Safety and Reactogenicity
Frequency of SAEs recorded in the RIX4414 and placebo groups were similar (P = 0.266). At least 1 SAE was recorded in 57 infants: 34 (5.1%, 95% CI: 3.5–7.0%) in the RIX4414 group and 21 (6.2%, 95% CI: 3.9–9.3%) in the placebo group during the study period (Table 2). In addition, 2 SAEs were reported by the investigators after study end because they considered them as clinically important. The most commonly reported SAEs were gastroenteritis (6) in the RIX4414 group and bronchiolitis (4) in the placebo group. Five vaccine-related SAEs (fever , gastroenteritis , hypernatremia , dehydration ) were recorded in 3 infants (2 infants in the RIX4414 group and 1 in the placebo group). During the follow-up period, 1 fatal SAE (bronchiolitis) was recorded in the placebo group, which was considered as not related to vaccination; no intussusception cases were reported.
During the 31-day postvaccination follow-up period, at least 1 unsolicited AE was reported in 196 (29.3%, 95% CI: 25.8–32.9%) and 138 (40.7%, 95% CI: 35.4–46.1%) infants in the RIX4414 and placebo groups, respectively (P < 0.05). The most commonly reported unsolicited AEs under system organ classification were general disorders (pyrexia [4.8% in RIX4414 and 8.3% in placebo] and irritability [1.6% in RIX4414 and 3.2% in placebo]), gastrointestinal disorder (diarrhea [2.7% in RIX4414 and 2.9% in placebo] and abdominal pain (2.2% in RIX4414 and 2.4% in placebo), and infection (gastroenteritis [2.4% in RIX4414 and 3.2% in placebo] and upper respiratory tract infection [2.1% in RIX4414 and 3.2% in placebo]) in both the groups during the 31-day postvaccination follow-up period. Grade 3 unsolicited AEs were reported at a low frequency in both groups (1.9% in RIX4414 and 6.5% in placebo).
The percentage of all and grade 3 solicited general AEs recorded during the 15-day postvaccination follow-up period were similar in both the RIX4414 and placebo groups (P > 0.05) with irritability being the most common AE reported (Fig. 2).
Similar percentages of gastroenteritis episodes were recorded in both groups from dose 1 up to 30–83 days post-dose 2 of RIX4414 vaccine/placebo (8.2% in the RIX4414 vaccine group and 10.6% in the placebo group). Rotavirus was isolated from 5 gastroenteritis episodes (RIX4414 = 3, Placebo = 2) with available stool samples. The onset of rotavirus gastroenteritis in the RIX4414 group was 1–5 days after vaccination, and in the placebo group it was 3–4 days after receiving placebo. G1P vaccine strain was isolated from all the 3 gastroenteritis episodes in the RIX4414 group (2 cases after dose 1 [8.5 ± 1.77 weeks of age] and 1 case after dose 2 [16.0 ± 3.03 weeks of age]), and G1P wild-type strain was isolated from both the gastroenteritis episodes in the placebo group (1 each after dose 1 [8.5 ± 1.78 weeks of age] and dose 2 [16.0 ± 2.95 weeks of age]).
Exploratory analysis by age strata showed that at least 1 SAE was reported in 5 (3.7%, 95% CI: 1.2−8.4%) and 8 (11.3%, 95% CI: 5.0–21.0%) RIX4414 and placebo recipients, respectively, belonging to group 1. Among group 2, 29 (5.4%, 95% CI: 3.7−7.7%) RIX4414 recipients and 15 (5.6%, 95% CI: 3.2–9.1%) placebo recipients reported at least 1 SAE. At least 1 unsolicited AE was reported in 30 (22.2%, 95% CI: 15.5−30.2%) RIX4414 infants and 22 (31.0%, 95% CI: 20.5–43.1%) placebo infants from group 1; in group 2, 166 (31.1%, 95% CI: 27.2−35.2%) and 116 (43.3%, 95% CI: 37.3–49.4%) RIX4414 and placebo recipients reported at least 1 unsolicited AE, respectively.
The antirotavirus IgA seroconversion rate at 30–83 days post-dose 2 of RIX4414 vaccine/placebo, was 85.7% (95% CI: 79.0–90.9%) in the RIX4414 group and 16.0% (95% CI: 8.8–25.9%) in the placebo group (Table 3). GMCs calculated on seropositive infants were 333.8 U/mL (95% CI: 266.5–418.1) in the RIX4414 group (N = 126) and 407.1 U/mL (95% CI: 147.7–1121.6) in the placebo group (N = 13).
