TIP Talk!

Thursday October 27, 2016

Vaccines take a long, research-intensive road to licensing


New vaccines are hardly new by the time they’re first offered to the public. Ten to 15 years of testing on their safety and effectiveness has usually taken place first. And they will continue to be examined by a panel of government experts for as long as they’re around.

Most Americans don’t know a great deal about the intensive, tightly regulated procedure to get a vaccine licensed, which is a shame. Figures from a recent survey indicate that belief in the safety of vaccines is in danger of slipping to new lows. And parents who use alternative remedies such as herbal supplements are less likely to vaccinate their children, a recent report found—and yet supplements receive no real oversight by the federal government before they come to market, as we'll discuss next week in our report on testing and assessments of supplements.

And yet vaccines, scrutinized at every step, are the ones arousing more Americans’ suspicions. That might change if the public understood the scrutiny these disease-preventers undergo.

How likely are Americans to think that vaccines are safe? A 2015 survey by the Pew Research Center offers some both heartening and unnerving insight. It polled people about just one vaccine that has been controversial ever since a thoroughly discredited study claimed it was associated with autism—the measles, mumps and rubella vaccine.

The good news: Most American adults realize that the MMR vaccine is safe. But when those results are broken down by age, a disturbing trend emerges: The younger they are, the less likely they are to understand the vaccine’s safety. People 65 and older—people who have been around long enough to see the scourge of some of the diseases that are now prevented by vaccines—were the most likely to believe in the safety of the MMR vaccine, at 91 percent. That figure dropped in parallel with the ages of the groups asked until, among the youngest group ages 18 to 29; only 77 percent believed it was safe.

Yet, like all other vaccines, the MMR vaccine has been tested and retested for safety, including numerous rigorous studies showing that it is not associated with autism, said Dr. Peter J. Hotez, dean of the National School of Tropical Medicine at Baylor College of Medicine and President of the Sabin Vaccine Institute.

Hotez would know. Not only is he the father of an autistic child, but he is developing vaccines intended to relieve suffering and save lives in developing tropical nations. One of those vaccines is to prevent schistosomiasis, a parasitic disease that sickens more than 250 million people a year, most of them in sub-Saharan Africa. It can cause serious damage to the bladder, kidneys, liver and intestines.

He’s been working on the development of the vaccine for more than a decade; safety trials began this past year. But that’s not long in the world of vaccine research; safety trials for a human hookworm vaccine, a parasitic disease that affects half a billion people a year, have been ongoing since 2007.

“We make and test vaccines,” Hotez said. “I know the rigor that is involved even to get to the Phase 1 trials” for human safety.

According to the History of Vaccines published by the College of Physicians of Philadelphia, there are many stages of testing and monitoring both before and after a vaccine is approved.

It starts with basic laboratory research on possible vaccine targets that might provoke an immune response—and even though one to two years of research might be involved, the history says, many of the vaccines never go further because they’re not effective enough. During vaccine development you also need to perform preclinical toxicology testing at laboratories so specialized and regulated, Hotez said, that his team cannot perform them in-house, but must send them out to be done elsewhere.

Only then, if the vaccines appear safe, is an entire package prepared for a new Investigational New Drug Application to  the U.S. Food and Drug Administration to allow Phase 1 trials to begin with human volunteers—but just on safety at this point. And if additional populations might get the vaccine, such as children, additional rounds of Phase 1 tests will be needed to be sure that anyone receiving the vaccine will tolerate it well.

If everything looks good, the History of Vaccines says, Phase 2 trials with human volunteers will continue assessing safety while also looking at immune response effectiveness, and the best dosages.

Phase 3 trials are much bigger, involving thousands of subjects to test the vaccine’s safety and effectiveness in a broader population. All the tests are randomized and double-blind—in other words, the researchers giving the doses to subjects don’t know who’s receiving the vaccine and who gets a placebo.

Only after substantial data from these trials prove to the FDA that the vaccine is both safe and effective will it become approved for use in the U.S. The FDA also will inspect the factories where it will be made, and testing must be done for every batch of vaccine to ensure safety.

But it doesn't stop there. The next stage of monitoring and testing has just begun.

The new vaccines are then subject to the Vaccine Adverse Event Reporting System. Anyone — from manufacturers to patients to doctors — can report any symptoms that they believe might have been related to a vaccine, even if they aren't sure the vaccine was the cause. Those reports are regularly analyzed to look for any troubling information—rare reactions, increases in certain reactions and the like. If any red flags are raised, more intense and focused studies are done to see if those who received the vaccine were more likely to have the specific side effect than those who didn't get vaccinated. 

In addition, according to the FDA, many approved vaccines are put though Phase 4 trials to test them once they’re on the market.

And the assessment continues as long as the vaccine is being administered to patients.

“After licensure, monitoring of the product and of production activities, including periodic facility inspections, must continue as long as the manufacturer holds a license for the product,” the FDA website says. “If requested by the FDA, manufacturers are required to submit to the FDA the results of their own tests for potency, safety, and purity for each vaccine lot. They may also be required to submit samples of each vaccine lot to the FDA for testing.”

But it doesn’t end with the FDA. The ongoing research on all vaccines as assessed regularly by the Advisory Committee on Immunization Practices, a vaccine panel of the U.S. Centers for Disease Control and Prevention.

Working groups of the committee specialize in the different vaccines, and the committee meets three times a year to discuss research and the findings of the working groups. It was ACIP that found earlier this year that the nasal mist form of the flu vaccine no longer appeared effective in children, leading to the CDC’s advice this year for children to get the flu shot instead of the mist.

It’s a slow process for researchers like Hotez, who is hoping to help millions of people with his work on vaccines for tropical diseases. But the ongoing testing should convince people about the safety of vaccines, he says.

Perhaps if more people knew about the painstaking and never-ending research on vaccines, the younger adults who have reservations about immunization will learn what older Americans clearly know: Vaccines have prevented many dangerous diseases from befalling the U.S. population, and have done it with a very high degree of safety.

The second part in this two-part series will compare vaccine safety testing to that of supplements. Stay tuned! 



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