Published online October 31, 2008
PEDIATRICS Vol. 122 No. 5 November 2008, pp. e1062-e1066 (doi:10.1542/peds.2008-1059)
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ARTICLE

Coadministration of RIX4414 Oral Human Rotavirus Vaccine Does Not Impact the Immune Response to Antigens Contained in Routine Infant Vaccines in the United States

Penelope H. Dennehy, MDa, Helen R. Bertrand, MDb, Peter E. Silas, MDc, Silvia Damaso, MScd, Leonard R. Friedland, MDd and Remon Abu-Elyazeed, MD, PhDd

a Department of Pediatrics, Rhode Island Hospital, Providence, Rhode Island
b Lowcountry Medical Associates, Charleston, South Carolina
c Wee Care Pediatrics, Layton, Utah
d GlaxoSmithKline Biologicals, King of Prussia, Pennsylvania and Rixensart, Belgium


   ABSTRACT
TOP
 ABSTRACT
METHODS
 RESULTS
 DISCUSSION
 AUTHOR CONTRIBUTIONS
 REFERENCES
 
OBJECTIVE. This study was conducted to confirm the absence of immune interference of 2 doses of RIX4414 (Rotarix) on routine infant vaccinations in the United States.

STUDY DESIGN. A total of 484 healthy infants aged 6 to 12 weeks were randomly assigned to 1 of 2 groups to receive 3 doses of Pediarix (combined diphtheria-tetanus-acellular pertussis-hepatitis B-poliovirus vaccine [DTaP-HBV-IPV]), Prevnar (7-valent pneumococcal conjugate vaccine [PCV7]), and ActHIB (Haemophilus influenzae type b conjugate vaccine [Hib]) at 2, 4, and 6 months of age with RIX4414 either coadministered at 2 and 4 months (Co-ad) or administered separately at 3 and 5 months (Sep-ad). Serum antibodies were measured 1 month after dose 3 of the DTaP-HBV-IPV, PCV7, and Hib vaccines.

RESULTS. Antibody responses to all antigens were similar in infants in both the Co-ad and Sep-ad groups. Seroprotective antibody concentrations against diphtheria, tetanus, hepatitis B, and poliovirus types 1, 2, and 3 were achieved by ≥97.9% of the infants in both groups. Antipolyribosyl ribitol phosphate antibody levels of ≥1.0 µg/mL were achieved by 88.3% to 89.4% of infants in both groups. In both groups, ≥97.8% of the infants were seropositive for antipertussis antibodies and the 7 pneumococcal serotypes. Predefined criteria for noninferiority between groups were reached for all antigens.

CONCLUSIONS. Two doses of RIX4414 coadministered with routine infant vaccines as recommended in the United States (DTaP-HBV-IPV, PCV7, and Hib) did not impair the immune response to any of the coadministered antigens.

Key Words: DTaP-HBV-IPV • Hib • 7-valent pneumococcal conjugate vaccine • human rotavirus vaccine

Abbreviations: CDC—Centers for Disease Control and Prevention • DTaP-HBV-IPV—combined diphtheria-tetanus-acellular pertussis, hepatitis B, and inactivated poliovirus vaccine • PCV7—7-valent pneumococcal conjugate vaccine • Hib—Haemophilus influenzae type b • Co-ad—coadministration group • Sep-ad—separate administration group • IgA—immunoglobulin A • SAE—serious adverse event • CI—confidence interval • ELU—ELISA units • GMC —geometric mean antibody concentration • GMT—geometric mean antibody titer • PRP—polyribosyl ribitol phosphate • PT—pertussis toxoid • FHA—filamentous hemagglutinin • HbsAg—hepatitis B virus surface antigen • PN—pneumococcal serotype

Rotavirus is the most common cause of severe gastroenteritis requiring hospitalization of infants and young children worldwide. By the age of 5 years, it is estimated that nearly every child has experienced at least 1 episode of rotavirus gastroenteritis and ~611 000 (range: 454 000–705 000) rotavirus-related deaths occur in this age group annually.1 In the United States, rotavirus-related hospitalization occurs in 1 in 80 children, equating to ~55 000 to 70 000 admissions per year.2

