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Safety, Tolerability and Immunogenicity of Pentavalent Rotavirus Vaccine Manufactured by a Modified Process

Martinón-Torres, Federico MD, PhD; Greenberg, David MD; Varman, Meera MD; Killar, John A. MS; Hille, Darcy MS, EMBA; Strable, Erica L. PhD; Stek, Jon E. MS; Kaplan, Susan S. MD, MHS

Pediatric Infectious Disease Journal: April 2017 - Volume 36 - Issue 4 - p 417–422
doi: 10.1097/INF.0000000000001511
Vaccine Reports

Background: Rotavirus is the leading cause of severe diarrhea in infants and young children. The current formulation of pentavalent rotavirus vaccine (RV5) must be stored refrigerated at 2–8°C. A modified formulation of RV5 (RV5mp) has been developed with stability at 37°C for 7 days and an expiry extended to 36 months when stored at 2–8°C.

Methods: This study ( identifier: NCT01600092; EudraCT number: 2012-001611-23) evaluated the safety, tolerability and immunogenicity of RV5mp versus the currently marketed RV5 in infants. To maintain blinding, both vaccine formulations were stored refrigerated at 2–8°C for the duration of the study. Immunogenicity endpoints were (1) serum neutralizing antibody titers to human rotavirus serotypes G1, G2, G3, G4 and P1A[8] and (2) proportion of subjects with a ≥3-fold rise from baseline for serum neutralizing antibody to human rotavirus serotypes G1, G2, G3, G4 and P1A[8] and serum antirotavirus immunoglobulin A.

Results: The RV5mp group (n = 505) and RV5 group (n = 509) had comparable safety profiles. There were no deaths and no vaccine-related serious adverse events in this study. With respect to immunogenicity, RV5mp was noninferior compared with RV5. Serum neutralizing antibody responses by country and breast-feeding status were generally consistent with the overall results.

Conclusions: RV5mp enhances storage requirements while maintaining the immunogenicity and safety profile of the currently licensed RV5. A vaccine that is stable at room temperature may be more convenient for vaccinators, particularly in places where the cold chain is unreliable, and ultimately will permit more widespread use.

From the *Translational Pediatrics and Infectious Diseases, Department of Pediatrics, Hospital Clínico Universitario de Santiago, Santiago de Compostela, Galicia, Spain; Grupo de Investigación en Genética, Vacunas, Infecciones y Pediatría (GENVIP), Instituto de Investigación Sanitaria de Santiago and Universidade de Santiago de Compostela (USC), Galicia, Spain; §Soroka University Medical Center, Pediatric Infectious Disease Unit, Beer Sheva, Israel; Department of Pediatrics, Creighton University, Omaha, Nebraska; and Merck & Co., Inc., Merck Research Laboratories, Kenilworth, New Jersey.

Accepted for publication October 18, 2016.

Funding for this research was provided by Merck, Sharp, & Dohme Corp., a subsidiary of Merck & Co., Inc. FMT research activities are funded by Instituto Carlos III (Intensificación de la actividad investigadora) and Fondo de Investigación Sanitaria (FIS; PI13/02382) of the Plan Nacional de I+D+I and Fondos FEDER. Other than employees of Merck & Co., Inc., all authors have been investigators for the sponsor. Employees may hold stock and/or stock options in the company. Although the sponsor formally reviewed a penultimate draft, the opinions expressed are those of the authorship and may not necessarily reflect those of the sponsor. All coauthors approved the final version of the manuscript. The other authors have no conflicts of interest to disclose.

F.M.-T., D.G. and M.V. contributed toward enrollment of subjects and/or data collection, analysis and interpretation of data and preparation of manuscript. J.E.S. and S.S.K. contributed toward analysis and interpretation of data and preparation of manuscript. J.A.K. and D.H. contributed toward study concept and design, analysis and interpretation of data and preparation of manuscript.

Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s website (

Address for correspondence: Susan Kaplan, MD, MHS, Merck & Co., Inc., 2000 Galloping Hill Rd., UG3CD-28, Kenilworth, NJ 07033. E-mail:

Rotavirus is the leading cause of severe diarrhea in infants and young children and, before the widespread introduction of rotavirus vaccines, is estimated to have caused 453,000 deaths or 37% of all deaths due to diarrhea among children less than 5 years of age worldwide in 2008.1 Most of the rotavirus gastroenteritis-related mortality occurs in developing countries where the access to treatment is suboptimal.2

Since initial approval in the US in 2006, the pentavalent rotavirus vaccine (RV5: RotaTeq; rotavirus vaccine, live, oral, pentavalent; Merck & Co., Inc., Kenilworth, NJ) has been licensed in over 100 countries including Canada, Australia and countries in the European Union, Latin America, Africa and Asia. Since the introduction of rotavirus vaccines, there have been rapid and significant reductions in rotavirus hospitalizations (49–92% decrease), all-cause diarrhea hospitalizations (17–55% decrease) and all-cause diarrhea deaths (22–50% decrease).3,4

The current formulation of RV5 must be stored refrigerated at 2–8°C.5 This presents challenges in countries where the ambient temperatures are high and the cold chain is not reliable. To better meet the needs of these countries, a modified formulation of RV5 (RV5mp) has been developed. The RV5mp is vaccine vial monitor compatible, with stability at 37°C for 7 days. In addition, the expiry will be extended from 24 to 36 months when stored at 2–8°C. It has the same human-bovine rotavirus reassortants [G1, G2, G3, G4 and P1A[8]] as the current RV5, with modifications to the buffer stabilizer, including the removal of sodium citrate and the addition of adipic acid and calcium chloride. The RV5mp will meet the same potency requirements for each serotype as RV5.

The primary purpose of this study was to demonstrate the noninferiority of RV5mp when compared with RV5 on the basis of immunogenicity. Additionally, this study assessed the safety and tolerability of RV5mp compared with RV5.

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Study Design

This randomized, double-blind, multicenter clinical trial (V260-035; identifier: NCT01600092; EudraCT number: 2012-001611-23) was conducted at 43 trial centers and 3 subsites worldwide (3 in Canada; 3 in Czech Republic; 4 in Denmark; 11 in Finland; 4 in Israel; 3 in Mexico; 3 in Poland; 3 in Spain; 3 in Sweden and 9 in the US) from April 2013 to March 2014. The protocol was approved by the ethical review committee of each country or site, and the study was conducted in conformance with applicable country or local requirements.

This study evaluated the safety, tolerability and immunogenicity of RV5mp versus the currently marketed RV5 in infants. The study was designed to have approximately 924 subjects randomized 1:1 to receive 3 oral doses of RV5mp or RV5. Study vaccine was allowed to be administered concomitantly with other licensed pediatric vaccines. Subjects were allocated to treatment assignment in blocks of 4 using a central randomized schedule generated by the sponsor. All study personnel, including investigators, study site personnel, subjects, monitors and central laboratory personnel, remained blinded to treatment allocation throughout the study. PPD Vaccines and Biologics, Wayne, PA, and Cincinnati Children’s Hospital Medical Center (CCHMC), Cincinnati, OH, were the central laboratories for this study.

Assuming that 80% of subjects (370 subjects/group) will have evaluable immunogenicity data 42 days postdose 3, the selected sample size of 924 subjects would have approximately 90% power to claim noninferiority on all 5 responses if RV5mp and RV5 are truly equivalent, and the responses to each antigen are independent. The probability of observing at least one serious adverse event (SAE) in this study depended on the number of subjects enrolled and the incidence rate of SAEs in the general population. If the incidence rate of an SAE is 0.35% (ie, 1 of every 286 subjects), then there was an 80% chance of observing at least one such SAE.

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Study Subjects

Healthy, afebrile infants (42–84 days of age) were eligible for the study. Once parental informed consent was obtained, the subject’s medical history (including age, gender, weight, race, medication use and health status) was recorded. Exclusion criteria included: history of abdominal disorders (including gastroenteritis, diarrhea or intussusception); known or suspected immunodeficiency, or residing in a household with an immunocompromised person; known hypersensitivity to any vaccine components; receipt of corticosteroids (2 mg/kg/dose) ≥2 weeks since birth or within 7 days of study entry; receipt of investigational vaccines within 14 days (inactivated vaccines) or 28 days (live vaccines) before study entry or if scheduled to be given during the study; or receipt of a blood transfusion or other blood-derived product.