Stratawise (group 1 and group 2) exploratory immunogenicity analysis revealed that the antirotavirus IgA seroconversion rate of participants in group 1 and group 2 who received RIX4414 vaccine were 75.9% (95% CI: 56.5–89.7%) and 88.1% (95% CI: 80.9–93.4%), respectively (Table 3). GMCs were calculated on seropositive infants that received RIX4414 vaccine—group 1 (N = 22): 236.5 U/mL (95% CI: 133.4–419.3) and group 2 (N = 104): 359.1 U/mL (95% CI: 280.6–459.5). The antirotavirus IgA seroconversion rates were similar between the countries (data not shown).
Administration of a live-attenuated rotavirus vaccine to preterm infants often raises the question of the safety of the vaccine in this population. In the present study, the safety and immunogenicity of the RIX4414 vaccine in a preterm infant population were assessed.
Results of this study demonstrated that 2 oral doses of RIX4414 vaccine were well-tolerated and immunogenic in preterm European infants. There was no evidence of a statistically significant difference in terms of frequency of SAEs recorded among the infants in the RIX4414 and placebo groups. Similar safety results were observed in preterm infants (gestational age <32 weeks) who received a live-attenuated pentavalent human-bovine reassortant rotavirus vaccine.15 A lower percentage of infants in the RIX4414 group recorded unsolicited symptoms when compared with the placebo group; however, this difference was not clinically significant. The safety and reactogenicity results observed in this study are in line with the safety profile of RIX4414 reported in previous studies with full-term infants.6,7,16 The percentage of gastroenteritis episodes reported in the study period was similar in both groups. There were 3 rotavirus gastroenteritis episodes reported in the RIX4414 group within the first 5 days after vaccination, with G1P vaccine strain isolated. This observation is not uncommon as it is a known fact that rotavirus vaccine shedding peaks during the first 7 days after vaccination.17
The overall serum antirotavirus IgA seroconversion rate of the RIX4414 vaccine was high when compared with placebo at 30–83 days post-dose 2 of RIX4414 vaccine/placebo (85.7% versus 16.0%). This is in line with a European study conducted on full-term infants where the antirotavirus IgA seroconversion rate was 86.5%.18 Thirteen infants who were administered placebo in the study seroconverted for antirotavirus IgA antibodies as evidenced by the high GMCs (407.1 U/mL). This GMC value indicated the possibility of natural rotavirus infection due to the circulation of wild-type rotavirus strains during the study period. Detection of wild-type G1P rotavirus type from the 2 gastroenteritis stool samples in the placebo group further emphasizes the fact that some infants in the placebo group may indeed have developed natural rotavirus infection during the study period. It is, however, difficult to rule out the possibility of asymptomatic rotavirus infections among the infants receiving the rotavirus vaccine.
In both the preterm infants belonging to group 1 and group 2, the immune response against the RIX4414 vaccine was good and >75% of infants had seroconverted 30–83 days post-dose 2. The seroconversion rates observed in the preterm infants in this study were similar to that observed in a study in 26 preterm infants of late gestational age vaccinated with RIX4414 in Taiwan (seroconversion rate post-dose 2 = 93.3%).19 Antirotavirus IgA antibody concentrations observed in seropositive preterm infants of group 1, 30–83 days after the second dose of the vaccine was236.5 U/mL as compared with 359.1 U/mL in preterm infants of group 2. The small number of infants in group 1 may be the reason for the absence of a significant difference (insufficient power). Although the immune response in preterm infants of gestational age 27–30 weeks (group 1) seems lower than the one observed in preterm infants of gestational age 31–36 weeks (group 2), it is within the range of immune responses observed in the healthy European infants,18 and thus no significant impact on the protection level is anticipated.
