Publications by authors named "Brigitte Cheuvart"

29 Publications

  • Page 1 of 1

Effectiveness of "Priorix" Against Measles and Mumps Diseases in Children Born After 2004 in the United Kingdom: A Retrospective Case-control Study Using the Clinical Practice Research Datalink GOLD Database.

Pediatr Infect Dis J 2021 Jun;40(6):590-596

From the GSK, 20 Avenue Fleming, Wavre, Belgium.

Background: Evidence on vaccine effectiveness (VE) may encourage vaccination and help fight the reemergence of measles and mumps in Europe. However, limited data exist on real-life effectiveness of individual measles, mumps and rubella (MMR) vaccines. This study evaluated VE of GSK's MMR vaccine ("Priorix") against measles and mumps.

Methods: This retrospective, case-control study used UK data from the Clinical Practice Research Datalink GOLD linked to the Hospital Episode Statistics database to identify children 1-13 years old diagnosed with measles or mumps from January 2006 to December 2018. Cases were matched to controls according to birth month/year and practice region. Cases were identified using clinical codes (without laboratory confirmation). "Priorix" exposure was identified using vaccine batch identifiers. Children exposed to other MMR vaccines were excluded. Adjusted VE was estimated for ≥1 vaccine dose in all children, and for 1 dose and ≥2 doses in children ≥4 years at diagnosis.

Results: Overall, 299 measles cases matched with 1196 controls (87.6% <4 years old), and 243 mumps cases matched with 970 controls (74.2% <4 years old) were considered. VE for ≥1 dose in all children was 78.0% (97.5% confidence interval: 67.2%-85.3%) for measles and 66.7% (48.1%-78.6%) for mumps. In children ≥4 years old, VE after 1 dose was 74.6% (-21.7% to 94.7%) for measles and 82.3% (32.7%-95.3%) for mumps, and VE after ≥2 doses was 94.4% (79.7%-98.5%) for measles and 86.5% (64.0%-94.9%) for mumps.

Conclusions: "Priorix" is effective in preventing measles and mumps in real-life settings.
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http://dx.doi.org/10.1097/INF.0000000000003111DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8104017PMC
June 2021

Seroprevalence of Infection in Patients With Chronic Obstructive Pulmonary Disease in England: Analysis of the AERIS Cohort.

COPD 2021 Jun 6;18(3):341-348. Epub 2021 May 6.

GSK, Wavre, Belgium.

Pertussis is underdiagnosed and underreported in adults and patients with underlying conditions. Patients with chronic obstructive pulmonary disease (COPD) may be at increased risk of severe pertussis. Understanding the true prevalence of pertussis infections in such patients is important. We therefore evaluated the seroprevalence of anti-pertussis toxin (PT) antibodies in a cohort of 40-85-year-old patients diagnosed with moderate, severe or very severe COPD enrolled (between June 2011 and June 2012) in the prospective, observational "Acute Exacerbation and Respiratory InfectionS in COPD" (AERIS; NCT01360398) study, conducted in England. Serum anti-PT antibodies were measured in 104 patients using an enzyme-linked immunosorbent assay on samples collected 12 months (M12) and 24 months (M24) after enrollment. Overall, 14/104 (13.5%) patients had anti-PT concentrations ≥50 IU/mL at M12 or M24, indicative of exposure to during the preceding 2-3 years. Of these, 6/104 (5.8%) had anti-PT ≥70 IU/mL, of whom 3/104 (2.9%) had anti-PT ≥120 IU/mL, indicative of exposure within 12 and 6 months, respectively. These results show a high circulation of in 40-85-year-old patients with moderate, severe or very severe COPD in England between 2012 and 2014, and call for enhanced immunization to prevent pertussis infections in such patients.
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http://dx.doi.org/10.1080/15412555.2021.1920904DOI Listing
June 2021

A prospective, multicentre, cohort study to assess the incidence of dengue illness in households from selected communities in Brazil (2014-2018).

Int J Infect Dis 2021 Apr 21;108:443-453. Epub 2021 Apr 21.

Instituto de Tecnologia em Imunobiológicos Bio-Manguinhos/Fiocruz, Avenida Brasil 4.365, Manguinhos, Rio de Janeiro - RJ, 21.040-900, Brazil.

Objectives: To estimate the incidence of dengue infection across geographically distinct areas of Brazil.

Methods: This prospective, household-based, cohort study enrolled participants in five areas and followed them up for up to 4 years (2014-2018). Dengue seroprevalence was assessed at each scheduled visit. Suspected dengue cases were identified through enhanced passive and active surveillance. Acute symptomatic dengue infection was confirmed through reverse-transcriptase quantitative polymerase chain reaction in combination with an antigenic assay (non-structural protein 1) and serology.