The oral live attenuated human rotavirus vaccine RIX4414 (Rotarix) was derived from the parent 89–12 human G1P[8] rotavirus strain, originally obtained from the stool of a 15-month-old child with a mild rotavirus diarrhea in December 1988.3 A candidate lyophilized vaccine (cloned passage 43 derivative from 89–12) for oral administration after reconstitution with a separately supplied liquid calcium carbonate buffer has been shown to be safe, well tolerated, immunogenic, and highly effective against rotavirus gastroenteritis hospitalizations, severe rotavirus gastroenteritis, and any rotavirus gastroenteritis attributable to multiple circulating strains (G1 and non-G1 rotavirus types, including G2, G3, G4, and G9).4–8 This vaccine is currently licensed as Rotarix in >100 countries, including the United States.

This study was undertaken to demonstrate that coadministration of the RIX4414 vaccine with routine infant vaccinations currently included in the Centers for Disease Control and Prevention (CDC) Advisory Committee on Immunization Practices,9 and the American Academy of Pediatrics10 and American Academy of Family Physicians11 schedules of recommended immunizations for infants in the United States does not impair the immune response to any of the antigens contained in each of the administered vaccines.


   METHODS
TOP
 ABSTRACT
 METHODS
RESULTS
 DISCUSSION
 AUTHOR CONTRIBUTIONS
 REFERENCES
 
Study Design
This was a phase III, randomized, multicenter study conducted in 44 sites in the United States. The study was conducted according to good clinical practice guidelines and the Declaration of Helsinki. Institutional review boards at each study center reviewed the protocol. Written informed consent was obtained from parents/guardians before enrollment.

Healthy infants 6 to 12 weeks of age were enrolled and randomized (1:1) into 2 groups. All infants received routine vaccination, with 3 doses of combined diphtheria-tetanus-acellular pertussis-hepatitis B-inactivated poliovirus vaccine (DTaP-HBV-IPV; Pediarix [GlaxoSmithKline Biologicals, Rixensart, Belgium]), 7-valent pneumococcal conjugate vaccine (PCV7; Prevnar [Wyeth Pharmaceuticals, Collegeville, PA]), and Haemophilus influenzae type b (Hib) conjugate vaccine (ActHIB [Sanofi Pasteur, Swiftwater, PA]) at 2, 4, and 6 months of age. The infants in the coadministration (Co-ad) group received 2 doses of RIX4414 coadministered with DTaP-HBV-IPV, PCV7, and Hib at 2 and 4 months of age. The infants in the separate administration (Sep-ad) group received 2 RIX4414 doses administered separately at 3 and 5 months of age. Influenza vaccine was offered (optional) to infants at 6 and 7 months of age. The study's primary objective was to demonstrate noninferiority of the infants in the Co-ad group compared with those in the Sep-ad group 1 month after completion of the third dose of DTaP-HBV-IPV, PCV7, and Hib.

Study Subjects
Healthy infants were eligible and were allowed to have received a single dose of hepatitis B vaccine at least 30 days before enrollment. Exclusion criteria included receipt of any investigational or nonregistered drug or any vaccine other than the study vaccines within 30 days of study entry; diphtheria, tetanus, pertussis, poliomyelitis, Hib, or Streptococcus pneumoniae vaccination or disease; previous rotavirus vaccination or hepatitis B disease; a history of hypersensitivity to any vaccine component; immunosuppressive or immunodeficient condition; major congenital defect; serious chronic illness; history of neurologic disorder, seizures, thrombocytopenia or coagulation disorders; and acute disease at the time of enrollment.

Vaccines
One dose of RIX4414 (Rotarix [GlaxoSmithKline Biologicals) contained not <106.0 median cell culture infective dose of live-attenuated RIX4414 human rotavirus strain. RIX4414 was administered orally. All other vaccines were administered intramuscularly into the anterolateral thigh.

