Mixed Rotavirus Vaccine Series Safe and Immunogenic

Ricki Lewis, PhD

January 29, 2016

Rotavirus vaccination series using either a single vaccine or a combination of the approved vaccines was equally safe and immunogenic, according to a study published online January 28 in Pediatrics.

The US Food and Drug Administration has approved two rotavirus vaccines: RV5 (RotaTeq, Merck & Co, Inc) is a live, oral vaccine that consists of five human/bovine reassortant rotaviruses containing five genes from human strains, administered in three doses, and RV1 (Rotarix, GlaxoSmithKline) is a live, attenuated rotavirus vaccine prepared from one human strain, given in two doses.

The Advisory Committee on Immunization Practices recommends using the same formulation for all doses given to a patient, but this is not always feasible. Rotavirus vaccination is so common that on occasion, a child will be given one dose of one product and another dose of the other product, a "mixed sequential schedule." One study of pediatric practices found this to occur about 3% of the time.

Safety and immunogenicity of such mixed vaccine regimens compared with receiving all doses of the same product had not been evaluated previously, and the results of the new study are reassuring. "If you are a physician who has faced challenges in keeping both or a consistent formulation of one of the two rotavirus vaccines in stock, the recent randomized, multicenter, open-label study by Libster et al will give you comfort that there is an evidence-based solution," Iona Munjal, MD, director, Pediatric Antimicrobial Stewardship Program, Department of Pediatrics, Division of Infectious Diseases at Children's Hospital at Montefiore, Bronx, New York, told Medscape Medical News.

Romina Libster, MD, from Vanderbilt University School of Medicine, Nashville, Tennessee, and colleagues compared safety and noninferiority of immunogenicity among five regimens: the two vaccines alone (RV5-RV5-RV5 and RV1-RV1) and three mixed groups (RV5-RV1-RV1, RV5-RV5-RV1, and RV1-RV5-RV5). The subjects were healthy infants aged between 6 and 15 weeks at the time of the first vaccination.

The study had two components. First, it examined whether the proportion of seropositive children (serum antirotavirus immunoglobulin A [IgA] ≥ 20 U/mL) at 1 month after the last dose in each mixed-vaccine group was noninferior to the proportion of seropositive infants receiving a single vaccine formulation matching the first dose for each mixed-vaccine group. Second, the investigation measured the neutralizing rotavirus antibody responses to the most common rotavirus serotypes (G1 - G4 and G9) at 1 month after the last vaccination. Seropositivity for neutralizing antibody was a titer of 10 or higher.

Between March 2011 and September 2013, 1393 infants were randomly assigned to a study group, with 1063 receiving three doses and 330 receiving two doses. Of these, 1384 (99%) had the first dose, 1309 (94%) the second dose, and 958 (90%) of 1063 the third dose, with 1236 (89%) infants completing the study. The trial groups were similar in race, sex, and age.

Similar safety and immune response was seen in all groups, with the proportion of children who were seropositive against at least one vaccine antigen 1 month after the last dose being between 77% and 96%. All sequential mixed-vaccine schedules were noninferior compared with the two single-vaccine groups. In fact, the proportion of seropositive infants against two antigens (WC3 and 89-12) was greater for the mixed-vaccine group of RV1-RV5-RV5 than for the RV1-RV1 group.

"This builds on prior knowledge that either of the rotavirus vaccine formulations appears to boost titers to other serotypes not contained within that vaccine strain," said Dr Munjal.

The most frequent adverse event was irritability, based on caregiver records of all symptoms during the 8 days after each vaccination.

The researchers conclude that, "our study has clearly shown that there is not an inhibition in immunogenicity with the sequential schedule and supports that vaccines may be given interchangeably." Mixing vaccine products for rotavirus "represents a safe and an immunogenic choice." However, they note that they did not assess efficacy directly.

"Their study demonstrates that mixing the licensed rotavirus vaccine formulations to complete a series is as good at generating an immune response as a single vaccine formulation. In addition, when stratified by the number of doses, there was also no difference in the safety for the mixed compared to the single vaccine groups," Dr Munjal said.

In an accompanying editorial, Carrie L. Byington, MD, from the University of Utah in Salt Lake City and Yvonne Maldonado, MD, from Stanford University in Palo Alto, California, write that the use of "real-world scenarios" to complement clinical trial results are important for both practicing physicians and those who draw up immunization guidelines.

Dr Munjal further points out that the window of opportunity to vaccinate against rotavirus is small, so "given the robust and noninferior response from mixing the two licensed products in this study, substituting appears very reasonable and would prevent a missed vaccine opportunity."

Dr Libster has consulted for Merck. One coauthor has consulted for Merck and been on a Data and Safety Monitoring Board for Novartis and received research funding from bioCSL, GlaxoSmithKline, Merck, Pfizer, Novartis, and Novavax. Another coauthor has laboratory service agreements with Merck and GSK. Dr Edwards has served as a Data and Safety Monitoring Board member for Novartis. Another coauthor has received funding from GSK, Novartis, Pfizer, and Sanofi Pasteur. Two other coauthors have been funded by GSK, Pfizer Inc, and Gilead. Another coauthor receives funding from Merck. Another coauthor holds publicly traded Abbott and Pfizer stock. The other authors, the editorialists, and Dr Munjal have disclosed no relevant financial relationships.

Pediatrics. Published online January 28, 2016. Article abstract, Ediorial extract

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