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Randomized subjects received 3 doses of RV5 (group 1; lot WL00051625) or RV5mp (group 2; lot WL00048142). The first dose of study vaccine was administered within 6–12 weeks of age with intervals of at least 4 weeks between doses, and the third dose was administered before 32 weeks of age or per local regulations (2 subjects in Israel received their third dose of vaccine at an age greater than 32 weeks). Each dose of study vaccine consisted of a 2-mL, oral solution of 5 live human-bovine reassortant rotaviruses, which contains a minimum of 2.0–2.8 × 106 infectious units per reassortant dose, depending on the serotype, and not greater than 116 × 106 infectious units per aggregate dose. All vaccine supplies were shipped as a refrigerated product to be stored between 2 and 8°C (35.6 to 46.4°F).

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The primary study objective was to summarize and compare the vaccine-induced serum neutralizing antibody (SNA) responses to human rotavirus serotypes G1, G2, G3, G4 and P1A[8] at 42 days postdose 3 between recipients of RV5mp and recipients of the current formulation of RV5.

The secondary study objectives were to (1) assess the safety and tolerability of RV5mp; (2) summarize the geometric mean titers (GMTs) of vaccine-induced serum antirotavirus immunoglobulin A (IgA) at 42 days postdose 3 in recipients of RV5mp and RV5 and (3) summarize the proportion of subjects with a ≥3-fold rise in SNA titer against human rotavirus serotypes G1, G2, G3, G4 and P1A[8] as well as antibody titers for serum antirotavirus IgA from baseline to 42 days postdose 3 in recipients of RV5mp and RV5.

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All subjects were followed up for safety during days 1–42 after each dose (date of vaccination considered day 1), with subjects’ parents/guardians completing a standardized vaccination report card (VRC).6 The VRC consisted of a cover page and 5 sections for the subject’s parent/legal guardian to record any adverse events (AEs), concomitant medications, concomitant vaccinations, body temperature, and episodes of vomiting and diarrhea (see appendix to reference 6). At the randomization visit, site study personnel trained the parent/legal guardian to complete the VRC and then reviewed completed VRCs with the parent/legal guardian at each subsequent office visit. The parent/legal guardian recorded AEs, concomitant medications, and concomitant vaccinations for 42 days after each dose and were also requested to record daily for 7 days the subject’s body temperature and episodes of vomiting or diarrhea starting with the date of vaccination. Parents were instructed to record an axillary temperature, with a subsequent rectal measurement for axillary temperatures ≥37°C. Fever was defined as a rectal temperature ≥38.1°C. All SAEs regardless of vaccine causality, all deaths, and any cases of intussusception were to be collected throughout the course of the study.

Stool samples (~5 g) were to be collected for subjects who experienced moderate to severe diarrhea and/or vomiting (defined as 3 or more looser-than-normal stools in 24 hours, 1 watery stool in 24 hours and/or forceful vomiting) within 14 days of study vaccination for rotavirus testing. Stool samples were to be collected no later than 7 days after the onset of symptoms, preferably within 3 days of onset. Collected stool samples were sent by sites to the central laboratory (PPD Vaccines and Biologics, LLC) and then forwarded by PPD Vaccines and Biologics, LLC to CCHMC for rotavirus antigen testing by enzyme immunoassay. If the rotavirus antigen test at CCHMC was positive for rotavirus, polymerase chain reaction testing was done by PPD Vaccines and Biologics, LLC to characterize any strains identified by genotype. The development and validation of the rotavirus stool antigen detection assay took place in the Laboratory for Clinical Studies, Division of Infectious Diseases Laboratory of CCHMC. The development and validation of the rotavirus VP4, VP6 and VP7 reverse transcription polymerase chain reaction/sequencing assay took place in the Merck Research Laboratories.

There were no safety hypotheses for this study. The postvaccination AE profiles for each group were assessed by comparing the percentages of subjects who experienced clinical AEs between treatment groups via point estimates with 95% confidence intervals (CIs).

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A 2- to 3-mL blood sample was collected at 2 time intervals (before dose 1 and 42 days postdose 3). All serum samples were shipped by the sites to the central laboratory (PPD Vaccines and Biologics, LLC) and then forwarded by the central laboratory to CCHMC for evaluation.