Assessment of Immunogenicity
A single blood sample was collected from all infants 1 month after the third dose of DTaP-HBV-IPV, PCV7, and Hib vaccines. The antirotavirus immunoglobulin A (IgA) antibody immune response against RIX4414 was measured 3 months after dose 2 of RIX4414 in infants in the Co-ad group, and 2 months after dose 2 of RIX4414 in infants in the Sep-ad group. Antipolio antibodies were assessed by using a microneutralization test. Serum antirotavirus IgA antibody concentrations were measured by using an enzyme-linked immunosorbent assay as developed by Ward et al.12 All other antibodies were assessed by using standardized enzyme-linked immunosorbent assay methods. Seroprotection was defined as an antibody concentration of ≥0.1 IU/mL for diphtheria and tetanus, ≥1.0 µg/mL for Hib, ≥10 mIU/mL for hepatitis B, and ≥1:8 dilution for poliovirus types 1, 2, and 3. Seropositivity was defined as ≥5 ELISA units (ELU)/mL for each pertussis antigen, ≥0.05 µg/mL for each of the 7 pneumococcal vaccine serotypes, and ≥20 U/mL for rotavirus IgA antibodies.

Assessment of Safety
Data regarding serious adverse events (SAEs) were collected during the entire study period, from dose 1 until 5 months after the last DTaP-HBV-IPV, PCV7, and Hib dose or within 7 months after the last dose of DTaP-HBV-IPV, PCV7, and Hib if the third dose was not given.

Statistical Analysis
Primary immunogenicity analyses were based on the according to protocol cohort, which included infants who met eligibility criteria, complied with the protocol, and had antibody results for at least 1 antigen. Seropositivity/seroprotection rates, as applicable, were calculated with 95% confidence intervals (CIs).13 Antibody geometric mean concentrations (GMCs) and titers (GMTs) were calculated with 95% CI for each antigen. Prespecified criteria for noninferiority of infants in the Co-ad group compared with those in the Sep-ad group required that the lower limit of the standardized asymptotic 95% CI14 on the difference (Co-ad minus Sep-ad group) was at least –10% in terms of the percentage of infants with seroprotective antibody levels against diphtheria, tetanus, polyribosyl ribitol phosphate (PRP), hepatitis B, and poliovirus types 1, 2, and 3; that the lower limit of the 95% CI on the GMC ratio (Co-ad/Sep-ad) was ≥0.67 for pertussis toxoid (PT), filamentous hemagglutinin (FHA), and pertactin; and that the lower limit of the 95% CI on the GMC ratio (Co-ad/Sep-ad) was ≥0.5 for each pneumococcal serotype.

The 95% CIs of GMC/GMT ratios between groups (Co-ad group/Sep-ad group) were computed by using an analysis-of-variance model on the log10 transformation of the concentrations/titers. The analysis-of-variance model included the vaccine group as only fixed effect.


   RESULTS
TOP
 ABSTRACT
 METHODS
 RESULTS
DISCUSSION
 AUTHOR CONTRIBUTIONS
 REFERENCES
 
Demographic Information
The study was conducted between June 13, 2006, and May 18, 2007. A total of 484 healthy infants were enrolled and randomized into the Co-ad (n = 249) and Sep-ad (n = 235) groups. Infants in the Co-ad and Sep-ad groups were similar in terms of gender, race, and ethnicity of participating infants. The majority of the infants were white, with a small number who were black, American Hispanic/Latino, and non-American Hispanic. As expected on the basis of the study design, infants in the Sep-ad group were approximately 1 month older than infants in the Co-ad group at the time of each RIX4414 dose. In the Co-ad and Sep-ad groups, respectively, 87.8% and 89.1% of infants had received hepatitis B vaccination before dose 1 of DTaP-HBV-IPV, PCV7, and Hib vaccines. In the Co-ad group, 180 infants were included in according-to-protocol cohort for immunogenicity and 137 infants in the Sep-ad group. It should be noted that 25 infants in the Sep-ad group withdrew before receiving the first dose of RIX4414 at month 3 (unroutine immunization visit).

