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Review of 20 Years of Data Concludes Vaccines Are "Remarkably Safe"


A comprehensive review of all safety-related label modifications of vaccines approved by the FDA between January 1996 and December 2015 found that vaccines are “remarkably safe” and confirmed population vaccination as a major public health strategy.

A comprehensive review of all safety-related label modifications of vaccines approved by the FDA between January 1996 and December 2015 found that vaccines are “remarkably safe” and confirmed population vaccination as a major public health strategy.

The retrospective cohort study, published in Annals of Internal Medicine, includes data from 57 vaccines against infectious diseases approved by the FDA within the 20-year window.

“Vaccination has greatly reduced morbidity, disability, and death from many infectious diseases,” the authors wrote. “The incidence of once common infections, such as measles, mumps, pertussis, rubella, and poliomyelitis, has decreased by more than 90%, and some diseases have been all but eliminated.”

Immunization programs have also resulted in financial savings, as direct costs from illness decrease when fewer individuals become sick.

However, vaccination rates have declined in recent years, “partly driven by reduced public trust and parental concerns over safety,” researchers said.

“If vaccines are perceived as unsafe, uptake in the population will decrease further, and the prevalence of infectious diseases and their associated morbidity and mortality will increase.”

The Vaccine Adverse Event Reporting System (VAERS) keeps track of the approximately 30,000 reports filed each year by health care professionals, vaccine manufacturers, and members of the public. Formed in 1990 by the FDA and CDC, the safety surveillance program is continuously monitored by the FDA for unexpected patterns or changes in rates of adverse events associated with vaccines. Although 85% to 90% of reports describe mild adverse effects, the remaining concerns may be addressed via additional clinical trials.

Using VAERS data, researchers analyzed postapproval safety modifications in vaccine labels approved by the FDA for use in the United States.

A cutoff date of 2015 was included so as to allow for at least 4 years of postmarketing surveillance for potential label modifications. Researchers identified both the initial and most recent labels published for each vaccine. Each most-recent label was then compared with the initial label and all available subsequent labels for any safety-related changes, including type of safety-related label change and clinical safety issue related to the label change.

Of all vaccines approved during the study window, the most common indication was seasonal influenza (n = 21), followed by combinations of vaccines for diphtheria, tetanus, pertussis, poliomyelitis, Haemophilus influenzae type b, hepatitis B, and hepatitis; meningococcus; human papillomavirus; and rotavirus. Researchers found that influenza vaccines were less likely to be associated with postapproval safety issues.

FDA approval of most vaccines (n=53) was supported by randomized controlled trials, while median cohort size of trials supporting initial approval was 4161 individuals (interquartile range [IQR], 2204-8634).

Within the 20-year window, analyses found:

  • 58 postapproval safety-related label modifications associated with 25 vaccines (49 warnings and precautions, 8 contraindications, and 1 safety-related withdrawal)
  • 55 modifications (95%) included additional safety information, and 3 (5%) pertained to the removal of prior warnings and precautions
  • Median time from vaccine approval to safety modifications was 5 years (IQR, 3-9 years)
  • The number of safety modifications published each year remained stable over time
  • Initial approval trial characteristics were similar in vaccines with and without a postmarketing safety-related label modification
  • The most common safety issue triggering label modifications (n = 21 [36%]) was expansion of population restrictions, including immunocompromised patients, those with specific pre-existing medical conditions, premature infants, and pregnant women
  • The second most common safety issue triggering label modification was allergies (n = 13 [22%]), mostly due to changes in latex-containing packaging (n = 12 of 13 [92%])
  • The most common source of safety data was postmarketing surveillance (n = 28 of 58 [48%])

RotaShield, for rotavirus infection, was the only vaccine withdrawn for safety and was recalled less than a year after marketing approval, based on safety signals identified from VAERS reports. “This single safety-related withdrawal emphasizes both the limitations of pre-market testing in detecting serious but rare adverse events and the rapid identification of these safety concerns by a robust post-marketing surveillance program almost immediately after widespread uptake of the new vaccine,” researchers said.

Of the safety modifications added over the 20 years:

  • 12 (21%) warned of postvaccination syncope (fainting)
  • 4 were related to infection transmission of live attenuated vaccines (n = 3 of 4 [75%], rotavirus shedding and transmission)
  • 3 (5%) warned of neurologic complications (febrile seizures in infants in 2 and Guillain—Barré syndrome in 1)
  • 2 warnings and 1 withdrawal (5%) were related to risk for intussusception (all in rotavirus vaccines)

One method of decreasing real-world adverse events experienced by preterm infants, pregnant women, or other populations is to include these at-risk vaccine recipients in future clinical trials supporting initial approval. Separate studies examining vaccines’ effects on these cohorts could also be carried out, in addition to implementing postmarketing surveillance programs specifically addressing the safety of these recipients.

Because outbreaks linked to intentional unvaccination are on the rise, “we believe our findings are of considerable importance for public health,” the researchers wrote.

“We report that a large cohort encompassing all vaccines approved over a 20-year period was found to be safe, with no important post-approval safety issues,” the authors concluded.


Tau N, Yahav D, Shepshelovich D. Postmarketing safety of vaccines approved by the U.S. Food and Drug Administration. Ann Intern Med. Published online July 27, 2020. doi:10.7326/M20-2726

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