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Pediatric Infectious Disease Journal:
doi: 10.1097/INF.0b013e3182490a2c
Vaccine Reports

Safety, Reactogenicity and Immunogenicity of the Human Rotavirus Vaccine in Preterm European Infants: A Randomized Phase IIIb Study

Omenaca, Felix MD, PhD*; Sarlangue, Jean MD, MSc; Szenborn, Leszek MD; Nogueira, Marta MD§; Suryakiran, Pemmaraju V. MSc; Smolenov, Igor V. MD, PhD; Han, Htay H. MB BS; ROTA-054 Study Group

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Author Information

*La Paz Hospital, Madrid, Spain

Hôpital des Enfants, CHU Bordeaux, France

Department of Pediatric Infectious Diseases, Medical University, Wroclaw, Poland

§Maternidade Alfredo da Costa, Lisbon, Portugal

GlaxoSmithKline Biologicals, Rixensart, Belgium

Accepted for publication December 30, 2011.

This study was sponsored and funded by GlaxoSmithKline Biologicals, Rixensart, Belgium. The sponsor was involved in all stages of the study, that is, from study design to data analysis and writing of the report, and also performed rotavirus enzyme-linked immunosorbent assay testing. The corresponding author had full access to all the data in the study and had final responsibility for the decision to submit for publication.

P.V.S., H.H.H. and I.V.S. are employed by the GlaxoSmithKline Group of Companies. H.H.H. and I.V.S. have stock ownership. J.W., H.C., F.O., X.C., J.R-C., E.R., J.D-D., D.M-P., J.M.M., F.C., J.C., J.A., J.C.T., J.S. and L.S. received honoraria/paid expert testimony/travel grants from GlaxoSmithKline Biologicals. E.R. and J.A. received consulting fees. The authors have no other funding or conflicts of interest to disclose.

Address for correspondence: Felix Omenaca, MD, PhD, Paseo de la Castellana 261, 28046 Madrid, Spain. E-mail: fomenaca.hulp@salud.madrid.org.

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Abstract

Background: Rotavirus disease is more severe in preterm infants than in full-term infants. This study assessed the safety, reactogenicity and immunogenicity of a human rotavirus vaccine, RIX4414, in European preterm infants.

Methods: A total of 1009 preterm infants were randomized (2:1, vaccine:placebo) and stratified into 2 groups: 20% of early (27–30 weeks, group 1) and 80% of late (31–36 weeks, group 2) gestational age preterm infants in each group. Two doses of RIX4414/placebo were administered to these preterm infants according to the recommended chronologic age for full-term infants with an interval of 30–83 days between doses. Serious adverse events were recorded throughout the study period. Solicited and unsolicited adverse events were recorded for 15 and 31 days post-each dose. Antirotavirus IgA concentrations (enzyme-linked immunosorbent assay cutoff = 20 U/mL) and geometric mean concentration were determined pre-dose 1 and 30–83 days post-dose 2 in a subset of 300 infants. This study is registered with ClinicalTrials.gov, number NCT00420745 (eTrack106481).

Results: Serious adverse events were reported at a similar frequency in both groups (P = 0.266). Fifty-seven infants reported at least 1 serious adverse event (5.1% [3.5–7.0] in the RIX4414 group and 6.8% [4.3–10.0] in the placebo group). During the 15-day postvaccination follow-up period, diarrhea, vomiting and fever occurred at a similar frequency in both groups; fever could have been due to concomitant vaccines. Five cases (RIX4414 = 3, Placebo = 2) of rotavirus gastroenteritis were reported. The onset of rotavirus gastroenteritis in the RIX4414 group was 1–5 days after vaccination (vaccine strain identified in all cases) and in the placebo group it was 3–4 days after receiving placebo (wild-type rotavirus identified from both cases). Antirotavirus IgA seroconversion rates at 30–83 days post-dose 2 were 85.7% (79.0–90.9) in the RIX4414 group and 16.0% (8.8–25.9) in the placebo group. Geometric mean concentrations were 202.2 U/mL (153.1–267.1) in the RIX4414 group and <20 U/mL in the placebo group. Seroconversion rate in groups 1 and 2 in RIX4414 recipients were 75.9% (95% confidence interval [CI]: 56.5–89.7%) and 88.1% (95% CI: 80.9–93.4%), respectively; the geometric mean concentrations in the respective groups were 110.2 U/mL (95% CI: 56.1–216.5) and 234.8 U/mL (95% CI: 173.4–318.0; exploratory analysis).

Conclusions: Two doses of RIX4414 were immunogenic and well-tolerated in European preterm infants.