Immunogenicity of Coadministered Vaccines
Antibody responses to all antigens were similar in infants in both groups after the 3-dose primary vaccination series (Tables 1 and 2). A total of 98.3% of infants in the Co-ad group had anti-PRP antibody concentrations of ≥0.15 µg/mL and 89.4% had concentrations of ≥1.0 µg/mL compared with 97.1% and 88.3%, respectively, in the Sep-ad group. At least 97.9% of infants in both groups had seroprotective antibody concentrations against diphtheria, tetanus, hepatitis B, and poliovirus types 1, 2, and 3. At least 97.8% were seropositive for PT, FHA, and pertactin and each of the 7 PCV7 serotypes.


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  		TABLE 1 Antibody Responses to Coadministered DTaP-HBV-IPV and Hib Vaccines 1 Month After Dose 3 of DTaP-HBV-IPV, Hib, and PCV7 (According-to-Protocol Immunogenicity Cohort)

 

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  		TABLE 2 Antibody Responses to Coadministered PCV7 1 Month After Dose 3 of DTaP-HBV-IPV, Hib, and PCV7 (According-to-Protocol Immunogenicity Cohort)

 
The infants in the Co-ad group were statistically noninferior to those in the Sep-ad group in terms of seroprotection rates against Hib, diphtheria, tetanus, hepatitis B, and poliovirus types 1, 2, and 3: the lower limits of the standardized asymptotic 95% CIs for the treatment difference were all greater than the prespecified limit of –10% (Fig 1A). Similarly, the infants in the Co-ad group were statistically noninferior to those in the Sep-ad group in terms of antibody GMCs against PT, FHA, pertactin, and antibodies against each PCV7 serotype: the lower limits of the 95% CIs on the GMC ratios were all greater than the prespecified limit of 0.67 for pertussis antibodies (Fig 1B) and 0.5 for each pneumococcal serotype (Fig 1C).


Figure 1
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  		FIGURE 1 Difference in seroprotection rates or GMC ratios between infants in the Co-ad and Sep-ad groups 1 month after dose 3 with DTaP-HBV-IPV, Hib, and PCV7 (according-to-protocol cohort for immunogenicity). a Lower limit of the 95% CI ≥ –10% (prespecified clinical limit for noninferiority); b lower limit of the 95% CI ≥ 0.67 (prespecified clinical limit for noninferiority); c lower limit of 95% CI ≥ 0.5 (prespecified clinical limit for noninferiority). PRN indicates pertactin; PN, indicates pneumococcal serotype.>

 
Immunogenicity of RIX4414
Three months after dose 2 of RIX4414, 78.8% (95% CI: 71.8–84.8) of infants in the Co-ad group had seropositive antirotavirus IgA concentrations, and in the Sep-ad group and at 2 months after dose 2 of RIX4414, 86.0% (95% CI: 78.5–91.6) of infants had seropositive antirotavirus IgA concentrations. The antirotavirus IgA GMC in infants in the Co-ad group was 110.0 U/mL (95% CI: 85.8–141.1) where blood sampling was performed 3 months after the second RIX4414 dose and was 188.2 U/mL (95% CI: 139.6–253.5) in infants in the Sep-ad group where the interval between the last RIX4414 dose and the blood sample was 2 months.

Safety
SAEs were reported by 29 infants during the entire study period: 15 (6.0%) infants in the Co-ad group and 14 (6.0%) infants in the Sep-ad group.

There were no deaths during the study. One SAE was considered by the investigator to be related to vaccination. This infant in the Co-ad group experienced fever requiring hospitalization 9 days after dose 1 of RIX4414, DTaP-HBV-IPV, PCV7, and Hib. One case of intussusception was reported in a 39-week-old female infant (Sep-ad group) 125 days after the second dose of RIX4414. The intussusception was reduced by surgery and resolved after 6 days.

