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8th Canadian Immunization Conference

Toronto, Ontario / November 30-December 3, 2008

Rotavirus (RV) is a major cause of gastroenteritis among infants and young children worldwide and is the most frequent cause of hospitalization for dehydrating diarrhea and vomiting in industrialized countries. It is evident that protecting infants and young children from this important cause of morbidity has significant clinical implications.

As reported during the recent ICAAC/IDSA meeting in Washington in October 2008, the live, oral, pentavalent RV vaccine reduced RV-related hospitalizations and emergency room (ER) visits by 100% during the 2007 to 2008 RV season, typically January through May of each year. Data were derived from a national post-licensure observational study which was based on a review of health insurance claims from approximately 61,000 infants in the US. From this cohort, 33,135 received all three doses of the RV vaccine as recommended while 27,954 did not.

Rather than rely on historical comparisons, the study compared those who received the RV vaccine with controls of a similar age who did not. This allowed investigators to generate an estimate of vaccine effectiveness during routine vaccination. It may be important to note, however, that the diagnosis of RV in this study did not require laboratory confirmation.

Analyses showed that the vaccine reduced the combined incidence of hospitalizations and ER visits related to RV gastroenteritis to 0.0 vs. 3.7 events per 1000 patient-years, with both hospitalizations and ER visits being reduced by 100%. “Thus, what we must be seeing here is herd immunity,” observed Dr. Paul Offit, Director, Vaccine Education Center, Children’s Hospital of Philadelphia, Pennsylvania, and co-developer of the pentavalent RV vaccine. Equally significant, the vaccine reduced medical care costs associated with RV-related hospitalizations and ER visits by 100%—to $0.0 vs. $12,021 per 1000 patient-years. The live, oral, pentavalent RV vaccine is indicated to prevent RV gastroenteritis caused by the serotypes G1, G2, G3, G4 and G serotypes that contain P1A[8] and is recommended for infants between the ages of six and 32 weeks, to be given as a three-dose series.

This remarkable success story was already apparent even one season after it had been approved by regulatory officials in 2006. In a separate presentation at IDSA, Dr. Steven Hatch, University of Massachusetts, Worcester, had reported that their hospital treated an average of about 65 cases of RV gastroenteritis per year before the vaccine was licensed. This fell to 37 during the 2007 season, the first full RV season following the licensure of the vaccine, and to three by the end of the 2008 season.

Recent Clinical Data

In an earlier report from the Centers for Disease Control (CDC) and Prevention in Atlanta, Georgia, researchers reported a significant reduction in the incidence of RV disease and associated medical care following the introduction of the live, oral pentavalent RV vaccine compared to previous years (Morbidity and Mortality Weekly Report June 26, 2008). Using data from two different surveillance systems, CDC investigators found that there was a marked reduction in the number of positive laboratory tests for RV gastroenteritis during the 2007 to 2008 RV season at 18% compared to a median of 41% from July 1991 through to June 2006. Data for this analysis was provided by the National Respiratory and Enteric Virus Surveillance System.

A second analysis, based on data provided by the New Vaccine Surveillance Network, noted a marked reduction in hospitalizations and ER as well as clinic visits related to RV gastroenteritis during the 2008 season compared with either 2006 or 2007. For example, among those children who presented to hospitals, ERs or outpatient clinics with acute gastroenteritis, 207 children had RV gastroenteritis in 2006, 259 had it in 2007 and only 18 children had evidence of RV gastroenteritis in 2008.

Additional data has demonstrated the impact of the new pentavalent RV vaccine on disease incidence. Researchers at Quest Diagnostics, Madison, New Jersey, calculated that they performed, on average, 27,625 RV tests during the peak season during the three years before the vaccine was licensed; of these, approximately one-quarter were positive for the virus. During the December 2007 to June 2008 season, the company carried out almost as many tests but fewer than 8% of them were positive for RV. This suggests that the number of positive RV tests fell approximately 70% over the last few years, even though only about 50% of eligible infants have been vaccinated.