Results: Among 3300 participants enrolled, baseline seroprevalence was 76.2%, although only 23.3% of participants reported a history of dengue. Of 1284 suspected symptomatic dengue cases detected, 50 (3.9%) were laboratory-confirmed. Based on 8166.5 person-years (PY) of follow-up, the incidence of laboratory-confirmed symptomatic infection (primary endpoint) was 6.1 per 1000 PY (95% confidence interval [CI]: 4.5, 8.1). Incidence varied substantially in different years (1.8-7.4 per 1000 PY). The incidence of inapparent primary dengue infection was substantially higher: 41.7 per 1000 PY (95% CI: 31.1, 54.6).

Conclusions: Our findings, highlighting that the incidence of dengue infection is underestimated in Brazil, will inform the design and implementation of future dengue vaccine trials.

Clinical Trial Registration: NCT01751139.
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http://dx.doi.org/10.1016/j.ijid.2021.04.062DOI Listing
April 2021

Impact of maternal diphtheria-tetanus-acellular pertussis vaccination on pertussis booster immune responses in toddlers: Follow-up of a randomized trial.

Vaccine 2021 03 19;39(11):1598-1608. Epub 2021 Feb 19.

GSK, Vaccines, 1300 Wavre, Belgium.

Background: Transplacentally transferred antibodies induced by maternal pertussis vaccination interfere with infant immune responses to pertussis primary vaccination. We evaluated whether this interference remains in toddlers after booster vaccination.

Methods: In a prior phase IV, observer-blind, placebo-controlled, randomized study (NCT02377349), pregnant women in Australia, Canada and Europe received intramuscular tetanus-reduced-antigen-content diphtheria-three-component acellular pertussis vaccine (Tdap group) or placebo (control group) at 27-36 weeks' gestation, with crossover immunization postpartum. Their infants were primed (study NCT02422264) and boosted (at 11-18 months; current study NCT02853929) with diphtheria-tetanus-three-component acellular pertussis-hepatitis B virus-inactivated poliovirus/Haemophilus influenzae type b vaccine (DTaP-HepB-IPV/Hib) and 13-valent pneumococcal conjugate vaccine. Immunogenicity before and after booster vaccination, and reactogenicity and safety of the booster were evaluated descriptively.

Results: 263 (Tdap group) and 277 (control group) toddlers received a DTaP-HepB-IPV/Hib booster. Pre-booster vaccination, observed geometric mean concentrations (GMCs) for the three pertussis antigens and diphtheria were 1.4-1.5-fold higher in controls than in the Tdap group. No differences were observed for the other DTaP-HepB-IPV/Hib antigens. One month post-booster vaccination, booster response rates for pertussis antigens were ≥ 92.1% and seroprotection rates for the other DTaP-HepB-IPV/Hib antigens were ≥ 99.2% in both groups (primary objective). Higher post-booster GMCs were observed in controls versus the Tdap group for anti-filamentous hemagglutinin (1.2-fold), anti-pertussis toxoid (1.5-fold) and anti-diphtheria (1.4-fold). GMCs for the other DTaP-HepB-IPV/Hib antigens were similar between groups. Serious adverse events were reported for three toddlers (controls, not vaccination-related). One death occurred pre-booster (Tdap group, not vaccination-related).

Conclusions: As a consequence of interference of maternal pertussis antibodies with infant immune responses to pertussis primary vaccination, pertussis antibody concentrations were still lower in toddlers from Tdap-vaccinated mothers before DTaP-HepB-IPV/Hib booster vaccination. After the booster, antibody concentrations were lower for filamentous hemagglutinin and pertussis toxoid but not for pertactin. The clinical significance of this interference requires further evaluation.

Clinical Trial Registration: ClinicalTrials.gov: NCT02853929.
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http://dx.doi.org/10.1016/j.vaccine.2021.02.001DOI Listing
March 2021

Association between rotavirus gastroenteritis and intussusception: suggested evidence from a retrospective study in claims databases in the United States.

Hum Vaccin Immunother 2021 01 1;17(1):269-277. Epub 2020 Jul 1.

GSK Vaccines , Wavre, Belgium.