All infants recovered from their SAEs except 1 infant in the Sep-ad group with a malignant brain neoplasm (atypical rhabdoid tumor). This infant was withdrawn from the study before receiving any dose of RIX4414. This SAE was not considered to be causally related to vaccination by the investigator.


   DISCUSSION
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
AUTHOR CONTRIBUTIONS
 REFERENCES
 
This is the first study, to our knowledge, to demonstrate with prespecified criteria that the RIX4414 oral human rotavirus vaccine does not impact the immune response to vaccines that are currently included in the CDC/Advisory Committee on Immunization Practices, American Academy of Pediatrics, and the American Academy of Family Physicians schedules of recommended immunizations for infants in the United States. A robust antibody response was observed in infants in both the Co-ad and Sep-ad groups 1 month after the third dose of DTaP-HBV-IPV, Hib, and PCV7 against all 17 antigens (diphtheria, tetanus, PT, FHA, pertactin, hepatitis B virus surface antigen [HbsAg], PRP, poliovirus serotypes 1, 2, and 3, and S pneumoniae serotypes 4, 6B, 9V, 14, 18C, 19F, and 23F) recommended for infant immunization in the United States. Prespecified criteria for demonstrating noninferiority of the antibody responses 1 month after dose 3 of the routine vaccines were met for all 17 antigens. These data are consistent with previous coadministration immunogenicity studies that showed no interference between Rotarix and infant vaccines routinely administered in the United States,15 Latin America,4,16 Singapore,5 and Europe.17

The exact immunologic mechanism by which oral, live rotavirus vaccines protect against rotavirus gastroenteritis is unknown. In the absence of this, published data indicate that a positive serum IgA response after vaccination may be considered a strong serologic correlate of vaccine induced immunity against rotavirus.18–21 After 2 doses of RIX4414, we observed a seropositivity rate of 78.8% in infants in the Co-ad group and 86.0% in infants in the Sep-ad group. This difference can likely be attributed to the influence of postvaccination blood sampling time point (blood samples were drawn from all infants at the same time point; ie, 3 months after dose 2 of RIX4414 in infants in the Co-ad group and 2 months after dose 2 of RIX4414 in infants in the Sep-ad group) and age at vaccination on antibody responses (infants in the Sep-ad group received RIX4414 at 3 and 5 months of age, whereas infants in the Co-ad group received RIX4414 at 2 and 4 months of age). A previous study in US and Canadian infants showed similar seropositivity rates: 78.2% (95% CI: 70.2–84.9) 2 months after 2 doses of RIX4414 containing 106.4 median cell culture infective dose.15 In all efficacy studies of RIX4414, the protective efficacy, especially against severe rotavirus gastroenterititis, paralleled but was always higher than the antirotavirus IgA seropositivity rate; thus indicating that antirotavirus IgA antibody response tends to underestimate the level of protective immunity elicited by the vaccine. Antirotavirus IgA seropositivity rates after 2 doses of the vaccine in both the Co-ad and Sep-ad groups in this study are comparable to those seen in Europe and Latin America, where vaccine efficacy after 2 doses has been demonstrated.6,8

Two doses of RIX4414 when coadministered with licensed routine infant vaccines recommended in the United States or when given separately have a similar safety profile. There was a single case of intussusception observed in this study in an infant 125 days after the second dose of RIX4414 vaccine. No increased risk of intussusception was observed in a large phase III safety study, specifically designed to evaluate intussusception, in which 63 225 infants in Latin America and Finland received 2 doses of RIX4414 at 2 and 4 months of age.6 The ongoing postmarketing surveillance of intussusception cases after the introduction of RIX4414 vaccine will confirm the results of the safety study.

Two doses of RIX4414 were immunogenic in US infants. By meeting the prespecified criteria for noninferiority, this study demonstrates that coadministration of RIX4414 with licensed routine infant vaccines recommended in the United States does not negatively impact the immune response to any of the antigens (PRP, HBsAg, poliovirus serotypes 1, 2, and 3, diphtheria, tetanus, PT, FHA, pertactin, and S pneumoniae serotypes 4, 6B, 9V, 14, 18C, 19F, and 23F) that are currently included in the recommended schedule of immunizations for infants in the United States. These data support concomitant administration of RIX4414 with DTaP, IPV, HepB, Hib, and PCV7.