Rotavirus disease continues to claim the lives of thousands of children <5 years of age, with the rate of hospital admission being highest in the 12- to 18-month age group (42.5 admissions per 10,000 children).1 Worldwide, rotavirus accounts for 25 million clinic visits, 2 million hospitalizations and >527,000 deaths each year.2,3

A live-attenuated, oral human rotavirus vaccine RIX4414, developed from the parent G1P[8] 89-12 vaccine strain for the immunization of infants4 has been found to be highly efficacious in 2 doses in various phase III studies conducted on full-term infants across Europe, Latin America and Asia in preventing severe rotavirus gastroenteritis.5–7 Effectiveness of RIX4414 against G2P[4] has been demonstrated in a Latin American study.8

Earlier studies have shown that preterm infants are at an increased risk of hospitalization due to gastroenteritis9 but are less likely to receive vaccination in a timely manner due to complications related to preterm births.10,11 Currently, the American Academy of Pediatrics and the Advisory Committee on Immunization Practices recommend that all preterm infants regardless of their gestational age receive rotavirus vaccination along with all other childhood vaccines at the same chronologic age as the full-term infants.12,13

The present study assessed the safety, reactogenicity and immunogenicity of the 2 oral doses of RIX4414 vaccine as compared with placebo in preterm infants across 4 European countries.

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MATERIALS AND METHODS

Subjects and Study Design

This phase IIIb, randomized (2:1, vaccine:placebo), double-blind placebo-controlled trial was conducted in 4 European countries—France, Portugal, Poland and Spain between January 2007 and March 2008. Vaccine doses were supplied by GlaxoSmithKline Biologicals (Rixensart, Belgium) based on a computer-generated randomization list. A block randomization system in the ratio of 2:1 (vaccine:placebo) was used to ensure balance between the treatment arms; vaccine doses were supplied to each participating country with respect to the randomization block size. The infants were also stratified based on their gestational age (20% of preterm infants of gestational age 27–30 weeks [group 1] and 80% of preterm infants of gestational age 31–36 weeks [group 2] in each treatment group).

Medically stable preterm infants, who did not require significant medical support or ongoing management for a debilitating disease and who had demonstrated a clinical course of sustained recovery discharged from the neonatal center on or before the day of first dose of RIX4414 vaccine/placebo administration were randomly allocated into groups to receive 2 oral doses of RIX4414 vaccine or placebo. Dose 1 of RIX4414 vaccine/placebo was administered according to the recommended chronologic age for full-term infants of 6–14 weeks (6–12 weeks in Spain). The interval between doses of study vaccine was 30–83 days; the same interval was also applicable between dose 2 and the last study visit.

Routine vaccinations against diphtheria, tetanus, pertussis, hepatitis B, Haemophilus influenzae type b and poliovirus (inactivated poliovirus vaccine) were administered concomitantly with the RIX4414 vaccine/placebo as per the local country’s recommendations. In France and Spain, concomitant vaccination against Streptococcus pneumoniae was allowed whereas vaccination against Neisseria meningitidis C was allowed in Portugal and Spain if there was an interval of at least 14 days with respect to the administration of the RIX4414 vaccine/placebo.

Infants were excluded from the study if they had received any investigational drug or vaccine other than the study vaccine, were allergic to any of the vaccine components, were immunosuppressed or had acute disease (presence of a moderate or severe illness with or without fever). They were ineligible to participate in the study if they had major congenital defects or serious chronic disease including any uncorrected congenital malformation of the gastrointestinal tract or other conditions such as necrotizing neonatal enterocolitis grade II or III.

The study was conducted following Good Clinical Practice and the Declaration of Helsinki, and the protocol was approved by the ethics committee of the respective countries and study centers. Written informed consent was obtained from the parents/guardians of infants before the initiation of any study-related procedures.

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Vaccines

The rotavirus vaccine RIX4414 (Rotarix), diluents and placebo were developed and manufactured by GlaxoSmithKline Biologicals, Rixensart, Belgium. A single dose of RIX4414 vaccine contained at least 106.0 median cell culture infective dose of the live-attenuated RIX4414 human rotavirus strain. The composition of placebo was similar to that of the RIX4414 vaccine but without the vaccine strain.

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Assessment of Safety and Reactogenicity

At each study visit, the investigator asked the parents/guardians of infants about the occurrence of any adverse event (AE). Parents/guardians were also instructed to contact the investigator immediately if they perceived any symptom that the child was experiencing as serious. The serious adverse events (SAEs) and AEs reported were duly documented by the investigator.

SAEs (any adverse event that resulted in death, was life-threatening, required hospitalization or prolongation of hospitalization, led to disability/incapacity) were recorded throughout the study period. Solicited (fever, fussiness/irritability, diarrhea, vomiting and loss of appetite) and unsolicited AEs were recorded during the 15- and 31-day postvaccination follow-up period after each dose, respectively. The intensity of each solicited AE was graded using a protocol-defined 3-point scale where grade 3 symptoms were defined as rectal temperature >39.5°C (fever), ≥6 looser than normal stool per day (diarrhea), ≥3 episodes of vomiting per day (vomiting), not eating at all (loss of appetite) and preventing normal activities (irritability/fussiness). The intensity of unsolicited AEs were also recorded and assigned to the following categories: grade 1 = mild, grade 2 = moderate and grade 3 = severe.

