Paul A. Offit, MD, Director, Vaccine Education Center at The Children’s Hospital of Philadelphia
In 1999, the simian-human reassortant rotavirus vaccine (RotaShield®) was taken off of the market because it was found to be a rare cause of intussusception, an intestinal blockage. The attributable risk was 10 per 100,000 vaccinees. At the time, it was hard to understand why RotaShield had caused this problem. All existing evidence didn’t support the notion that natural rotavirus infection caused intussusception. So why should a vaccine, which replicates at the intestinal mucosal surface much less efficiently than natural virus, cause a problem that isn’t caused by natural virus?
In 2006, the pentavalent bovine-human reassortant rotavirus vaccine (RotaTeq®) was licensed and recommended for all infants. Since then, about 50 million doses have been administered in the United States. Similarly, in 2008, the monovalent attenuated human rotavirus vaccine (RotaRix®) was also licensed and recommended for universal use; about 10 million doses have now been administered. With millions of children now vaccinated with these two newer rotavirus vaccines, two recent papers have now addressed the question of whether RotaTeq and RotaRix are also rare causes of intussusception.
Yih and coworkers evaluated data from a program called PRISM (Post-Licensure Rapid Immunization Safety Monitoring), which is directed by the Centers for Biologics and Research of the FDA (Yih WK, et al. Intussusception risk after rotavirus vaccination in U. S. infants. New Engl J of Med. 2014 Feb 6;370:503-12). These researchers found that the attributable risk for intussusception following RotaTeq was 1.5 per 100,000 vaccinees (about seven-fold less than that found after RotaShield). The number of children inoculated with RotaRix was too small for adequate evaluation using PRISM.
A second article in the same journal evaluated the risk of intussusception following both RotaTeq and RotaRix using a different data set: the Vaccine Safety DataLink (Weintraub ES, et al. Risk of intussusception after monovalent rotavirus vaccination. New Engl J of Med. 2014 Feb 6;370:513-9). These investigators found that RotaRix was also a rare cause of intussusception with an attributable risk of 5.3 per 100,000 (about half that of RotaShield); RotaTeq was not associated with intussusception in this study.
What do these data teach us? The findings with RotaRix are particularly instructive. RotaRix is a live weakened virus originally obtained from a young boy with rotavirus diarrhea in Cincinnati in 1989. If RotaRix is a rare cause of intussusception, it raises the question of whether natural rotavirus infection is also a rare cause of intussusception. This question can be answered by evaluating the incidence of intussusception in the United States since the introduction of RotaTeq and RotaRix. Because the incidence of natural rotavirus infections has decreased dramatically, we have essentially replaced natural rotavirus with vaccine viruses. The CDC recently presented data showing that the incidence of intussusception has stayed about the same. This means that, in all likelihood, the attributable risk of intussusception following vaccination is about the same as that following natural infection.
If parents are concerned about whether rotavirus vaccination causes intussusception, they should be reassured that it does not appear that rotavirus vaccines have altered the incidence of intussusception in the United States.
In 2009, an unusual side effect was observed in a group of European and Scandinavian people who received a swine flu vaccine that contained the adjuvant, squalene. About 1 of every 55,000 people who received the vaccine developed narcolepsy: a disorder characterized by excessive sleepiness during the day, a sudden loss of muscle tone and strength, and rapid eye movement abnormalities.
Several important facts are known about narcolepsy. It’s caused by a loss of the 70,000 neurons in the hypothalamus that make a peptide called hypocretin, which is responsible for wakefulness. Also, the disease is far more common in people who have a particular genetic background (HLA-DQA1).
Alberto De la Herrán-Arita and colleagues at Stanford University School of Medicine appear to have figured out what happened (De la Herrán-Arita AK, Kornum BR, Mahlios J, et al., CD4+ cell autoimmunity to hypocretin/orexin and cross-reactivity to a 2009 H1N1 influenza A epitope in narcolepsy. Sci Transl Med.2013 Dec 18;5(216):216ra176). The Stanford researchers found a peptide on the influenza hemagglutinin that mimics hypocretin. So when people were immunized with the swine flu vaccine, those with HLA-DQA1 were more likely to develop an immune response (T cells) against their own hypocretin than those who didn’t get the vaccine or those who didn’t have that genetic susceptibility.
More research is required. People in the United States, for example, received an unadjuvanted vaccine and didn’t develop narcolepsy. It would be interesting to know whether the same side effect would have occurred in Europe and Scandinavia if their vaccine had not contained squalene as an adjuvant.
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