The etiology of intussusception (IS), a serious gastrointestinal obstruction, remains unclear. Limited evidence suggests a role for viral infection. We investigated the risk of IS after rotavirus gastroenteritis (RV GE) in the first year of life. In this retrospective, self-controlled case series (SCCS), we assessed the risk of IS after RV GE using data from United States administrative claims databases. Incidence rate ratios (IRR) of IS were calculated for the 7- and 21-day risk periods after RV GE (main analysis) or after fracture (sensitivity analysis). A total of 290,912,068 subjects were screened; 42 presented claims for RV GE and IS, and 66 for fracture and IS. The IRRs of IS after RV GE were 79.6 (95% confidence interval, CI: 38.6-164.4) and 25.5 (95% CI: 13.2-49.2) in the 7- and 21-day risk periods. The sensitivity analysis showed an association between IS and fracture for both periods, suggesting potential confounding. Post-hoc analyses did not confirm the association between fracture and IS but suggested a potential association between RV GE and IS. A temporal association between RV GE and IS was detected using claims databases. Due to some limitations of the data sources, this association should be further investigated.
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http://dx.doi.org/10.1080/21645515.2020.1770514DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7872044PMC
January 2021

Ten-Year Antibody Persistence and Booster Response to MenACWY-TT Vaccine After Primary Vaccination at 1-10 Years of Age.

Hum Vaccin Immunother 2020 06;16(6):1280-1291

Pfizer Vaccine Clinical Research and Development, Pfizer Inc , Collegeville, PA, USA.

This phase 3B, open-label, extension study (NCT01962207) evaluated long-term persistence of antibodies induced by the quadrivalent meningococcal vaccine conjugated to tetanus toxoid (MenACWY-TT) compared with the meningococcal serogroup C vaccine conjugated to CRM (MenC-CRM) and the quadrivalent meningococcal polysaccharide vaccine (MenACWY-PS) 6 to 10 y after primary vaccination in toddlers (aged 1-<2 y; MenACWY-TT and MenC-CRM) and children (aged 2-<11 y; MenACWY-TT and MenACWY-PS). Antibody responses against meningococcal serogroups A, C, W, and Y were assessed by serum bactericidal antibody assays using rabbit (rSBA) or human (hSBA) complement. A MenACWY-TT booster dose at Year 10 was given to all eligible subjects regardless of the primary vaccine received. At Year 10, the percentages of subjects with rSBA titers ≥1:8 for serogroups A, C, W, and Y were as follows: MenACWY-TT (toddlers), 65.6%, 82.8%, 31.3%, 43.8%, respectively; MenC-CRM, 88.2% for serogroup C; MenACWY-TT (children), 88.9%, 84.1%, 67.1%, 65.9%; and MenACWY-PS, 28.6%, 81.0%, 23.8%, and 23.8%. Corresponding percentages for hSBA titers ≥1:4 were as follows: MenACWY-TT (toddlers), 31.1%, 91.9%, 44.4%, 41.4%; MenC-CRM, 93.8% for serogroup C; MenACWY-TT (children), 34.8%, 91.1%, 61.2%, 72.6%; and MenACWY-PS, 33.3%, 100.0%, 26.3%, and 44.4%. One month after the MenACWY-TT booster, the percentage of subjects with vaccine response ranged from 75.7% to 100.0% across serogroups in all study groups. Postbooster vaccine responses were generally comparable between groups across serogroups. No new safety signals were identified. Antibody responses persisted 10 y after MenACWY-TT vaccination. The MenACWY-TT booster dose was well tolerated and elicited robust immune responses.
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http://dx.doi.org/10.1080/21645515.2020.1746110DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7482884PMC
June 2020

A phase 2b/3b MenACWY-TT study of long-term antibody persistence after primary vaccination and immunogenicity and safety of a booster dose in individuals aged 11 through 55 years.

BMC Infect Dis 2020 Jun 18;20(1):426. Epub 2020 Jun 18.

Pfizer Vaccine Clinical Research and Development, Collegeville, PA, USA.

Background: A previous phase 2 study demonstrated the immunogenicity of a single dose of meningococcal A, C, W, Y-tetanus toxoid conjugate (MenACWY-TT) or polysaccharide (MenACWY-PS) vaccine for up to 5 years in individuals aged 11-55 years. This follow-up study evaluated long-term antibody persistence up to 10 years and the immunogenicity and safety of a single MenACWY-TT booster dose given 10 years after primary vaccination.

Methods: Blood draws were conducted annually in Years 7-10. At Year 10, all subjects received a MenACWY-TT booster dose. Blood was drawn at 1 month and safety data were collected ≤6 months postbooster. Study endpoints included immunogenicity during the persistence phase (primary), and immunogenicity and safety during the booster phase (secondary). Statistical analyses were descriptive.