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Gastroenteritis Stool Analysis

Stool samples were collected from all infants by the parents/guardians during each gastroenteritis episode (defined as diarrhea [≥3 looser than normal stools in a 24-hour period] with or without vomiting) between dose 1 and 30–83 days post-dose 2. Stool samples were collected at the earliest and no later than 7 days after the commencement of diarrhea. The stool samples were tested for the presence of rotavirus antigens (enzyme-linked immunosorbent assay, GlaxoSmithKline Biologicals laboratory, Rixensart, Belgium). Rotavirus antigen-positive stool samples were tested by reverse transcriptase polymerase chain reaction for VP7 and VP4 genes at DDL Diagnostic Laboratory, the Netherlands, to determine the G and P types, respectively.14 If G1 type was detected, the vaccine strain was distinguished from wild-type strain by sequence analysis or equivalent approach.

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Assessment of Immunogenicity

Blood samples collected from a subset of 300 infants on the day of first vaccination with RIX4414/placebo (prevaccination) and 30–83 days post-dose 2 were tested to measure the antirotavirus IgA antibody concentrations. Serum antirotavirus IgA antibody concentrations were measured using the enzyme-linked immunosorbent assay at GlaxoSmithKline Biologicals laboratory. The assay cutoff was set at 20 U/mL based on the test designed by R.L.Ward.4 The antirotavirus IgA seroconversion rate (antirotavirus IgA antibody concentration ≥20 U/mL in subjects initially seronegative) and corresponding geometric mean concentrations (GMCs) were calculated with exact 95% confidence interval (CI).

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Statistical Analyses

All statistical analyses were performed using SAS version 9.1 (SAS, Cary, NC) and Proc StatXact version 7 (Cytel, Inc., Cambridge, MA). Analysis of safety (primary endpoint) and unsolicited AEs (secondary endpoint) was done on the total vaccinated cohort, which included all infants who received at least 1 dose of RIX4414 vaccine/placebo. Assessment of reactogenicity and immunogenicity (secondary endpoints) were performed on a subset of 300 infants. The according to protocol cohort for immunogenicity included infants who complied with inclusion/exclusion criteria, vaccination and blood sampling schedules and for whom immunogenicity data were available.

The percentage of infants reporting at least 1 SAE throughout the study period with exact 95% CI were tabulated by group and compared between groups using 2-sided asymptotic standardized 95% CI for group difference (RIX4414 minus placebo). Solicited and unsolicitedAEs were recorded with exact 95% CI during the 15- and 31-day postvaccination follow-up period, respectively. Apart from the primary endpoint, all other group comparisons were exploratory in nature, and the 95% CI for these group differences were based on asymptotic standardized CI.

In this placebo-controlled study, a sample size of 999 infants with a 2:1 randomization scheme had 90% power to rule out an increase of SAEs in the 4–7% range in the RIX4414 group when compared with the placebo group. For the immunogenicity analysis, the immunogenicity subset (N = 300) was included taking into consideration that 20% of infants might not be evaluable for immunogenicity.

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RESULTS

Demography

A total of 1009 infants (France = 78, Poland = 435, Portugal = 142, Spain = 354) were enrolled to receive at least 1 dose of the RIX4414 vaccine/placebo. Twenty-one infants were withdrawn from the study: 15 from the vaccination group and 6 from the placebo group. The trial profile with reasons for withdrawal and elimination has been described in Figure 1. In both the RIX4414 and placebo groups, the gestational age ranged between 26 and 36 weeks, whereas chronologic age at dose 1 of RIX4414 vaccine/placebo ranged between 5 and 14 weeks. The proportion of males and females was similar in both groups, and the majority of infants were of white/Caucasian or European heritage (Table 1).

Table 1
Table 1
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Figure 1
Figure 1
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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 [2], gastroenteritis [1], hypernatremia [1], dehydration [1]) 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.

Table 2
Table 2
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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).

Figure 2
Figure 2
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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[8] 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[8] 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.

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Immunogenicity

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).

Table 3
Table 3
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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).

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DISCUSSION

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[8] 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[8] 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

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CONCLUSION

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.