The primary immunogenicity endpoints were the SNA titers to human rotavirus serotypes G1, G2, G3, G4 and P1A[8] included in the vaccine.7,8 The secondary immunogenicity endpoints included serum antirotavirus IgA9 and proportion of subjects with a ≥3-fold rise from baseline for SNA to human rotavirus serotypes G1, G2, G3, G4 and P1A[8], as well as for serum antirotavirus IgA.

For noninferiority regarding the GMTs for all 5 immunogenicity endpoints, the GMT ratio and associated 95% CI were calculated from a constrained longitudinal data analysis on the log-transformed baseline and postvaccination titer values.10 This analysis used all available data at both baseline and postvaccination and used country as a covariate in the model. Success criteria required that the lower bound of the 95% CI of the GMT ratio for each serotype be >0.67 (corresponding to a no more than 1.5-fold decrease in the GMT of RV5mp compared with RV5). This allows exclusion of a decrease in GMT of 1.5-fold for RV5mp compared with RV5 for all antigens.

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Study Subjects

Overall, 97.1% (985/1014) of vaccinated subjects received all 3 doses and completed study follow-up (Fig. 1). The 6 randomized subjects who were not vaccinated included 3 subjects who were determined by the investigator to be screen failures and 3 subjects who were withdrawn by his/her parent/legal guardian before study vaccination. The number of subjects discontinued from the study was low (35; 3.4%) and were similar in the 2 vaccination groups. The most common reason for study discontinuation was parent withdrawal of consent (17; 1.7%).

Subjects in both vaccination groups were similar with respect to age, race, birth weight, gestational age and breast-feeding status (Table 1). A higher percentage of males (53.7%) were enrolled across both vaccination groups. Approximately 52% of the study population reported a medical condition prestudy that were equally distributed across the 2 vaccination groups (Table, Supplemental Digital Content 1, The most common medical conditions were neonatal jaundice (7.8%) and gastroesophageal reflux disease (6.1%). Only 23.3% of subjects received any prior medications, and these were similar across vaccination groups. The most common prior therapy categories were vitamins (45.1%) and vaccines (10.1%) (Table, Supplemental Digital Content 1, Concomitant medications increased to 86.2% across vaccination groups, compared with the use of therapies before study start. This was largely due to the increase in use of vitamins (47.5%) and analgesics (49.0%). The majority of the subjects with concomitant analgesic use received acetaminophen for indications related to fever, irritability, common cold, upper respiratory infection and teething. The percentage of subjects with any concomitant medication was comparable across vaccination groups.

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Overall, clinical AEs were reported by 86.5% of vaccinated subjects with 50.8% of vaccinated subjects reporting a vaccine-related AE (Table 2). The most common AEs were diarrhea (32.5%), pyrexia (29.9%), vomiting (20.7%), nasopharyngitis (14.9%), upper respiratory tract infection (14.3%) and irritability (14.1%). The most common vaccine-related AEs were diarrhea (24.4%), pyrexia (16.6%) and vomiting (14.1%). The majority of the AEs reported were of mild to moderate intensity and generally comparable between the 2 groups.

The incidence of SAEs occurring any time after vaccination for the entire study period was low: 3.9% in the RV5mp group and 2.4% in the RV5 group. The most common SAE was bronchiolitis [3 (0.6%) in the RV5mp group and 1 (0.2%) in the RV5 group] (Table, Supplemental Digital Content 2, There were no deaths and no SAEs considered by the investigator to be vaccine related in this study.

The RV5mp group and RV5 group had comparable safety profiles with respect to the prespecified AEs of interest: diarrhea, vomiting, elevated temperature, irritability and intussusception. A total of 2 subjects discontinued the study as a result of AEs of intussusception, which were considered serious. The 2 cases of intussusception reported were in the RV5mp group, and they occurred more than 30 days postdose 2 at ~5 months of age, the time of peak incidence for naturally occurring intussusception in the absence of rotavirus vaccination.

Overall, 56.7% of subjects had a maximum temperature of <38.1°C, 22.2% of subjects had a maximum temperature of ≥38.1 and <38.5°C, 18.0% of subjects had a maximum temperature of ≥38.5 and <39.5°C and 3.1% of subjects had a maximum temperature of ≥39.5°C, rectal or rectal equivalent, days 1 to 7 after vaccination. The number of subjects with elevated temperatures postvaccination was generally similar between the 2 vaccination groups.