Results: A total of 311 subjects were enrolled in the persistence phase (MenACWY-TT, 235; MenACWY-PS, 76); 220 were enrolled in the booster phase (MenACWY-TT, 164; MenACWY-PS, 56). Descriptive analyses indicated that at Years 7-10, the percentages of subjects achieving serum bactericidal antibody assay using baby rabbit complement (rSBA) titers ≥1:8 and ≥1:128 were higher for serogroups A, W, and Y in the MenACWY-TT versus MenACWY-PS group; percentages were similar across groups for serogroup C. rSBA geometric mean titers (GMTs) for serogroups A, W, and Y were higher in the MenACWY-TT group and slightly higher in the MenACWY-PS group for serogroup C. One month postbooster, all primary MenACWY-TT and ≥98.1% of primary MenACWY-PS recipients had rSBA titers ≥1:8. For all serogroups, rSBA GMTs postbooster were higher in the MenACWY-TT versus MenACWY-PS group. Most local and general reactogenicity events were similar between groups and mild to moderate in severity. Adverse events at 1 month postbooster were 9.1% for the MenACWY-TT and 3.6% for the MenACWY-PS groups; all were nonserious.

Conclusions: Immune responses to a single MenACWY-TT primary dose administered at age 11-55 years persisted in >70% of individuals evaluated at Years 7-10. A MenACWY-TT booster dose administered at Year 10 was safe and immunogenic with no new safety signals observed. These results provide important insights regarding long-term protection from primary vaccination and the benefits of booster dosing.

Trial Registration: Clinicaltrials.gov, NCT01934140. Registered September 2013.
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http://dx.doi.org/10.1186/s12879-020-05104-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7301505PMC
June 2020

Immunogenicity, transplacental transfer of pertussis antibodies and safety following pertussis immunization during pregnancy: Evidence from a randomized, placebo-controlled trial.

Vaccine 2020 02 24;38(8):2095-2104. Epub 2019 Nov 24.

GSK, Wavre, Belgium. Electronic address:

Background: Pertussis immunization during pregnancy is recommended in many countries. Data from large randomized controlled trials are needed to assess the immunogenicity, reactogenicity and safety of this approach.

Methods: This phase IV, observer-blind, randomized, placebo-controlled, multicenter trial assessed immunogenicity, transplacental transfer of maternal pertussis antibodies, reactogenicity and safety of a reduced-antigen-content diphtheria-tetanus-three-component acellular pertussis vaccine (Tdap) during pregnancy. Women received Tdap or placebo at 27-36 weeks' gestation with crossover ≤ 72-hour-postpartum immunization. Immune responses were assessed before the pregnancy dose and 1 month after, and from the umbilical cord at delivery. Superiority (primary objective) was reached if the lower limits of the 95% confidence intervals (CIs) of the pertussis geometric mean concentration (GMC) ratios (Tdap/control) in cord blood were ≥ 1.5. Solicited and unsolicited adverse events (AEs) and pregnancy-/neonate-related AEs of interest were recorded.

Results: 687 pregnant women were vaccinated (Tdap: N = 341 control: N = 346). Superiority of the pertussis immune response (maternally transferred pertussis antibodies in cord blood) was demonstrated by the GMC ratios (Tdap/control): 16.1 (95% CI: 13.5-19.2) for anti-filamentous hemagglutinin, 20.7 (15.9-26.9) for anti-pertactin and 8.5 (7.0-10.2) for anti-pertussis toxoid. Rates of pregnancy-/neonate-related AEs of interest, solicited general and unsolicited AEs were similar between groups. None of the serious AEs reported throughout the study were considered related to maternal Tdap vaccination.

Conclusions: Tdap vaccination during pregnancy resulted in high levels of pertussis antibodies in cord blood, was well tolerated and had an acceptable safety profile. This supports the recommendation of Tdap vaccination during pregnancy to prevent early-infant pertussis disease.

Clinical Trial Registration: ClinicalTrials.gov: NCT02377349.
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http://dx.doi.org/10.1016/j.vaccine.2019.10.105DOI Listing
February 2020

Impact of tetanus-diphtheria-acellular pertussis immunization during pregnancy on subsequent infant immunization seroresponses: follow-up from a large randomized placebo-controlled trial.

Vaccine 2020 02 24;38(8):2105-2114. Epub 2019 Nov 24.

GSK, Wavre, Belgium. Electronic address:

Background: Pertussis immunization during pregnancy results in high pertussis antibody concentrations in young infants but may interfere with infant immune responses to post-natal immunization.