   AUTHOR CONTRIBUTIONS
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
 AUTHOR CONTRIBUTIONS
REFERENCES
 
All authors participated in the design or implementation and interpretation of the study, the writing and reviewing of the manuscript, and the decision to submit the manuscript for publication; Drs Abu-Elyazeed and Friedland led the clinical team at GlaxoSmithKline; and Dr Damaso conducted the data analysis.


   ACKNOWLEDGMENTS
 
This study was funded by GlaxoSmithKline Biologicals (King of Prussia, PA).

We thank the infants and their families for participating in this trial and all investigators, the study nurses, and other staff members for contributing in many ways to this study. We are indebted to B. Cheuvart for contribution to study design/analytical plan, J. Wolter for contribution to technical writing aspects, and N. VanDriessche (XpePharma, Rixensart, Belgium) for editorial assistance.


   FOOTNOTES
 
Accepted Jul 8, 2008.

Address correspondence to Penelope H. Dennehy, MD, Rhode Island Hospital, Division of Pediatric Infectious Diseases, 593 Eddy St, Providence, RI 02903. E-mail: pdennehy{at}lifespan.org

Financial Disclosure: Drs Abu-Elyazeed, Damaso, and Friedland are employees of GlaxoSmithKline Biologicals and report ownership of stock options; Dr Silas received honoraria or paid expert testimony or travel grants from GlaxoSmithKline Biologicals; and Drs Dennehy and Bertrand have indicated they have no financial relationships relevant to this article to disclose.

These data have been presented in part as a poster at the Interscience Conference on Antimicrobial Agents and Chemotherapy; September 17–20, 2007; Chicago, IL.

This clinical trial was registered at www.clinicaltrials.gov (NCT00334607; eTrack107531).


What's Known on This Subject

The oral live attenuated human rotavirus vaccine Rotarix is well tolerated, immunogenic, and highly effective against rotavirus gastroenteritis hospitalizations. Rotarix has been used with many vaccines given to infants but has not been given previously with the vaccines in the US schedule.

 

What This Study Adds

This study demonstrates that coadministration of the RIX4414 vaccine with routine infant vaccinations currently included in the schedules of recommended immunizations for infants in the United States does not impair the immune response to any of the administered vaccines.

 


