COVID-19 vaccines are on the fast-track to approval. How will we know they’re safe?

More than 30 candidate vaccines for COVID-19 have reached human trials since the pandemic began only months ago. But given that most vaccines take years to develop, how will we know that the first coronavirus vaccine to earn approval is safe and effective enough for widespread use?  

Experts told Live Science that all candidate COVID-19 vaccines must pass through the same phases of clinical trials before earning approval from the U.S. Food and Drug Administration (FDA), as would any other vaccine. Provided that the trials include many participants, numbering in the thousands, and include thorough protocols to track side effects, the public can be confident that the approved vaccines are safe, they said. 

“A sub-par vaccine that produces side effects without protecting against infection would be problematic,” Ali Salem, a chair and professor of pharmaceutical sciences at the University of Iowa College of Pharmacy, told Live Science in an email. But such a vaccine “would be expected to fail the FDA guidelines on efficacy and safety, and therefore, not be appropriate for release into the market.”

What’s more, the odds are good that an effective vaccine can be found: Infectious disease vaccine candidates pass the FDA approval process at consistently higher rates than other drug types; for instance, about a third of those vaccine candidates are ultimately approved, compared with less than 8% of cancer drugs, according to a 2019 study in the journal Biostatistics.

To ensure a vaccine would be safe in all recipients, whether young, eldery, healthy or with risk factors for severe COVID-19, each of these subpopulations would need to be represented in clinical trials, said Maria Elena Bottazzi, the associate dean at Baylor University’s National School of Tropical Medicine. Representative trials also ensure that, if a vaccine works well in one group but not another, the vaccine will be approved only for the former group, she added. 

Rigorous human trials 

In June, the FDA issued guidelines for the approval of COVID-19 vaccines. In those guidelines, the agency described what safety evaluations a vaccine would need to pass and noted that a vaccine should show at least 50% efficacy in clinical trials, meaning that under perfect conditions, people who get the vaccine would be at least half as less likely to be infected with the coronavirus compared with unvaccinated people.   

“This is a common guideline for flu vaccine testing from the FDA and has been shown in the past to be an effective marker for determining vaccine efficacy,” Salem said.

The efficacy of “50% is lower protection than we see with some other vaccines, but reducing the case burden by 50% is still significant,” Dr. Sarah George, an associate professor of infectious diseases and immunology at Saint Louis University, told Live Science in an email. “Remember, every case you stop from happening means you’ve also interrupted the transmission cycle, so [the 50% cutoff is] appropriate.” With fewer people to infect, the virus cannot spread through a community as quickly; combined with other disease mitigation measures like social distancing and mask wearing, vaccines can drastically reduce the chances of an infected person passing on the virus.

Scientists can begin to assess a vaccine’s efficacy in Phase 2 and Phase 3 clinical trials by monitoring how the body responds to the inoculation, according to the U.S. Centers for Disease Control and Prevention (CDC). Ideally, the immune system would make neutralizing antibodies that target the SARS-CoV-2 virus and thus protect the vaccinated person, if they are ever exposed to the pathogen. 

Phase 3 trials, which include hundreds to tens of thousands of volunteers, can begin to reveal differences in infection rates between vaccinated and unvaccinated people — but those trends become clearer the more people who are included in the trial, and the longer the trial lasts.

Dr. Anthony Fauci, director of the National Institute of Allergy and Infectious Diseases, said in April that a promising COVID-19 vaccine that prompts a strong immune response in Phase 2 trials could potentially be approved for emergency use without a full Phase 3 trial, Live Science previously reported. Phase 3 trials for vaccines typically last several years, according to the CDC, but given the pressing need, a coronavirus vaccine could potentially be granted emergency approval in less time, Fauci said. The trial process can also be sped up through combined trials, where several trial phases are run simultaneously.  

While the idea of condensed or combined trials may seem risky, “that doesn’t mean they’re cutting off the follow-up of these individuals,” Bottazzi said. “Importantly, beyond Phase 3 there’s a clear strategy and guidance [from the FDA] on post-market surveillance,” which involves monitoring people who receive an approved vaccine for infections and side effects that may not appear in clinical trials, she said. 

But the fact remains that “antibody responses alone cannot be used to determine effectiveness of a vaccine and its ability to prevent infection,” or to reduce the severity of infection, Salem noted. Those metrics can be calculated only through large, often lengthy, Phase 3 trials and thorough post-market surveillance. In other words, completely skipping over Phase 3 would be risky.

Spotting side effects 

In Phase 1 clinical trials, participants receive different doses of a vaccine and are monitored for any related side effects, according to the FDA. Phase 2 and 3 trials continue to monitor for side effects associated with the vaccine, while also focusing on how the vaccine interacts with the immune system.   

A Phase 3 trial would be expected to reveal the most common severe side effects of a coronavirus vaccine, particularly if the Phase 3 trials “involve tens of thousands of people,” George said. However, post-market surveillance will still be needed to ensure that the rate of side effects remains low in larger populations, Salem added.