Methods: This phase IV, multi-country, open-label study assessed the immunogenicity and safety of infant primary vaccination with DTaP-HepB-IPV/Hib and 13-valent pneumococcal conjugate vaccine (PCV13). Enrolled infants (6-14 weeks old) were born to mothers who were randomized to receive reduced-antigen-content diphtheria-tetanus-three-component acellular pertussis vaccine (Tdap group) or placebo (control group) during pregnancy (27-36 weeks' gestation) with crossover immunization postpartum. All infants received 2 or 3 DTaP-HepB-IPV/Hib and PCV13 doses according to national schedules. Immunogenicity was assessed in infants pre- and 1 month post-primary vaccination. The primary objective was to assess seroprotection/vaccine response rates for DTaP-HepB-IPV/Hib antigens 1 month post-primary vaccination.

Results: 601 infants (Tdap group: 296; control group: 305) were vaccinated. One month post-priming, seroprotection rates were 100% (diphtheria; tetanus), ≥98.5% (hepatitis B), ≥95.9% (polio) and ≥94.5% (Hib) in both groups. Vaccine response rates for pertussis antigens were significantly lower in infants whose mothers received pregnancy Tdap (37.5-77.1%) versus placebo (90.0-99.2%). Solicited and unsolicited adverse event rates were similar between groups. Serious adverse events occurred in 2.4% (Tdap group) and 5.6% (control group) of infants, none were vaccination-related.

Conclusions: Pertussis antibodies transferred during pregnancy may decrease the risk of pertussis infection in the first months of life but interfere with the infant's ability to produce pertussis antibodies, the clinical significance of which remains unknown. Safety and reactogenicity results were consistent with previous experience.

Clinical Trial Registration: ClinicalTrials.gov: NCT02422264.
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http://dx.doi.org/10.1016/j.vaccine.2019.10.104DOI Listing
February 2020

Immunogenicity and safety following primary and booster vaccination with a hexavalent diphtheria, tetanus, acellular pertussis, hepatitis B, inactivated poliovirus and Haemophilus influenzae type b vaccine: a randomized trial in the United States.

Hum Vaccin Immunother 2019 4;15(4):809-821. Epub 2019 Jan 4.

c GSK , Wavre , Belgium.

Combined hexavalent diphtheria-tetanus-acellular pertussis-hepatitis B-inactivated poliomyelitis and Haemophilus influenzae type b vaccine (DTaP-HBV-IPV/Hib) can further reduce the number of injections in pediatric immunization schedules of countries currently using pentavalent DTaP combination vaccines. This open-label, randomized, multicenter study (NCT02096263) conducted in the United States evaluated the immunogenicity and safety of DTaP-HBV-IPV/Hib vaccine compared with concomitant administration of DTaP-HBV-IPV and Hib or DTaP-IPV/Hib and HBV vaccines. We randomized (1:1:1) infants to receive 3-dose priming with DTaP-HBV-IPV/Hib boosted with DTaP+ Hib, DTaP-HBV-IPV+ Hib boosted with DTaP+ Hib, or DTaP-IPV/Hib+ HBV boosted with DTaP-IPV/Hib, at 2, 4, 6, and 15-18 months of age. We enrolled and vaccinated 585 participants, 486 received a booster, and 476 completed the study. Of these, 466 participants were included in the primary and 408 in the booster according-to-protocol cohorts for immunogenicity. We demonstrated non-inferiority of DTaP-HBV-IPV/Hib vaccine to DTaP-HBV-IPV+ Hib co-administered vaccines in terms of geometric mean concentrations for pertussis antibodies post-primary vaccination. Post-primary vaccination, seroprotection/seropositivity rates for all vaccine antigens were similarly high between DTaP-HBV-IPV/Hib (≥ 94.8%), DTaP-HBV-IPV+ Hib (≥ 98.1%) or DTaP-IPV/Hib+ HBV (≥ 97.8%) groups. We observed robust immune responses post-booster, indicating effective priming by the 3 regimens. Reactogenicity was similar in the 3 groups. Twenty-eight serious adverse events were reported during the study; 3 were considered related to vaccination and resolved by the end of the study. These results confirm that DTaP-HBV-IPV/Hib could be a valuable additional source of pediatric DTaP, IPV, HBV, and Hib-containing vaccine in countries that currently use multivalent vaccines.
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http://dx.doi.org/10.1080/21645515.2018.1549449DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6605854PMC
February 2020

Immunogenicity and safety of the Haemophilus influenzae type b and Neisseria meningitidis serogroups C and Y-tetanus toxoid conjugate vaccine co-administered with human rotavirus, hepatitis A and 13-valent pneumococcal conjugate vaccines: results from a phase III, randomized, multicenter study in infants.

Hum Vaccin Immunother 2019 5;15(2):327-338. Epub 2018 Oct 5.

d GSK , Wavre , Belgium.

