In a study published today in The Lancet, ROTATEQ® (rotavirus vaccine, live, oral, pentavalent), MSD’s rotavirus vaccine, reduced the number of cases of severe rotavirus gastroenteritis by nearly half (48 percent) in infants evaluated in developing countries in Asia (Bangladesh and Vietnam) and by 39 percent in infants evaluated in developing countries in Africa (Ghana, Kenya, and Mali) through nearly two years of follow-up. This is the first study demonstrating efficacy for any rotavirus vaccine in developing countries in Asia and the first study to show efficacy for ROTATEQ in developing countries of Asia and Africa.
“We are encouraged by the data,” said study investigator Dr. Khalequz Zaman, International Centre for Diarrhoeal Disease Research, Dhaka, Bangladesh. “In this study, ROTATEQ prevented severe rotavirus gastroenteritis in infants in regions in Africa and Asia where the disease burden is quite high and rotavirus vaccines are needed the most.”
ROTATEQ is an oral pentavalent vaccine indicated for the prevention of rotavirus gastroenteritis in infants and children caused by the serotypes G1, G2, G3, G4, and G-serotypes that contain P1A (e.g., G9). ROTATEQ may be administered as early as 6 weeks of age. The first dose should be administered at 6 to 12 weeks of age, with the subsequent doses administered at a minimum interval of four weeks between each dose.
ROTATEQ should not be administered to infants with a demonstrated history of hypersensitivity to any component of the vaccine. Infants with Severe Combined Immunodeficiency Disease (SCID) should not receive ROTATEQ. Cases of gastroenteritis associated with vaccine virus have been reported post-marketing in infants with SCID.
Rotavirus gastroenteritis is the leading cause of diarrheal disease mortality among children under 5 years of age, resulting in an estimated 527,000 deaths per year globally, mostly in Asia and Africa. It is highly prevalent and highly contagious, infecting nearly all children by age 5, often more than once in both developed and developing countries.
“Given the impact of rotavirus gastroenteritis in the developing world, reduction in severe rotavirus disease represents a critically important public health goal,” said Mark Feinberg, M.D., Ph.D., vice president, Medical Affairs and Policy, Merck Vaccines. “Merck is committed to advancing global health by improving access to ROTATEQ in areas most affected by the severe consequences of rotavirus disease.”
In 2009, the World Health Organization’s (WHO) Strategic Advisory Group of Experts recommended to expand rotavirus vaccine use to all regions of the world. The efficacy data for ROTATEQ in Asia and Africa, along with effectiveness data in Nicaragua, helped inform the WHO’s recommendation for expansion of the rotavirus vaccine to all regions. This recommendation led to global WHO-pre-qualification of ROTATEQ, accelerating the availability of vaccines in the developing world.
About the Study
More than 7,500 infants between 4 and 12 weeks of age from five developing countries in Asia (Bangladesh and Vietnam) and Africa (Ghana, Kenya, and Mali) were enrolled in the two-year randomized, double-blind, placebo-controlled clinical trial. The trial was designed to evaluate the efficacy of three doses of ROTATEQ (n=3,751) against severe rotavirus gastroenteritis versus placebo (n=3,753) in low income countries with high incidence of diarrheal disease mortality.
The study was coordinated through a partnership between Merck and the Rotavirus Vaccine Program (RVP), a collaboration between PATH, an international non-profit organization, WHO and the U.S. Centers for Disease Control and Prevention. Clinical trial investigators in Asia and Africa partnered with Merck and RVP to conduct the trial. The Merck and RVP partnership was initiated by the GAVI Alliance in an effort to introduce rotavirus vaccine in the developing world. The study was funded by RVP with a grant from the GAVI Alliance and was co-sponsored by Merck.
In this study, infants received ROTATEQ or placebo at approximately 6, 10, and 14 weeks of age with routine infant vaccines. Infants between 4 and 12 weeks of age who were free of symptoms of active gastrointestinal disease and could be adequately followed for safety were eligible. The primary endpoint was rotavirus gastroenteritis, irrespective of serotype, occurring 14 days or more after the third dose of ROTATEQ or placebo until the end of the study. Gastroenteritis was defined as three or more watery or looser than normal stools within a 24 hour period or forceful vomiting. Severity of rotavirus gastroenteritis was defined by a 20 point clinical scoring system (modified Vesikari system), with those cases with a score of 11 or more being classified as severe.
In Asia, 1,018 infants were randomly assigned to receive ROTATEQ and 1,018 infants received placebo; median follow-up time in both groups, from 14 days after the third dose of vaccine or placebo until final disposition, was 498 days. Over the entire study period, there were 38 cases of severe rotavirus gastroenteritis in the vaccine group, compared with 71 cases reported in the placebo group, resulting in a vaccine efficacy of 48.3 percent (95 percent CI 22.3, 66.1 percent) at sites in Asia. Through nearly two years of follow up, vaccine efficacy was 42.7 percent (95 percent CI 10.4, 63.9 percent) in Bangladesh and 63.9 percent (95 percent CI 7.6, 90.9 percent) in Vietnam.
In Africa, 2,733 infants were randomly assigned to receive ROTATEQ and 2,735 infants received placebo; median follow-up time in both groups was 527 days starting 14 days after the third dose of vaccine or placebo.
Over the entire study period, there were 79 cases of severe rotavirus gastroenteritis reported in the vaccine group, compared with the 129 cases reported in the placebo group, resulting in a vaccine efficacy of 39.3 percent (95 percent CI 19.1, 54.7 percent) at sites in Africa.
Efficacy was 55.5 percent (95 percent CI 28.0, 73.1 percent) in Ghana, 63.9 percent (95 percent CI < 0, 89.8 percent) in Kenya, and 17.6 percent (95 percent CI < 0, 45.0 percent) in Mali through nearly two years of follow up.
