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October 19, 2011

Lessons From the US Rotavirus Vaccination Program

Author Affiliations

Author Affiliations: Division of Viral Diseases, National Center for Immunization and Respiratory Diseases, Centers for Disease Control and Prevention, Atlanta, Georgia (Drs Patel and Parashar), and Fogarty International Center, National Institutes of Health, Bethesda, Maryland (Dr Glass).

JAMA. 2011;306(15):1701-1702. doi:10.1001/jama.2011.1475

Every winter, children, parents, and clinicians in the United States have to deal with the annual seasonal outbreak of rotavirus, the most common cause of severe diarrhea in children worldwide. Before the implementation of routine vaccination against rotavirus in 2006, most US children had experienced an episode of rotavirus diarrhea by the age of 5 years, an estimated 400 000, or 1 child in 6, required outpatient treatment and about 55 000 to 70 000 children, or 1 in 50, were hospitalized.1 The health consequences of this annual event in the United States were unsettling and were estimated to cost more than $1 billion per year.1

When the first new rotavirus vaccine was licensed in 2006,1 uncertainty existed about whether parents would agree to have their infants immunized and whether clinicians would actively promote its use. Rotavirus vaccines had been severely stigmatized in 1999 when an earlier vaccine, tetravalent rhesus-human reassortant vaccine (RotaShield, Wyeth Laboratories) was abruptly removed from the market because of its link with intussusception, an uncommon form of intestinal obstruction. To assess whether the next generation of rotavirus vaccines harbored the same complication, the US Food and Drug Administration (FDA) required manufacturers to enroll and follow up more than 60 000 infants in clinical trials. Merck and GlaxoSmithKline set off cautiously to conduct multicenter trials of the pentavalent human-bovine WC3 reassortant rotavirus vaccine (RotaTeq, Merck & Co) and the RIX4144 strain human rotavirus vaccine (Rotarix, GlaxoSmithKline Biologicals), ultimately recruiting more than 70 000 infants each, some of the largest and most costly licensure trials ever conducted.1 Neither vaccine was associated with intussusception in these trials.

Over the past 4 years, uptake of the new vaccines has been remarkable. In the United States, the vaccines are expensive, about $200 for the series, but this hurdle of cost was addressed in part by Centers for Disease Control and Prevention's (CDC’s) Vaccines for Children Program, a federally funded program that provides vaccines at no cost to those unable to pay. By 2010, nearly 60% of US children aged 19 to 35 months were immunized against rotavirus.2 Because rotavirus diarrhea affects children in the first 5 years of life, it may soon be possible to evaluate the full benefit of the vaccine.

For the past decade, the CDC has monitored rotavirus activity in the United States from laboratories that document weekly the number of fecal specimens from children seeking care for diarrhea and the percentage of these specimens that test positive for rotavirus. In 2008, the effects of the rotavirus immunization program were first noted from this surveillance program when the number of rotavirus detections decreased by 64%; these declines have been sustained through 2010.3 Reports assessing discharge data from hospitals around the country noted that hospitalizations for acute gastroenteritis declined by 45% during the 2008 winter rotavirus season, averting approximately 50 000 hospitalizations nationwide.4,5 An unanticipated finding was that hospital admissions for diarrhea also declined among unvaccinated individuals aged 5 through 24 years, suggesting that the vaccine was having a herd effect, perhaps by preventing rotavirus transmission from a younger immunized cohort.5

More recently, a series of independent regional studies have documented excellent performance of the vaccine against rotavirus disease and documented an 85% to 90% reduction in hospital discharges and visits to emergency departments.6,7 Previously, diarrheal illnesses were reported on 10% to 12% of all hospital discharge records for children younger than 5 years, and surveillance indicated that rotavirus accounted for about 40% to 50% of these events. Consequently, an 85% to 90% reduction in this disease from vaccination should lead to a 4% to 6% reduction in total hospitalizations for children younger than 5 years with the commensurate savings in hospital and indirect costs.

The introduction of rotavirus vaccines has not been without challenges. In 2010, the identification of porcine circovirus (PCV) in Rotarix led to a temporary suspension of this vaccine; PCV genetic material was also later identified in RotaTeq. More recently, both Rotarix and RotaTeq have been associated with a low-level but elevated risk of intussusception—about 5- to 10-fold lower than that seen with Rotashield—in postlicensure studies in Latin America and Australia.8 An increased risk of intussusception has not been documented in the United States, but available US data cannot reliably exclude a risk similar to that seen in international settings. Various regulatory and scientific committees—including the FDA, the CDC’s Advisory Committee on Immunization Practices, and the World Health Organization (WHO)—have reviewed the data on PCV and intussusception and have supported continued use of rotavirus vaccines.

The benefits of the rotavirus vaccine program raise several cogent issues in the current national debate on health care. First, the impact demonstrates that long-term investments in research on new prevention strategies can directly and measurably decrease health care use and costs. The development of rotavirus vaccines represents the results of more than 3 decades of research funded initially by the government and subsequently by industry to manufacture and test vaccines. The total investment by the US government in research to understand rotavirus—virology, immunology, epidemiology, and vaccinology—has been modest but has encouraged industry investment to develop a major new product. The return to the US public should be much greater and increase as the cost of the vaccines decreases. Moreover, WHO has recommended rotavirus vaccine for the immunization of all children worldwide, opening a global market for these vaccines that were initially developed to target children in upper- and middle-income countries. More importantly, rotavirus is associated with an estimated 500 000 deaths worldwide each year, the majority of which occur in low- and middle-income countries.9

Second, introduction of rotavirus vaccination underscores the importance of rigorous monitoring and evaluation of new interventions. The rapid accumulation of undisputable evidence regarding the health and economic benefits of rotavirus vaccination in US children has been a strong driver of vaccine adoption and use among parents and clinicians. Moreover, the decision to continue vaccination after emerging safety concerns of PCV contamination and intussusception was largely based on the well-documented benefits from vaccination that outweighed the potential risks.

Rotavirus vaccine implementation needs to be extended to all countries. In Mexico, use of rotavirus vaccines for only 3 years has reduced the number of deaths due to childhood diarrhea by about 700 per year since vaccination, reaffirming the life-saving potential of these vaccines.10 This successful experience also needs to be replicated for other childhood infections, like respiratory syncytial virus, that with breakthroughs in research, might soon be preventable with vaccines.

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Article Information

Corresponding Author: Manish Patel, MD, MSc, Centers for Disease Control and Prevention, 1600 Clifton Rd, MS A34, Atlanta, GA 30333 (mpatel@cdc.gov).

Conflict of Interest Disclosures: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported.

Disclaimer: The opinions presented herein are those of the authors and do not represent the views of the US government or the respective agencies.

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