The Johnson & Johnson/Janssen Vaccine “Pause” Is Actually Not A Rare Occurrence

Contrary to what many anti-vaccine groups and individuals state on social media or in the press, there is actually a very robust surveillance system for adverse events from vaccination. In the United States, local, state and federal health agencies are on the lookout for adverse events. Healthcare providers receive reports of adverse events from any of their patients and report those to the Centers for Disease Control and Prevention (CDC) via the Vaccine Adverse Events Reporting System (VAERS). Academic institutions also conduct safety and efficacy trials because there is grant money associated with conducting such studies as well as opportunities for advancement for those who identify issues and publish them in the medical literature. Then there are the vaccine manufacturers. Because they are in competition with each other, they also conduct studies into the safety and efficacy of their competitors’ products.

When the Janssen/Johnson & Johnson (“J&J”) vaccine allocation was paused last week, it did not come as a surprise to epidemiologists worldwide. We all knew that it was a matter of time before one of the three vaccines licensed under an Emergency Use Authorization (EUA) by the Food and Drug Administration (FDA) would be paused because of adverse events reported through the formal reporting systems or through informal means, i.e. the media. This is because very rare events — those in the order of about 1 in 1 million — are not picked up in traditional safety studies of tens of thousands or even hundreds of thousands of participants. It is mostly in post-marketing surveillance that these vents are detected because millions of people are vaccinated.

The Dengue Vaccine in The Philippines

Also, this is not the first time a vaccine is paused or even taken off the market due to an increase in the number of adverse events associated with it. In 2019, after reports of children dying after receiving the dengue vaccine Dengvaxia, the government of the Philippines stopped the administration of the vaccine and started criminal investigations into the deaths. According to National Public Radio:

“Typically, a vaccine works by triggering the immune system to make antibodies against the virus. These antibodies then fight off the virus during an infection.
But dengue is a tricky virus. Dengue antibodies don’t always protect a person. In fact, these antibodies can make an infection worse. The dengue virus actually uses the antibodies to help it spread through the body. So a second infection with dengue — when your blood already has antibodies in it — can actually be worse than the first; a person is at a higher risk of severe complications like plasma leakage syndrome.
In its follow-up study, Sanofi found evidence that Dengvaxia acts like the first infection for a person who has not been previously infected. The body produces antibodies against the vaccine, which have a similar potential for harm.
The increased risk seems small. The vaccine raises the risk of hospitalization after a dengue infection from about 1.1% to 1.6%, the follow-up study from Sanofi found. So out of 1 million kids in the Philippines, the vaccine would cause about 1,000 to be hospitalized over five years, Sanofi estimated. (On the other hand, the vaccine would prevent about 12,000 hospitalizations for a new dengue infection in children who have had a prior dengue infection during this same time period.)
But in the world of vaccines, that’s not an acceptable risk. A risk needs to be exceedingly small to be tolerated. For example, with the measles vaccine, the risk of encephalitis is about 1 in 1 million, or 1,000 times less than the risk from a measles infection, WHO says.
WHO eventually changed its recommendation. The agency now says the vaccine is safe only for children who have had a prior dengue infection.”

“Rush To Produce, Sell Vaccine Put Kids In Philippines At Risk”, National Public Radio, May 3, 2019.

Rotavirus Vaccine in the United States

Back in 1999, the Advisory Committee on Immunization Practices (ACIP) recommended that RotaShield, a vaccine against rotavirus, be withdrawn from the market and not administered to children anymore. The problem was that the clinical trials of that vaccine failed to find an increased risk of intussusception, a potentially life-threatening condition in which the intestine telescopes into itself. Rotavirus infection itself can cause intussusception, and even the more modern rotavirus vaccines currently on the US vaccine schedule can cause it, though not at the rate of the disease itself. Like with the dengue vaccine, it was post-marketing surveillance that caught the issues with RotaShield. Here is how one researcher put it:

“From September 1, 1998 to July 7, 1999, 15 cases of intussusception among infants who had received RRV-TV were reported to the Vaccine Adverse Event Reporting System (VAERS). Of the 15 infants, 11 developed intussusception following the first of the three dose series and 12 developed the symptoms within one week of receiving any dose of RRV-TV. Intussusception was confirmed radiographically in all 15 patients. Eight infants required surgical reduction, and one required resection of 18 cm of the distal ileum and proximal colon. Histopathological examination of the distal ileum indicated a lymphoid hyperplasia and ischemic necrosis. All infants recovered. The median age of the patients was three months, and reports were received from seven states. Based on prevaccine data on the incidence of intussusception in the United States and based on vaccine distribution data, 14.7 cases of intussusception were to be expected within one week of receipt of rotavirus vaccine due to temporal association without causation. However, in light of under-reporting of vaccine-associated adverse effects, these data suggested an increased risk of intussusception following rotavirus vaccination. In addition, surveillance data from the Northern California Kaiser Permanente Health Maintenance Organization and from the states of Tennessee and Minnesota also showed a trend towards the increased risk of intussusception following receipt of rotavirus vaccine. Although none of these findings were found to be conclusive, the consistency of the findings from the three data sources raised strong concerns. Based on these concerns, the Centers for Disease Control and Prevention (Atlanta, Georgia) recommended postponing administration of RRV-TV to children scheduled to receive the vaccine at least until November 1999. The manufacturer in consultation with the Food and Drug Administration voluntarily ceased further distribution of the vaccine.
By the beginning of October 1999, 101 confirmed and presumed cases of intussusception had been reported to VAERS. The rate of reporting increased greatly after the July 1999 announcement of the temporary postponement of rotavirus vaccination. Fifty-two patients required surgery, nine required bowel resection and one patient died. Fifty-seven of these children developed intussusception within seven days of vaccine dose, and 70% developed their intussusception after the first dose. There was a clear clustering of cases from day 3 to day 8 after the dose of vaccine. In case-control studies, risk ratios of developing postvaccine intussusception varied from seven to 30, depending on the study and type of analysis. It was estimated that these data would have translated into around 1200 potential additional cases of intussusception annually in the United States if rotavirus vaccine policy had been fully implemented. Based on these data, the ACIP concluded that intussusception frequency was significantly increased in the first one to two weeks after vaccination, particularly after the first dose, and decided to withdraw its rotavirus vaccine recommendations. The American Academy of Pediatrics also withdrew its recommendations. On October 15, 1999, Wyeth-Lederle Vaccines announced that it was withdrawing the Rotashield vaccine from the market and requested the immediate return of all distributed doses.”