This phase III, open-label, randomized study (NCT01978093) evaluated the immunogenicity and safety of co-administered Haemophilus influenzae type b-Neisseria meningitidis serogroups C and Y-tetanus toxoid conjugate vaccine (Hib-MenCY-TT) with human rotavirus vaccine (HRV), hepatitis A vaccine (HAV) and 13-valent pneumococcal conjugate vaccine (PCV13). We randomized 600 infants (1:1) to receive 4 doses of Hib-MenCY-TT at 2, 4, 6 and 12-15 months of age or 3 doses of Hib vaccine conjugated to N. meningitidis outer membrane protein complex (Hib-OMP) at 2, 4 and 12-15 months of age. All infants received HRV at 2 and 4 months of age, PCV13 at 2, 4, 6 and 12-15 months of age, HAV at 12-15 and 18-21 months of age, and diphtheria-tetanus-acellular pertussis-hepatitis B-inactivated poliovirus vaccine at 2, 4 and 6 months of age. We measured immune responses against HRV, HAV and Hib with enzyme-linked immunosorbent assays, and against MenC/MenY with serum bactericidal assays using human complement. The 4-dose vaccination series with Hib-MenCY-TT induced a robust immune response against Hib, which was non-inferior to that induced by a 3-dose vaccination series with Hib-OMP, and against MenC and MenY. Hib-MenCY-TT did not interfere with immune responses to concomitantly administered HRV, PCV13 and HAV. We did not identify any safety concern. In conclusion, we showed that 4-dose vaccination series with Hib-MenCY-TT during infancy did not interfere with immune responses of co-administered HRV, PCV13 and HAV, induced robust immune responses against Hib, MenC and MenY, and had a clinically acceptable safety profile.
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http://dx.doi.org/10.1080/21645515.2018.1526586DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6422469PMC
February 2020

Immunogenicity and safety of the quadrivalent meningococcal vaccine MenACWY-TT co-administered with a combined diphtheria-tetanus-acellular pertussis vaccine versus their separate administration in adolescents and young adults: A phase III, randomized study.

Vaccine 2018 07 28;36(31):4750-4758. Epub 2018 Jun 28.

GSK, Wavre, Belgium. Electronic address:

Background: This study evaluated the immunogenicity and safety of quadrivalent meningococcal conjugate vaccine using tetanus (T) toxoid as carrier protein (MenACWY-TT) co-administered with combined diphtheria-tetanus-acellular pertussis vaccine (Tdap) versus their separate administration in adolescents and young adults.

Methods: In this phase III, randomized, partially-blind study (NCT01767376), healthy 11-25-year-olds (N = 660) were randomized (1:1:1) to receive MenACWY-TT and Tdap at Month 0 (Co-ad group), MenACWY-TT at Month 0 and Tdap at Month 1 (ACWY_Tdap group) or Tdap at Month 0 and MenACWY-TT at Month 1 (Tdap_ACWY group). Immune responses to MenACWY-TT were measured by serum bactericidal assay using rabbit complement (rSBA). Anti-diphtheria (D), anti-tetanus (T), anti-pertussis toxin (PT), anti-filamentous hemagglutinin (FHA) and anti-pertactin (PRN) antibody concentrations were assessed using enzyme-linked immunosorbent assays. Non-inferiority of immunogenicity was assessed using pre-defined clinical criteria. Safety was also evaluated.

Results: Non-inferiority of immunogenicity of MenACWY-TT and Tdap when co-administered versus their separate administration was demonstrated in terms of rSBA geometric mean titers (GMTs) for 4 meningococcal serogroups and of the percentage of participants with antibody concentrations >1 IU/ml for D and T. Among the pertussis antigens, non-inferiority criteria for geometric mean concentrations (GMCs) were reached for PT, but not met for FHA and PRN. Across all groups, ≥93.2% of participants had vaccine responses to each meningococcal serogroup, ≥99.1% were seroprotected against T and D, and ≥85.5% had booster responses to each pertussis antigen. Robust increases in antibody GMTs/GMCs were observed for all antigens between pre-and post-vaccination. Both vaccines had clinically acceptable safety profiles.

Conclusion: Immune responses to MenACWY-TT and to the T and D antigens from Tdap were not impacted by their co-administration. The lower antibody concentrations observed against the pertussis components may be of limited clinical relevance since robust anti-pertussis booster responses were observed. This study supports concurrent administration of the 2 vaccines in adolescents.
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http://dx.doi.org/10.1016/j.vaccine.2018.04.034DOI Listing
July 2018

Lot-to-lot consistency, safety and immunogenicity of 3 lots of Haemophilus influenzae type b conjugate vaccine: results from a phase III randomized, multicenter study in infants.

