Question: What is the safety of the rotavirus vaccines, including the latest information on possible contamination issues?
Answer: Rotavirus is the leading cause of severe gastroenteritis among infants and young children, particularly those aged 6 months to 2 years. Clinical features of rotavirus infection include severe, watery diarrhea, fever, abdominal pain, and vomiting, which may lead to severe dehydration and possibly death.1,2 Before the rotavirus vaccine was introduced in 2006, nearly all children in the United States were infected by rotavirus before 5 years of age. During that time, more than 400,000 physician visits and more than 200,000 emergency department visits occurred each year in the United States that were attributed to the infection.2 Internationally, rotavirus is responsible for half a million deaths each year in children younger than 5 years.1,3
In 1998, FDA approved Wyeth-Ayerst’s oral tetravalent human–rhesus rotavirus reassortant vaccine (RRV-TV; RotaShield). Although this vaccine was proven to effectively prevent rotaviral diarrhea, it was voluntarily withdrawn from the market in October 1999 because of concerns regarding intussuception, which is a condition that causes the proximal segment of the bowel to telescope into the adjacent portion of the distal bowel. In 2001, a workshop was held to further investigate this association. A case–control series analysis and retrospective cohort study demonstrated epidemiological evidence that a causal relationship did in fact exist between RotaShield and intussuception, with a population attributable risk of 1 per 10,000 vaccinees (range 1 in 5,000 to 1 in 12,000).4 In contrast, the incidence of intussusception-related hospitalization in infants and children is estimated to be between 18 to 56 cases per 100,000 individuals.5 Currently, two FDA-approved rotavirus vaccines are available on the U.S. market: RotaTeq (Merck) and Rotarix (GlaxoSmithKline). In February 2006, FDA approved RotaTeq, a live, oral, pentavalent human–bovine rotavirus reassortant vaccine that is given as a three-dose series (2, 4, and 6 months). Rotarix, a live, oral, monovalent human attenuated rotavirus vaccine that is completed in two doses (2 and 4 months), was approved in April 2008.
Two Phase III trials examined the safety and efficacy of the RotaTeq vaccine. The Rotavirus Efficacy and Safety Trial (REST) was a randomized placebo-controlled trial that evaluated healthy infants aged 6 to 12 weeks (n = 68,038). Investigators evaluated all infants for intussusception and found that it occurred in six RotaTeq recipients and five placebo recipients within 42 days after any dose (multiplicity-adjusted relative risk [RR] 1.6 [95% CI 0.4 to 6.4). REST investigators therefore concluded that no evidence supported RotaTeq vaccine increasing the risk of intussusception compared with placebo.6 Detailed safety information was collected from 11,711 infants from REST and two smaller studies to determine other potential adverse events with the vaccine.7 Pooled data from these studies found that fever, as reported by parents and/or guardians, was similar between placebo and RotaTeq groups (42.8% vs. 42.6%) within 42 days after any dose. The incidences of diarrhea and vomiting were small but statistically greater amongst vaccine recipients compared with placebo (24.1% vs. 23.1% and 15.2% and 13.6%, respectively; P < 0.05) within 42 days after any dose.7 In another randomized clinical trial, the safety and efficacy of the RotaTeq vaccine were evaluated at the end of its 24-month shelf life. The trial found no statistically significant increase in vomiting, diarrhea, or irritability among recipients of the vaccine compared with placebo but found a higher rate of fever after the first dose in those who received RotaTeq compared with placebo (13.4% vs. 8.8%, P = 0.01).8
The safety of the Rotarix vaccine was evaluated in eight randomized, double-blind, placebo-controlled, Phase II and III trials.9–16 A Phase III trial studied 63,225 healthy infants and found that the vaccine did not increase the risk for intussusception within 31 days after any dose compared with placebo; 6 confirmed cases occurred among 31,673 infants who received Rotarix compared with 7 cases in 31,552 infants who received placebo (RR 0.85 [95% CI 0.30–2.42], P = 0.78).16 In seven clinical trials, detailed safety information was collected from parents and/or caregivers for 8 days following Rotarix vaccine administration. Adverse events occurring 8 days after the first dose were solicited and included fussiness/crying (Rotarix 52%, placebo 52%), cough/runny nose (Rotarix 28%, placebo 30%), vomiting (Rotarix 13%, placebo 11%), fever (Rotarix 25%, placebo 33%), and loss of appetite (Rotarix 25%, placebo 25%). Results of these studies revealed that adverse events occurred at similar rates between vaccine and placebo groups; however, no p-values or confidence intervals were reported.17
Summary: Frequency of adverse events/effects for RotaTeq and Rotarix7,17
Results from a postmarketing study sponsored by GlaxoSmithKline suggested that a small increase in risk for intussusception might occur within the first 31 days after vaccination with Rotarix (RR 1.8 [99% CI 1.0–3.1]).18 A clustering of 18 cases was observed in this study during the first week after the first dose, which corresponds to a intussusception rate four to five times higher than in later periods after vaccination.19 Based on these data, the estimated incidence of intussusception in the United States is 0 to 4 cases per 100,000 vacinees.18 Presently, the manufacturer of Rotarix is conducting an ongoing postmarketing study to assess the potential risk of intussusception; however, data to allow detection of risk are insufficient.
