A double-blind, randomized, placebo-controlled design was utilized with the RIX4414 rotavirus vaccine administered at three different virus concentrations. Infants were randomly assigned to one of the three study groups or the placebo group. Infants in the vaccine groups received two oral doses of the vaccine at the age of two and four months. An identical placebo containing the same constituents as the vaccine except for the vaccine virus was used as the control. The vaccine was given concomitantly with other routine vaccinations. To determine immunogenicity, blood samples were obtained from all infants immediately before the first vaccination to exclude previous rotavirus infection. Blood samples were obtained two months after the first second vaccine doses and again at one year to measure anti-rotavirus IgA antibodies. Additionally, stool was obtained from 25% of the study sample and tested for rotavirus viral shedding, with differentiation between wild type and vaccine also being performed.
There were 2,155 infants enrolled in this study from three countries in South America, allowing for slightly more than 500 infants in each group. The study began in May 2001, and the final one-year follow-up was completed in April 2003. The anti-rotavirus IgA seroconversion rates two months after first and second doses were 38%-43% and 61%-65%, respectively. This compared with a 5.3% seroconversion rate in the control group, which was determined to be a wild type virus. Vaccine take after two doses was shown in all three vaccine study groups, ranging from 65% to 75% for the lowest to highest vaccine concentration groups. Reactogenicity and safety was evaluated by monitoring incidences of fever, diarrhea, vomiting, irritability, and loss of appetite during the 15 days after vaccine administration. The results were similar for the four study groups suggesting no significant reactogenicity. There were 220 serious adverse events reported including one intussusception. However, none of these events was determined to be related to the vaccine. The RIX4414 vaccine was demonstrated to effectively protect against severe gastroenteritis caused by G1 type rotavirus and also was shown to provide some cross protection to other serotypes.
This well-designed study demonstrated a statistically significant reduction in gastroenteritis due to rotavirus infection, especially of the predominant G1 serotype, after two doses of the RIX4414 human rotavirus vaccine. Objective measures of viral shedding and IgA seroconversion support the efficacy of the vaccine. This study provided a large sample population with good controls.
An important and possibly confounding variable not addressed by the study was breastfeeding status of the infants. There is clinical evidence demonstrating the protective properties of secretory IgA in human milk against rotavirus infection, and this could have influenced the observed severity of disease in the sample population. It would have been interesting to isolate breastfeeding status as a study variable and note any effect on the results of the study.
Aside from this observation, this study appears to show a promising new oral rotavirus vaccine. As further research on the RIX4414 vaccine continues, there is hope that this vaccine could make a significant positive impact on morbidity and hospitalization rates for rotavirus infections worldwide. TH