Vaccine 2017 06 20;35(28):3564-3574. Epub 2017 May 20.

GSK, 1250 South Collegeville Road, Collegeville, PA 19426, United States.

Background: Vaccination against Haemophilus influenzae type b (Hib) is included in routine pediatric immunization schedule in the United States. Previous vaccine shortages have created the need for additional options for Hib vaccination.

Methods: This phase III, randomized, multi-centered study (NCT01000974) evaluated the safety and immunogenicity of a monovalent tetanus toxoid-conjugate Hib vaccine (Hib-TT) compared to a monovalent (Hib-TT control) and a combination Hib-TT vaccine. We hierarchically assessed lot-to-lot consistency of 3 Hib-TT lots and non-inferiority of Hib-TT to Hib-TT control. We co-administered routine pediatric vaccines with Hib-TT vaccines at 2, 4, 6months (primary vaccination) and 15-18months of age (booster vaccination). We recorded adverse events (AEs) for 4 (solicited) and 31days (unsolicited) post-vaccination and serious AEs (SAEs) throughout the study.

Results: Of 4009 enrolled children, 3086 completed booster phase. Lot-to-lot consistency was not demonstrated. The study met statistical criteria for non-inferiority of Hib-TT to Hib-TT control in terms of immune responses to Hib and co-administered vaccines' antigens, but not in terms of participants achieving post-primary vaccination anti-PRP levels ≥1µg/mL. Because of the hierarchical nature of the objectives, non-inferiority could not be established. In all groups, 92.5-96.7% and 99.6-100% of participants achieved anti-PRP levels ≥0.15µg/mL, while 78.3-89.8% and 97.9-99.1% had anti-PRP levels ≥1µg/mL, post-primary and post-booster vaccination, respectively. Immune responses to co-administered vaccines and reported incidence of AEs were comparable among groups. We recorded SAEs for 107/2963 (3.6%), 24/520 (4.6%), and 21/520 (4.0%) children post-primary vaccination, and 29/2337 (1.2%), 4/435 (0.9%), and 2/400 (0.5%) children post-booster vaccination with Hib-TT, Hib-TT control and combination Hib-TT vaccine, respectively; 6/5330 (0.1%) SAEs in the Hib-TT groups were considered vaccine-related.

Conclusion: Hib-TT induced seroprotective antibody concentrations in the majority of participants and was well-tolerated when co-administered with routine pediatric vaccines according to a 3+1 schedule.
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http://dx.doi.org/10.1016/j.vaccine.2017.05.018DOI Listing
June 2017

Immunogenicity and safety of primary and booster vaccination with 2 investigational formulations of diphtheria, tetanus and Haemophilus influenzae type b antigens in a hexavalent DTPa-HBV-IPV/Hib combination vaccine in comparison with the licensed Infanrix hexa.

Hum Vaccin Immunother 2017 07 24;13(7):1505-1515. Epub 2017 Mar 24.

g GSK , Wavre , Belgium.

Safety and immunogenicity of 2 investigational formulations of diphtheria, tetanus and Haemophilus influenzae type b antigens of the combined diphtheria-tetanus-acellular pertussis-hepatitis B-inactivated poliomyelitis-Hib vaccine (DTPa-HBV-IPV/Hib) were evaluated in a Primary (NCT01248884) and a Booster vaccination (NCT01453998) study. In the Primary study, 721 healthy infants (randomized 1:1:1) received 3 doses of DTPa-HBV-IPV/Hib formulation A (DTPa-HBV-IPV/Hib), or B (DTPa-HBV-IPV/Hib) or the licensed DTPa-HBV-IPV/Hib vaccine (Infanrix hexa, GSK; control group) at 2, 3, 4 months of age. Infants were planned to receive a booster dose at 12-15 months of age with the same formulation received in the Primary study; however, following high incidence of fever associated with the investigational formulations in the Primary study, the Booster study protocol was amended and all infants yet to receive a booster dose (N = 385) received the licensed vaccine. In the Primary study, non-inferiority of 3-dose vaccination with investigational formulations compared with the licensed vaccine was not demonstrated due to anti-pertactin failing to meet the non-inferiority criterion. Post-primary vaccination, most infants had seroprotective levels of anti-diphtheria (100% of infants), anti-tetanus antigens (100%), against hepatitis B (≥ 97.5% across groups), polyribosyl-ribitol-phosphate (≥ 88.0%) and poliovirus types 1-3 (≥ 90.5%). Seropositivity rates for each pertussis antigen were 100% in all groups. Higher incidence of fever (> 38°C) was reported in infants receiving the investigational formulations (Primary study: 75.0% [A] and 72.1% [B] vs 58.8% [control]; Booster study, before amendment: 49.4% and 46.6% vs 37.4%, respectively). The development of the investigational formulations was not further pursued.
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http://dx.doi.org/10.1080/21645515.2017.1294294DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5512790PMC
July 2017

Effect of human rotavirus vaccine on severe diarrhea in African infants.

