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PRIORITY PRESS - 5th International Conference on Vaccines for Enteric Diseases

Málaga, Spain / September 9-11, 2009

Rotavirus (RV) is the most common cause of severe gastroenteritis (GE) in infants and young children worldwide. It causes approximately half a million deaths each year among children aged <5 years, with 90% of deaths occurring in developing countries. Worldwide, around 40% of all pediatric hospitalizations for diarrhea are attributable to RV infections. Two oral RV vaccines are in use worldwide: a pentavalent human-bovine reassortant and a monovalent vaccine. In June 2009, the World Health Organization’s Strategic Advisory Group of Experts (SAGE) recommended inclusion of RV vaccination of infants into the all-national immunization programs as part of a comprehensive strategy to control diarrheal disease.

Clinical Development of the Pentavalent Human-bovine Reassortant Vaccine

Multicentre phase III studies conducted in over 70,000 individuals in 11 countries between 2001 and 2005 showed that the three-dose regimen of the vaccine was efficacious, immunogenic and well tolerated, with no increased clinical risk of intussusception, reported Dr. Max Ciarlet, North Wales, Pennsylvania. The largest trial, REST (Rotavirus Efficacy and Safety Trial), randomly assigned participants to receive either three doses of vaccine or placebo administered at four- to 10-week intervals.

In patients followed for up to two years, hospitalizations, emergency department (ED) visits and office visits for RVGE were reduced by 96%, 94% and 86%, respectively. Breastfeeding did not appear to diminish its efficacy (68.3% and 68% against any RVGE in infants never or exclusively breast-fed and and 100% against severe RVGE in both groups). In 1581 premature infants, the rate of hospitalizations and ED visits due to RVGE was reduced by 100% and the vaccine prevented 73% of RVGE of any severity. Other post-hoc analyses indicated that the pentavalent vaccine provided consistently high protection against RVGE-attributable hospitalizations and ED visits due to RVGE between doses, starting <u>></u>14 days’ post-dose 1. “The early protection afforded against severe RVGE may be particularly beneficial to infants vaccinated during RV epidemic seasons,” Dr. Ciarlet told delegates.

A Finnish extension study of REST showed durable efficacy of 94% in reducing RVGE-associated healthcare encounters (combined hospitalizations and ED visits), regardless of RV serotype (G1-G4 and G9) for up to 3.1 years.

Evaluating Impact and Safety

The pentavalent vaccine became available in the US in February 2006 and was the only RV vaccine available until April 2008. It was therefore possible to evaluate its impact and safety in routine use during 2006 to 2008, Dr. Ciarlet explained.

Hospital studies in seven cities showed a marked decrease (85% to 98%) in RV cases in 2008 vs. previous years. Data from the National Diagnostics Laboratory showed a 76% reduction in RV prevalence in children aged <1 year between the years 2003-2006 and 2008. A decline was seen in every age group, including children aged 2 to 5 years, who were unlikely to have been vaccinated, Dr. Ciarlet noted.

Data from a large national US health insurance claims database were used to compare outcomes among infants who received three doses of the pentavalent vaccine and those who received three doses of a reference vaccine (DTaP) but were not vaccinated with the pentavalent. The vaccine was shown to be 100% effective in reducing hospitalizations and ED visits for RVGE and 96% effective in reducing physician visits.

Up to 30 days’ post-vaccination, there were six cases of chart-confirmed intussusception with vaccine and five in controls (relative risk 0.8). The safety monitoring committee concluded that there were no additional specific patterns of diagnoses that suggested a safety concern.

Nationwide Monitoring

Dr. Umesh D. Parashar, Centers for Disease Control and Prevention (CDC), Atlanta, Georgia, told delegates here that in the US, uptake of the monovalent vaccine is still relatively small and most current available data on vaccine impact relate to the pentavalent vaccine. Insurance databases show that uptake of the pentavalent vaccine in infants aged <1 year began shortly after approval in 2006, then increased steadily to 60% to 70% by early 2008. In 2007, the vaccine was primarily given in infants but by 2008, 40% of 2- to 4-year-olds had received at least one dose. “RV vaccine uptake is continuing to increase and is approaching levels for other routine vaccines,” Dr. Parashar observed.

