Poland, MD
“All that has to happen is one significant harmful side effect and you have to start over,” Poland says.
After completion of all three phases, companies apply to the FDA for a license to market and publicly administer the vaccine. Some vaccines undergo a fourth phase to study effects while the vaccine is being publicly administered — a process that can involve thousands of people over several years.
Overall, notes Jones, of Harvard, “The risks of vaccines are lower now than in the past because production is much better than it used to be.”
Can it happen faster?
Efforts are underway to accelerate the process to fight COVID-19.
The National Institutes of Health (NIH) launched a Phase I trial on March 16 with 45 human volunteers using a messenger RNA vaccine that did not go through a full round of animal testing first. The NIH said scientists “were able to quickly develop” the vaccine by adapting ongoing research into a vaccine for “related coronaviruses” that had been subject to animal testing. The NIH estimates that Phase I could last about 14 months.
Particularly telling is the project’s mix of public and private partners: The NIH says the development, study, and manufacturing of the vaccine involves its National Institute of Allergy and Infectious Disease, the biotech firm Moderna, Kaiser Permanente Washington Health Research Institute, and the Coalition for Epidemic Preparedness Innovations (CEPI), a global partnership based in Norway.
Such partnerships are essential. Because the process from conception to market grows more complicated and expensive at each step, labs usually find government, philanthropic, and business partners to fund the studies, revisions, and approvals, with private companies typically taking on the ultimate manufacturing and distribution. CEPI projects that bringing several COVID-19 vaccines to trial will cost $2 billion.
“Vaccine development is a tough space to be in because the risk is high, the timelines are long, and it’s expensive,” says Peter Hotez, MD, dean of Baylor’s National School of Tropical Medicine, who oversees a COVID-19 vaccine project there.
What’s more, private and government labs throughout the United States and in other countries are moving on vaccine development as well — and ultimately, only a few are likely to get through the tests and make it to market. China’s Academy of Military Medical Sciences reports that it started recruiting volunteers for a clinical trial of a vaccine. German companies BioNTech (partnering with Pfizer) and CureVac say they plan to start clinical trials as soon as this month. Sanofi Pasteur of France is researching a vaccine with expert and financial support from the U.S. Department of Health and Human Services.
Researchers at university labs say it’s possible to get a novel coronavirus vaccine ready for public deployment within 12 to 24 months from the start of the research, as federal officials project. Still, Hotez says, “That’s an optimistic scenario.”
Researchers hope they can fulfill the projections. “All of us have families, too,” Poland says. “We’re as anxious to see this get done as anybody.
“Yet at the same time, if we aren’t deliberate and careful, we could harm people. We have to remember that.”