The second-generation rotavirus vaccine appears to raise the risk of intussusception in a similar manner as its predecessor, but its benefits still far outweigh that risk, according to a report in the June 16 issue of the New England Journal of Medicine.
Case series and case-control analyses of immunization data from Mexico and Brazil indicate that the short-term risk of intussusception is approximately 1 in every 51,000-68,000 infants receiving the rotavirus vaccine (RV1, Rotarix), which translates to an annual "excess of 96 hospitalizations ... and 5 deaths in the two countries combined." This risk is far exceeded by "the real-world benefits of RV1 vaccination, which has annually prevented more than 80,000 hospitalizations and 1,300 deaths in Mexico and Brazil," said Dr. Manish M. Patel of the Centers for Disease Control and Prevention, Atlanta, and his associates.
"These emerging data on safety and benefits have been reviewed by the World Health Organization as well as by regulatory agencies and immunization advisory committees in Brazil, Mexico, and the United States. ... [T]hese groups unanimously favored continuing the recommendation that rotavirus vaccination be administered to infants to prevent severe and potentially fatal rotavirus disease," the investigators noted (N. Engl. J. Med. 2011;364:2283-92).
They undertook this study because, after Brazil and Mexico added RV1 to their national childhood immunization programs in 2007, "the combined annual birth cohort of approximately 6 million in these two countries provided an opportunity to assess whether routine vaccination with RV1 was associated with intussusception," Dr. Patel and his colleagues wrote.
Using hospital records, they identified 615 infants who developed intussusception (285 in Mexico and 330 in Brazil) and matched them with 2,050 control infants (739 in Mexico and 1,311 in Brazil). Of these, 594 case patients (97%) and 2,033 controls (99%) had a history of vaccination confirmed by a vaccination card.
In Mexico, intussusception was significantly more likely to develop in the first week after the first dose of the vaccine than during other periods, with an incidence ratio of 5.3.
"This corresponds to the dose and period in which there is peak intestinal replication of vaccine virus and in which a local inflammatory response in the lymphatic tissue or intestines may occur – a response that has been implicated in the pathogenesis of intussusception," the investigators said.
In contrast, "neither a clustering of cases after the first dose nor a risk of the magnitude noted in Mexico was observed in Brazil. However, a small but significantly elevated rate was noted 1-7 days after the second dose," they said.
This absence of risk with the first RV1 dose was at first "perplexing." However, RV1 is administered together with oral poliovirus vaccine in Brazil but with inactivated poliovirus vaccine in Mexico. The first dose of oral polio vaccine is known to decrease the immunogenicity of RV1 when the two are given together, which may in turn reduce the risk of RV1-associated intussusception.
"Other factors, such as differences in the diets of the infants, breastfeeding practices, the natural risk of intussusception, and maternal antibody levels, might also have contributed to the variation in risk between Mexico and Brazil," Dr. Patel and his associates wrote.
"Our benefit-risk analysis indicated that an RV1 vaccination program would avert 663 deaths and 11,551 hospitalizations due to rotavirus disease in Mexico and 640 deaths and 69,572 hospitalizations in Brazil among children younger than 5 years of age.
"In contrast, we predict that a vaccination program would cause 41 excess hospitalizations (approximately 1 per 51,000 vaccinated infants) and 2 deaths due to intussusception in Mexico and 55 excess hospitalizations (approximately 1 per 68,000 vaccinated infants) and 3 deaths in Brazil," the researchers said.
They emphasized that the experience in Mexico may not apply to developing countries, most of which use the oral poliovirus vaccine. In addition, the immune response to rotavirus vaccination, as well as fecal shedding of vaccine strains of the virus, are generally lower in developing than in industrialized countries, which may indicate a difference in intussusception risk.
This study was funded in part by the GAVI Alliance under a collaborative agreement with the Program for Appropriate Technology in Health (PATH) and in part by the U.S. Department of Health and Human Services. Rotarix is a product of GlaxoSmithKline. Dr. Patel and his coinvestigators reported no relevant financial disclosures.