For instance, only about 1 to 2 percent of people who get a flu shot develop a fever, Live Science previously reported. That type of side effect will appear in clinical trials, but rare side effects may not crop up until after a vaccine is approved. For example, the rotavirus vaccine, which protects against a severe diarrheal disease, was approved and only later linked to an intestinal disorder called intussusception, where one part of the intestines slides over the adjacent part like a telescope, Live Science previously reported. A 2014 study linked the vaccine  to 15 extra cases of intussusception per 1 million vaccinated infants — but experts note that the benefits of the vaccine outweigh this small risk. 

One side effect vaccine developers can watch out for in clinical trials is called antibody dependent enhancement (ADE), a phenomenon that paradoxically leaves the body more vulnerable to infection after inoculation, Live Science previously reported. ADE may occur, for instance, when the body generates too few antibodies to kill the virus, but those few antibodies latch onto the virus and usher it to vulnerable cells.

Candidate vaccines for animal coronaviruses and SARS-CoV, which caused outbreaks of severe acute respiratory syndrome in the 2000s, triggered ADE-like effects in animals, according to an opinion piece published March 16 in the journal Nature

Such responses to a COVID-19 vaccine could emerge in animal studies but should still be monitored in the context of human trials, particularly the longer, larger Phase 3 trials. As Phase 1 and Phase 2 trials last a few months each, few participants in the trials would be likely to catch COVID-19 during the study period. Robust evidence of ADE would be more likely to emerge once more participants caught the virus, as might be expected in a Phase 3 trial.

“A sign of ADE, or a similar problem, would be if the people who got the vaccine in the trials actually had higher attack rates of COVID-19 than the people who got placebo,” meaning the virus was more likely to infect the vaccinated group, George said. Any vaccine linked to ADE would not advance to further trials or earn FDA approval, she added. If data gathered in any phase “raise significant concerns about either safety or effectiveness,” the FDA can require that another round of studies be conducted, or that the trial be stopped altogether, according to the American Association of Medical Colleges.

That said, if hints of ADE did surface, vaccine developers could potentially identify and remove the parts of the vaccine that trigger the reaction, George said. Those epitopes — or surface proteins on the virus that the  vaccine primes the immune system to target — couldn’t be identified in advance of animal or human trials, she said. Modifying a vaccine to this extent might require additional safety and efficacy studies, or that the whole approval process start over again, depending on the FDA’s guidance.

First COVID-19 vaccine likely won’t be the last 

Well-designed clinical trials will tell us if a COVID-19 vaccine is safe and effective, but they cannot answer one crucial question: How long will the vaccine protect a person from the virus?

Immunity to common coronaviruses, which cause symptoms of the common cold, dwindles within about one to three years, Live Science previously reported. Similarly, past studies of SARS and the coronavirus called Middle East respiratory syndrome (MERS) hinted that people may remain immune to the coronaviruses for at least two or three years after their initial infection. A COVID-19 vaccine should prompt a similar immune response to the natural infection, and therefore, immunity granted by the vaccine may also wane through time.   

“We do not know how long that protection will last, and we probably need to look at other formulations to improve on that front” after an initial vaccine gets approved, Bottazzi said. “That’s why we most likely will have first, second, third generations of vaccines.”

In addition to designing vaccines that grant long-lasting immunity, developers may need to come up with different formulations for people of different demographics. For example, “separate studies in children will have to be done once we have one [vaccine] approved for adults,” George said.

“You already see this, for instance, with the flu vaccine,” which comes in different formulations designed for young and elderly people, Bottazzi said; people over 65 can opt to receive a high-dose flu shot or adjuvanted flu shot, which contains added ingredients to jumpstart their immune response, according to the CDC. When a COVID-19 vaccine does get approved, it will be important to clearly communicate, how much protection it’s expected to confer, and which populations would most benefit from receiving it, she added.

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The FDA may also set different safety thresholds that a given vaccine must pass to be approved for different demographics, George said. Those thresholds would be based on what side effects emerge in clinical trials and whether those side effects present more risk than benefit in a given group, she said. For instance, the COVID-19 death rate among U.S. children is about 0.03%, according to a report from the American Academy of Pediatrics and the Children’s Hospital Association; by comparison, the death rate among people over 65 has been estimated at about 5.6%, according to a report published on the preprint server OSF Preprints. A vaccine that causes rare side effects may be unacceptable for children, who are at fairly low risk of severe infection and death from the virus, but acceptable for older people who would likely suffer worse complications from the infection itself.

While the first COVID-19 vaccine may not work for everyone, or may offer only partial immunity, “I think it’s a good start,” Bottazzi said. In the short-term, a moderately effective vaccine would prevent a subset of people from catching COVID-19 and slow viral transmission in the wider community by limiting the number of potential infections. Vaccinated people who still caught COVID-19 would likely contract a less severe illness than unvaccinated people, reducing the burden on the health care system and the mortality rate, overall, she said. And given that the long-term impacts of the infection remain unknown, a vaccine may protect people from future health complications, as well, she added.

“An effective vaccine against SAR-CoV-2 remains our greatest chance of getting COVID-19 under control and having life go back to normal,” Salem said.

Originally published on Live Science. 

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