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ACKNOWLEDGMENTS

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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REFERENCES

1. Payne DC, Staat MA, Edwards KM, et al. Active, population-based surveillance for severe rotavirus gastroenteritis in children in the United States. Pediatrics. 2008;122:1235–1243

2. Centers for Disease Control and Prevention (CDC).. Rotavirus surveillance—worldwide, 2001–2008. MMWR Morb Mortal Wkly Rep.. 2008;57:1255–1257

3. Rotavirus vaccines. . WHO Position paper. Wkly Epidemiol Rec.. 2007;82:285–296

4. Bernstein DI, Smith VE, Sherwood JR, et al. Safety and immunogenicity of live, attenuated human rotavirus vaccine 89-12. Vaccine. 1998;16:381–387

5. Vesikari T, Karvonen A, Prymula R, et al. Efficacy of human rotavirus vaccine against rotavirus gastroenteritis during the first 2 years of life in European infants: randomised, double-blind controlled study. Lancet. 2007;370:1757–1763

6. Ruiz-Palacios GM, Pérez-Schael I, Velázquez FR, et al. Human Rotavirus Vaccine Study GroupSafety and efficacy of an attenuated vaccine against severe rotavirus gastroenteritis. N Engl J Med. 2006;354:11–22

7. Phua KB, Lim FS, Lau YL, et al. Safety and efficacy of human rotavirus vaccine during the first 2 years of life in Asian infants: randomised, double-blind, controlled study. Vaccine. 2009;27:5936–5941

8. Correia JB, Patel MM, Nakagomi O, et al. Effectiveness of monovalent rotavirus vaccine (Rotarix) against severe diarrhea caused by serotypically unrelated G2P[4] strains in Brazil. J Infect Dis. 2010;201:363–369

9. Newman RD, Grupp-Phelan J, Shay DK, et al. Perinatal risk factors for infant hospitalization with viral gastroenteritis. Pediatrics. 1999;103:E3

10. Davis RL, Rubanowice D, Shinefield HR, et al. Immunization levels among premature and low-birth-weight infants and risk factors for delayed up-to-date immunization statusCenters for Disease Control and Prevention Vaccine Safety Datalink Group. JAMA. 1999;282:547–553

11. Langkamp DL, Hoshaw-Woodard S, Boye ME, et al. Delays in receipt of immunizations in low-birth-weight children: a nationally representative sample. Arch Pediatr Adolesc Med. 2001;155:167–172

12. Committee on Infectious Diseases; American Academy of Pediatrics.. Prevention of rotavirus disease: updated guidelines for use of rotavirus vaccine. Pediatrics.. 2009;123:1412–1420

13. Cortese MM, Parashar UD. Centers for Disease Control and Prevention (CDC)Prevention of rotavirus gastroenteritis among infants and children: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep. 2009;58(RR-2):1–25

14. van Doorn LJ, Kleter B, Hoefnagel E, et al. Detection and genotyping of human rotavirus VP4 and VP7 genes by reverse transcriptase PCR and reverse hybridization. J Clin Microbiol. 2009;47:2704–2712

15. Goveia MG, Rodriguez ZM, Dallas MJ, et al. Safety and efficacy of the pentavalent human-bovine (WC3) reassortant rotavirus vaccine in healthy premature infants. Pediatr Infect Dis J. 2007;26:1099–1104

16. Cheuvart B, Friedland LR, Abu-Elyazeed R, et al. The human rotavirus vaccine RIX4414 in infants: a review of safety and tolerability. Pediatr Infect Dis J. 2009;28:225–232

17. Phua KB, Quak SH, Lee BW, et al. Evaluation of RIX4414, a live, attenuated rotavirus vaccine, in a randomized, double-blind, placebo-controlled phase 2 trial involving 2464 Singaporean infants. J Infect Dis. 2005;192(suppl 1):S6–S16

18. Vesikari T, Karvonen A, Prymula R, et al. Immunogenicity and safety of the human rotavirus vaccine Rotarix co-administered with routine infant vaccines following the vaccination schedules in Europe. Vaccine. 2010;28:5272–5279

19. Huang LM, Chang LY, Tsou TP, et al. Immunogenicity of RIX4414 (Rotarix™), an oral human rotavirus vaccine, in premature infants from Taiwan. Presented at: The World Congress for Pediatric Infectious Diseases, November 15–18, 2007; Bangkok.

20. Bonhoeffer J, Siegrist CA, Heath PT. Immunisation of premature infants. Arch Dis Child. 2006;91:929–935

21. Chan J, Nirwati H, Triasih R, et al. Maternal antibodies to rotavirus: could they interfere with live rotavirus vaccines in developing countries? Vaccine. 2011;29:1242–1247

22. Vesikari T, Van Damme P, Giaquinto C, et al. European Society for Paediatric Infectious Diseases/European Society for Paediatric Gastroenterology, Hepatology, and Nutrition evidence-based recommendations for rotavirus vaccination in Europe. J Pediatr Gastroenterol Nutr.. 2008;46(suppl 2):S81–122

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Keywords:

gastroenteritis; gestational age; transplacental antibody transfer

© 2012 Lippincott Williams & Wilkins, Inc.

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