Data from the National Laboratory Surveillance network come from 90 sentinel laboratories that report weekly to the CDC on the number of RV tests performed and the number that were positive. Between 2000 and 2006, the disease showed year-to-year fluctuation but no major variability, Dr. Parashar reported. In 2007, after introduction of the vaccine, there was some reduction in RV activity, but the 2008 season saw marked decreases throughout the system. Hospital discharge data from 18 US states, covering about 50% of the population, showed that the hospitalization rate for all-cause diarrhea in children age <5 years in the prevaccine era was 96.3 per 10,000. Consistent with the laboratory data, the rate fell slightly to 85.5 per 10,000 in 2007 but in 2008, it was reduced to 55.5 per 10,000.

Similar trends were revealed by active surveillance data from the CDC New Vaccine Surveillance Network. Among children aged <3 years with GE enrolled during January to April of each year, the percentage of fecal specimens testing positive for RV was 50% in 2006, 45% in 2007 and 6% in 2008. Between 2006 and 2008, RV hospitalization rates dropped dramatically by 84%, although vaccine coverage was only 36%. Surprisingly, an 85% decline was seen in children aged 2 to <3 years, who were too old to have received the vaccine when it was first introduced. “Collectively, these data raise the question of whether there might be indirect benefits attributable to herd immunity from RV vaccine,” Dr. Parashar suggested.

Safety Monitoring

The safety of rotavirus vaccination is being assessed in the US through a national passive surveillance system, the Vaccine Adverse Event Reporting System (VAERS), managed jointly by the FDA and CDC, and through active surveillance by the Vaccine Safety Datalink (VSD), a collaborative project between the CDC and several large US health maintenance organizations that link computerized patient-level vaccination data to medical outcomes, including potential adverse events. No increased risk of intussusception has been identified through either active or passive surveillance.

Between February 2006 and March 2008, VAERS recorded 267 cases of intussusception reported after vaccination. There was no discernible pattern after doses 2 and 3. There appeared to be a clustering of intussusception cases during the seven days after dose 1 compared with doses 2 and 3, but the implications of this are unclear since it cannot be assumed that all cases are reported or all doses distributed are administered, Dr. Parashar cautioned. VSD data showed that up to June 2008, there were five reports of intussusception reported within 30 days of vaccination, within the rate expected by chance alone, of which two occurred following dose 1 (day 11 and 19). Only two cases were validated by record review, neither following dose 1. Although VSD data did not show evidence of increased risk, the available sample size was insufficient to evaluate the low level of risk for intussusception. “It is too early to exclude a low level of risk,” Dr. Parashar commented.

Global Perspective: Developing Countries

From 1999 to 2009, the WHO estimated that >5 million children died from RV. “We should try to make the next decade the decade of RV prevention,” stated Dr. Kathleen M. Neuzil, PATH, University of Seattle, Washington. “The potential for disease reduction is enormous.” SAGE has stressed the need for clinical data from Asia and Africa, where vaccine efficacy appears lower than in developed countries. Dr. Neuzil commented on three randomized clinical trials presented at the meeting, one each with the monovalent and pentavalent vaccines in Africa and one with the pentavalent vaccine in Asia. Results from all three studies showed comparable vaccine efficacy of about 60%. Based on conservative estimates of vaccine uptake and coverage, this would translate into 1.5 million lives saved between 2010 and 2025. Globally, over 1 million hospitalizations could be prevented. “There is a lot of disease left to prevent,” Dr. Neuzil stressed. Ongoing clinical trials are aiming to better understand vaccine efficacy in developing countries.