Of the 51 subjects with moderate and/or severe diarrhea/vomiting within 14 days of vaccination who had stool samples tested, 47 (92.2%) were negative for rotavirus. All 4 subjects [3 in the RV5mp group (2 postdose 1 and 1 postdose 2) and 1 in the RV5 group (postdose 1)] with rotavirus positive stool specimens were determined to have vaccine strain rotavirus. The 4 subjects with vaccine virus in the stool had an AE of diarrhea and/or vomiting onset on day 1 or 2, and stool samples were collected on days 2 through 8.

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The primary immunogenicity hypothesis was met for all 5 serotypes (Table 3); therefore, noninferiority with respect to immunogenicity can be asserted for the RV5mp group as compared with the RV5 group. Of note, the GMT for G3 was higher in the RV5mp group compared with the RV5 group.

At baseline, the GMTs were comparable between the vaccination groups across all serotypes (Table 4). At postdose 3, the results indicate that for serotype G3, the 95% CIs for GMTs and proportion of subjects with a 3-fold rise did not overlap between vaccination groups, and the RV5mp group had a higher response. For the other serotypes (G1, G2, G4 and P1A), the 95% CIs for GMTs and proportion of subjects with a ≥3-fold rise were comparable between the vaccination groups. The observed GMTs and proportion of subjects with a ≥3-fold rise of serum antirotavirus IgA from baseline to ~42 days postdose 3 for the 2 groups were also comparable. Furthermore, SNA responses to serotypes G1, G2, G3, G4 and P1A and serum antirotavirus IgA responses by country and breast-feeding status were generally consistent with the overall results (Tables, Supplemental Digital Content 3, and Supplemental Digital Content 4,

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RV5 is a pentavalent vaccine composed of 5 bovine-human mono-reassortment strains containing genes encoding the human G1, G2, G3, G4 and P1A[8] antigens along with the genes encoding the bovine G6 and P7[5] proteins and all other bovine RV proteins.5 The accumulated real-life experience with RV5 worldwide has shown an outstanding effectiveness and impact against rotavirus disease.11,12 Furthermore, RV5 might be effective against other clinical forms of rotavirus infection like seizures.13–15 In 2009, World Health Organization recommended that RV vaccination should be included in the national immunization schedules of all member states.16,17 These recommendations were reinforced in January 2013, and rotavirus vaccines are now being increasingly used worldwide, having been made available to eligible countries through Global Alliance for Vaccines and Immunizations. Any attempt to improve vaccine storage flexibility may improve access to RV5, particularly in low- and middle-income countries.

Successful delivery of any live vaccine like RV5 requires that the vaccine be stable under usual conditions of storage and handling. Vaccine conservation and storage properties constitute a challenge particularly in countries where facilities to keep cold chain are limited and/or ambient temperatures are high. RV5 in its current formulation must be refrigerated (2–8°C) for storing while the modified formulation, RV5mp, allows storage at 37°C for 1 week and prolongs expiry time from 2 to up to 3 years when refrigerated. These advantages have been achieved through the modification of the buffer stabilizer, without affecting/impacting the immunogenicity of the vaccine and with an acceptable safety profile. The size of this study was not powered to evaluate the occurrence of rare AEs, including intussusception. Although it is notable that 2 cases of intussusception were reported in the RV5mp group compared with the RV5 group, these 2 cases occurred in remote proximity to vaccination (>30 days postdose 2) and during the peak time for intussusception in this age group.18 When demonstrated in observational studies, the small increased risk of intussusception after rotavirus vaccination has primarily been observed in the 1- to 21-day period postdose 1.19,20 In the context of these data, it is likely that these 2 cases occurred in the RV5mp group due to chance rather than due to vaccination.

RV5mp has an immunogenicity and safety profile noninferior to the currently licensed RV5. This study confirms the suitability of the new manufacturing process that allows stability up to 37°C for 7 days and extends the expiry up to 3 years when stored at 2–8°C, clearly improving vaccine storage flexibility. Because the purpose of this study was to compare the immunogenicity of RV5mp to RV5 on the basis of noninferiority, the vaccine was stored under optimal conditions (ie, refrigeration). The revised storage specifications for RV5mp are supported by analytical studies that measured key vaccine attributes when stored under differing temperature conditions. A real-world observational study of the safety and effectiveness of the RV5mp compared with RV5 has been initiated in Mali, with ongoing surveillance for rotavirus gastroenteritis and intussusception. This study will provide additional data on the safety and effectiveness of RV5mp in real-world use in a developing world setting.