Delage G. (2000). Rotavirus vaccine withdrawal in the United states; the role of postmarketing surveillance. The Canadian journal of infectious diseases = Journal canadien des maladies infectieuses11(1), 10–12. https://doi.org/10.1155/2000/414396

Influenza Vaccine and Guillain-Barré Syndrome

In 1976, soldiers at Fort Dix in New Jersey started coming down with a novel influenza virus. Fearing an impending influenza pandemic, the United States government began mass production of a vaccine against the New Jersey strain. As the vaccine was rolled out, reports of a serious neurological condition called Guillain-Barré (GBS) started being received by health authorities across the country. Here is how a paper written in 1979 described the situation:

“Because of an increase in the number of reports of Guillian-Barre syndrome (GBS) following A/New Jersey influenza vaccination, the National Influenza Immunization Program was suspended December 16, 1976 and nationwide surveillance for GBS was begun. This surveillance uncovered a total of 1098 patients with onset of GBS from October 1, 1976, to January 31, 1977, from all 50 states, District of Columbia, and Puerto Rico. A total of 532 patients had recently received an A/New Jersey influenza vaccination prior to their onset of GBS (vaccinated cases), and 15 patients received a vaccination after their onset of GBS. Five hundred forty-three patients had not been recently vaccinated with A/New Jersey influenza vaccine and the vaccination status for 8 was unknown. Epidemiologic evidence indicated that many cases of GBS were related to vaccination. When compared to the unvaccinated population, the vaccinated population had a significantly elevated attack rate in every adult age group. The estimated attributable risk of vaccine-related GBS in the adult population was just under one case per 100,000 vaccinations. The period of increased risk was concentrated primarily within the 5-week period after vaccination, although it lasted for approximately 9 or 10 weeks.”

Schonberger LB, Bregman DJ, Sullivan-Bolyai JZ, Keenlyside RA, Ziegler DW, Retailliau HF, Eddins DL, Bryan JA. Guillain-Barre syndrome following vaccination in the National Influenza Immunization Program, United States, 1976–1977. Am J Epidemiol. 1979 Aug;110(2):105-23. doi: 10.1093/oxfordjournals.aje.a112795. PMID: 463869.

GBS is a known complication of viral infections like influenza. From time to time, people who are predisposed to GBS (it is an auto-immune condition) can develop it after a viral infection or a vaccine. (This is why it is extremely important for you to read through the screening questions and give honest answers before being vaccinated.) After the reports of GBS in 1976 and 1977, the vaccine campaign was stopped. The influenza pandemic never materialized, and the public’s trust in the vaccination program was damaged for some time.

The Cutter Incident

In 1954, the first polio vaccine field trials took place in different cities in the United States. By 1955, the vaccine was deemed a success, and large-scale vaccination campaigns took place. Before the vaccine, millions of children were infected by the virus, and about 1% of them went on to develop poliomyelitis, a degenerative disease of the nervous system. Parents across the world feared that their children would contract the virus, so Salk’s injectable vaccine and Sabin’s oral vaccine were more than welcomed by most parents.

To make the injectable vaccine, poliovirus had to be inactivated (killed) in the laboratory before being processed into the vaccine. For this purpose, several independent laboratories in the United States and Canada were given license to perform the process. One such laboratory, Cutter Laboratories in California, made a series of missteps that resulted in vaccines with viable virus. Known as the “Cutter Incident,” the vaccines produced in that laboratory caused an estimated 400,000 cases of polio, paralyzing 200 children and killing 10.

Like with other adverse events, the Cutter Incident led to distrust of the polio vaccine. However, the Sabin vaccine (oral polio vaccine) was given authorization just in time to take over for the injectable vaccine. That vaccine remained in use in the United States until the 1990s, when polio was eliminated from the Americas. It was then that a switch back to injectable vaccine started.

And So On and So Forth

The “pause” of the J&J vaccine (or the pauses on the AztraZeneca vaccine in Europe) is not going to be the last time that vaccine administration is interrupted. It will continue to happen, and there will come the time in the modern history of vaccines that a vaccine is going to be taken off the market. This is further evidence that the systems of surveillance for adverse events are working, and that the science of vaccination has room for improvement. Nevertheless, the vaccines on the current schedule in the United States have an excellent track record of safety. And, if a vaccine goes to market and it is found that the clinical trials were not adequate to detect rare outcomes, the public should rest assured that scientists and public health practitioners have no qualms about pausing, investigating and, if necessary, withdrawing a vaccine from the market.

Author: René F. Najera, DrPH

I am the editor of the History of Vaccines site, an online project by the College of Physicians of Philadelphia. All opinions expressed on these blog posts are not necessarily those of the College or any of my employers. Check out my professional profile on LinkedIn: https://www.linkedin.com/in/renenajera Feel free to follow me on Twitter: @EpiRen