In post-hoc analyses, overall efficacy against severe rotavirus gastroenteritis in Asian infants was 51 percent (95 percent CI 12.8, 73.3 percent) in the first year of life and 45.5 percent (95 percent CI 1.2, 70.7 percent) in the second year of life. Efficacy in Bangladesh was 45.7 percent (95 percent CI < 0, 71.8 percent) in the first year of life and 39.3 percent (95 percent CI < 0, 69.7 percent) in the second year of life. Efficacy in Vietnam was 72.3 percent (95 percent CI < 0, 97.2 percent) in the first year of life and 64.6 percent (95 percent CI < 0, 93.9 percent) in the second year of life.
Overall efficacy against severe rotavirus gastroenteritis in African infants was 64.2 percent (95 percent CI 40.2, 79.4 percent) in the first year of life and 19.6 percent (95 percent CI < 0, 44.4 percent) in the second year of life. Efficacy in Ghana was 65.0 percent (95 percent CI 35.5, 81.9 percent) in the first year of life and 29.4 percent (95 percent CI < 0, 70.7 percent) in the second year of life. Efficacy in Kenya was 83.4 percent (95 percent CI 25.5, 98.2 percent) in the first year of life and less than 0 percent (95 percent CI < 0, 82.3 percent) in the second year of life. Efficacy in Mali was 1.0 percent (95 percent CI < 0, 81.6 percent) in the first year of life and 19.2 percent (95 percent CI < 0, 47.3 percent) in the second year of life. The surveillance system in the study protocol was designed to detect participants presenting to healthcare facilities. However, in Mali, for cultural reasons, many cases of severe diarrhea were preferentially taken to traditional healers during the first year of the study. Strengthening of the surveillance system after the first year of the study resulted in a 12-fold increase in detection of severe rotavirus gastroenteritis in Mali in the second year of life, and a higher point estimate of efficacy in the second year than in the first year. The proportion of subjects with reported serious adverse events (SAEs) was comparable between the vaccine and placebo groups in Asia (2.5 percent in ROTATEQ group, 2.0 percent in placebo group) and Africa (1.5 percent in ROTATEQ group, 1.7 percent in placebo group). The most frequent serious adverse event was pneumonia in Asia (1.2 percent in ROTATEQ group, 1.5 percent in placebo group) and gastroenteritis in Africa (0.6 percent in either ROTATEQ or placebo group). One confirmed case of intussusception (in Vietnam), in the placebo group (at Day 97 post-Dose 3), was reported during the clinical trial. “This study provided insights into how vaccine immune responses and efficacy varied in developing countries,” said Max Ciarlet, Ph.D., associate director, Merck Research Laboratories. “Several factors may adversely affect immune response and efficacy of vaccines in these regions, including poor nutrition, the presence of other intestinal bacteria and viruses, and co-infections in the digestive system.” Select Safety Information about ROTATEQ No safety or efficacy data are available from clinical trials regarding the administration of ROTATEQ to immunocompromised patients such as individuals with malignancies or who are otherwise immunocompromised; individuals receiving immunosuppressive therapy; individuals infected with HIV; or individuals who received a blood transfusion or blood products, including immunoglobulins within 42 days. More than 71,000 infants were evaluated in three Phase 3, placebo-controlled clinical trials. Parents/guardians were contacted on days 7, 14, and 42 after each dose regarding intussusception and any other serious adverse events. In the Rotavirus Efficacy and Safety Trial (REST) of more than 69,000 infants, ROTATEQ did not increase the risk of intussusception relative to placebo. There were no confirmed cases of intussesception during the 42-day period after dose one and no clustering of cases among vaccine recipients at any time period after any dose. Four cases of intussusception were reported in children who had received placebo following the one-year safety follow-up period. In a subset of more than 11,000 infants in these trials, the presence of adverse events was reported for 42 days after each dose. The most commonly reported adverse experiences with ROTATEQ (frequency >1/10) include upper respiratory infection, diarrhea, vomiting, pyrexia, otitis media, irritability, and cough.
The following adverse experiences have been spontaneously reported during post-approval use of ROTATEQ: urticaria and gastroenteritis with vaccine viral shedding in infants with SCID. Because these experiences were reported voluntarily from a population of uncertain size, it is not possible to reliably estimate their frequency or to establish a causal relationship to vaccine exposure.
In a prospective post-marketing observational study conducted using a large medical claims database, the risks of intussusception or Kawasaki disease resulting in emergency department visits or hospitalizations during the 30 days following any dose of vaccine were analyzed among 85,150 infants receiving one or more doses of ROTATEQ.
During the 0-30 day follow-up period after vaccination, there were no statistically significant differences in the rates of intussusception or Kawasaki disease compared with the expected background rates. In addition, there was no statistically significant increased risk of these adverse events during the 0-30 day follow-up period when comparing the 17,433 person-years of follow-up among infants receiving ROTATEQ (n equals 85,150) with the 12,339 person-years of follow up among a concurrent control group of infants who received DTaP, but not ROTATEQ (n equals 62,617).
There were six confirmed cases of intussusception among infants vaccinated with ROTATEQ compared with five among the concurrent controls vaccinated with DTaP (relative risk equals 0.8, 95 percent CI 0.22-3.52). There was one chart-confirmed case of Kawasaki disease identified among infants vaccinated with ROTATEQ and one chart-confirmed case of Kawasaki disease among concurrent DTaP controls (relative risk equals 0.7, 95 percent CI 0.01-55.56). In the general safety analyses, the Safety Monitoring Committee did not identify any specific safety concerns.
ROTATEQ® is a registered trademark of Merck & Co. Inc., Whitehouse Station, N.J., USA