This study had some limitations—first, any interpretation of results between the preterm infants in group 1 and group 2 (safety, reactogenicity and immunogenicity) has to be exercised with caution as the study was not designed to allow such comparison; second, this study included data for preterm infants from ≥27 weeks of age and cannot be extrapolated to infants younger than this age; third, because the study was designed to administer RIX4414 vaccine/placebo along with routine vaccines concomitantly, this did not allow differentiating whether the reactogenicity observed in the vaccine group was due to RIX4414 vaccine or coadministered childhood vaccines. However, RIX4414 vaccine coadministered with routine childhood vaccines did not seem to increase the reactogenicity as compared with the reactogenicity observed in the placebo group coadministered with similar routine childhood vaccines; finally, the presence of maternal antibodies was not evaluated in this study. Published literatures suggest that immaturity of the immune system and the presence of maternal antibody may impact vaccine responses among preterm infants.20,21
Considering that the preterm infants are at a greater risk of hospitalizations due to gastroenteritis,9 the European Society for Pediatric Infectious Diseases/European Society for Pediatric Gastroenterology, Hepatology and Nutrition guidelines and the Advisory Committee on Immunization Practices have suggested that the benefits of rotavirus vaccination far outweigh the potential risks.13,22 Based on these recommendations, all medically stable, healthy preterm infants may receive rotavirus vaccine at the chronologic age similar to full-term infants at the discretion of the medical practitioner.22 Further to the above recommendations, the World Health Organization has also indicated that the immunogenicity of rotavirus vaccine is not impaired by the preterm condition of infants.3
The results from this study provide much needed safety data for the introduction of 2 oral doses of RIX4414 vaccine in preterm infants in Europe. The vaccine was well tolerated and immunogenic and can be recommended for use in preventing rotavirus disease in this specific population. However, RIX4414 vaccine is to be administered to medically stable preterm infants at the time or after discharge from the neonatal unit.
The authors thank the infants and their families for participating in this trial, all investigators, the study nurses and other staff members for contributing in many ways to this study, in particular: Drs Carmen Carvalho (Maternidade Júlio Dinis; Serviço de Neonatologia- Centro Hospitalar do Porto, Portugal), Clément Castella (Hôpital des Enfants, CHU Bordeaux, France), Olivier Claris (Hôpital Edouard Herriot, Lyon, France), Christophe Dupont (Hôpital St Vincent de Paul, Paris, France), Gilberta Fontes Santos (Maternidade Júlio Dinis; Serviço de Neonatologia, Centro Hospitalar do Porto, Portugal), Catherine Gire (Hôpital Nord-Enfants, Marseille, France), Bernard Guillois (CHU Clémenceau, Caen, France), Nadine Kacet (Hôpital Jeanne de Flandre, Lille, France), André Labbe (Hôtel Dieu, Clermont-Ferrand, France), Esmeralda Pereira (Maternidade Alfredo de Costa, Lisbon, Portugal), Frederico Leal (Hospital D. Estefânia, Lisbon, Portugal) and António Lucas (Hospital S Francisco Xavier, Lisbon, Portugal).
The authors are indebted to Paul Gillard and Silvia Damaso for their contribution to study design; to Keerthi Thomas and the data management team for acquisition of data; to Yolanda Guerra and the safety team for management of safety information; to Catherine Bougelet and the team for laboratory testing; to DDL Diagnostic Laboratory, the Netherlands, for performing the reverse transcriptase polymerase chain reaction and VP4 and VP7 genotyping; to Bruno Anspach and Aurélie Van Damme for global study management; to Janet Reyes, Pilar Garcia-Corbeira, Eduardo Fernandez-Ruiz, Alexandra Santa Marta, Nathalie Clyti, Christine Peurichard and Véronique Dejos-Conant for country study management. The authors thank Geetha Subramanyam and Nancy Van-Driessche (both employees of GlaxoSmithKline) for providing writing and editorial support in preparing this manuscript.
Human Rotavirus Vaccine (ROTA-054) Study Group:Juan C. Tejedor, MD (Hospital de Móstoles, Madrid, Spain), Javier Castro,MD (Hospital 12 de octubre, Madrid, Spain), Javier Arístegui, MD (Hospital de Basurto, Spain), Fernando Centeno, MD (Hospital Rio Hortega, Valladolid, Spain), José M. Merino,MD (Hospital General Yagüe, Burgos, Spain), David Moreno-Pérez MD (Hospital Materno Infantil Carlos Haya, Málaga, Spain), Javier Díez-Delgado, MD (Hospital de Torrecárdenas, Almeria, Spain), Jesús Ruiz-Contreras, MD (Hospital 12 de octubre, Madrid, Spain), Xabier Carbonell, MD (Hospital Clinic, Barcelona, Spain), Enriqueta Román, MD (Hospital de Fuenlabrada, Madrid, Spain), Barbara Pajek, MD (Private outpatient clinic “Michalkowice” s.c., Siemianowice Slaskie, Poland), Jacek Wysocki, MD (University School of Medical Sciences & Regional Medical Centre for Mother and Child, Poznan, Poland), Hanna Czajka, MD, PhD (Regional Children Hospital, Krakow, Poland), Rosalina Barroso, MD (Hospital Fernando Fonseca, Lisbon, Portugal) and Augusta Areias, MD (Maternidade Júlio Dinis, Porto, Portugal).
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Keywords:© 2012 Lippincott Williams & Wilkins, Inc.
gastroenteritis; gestational age; transplacental antibody transfer