   REFERENCES
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
 AUTHOR CONTRIBUTIONS
 REFERENCES
 

  1. Parashar UD, Hummelman EG, Bresee JS, Miller MA, Glass RI. Global illness and deaths caused by rotavirus disease in children. Emerg Infect Dis. 2003;9 (5):565 –572[Web of Science][Medline]
  2. Glass RI, Parashar UD, Bresee JS, et al. Rotavirus vaccines: current prospects and future challenges. Lancet. 2006;368 (9532):323 –332[CrossRef][Web of Science][Medline]
  3. Bernstein DI, Smith VE, Sherwood JR, et al. Safety and immunogenicity of live, attenuated human rotavirus vaccine 89–12. Vaccine. 1998;16 (4):381 –387[CrossRef][Web of Science][Medline]
  4. Salinas B, Perez S, I, Linhares AC, et al. Evaluation of safety, immunogenicity and efficacy of an attenuated rotavirus vaccine, RIX4414: a randomized, placebo-controlled trial in Latin American infants. Pediatr Infect Dis J. 2005;24 (9):807 –816[CrossRef][Web of Science][Medline]
  5. Phua KB, Emmanuel SC, Goh P, et al. A rotavirus vaccine for infants: the Asian experience. Ann Acad Med Singapore. 2006;35 (1):38 –44[Web of Science][Medline]
  6. Ruiz-Palacios GM, Perez-Schael I, Velazquez FR, et al. Safety and efficacy of an attenuated vaccine against severe rotavirus gastroenteritis. N Engl J Med. 2006;354 (1):11 –22[Abstract/Free Full Text]
  7. Vesikari T, Karvonen A, Puustinen L, et al. Efficacy of RIX4414 live attenuated human rotavirus vaccine in Finnish infants. Pediatr Infect Dis J. 2004;23 (10):937 –943[CrossRef][Web of Science][Medline]
  8. 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 (9601):1757 –1763[CrossRef][Web of Science][Medline]
  9. Kroger AT, Atkinson WL, Marcuse EK, Pickering LK; Advisory Committee on Immunization Practices, Centers for Disease Control and Prevention. Centers for Disease Control and Prevention. General recommendations on immunization recommendations of the Advisory Committee on Immunization Practices (ACIP) [published corrections appear in MMWR Morb Mortal Wkly Rep. 2006;55(48):1303; MMWR Morb Mortal Wkly Rep. 2007;56(11):256; and Pediatrics. 2007;119(5):1008]. MMWR Recomm Rep. 2006;55 (RR-15):1 –48[Medline]
  10. American Academy of Pediatrics. General recommendations on immunization: recommendations from the advisory committee on immunization practices. Pediatrics. 2007;119 (5):1008[Free Full Text]
  11. American Academy of Family Physicians. Recommended childhood immunization schedule 2008. Available at: www.aafp.org/online/en/home/clinical/immunizationres/child.html. Accessed September 10, 2008
  12. Ward RL, Bernstein DI, Shukla R, et al. Effects of antibody to rotavirus on protection of adults challenged with a human rotavirus. J Infect Dis. 1989;159 (1):79 –88[Web of Science][Medline]
  13. Clopper CJ, Pearson ES. The use of confidence of fiducial limits illustrated in the case of the binomial. Biometrika. 1934;26 :404 –413[Free Full Text]
  14. Newcombe RG. Interval estimation for the difference between independent proportions: comparison of eleven methods. Stat Med. 1998;17 (8):873 –890[CrossRef][Web of Science][Medline]
  15. Dennehy PH, Brady RC, Halperin SA, et al. Comparative evaluation of safety and immunogenicity of two dosages of an oral live attenuated human rotavirus vaccine. Pediatr Infect Dis J. 2005;24 (6):481 –488[CrossRef][Web of Science][Medline]
  16. Araujo EC, Clemens SA, Oliveira CS, et al. Safety, immunogenicity, and protective efficacy of two doses of RIX4414 live attenuated human rotavirus vaccine in healthy infants [in Portugese]. J Pediatr (Rio J). 2007;83 (3):217 –224[Medline]
  17. Vesikari T, Karvonen A, Prymula R, et al. Immunogenicity and reactogenicity of Rotarix, an oral human rotavirus vaccine, when co-administered with specific childhood vaccinations in healthy infants in Europe. Presented at: ESPID; European Society for Paediatric Infections; May 3–5, 2006; Basel, Switzerland
  18. O'Ryan M. Rotarix (RIX4414): an oral human rotavirus vaccine. Expert Rev Vaccines. 2007;6 (1):11 –19[CrossRef][Web of Science][Medline]
  19. Matson DO, O'Ryan ML, Herrera I, Pickering LK, Estes MK. Fecal antibody responses to symptomatic and asymptomatic rotavirus infections. J Infect Dis. 1993;167 (3):577 –583[Web of Science][Medline]
  20. Coulson BS, Grimwood K, Hudson IL, Barnes GL, Bishop RF. Role of coproantibody in clinical protection of children during reinfection with rotavirus. J Clin Microbiol. 1992;30 (7):1678 –1684[Abstract/Free Full Text]
  21. Franco MA, Angel J, Greenberg HB. Immunity and correlates of protection for rotavirus vaccines. Vaccine. 2006;24 (15):2718 –2731[CrossRef][Web of Science][Medline]
PEDIATRICS (ISSN 1098-4275). ©2008 by the American Academy of Pediatrics

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