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PRIORITY PRESS - 27th Annual Meeting of the European Society for Pediatric Infectious Diseases

Brussels, Belgium / June 9-13, 2009

Rotavirus (RV) is a common infection that causes gastroenteritis (GE) in infants and young children. In Canada, approximately 20% of all childhood GE is caused by RV, according to the National Advisory Committee on Immunization (NACI) (CCDR 2008;34:ACS-1). It is associated with major utilization of healthcare resources: approximately 35% of children with RV GE (RGE) see a physician, 15% visit an emergency room (ER) and 7% require hospitalization. Among the rotaviruses affecting humans, five main G serotypes—G1, G2, G3, G4 and G9—are the most prevalent. The prevalence of each of these serotypes varies from year to year. Except for non-G1 serotypes, which are less common, each of the other G types can predominate and cause >50% of illness in some years.

There are two live attenuated oral RV vaccines for the prevention of severe acute GE in infants: a human RV vaccine with G1P[8] serotype characteristics and an oral pentavalent human-bovine (WC3) reassortant vaccine expressing human G1, G2, G3, G4 and P1A[8] antigens. The latter vaccine is administered as three separate doses, the first between 6 and 12 weeks of age, with subsequent doses given at intervals of four to 10 weeks between each dose.

Researchers here this week also presented data from a phase III clinical trial of the live attenuated monovalent vaccine, which demonstrated a 61.2% efficacy rate in preventing severe RGE in 4939 healthy infants in Africa.

Rotavirus Efficacy and Safety Trial

During the investigational period of the oral pentavalent vaccine, a large, international phase III trial, REST (Rotavirus Efficacy and Safety Trial), enrolled approximately 70,000 healthy infants aged 6 to 12 weeks. They were randomly assigned to receive either three doses of the oral vaccine or placebo administered at four- to 10-week intervals (Vesikari et al. N Engl J Med 2006; 354(1):23-33). The infants were followed for one year and in some cases up to two years. Among those included in the per-protocol analysis (28,646 in the vaccine group and 28,488 in the placebo group), the pentavalent vaccine reduced G1-G4 RV-associated hospitalizations or ER visits by 94.5% and office or clinic visits by 86%. There was also a reduction of 58.9% in all GE-related hospitalizations after the first dose. A substudy showed 74% efficacy against any G1-G4 RGE through the first full RV season after vaccination and 98% efficacy against severe GE.

Finnish Extension Study

After REST, investigators sought to determine whether protection persisted after completion of a course of three doses of vaccine or between the first, second and third doses. These questions were addressed in the Finnish Extension Study (FES), explained lead investigator Dr. Timo Vesikari, Professor of Biology, University of Tampere Medical School, and Chief of Pediatric Infectious Disease, Tampere University Hospital, Finland.

In FES, 20,736 of the 23,429 infants enrolled in REST in Finland were followed for up to 3.1 years following the third vaccine dose. Overall, in the REST+FES per-protocol population, the vaccine reduced healthcare encounters by 94%, regardless of RV serotype. No decline in protection was observed over three years, with 94% efficacy against healthcare encounters observed in years 1 and 2 and 100% in year 3. “This is particularly important since severe RGE occurs up to the third year of life and beyond,” Prof. Vesikari noted. During REST+FES, a significant reduction against RV-associated healthcare resource utilization was achieved for up to 3.1 years against all five main serotypes, including G2. Of note, a 94% reduction in RGE-related healthcare encounters was seen against non-vaccine serotype G9, which is becoming increasingly prevalent in Europe, suggesting that protection by the vaccine is not necessarily G-type-specific. Prof. Vesikari declared he was especially satisfied with a 62% reduction seen in healthcare encounters related to any acute GE measured in 21,000 infants immediately after dose 1 in up to 3.1 years of follow-up. “With this vaccine, we can cut about two-thirds of health care encounters due to GE of any cause,” he told delegates.

Prof. Vesikari also reported that a post-hoc analysis of REST data has confirmed that the oral pentavalent vaccine provides “very high” early protection, starting from 14 days after the first dose and between doses, before completion of the series of vaccinations. He stressed the need for early protection, since some severe RGE occurs in the first months of life. Reductions in ER visits and hospitalizations due to G1-G4 RV in children who received three doses were 100% between doses 1 and 2 and 91% between doses 2 and 3. “The early protection of [the oral pentavalent vaccine] is particularly beneficial for infants vaccinated during RV epidemic seasons,” Prof. Vesikari remarked, stressing that infants should receive all three doses to fully benefit from the demonstrated protection.

Prof. Marc Van Ranst, University of Leuven, and Head, Diagnostic Virology Laboratory, University Hospitals, Leuven, Belgium, cautioned that the RV genotype spectra that are circulating often differ every season and that novel RV genotypes are continuously emerging. Continuous and long-term RV genotype surveillance will be necessary to ensure that vaccines match this dynamic diversity. “The vaccines that we are currently using now to protect against RV will not be the vaccines that we will be able to use to protect worldwide 20 years from now,” Prof. Van Ranst predicted.

Varicella Vaccine Dosing

In Canada, NACI recommends a single-dose vaccine strategy for children aged 12 to 18 months as part of routine immunization (Canadian Immunization Guide, 7th edition, 2006). In contrast, the US recommends a second dose of varicella vaccine, with the first dose administered at age 12 to 15 months and the second dose at age 4 to 6 years (Marin et al. MMWR Recomm Rep 2007;56(RR-4):1-40). This followed a randomized clinical trial comparing the efficacy of one dose of vaccine with that of two doses, in which the cumulative rate of breakthrough varicella over 10 years was 3.3-fold lower among children who received two doses than those who received one dose (Kuter et al. Pediatr Infect Dis J 2004;23(2):132-7).

Further evidence that administration of a second dose of varicella vaccine may have significant advantages for reducing the burden of varicella-related disease was presented by Dr. Roman Prymula, Professor of Epidemiology, and Dean, Faculty of Military Health Sciences, University of Defence, Hradec Kralove, Czech Republic. In a phase III multicentre study conducted by Prof. Prymula and his colleagues, a two-dose course of live attenuated (Oka) strain varicella vaccine was administered in 121 healthy children aged 11 to 21 months at the time of the first vaccination (interval between doses, 42 to 56 days).

Seropositivity after dose 1 was high at 99.1% and reached 100% after dose 2. A ninefold increase in geometric mean titres of varicella antibody was observed following the second dose vs. the first dose. The two-dose regimen was well tolerated. The most frequently reported solicited local reaction after both doses was redness at the injection site (27.9% post-dose 1 and 38% post-dose 2). Eight serious adverse events were reported in five participants. None of the events was considered to be vaccine-related and all events resolved without sequelae. No adverse event led to premature study or vaccine discontinuation. Prof. Prymula observed that this increase in anti-varicella vaccine antibody titres after the second dose was in line with previously reported findings for two doses of varicella vaccine.