In the current study, RV5mp was well tolerated and had a similar safety profile to RV5; the rates of AEs reported were consistent with the data obtained from the clinical development of RV5. Furthermore, RV5mp seems to significantly improve the immune response to one of the antigens (G3). The changes in the vaccine buffer formulation, although minor, might explain the increased response to G3 serotype. Changes in vaccine formulation can produce conformational changes in the antigenic epitopes and can affect the immunogenicity of the vaccine.21,22 The scientific literature contains information on the structure of the rotavirus VP7 glycoprotein and its arrangement as part of the thin outer icosahedral shell of the rotavirus particle.23,24 In the cryoelectron microscopy reconstruction of rotavirus particles, VP7 appears to form trimers that further assemble into the capsid’s outer shell.20 Recombinant VP7 assembly into trimers is dependent on the presence of calcium, and the assembly of VP6 and VP7 into virus particles lacking the VP4 spikes requires the presence of 50 mM calcium chloride to allow the reassembled particles to authentically present trimeric VP7.25,26 The role of calcium in the reassembly process is thought to be in mediating the trimerization of VP7, a prerequisite for assembly with double-layered particles. Infectious triple-layered particles can be reassembled by combining double-layered particles, VP7 and VP4, and calcium in an acidic environment.24 Conversely, removal of calcium from the virus particle through use of a chelator results in the outer capsid dissociation and VP7 trimers falling apart to monomers.24 Because an intact triple-layered particle is required for infection, it can be argued that maintaining calcium association with virions is critical for stability.27 Finally, the crystal structure of a neutralizing antibody for rotavirus shows the antibody binding across the VP7 trimer and making contacts with outer intersubunit contacts between the VP7 trimers.28 Thus, maintaining the trimeric VP7 with calcium would be beneficial to immunogenicity. Changes in the identity or concentration of vaccine formulation excipients can impact the amount of calcium available to stabilize the trimeric VP7 on infectious rotavirus particles; RV5mp contains calcium chloride to improve stability. Although this does not explain why G3 shows the biggest impact on immunogenicity, it seems plausible that each reassortant would have a different calcium-binding affinity based on the VP7 protein it is expressing and perhaps G3 has the lowest binding affinity. The actual impact on clinical efficacy of the increased titers of antibodies against G3 serotype is unknown, if we take into account that a robust immune correlate of clinical efficacy for rotavirus vaccines is lacking.29

In conclusion, RV5mp enhances storage requirements while maintaining the immunogenicity and safety profile for adverse events frequently observed with the currently licensed RV5. A vaccine that is stable at room temperature for short durations may be more convenient for vaccinators and ultimately will permit more widespread use, which is the ultimate goal of any vaccine.

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The authors would like to thank all the subjects who participated in this study and their parents or legal guardian; Margaret Nelson for protocol development and study conduction; Angela Ngai for protocol development, study conduct and data analysis and interpretation; and the V260 P035 study investigators from Canada: G. Caouette, M. Dionne, E. Rubin, Czech Republic: J. Fabianova, R. Ruzkova, L. Tyce, Denmark: A.S. Johansen, K. Kristensen, A.V. Nielsen, W. Petersen, Finland: A. Ahonen, A. Forsten, T. Haapaniemi, T. Karppa, S. Kokko, T. Korhonen, P.-M. Lagerstrom-Tirri, I. Seppä, I. Volanen, Israel: S. Ashkenazi, D. Greenberg, E. Somekh, Poland: A. Boguradzka, T. Jackowska, T. Wysocki, Mexico: P.S. Lozada, J.A.V. Narvaez, M.M. Parra, Spain: J.B. Acuna, J.D. Domingo, C.D. Gonzalez, F. Martinón-Torres, Sweden: N. Brodszki, F. Nasta, M.R. Rinder, S.A. Silfverdal and USA: J.A. Hoekstra, D.C. Hurley, A.D. Johnston, S.Z. Khamis, M.L. Leonardi, J.S. Shepard, M. Varman.

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pentavalent rotavirus vaccine; safety; immunogenicity

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