Preliminary data conducted in the Vaccine Safety Datalink (VSD) of 800,000 doses or more of RotaTeq have shown no increased risk of intussusception.18,19 Postmarketing monitoring for intussusception after RotaTeq vaccination is presently being conducted by CDC and FDA through evaluation of reports from the Vaccine Adverse Event Reporting System (VAERS) and VSD. From February 1, 2006, to February 15, 2007, the number of cases reported to VAERS did not exceed the number of expected background cases for either 1 to 7 days (RR 0.61 [95% CI 0.29–1.18]) or 1 to 21 days (0.32 [0.17–0.55]) after RotaTeq administration. Similarly, data from the VSD do not indicate that RotaTeq is associated with intussusception.20 According to VSD, during the period between May 21, 2006, and September 25, 2007, 3 cases of intussusception occurred among 111,521 RotaTeq recipients compared with 9 cases among 186,722 non-RotaTeq recipients (0.84 [0.14–3.92]). Further, the risk of intussusception with RotaTeq appears to be not of the same magnitude as the risk of intussusception associated with RotaShield, but monitoring of RotaTeq continues for assessment of its full safety profile.21
Despite this, postmarketing surveillance data from Australia have suggested an increased risk of intussusception in infants aged 1 month to less than 3 months during the first week after vaccination with either RotaTeq or Rotarix (RR 5.3 [95% CI 1.1–15.4] and 3.5 [0.7–10.1], respectively).22 Extensive postmarketing studies investigating the possible association and extent between both vaccines and the risk for intussusception therefore continue in the United States and other countries.
In March 2010, FDA became aware of the presence of porcine circovirus (PCV) type 1 (PCV1) in Rotarix.23 PCV1 is a small, single-stranded circular DNA virus that is common in and can cause illness in pigs. After the virus was discovered, FDA recommended that health care providers temporarily suspend the use of Rotarix while the manufacturer investigated this virus further. In April 2010, FDA released a statement from the U.S. Academic Researchers Group that found that viral sequences not related to the vaccine strain were found in Rotarix.24 However, the reported sequences were previously known, are associated with vaccine production, and have been determined to pose no safety risk. This group also confirmed the presence of DNA sequences of a simian endogenous retrovirus that resembled a monkey virus called simian type D retrovirus (SRV-1). Further analysis concluded that the virus occurs naturally in the Vero cell line used to produce Rotarix and RotaTeq and are not able to further replicate.
On May 6, 2010, Merck also identified fragments of PCV1 and PCV2 in RotaTeq.25 PCV2, like PCV1, is not known to cause infection or illness in humans. Subsequently, FDA, in consultation with the Vaccines and Related Biological Products Advisory Committee, concluded that because no evidence existed that PCV1 or PCV2 can cause infection or illness in humans, the benefits of vaccination outweigh the theoretical risk for harm and therefore clinicians should resume use of Rotarix and continue use of RotaTeq.26
Overall, the safety of both RotaTeq and Rotarix vaccine are comparable. The main differences are in their composition and administration schedules. At present, the Advisory Committee on Immunization Practices does not express a preference for one vaccine over the other.3 Further, a consensus statement from the World Health Organization, FDA, CDC stated that the documented benefits of both vaccines outweigh the suggested increased risk for intussusception or any other potential risks.18,19
Karl Hess, PharmD, FCPhA
Assistant Professor of Pharmacy Practice and Administration
College of Pharmacy
Western University of Health Sciences