These findings again support a rapid and impressive herd immunity effect with the new oral vaccine. “When babies are first infected with RV, they excrete tremendous amounts of RV in their stool so it affects not only the infant but everyone else around them,” Dr. Offit explained. “So with the vaccine, you are decreasing a lot of viral shedding and further exposure to the virus.” This does not imply that infants will no longer require the RV vaccine series, he hastened to add. Like influenza, RV is still circulating throughout the community even when there is significant herd immunity, he noted. “You can eliminate polio... but you cannot eliminate influenza or RV,” Dr. Offit cautioned.

When developing the vaccine, Dr. Offit and colleagues found that the main challenge was to separate out viral pathogenicity from viral immunogenicity. “The hope was then to create a recombinant vaccine that contains the genes that produce the antibodies that protect infants against disease but not the genes that contain the proteins that make them sick.”

Burden of Disease

A comprehensive measurement of the burden of disease caused by RV here in Canada is expected to be published in December. As pediatricians, however, both Dr. Offit and Dr. John Yaremko, Associate Professor of Pediatrics, McGill University, Montreal, Quebec, already understand how the infection can affect a family. “I think what drove it home for me is that we saw a child in our ER die from RV gastroenteritis,” Dr. Offit recalled. The mother had done everything she was told to do for the sick infant but only about 24 hours after symptom onset, the child’s vomiting had been so severe and persistent that there was nothing the ER team could do to stave off the ravages of dehydration caused by the gastroenteritis.

Dr. Yaremko himself has seen his share of RV gastroenteritis and neither he nor the parents find it trivial. “There is no question that RV is the most common cause of gastroenteritis in children under the age of 5 and especially under the age of 2,” he confirmed. In fact, almost all children develop at least one episode of the illness before their second birthday, he added. What is different about gastroenteritis caused by RV is that not only do children develop diarrhea, vomiting and fever with it, “they are much more likely to get dehydrated from this virus.” Although oral hydration can sometimes reverse this dehydration, it is more of a challenge to rehydrate very young children, he added—“so they end up in the ER for intravenous rehydration and all of its associated costs.”

Furthermore, it is not just the infant who is afflicted by this very unpleasant infection. Because RV is so contagious, it is very common for at least one other family member to be affected with RV as well. The soon to be published study will reveal that up to 50% of the families surveyed were getting at least a second case of RV gastroenteritis. This included about one-third of the parents who then had to miss work, not only to take care of their sick infant but also to take care of themselves.

“RV gastroenteritis is well worth preventing because the illness is severe and unpleasant, it is very common, and second and third cases often occur in the families when infants get sick,” Dr. Yaremko stated. “From a societal point of view, RV infection has a very high cost because it is associated with so many office and ER visits and hospitalizations. If we can avoid all of this, prevention probably will save money down the road.”

IMPACT, a surveillance program of the Public Health Agency of Canada, is currently tracking RV infection rates in children hospitalized for gastroenteritis. As noted by Dr. Nicole Le Saux, Division of Infectious Diseases, Children’s Hospital of Eastern Ontario, and one of the principal investigators of IMPACT, “The other aspect of the RV surveillance program is to look at the characteristics of the children who come to the ER with RV gastroenteritis and to see how much it costs in the ER as there is a lot of it in the community.”

Related sessions of interest at this meeting:

“Vaccinated Children Among Hospitalized Meningococcal Cases Across Canada, IMPACT 2002-2006.” Julie Bettinger, Nicole Le Saux, David W. Scheifele, Scott A. Halperin, Wendy Vaudry, Raymond Tsang, IMPACT Investigators.

“Trivalent Influenza Vaccine Effectiveness Against Infant/toddler Hospitalization During Three Canadian Winters: A Report from the Immunization Monitoring Program - Active (IMPACT).” Gaston De Serres, IMPACT Investigators.

“Genetic Analysis of Invasive Neisseria Meningitidis Strains in Canada Monitored by the IMPACT Program from 2002 to 2006.” Raymond Tsang, IMPACT Investigators.

“The Effect of Routine Vaccination on Invasive Pneumococcal Infection in Canadian Children: 2000-2007. A Report from the IMPACT Network.” Julie Bettinger, IMPACT Investigators.

“Communicating the Benefits and Risks with Clarity and Confidence: Communicating Science to the Public.” Paul A. Offitt.