Malawi Med J 2016 09;28(3):108-114

Rotavirus Vaccine Program, PATH, Seattle, Washington, U.S.A.

Background: Rotavirus is the most common cause of severe gastroenteritis among young children worldwide. Data are needed to assess the efficacy of the rotavirus vaccine in African children.

Methods: We conducted a randomized, placebo-controlled, multicenter trial in South Africa (3166 infants; 64.1% of the total) and Malawi (1773 infants; 35.9% of the total) to evaluate the efficacy of a live, oral rotavirus vaccine in preventing severe rotavirus gastroenteritis. Healthy infants were randomly assigned in a 1:1:1 ratio to receive two doses of vaccine (in addition to one dose of placebo) or three doses of vaccine - the pooled vaccine group - or three doses of placebo at 6, 10, and 14 weeks of age. Episodes of gastroenteritis caused by wild-type rotavirus during the first year of life were assessed through active follow-up surveillance and were graded with the use of the Vesikari scale.

Results: A total of 4939 infants were enrolled and randomly assigned to one of the three groups; 1647 infants received two doses of the vaccine, 1651 infants received three doses of the vaccine, and 1641 received placebo. Of the 4417 infants included in the per-protocol efficacy analysis, severe rotavirus gastroenteritis occurred in 4.9% of the infants in the placebo group and in 1.9% of those in the pooled vaccine group (vaccine efficacy, 61.2%; 95% confidence interval, 44.0 to 73.2). Vaccine efficacy was lower in Malawi than in South Africa (49.4% vs. 76.9%); however, the number of episodes of severe rotavirus gastroenteritis that were prevented was greater in Malawi than in South Africa (6.7 vs. 4.2 cases prevented per 100 infants vaccinated per year). Efficacy against all-cause severe gastroenteritis was 30.2%. At least one serious adverse event was reported in 9.7% of the infants in the pooled vaccine group and in 11.5% of the infants in the placebo group.

Conclusions: Human rotavirus vaccine significantly reduced the incidence of severe rotavirus gastroenteritis among African infants during the first year of life. (ClinicalTrials.gov number, NCT00241644.).
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5117000PMC
September 2016

Characterization of an age-response relationship to GSK's recombinant hepatitis B vaccine in healthy adults: An integrated analysis.

Hum Vaccin Immunother 2015 ;11(7):1726-9

a GSK Vaccines ; Wavre , Belgium.

The immune system becomes less effective with age, and older age is associated with an increased susceptibility to diseases and reduced responses to vaccination. Furthermore, some adult populations, such as those with diabetes mellitus, are at increased risk of acute hepatitis B virus (HBV) infection. Decreasing responses to vaccination with advanced age have been described, but it is not known at what age immunogenicity starts to reduce, or until what age immunogenicity remains acceptable (for example ≥ 80% seroprotection post-vaccination). We characterized the relationship between age and seroprotection rate induced by recombinant HBV vaccination by conducting a pooled analysis of clinical trial data. Healthy adults aged ≥ 20 y who had been vaccinated with 20 μg HBV vaccine (Engerix™ B, GSK Vaccines, Belgium) in a 0, 1, 6 months schedule in 11 studies since 1996 were included. The observed seroprotection rate, defined as an anti-HBV surface antigen antibody concentration ≥ 10 mIU/ml was 94.5% in the whole population (N = 2,620, Total vaccinated cohort), ranging from 98.6% in adults vaccinated at age 20-24 years, to 64.8% in those vaccinated at age ≥ 65 y A model on seroprotection rates showed a statistically significant decrease with age, and predicted that the anti-HBs seroprotection rate remains ≥ 90% up to 49 y of age and ≥ 80% up to 60 y of age. Individuals at risk of HBV infection should be vaccinated as early in life as possible to improve the likelihood of achieving seroprotection. Additional studies are needed to identify whether unvaccinated individuals older than 60 y would benefit from regimens that include additional or higher vaccine doses.
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http://dx.doi.org/10.1080/21645515.2015.1039758DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4514334PMC
April 2016

A randomized study to evaluate the immunogenicity and safety of a heptavalent diphtheria, tetanus, pertussis, hepatitis B, poliomyelitis, haemophilus influenzae b, and meningococcal serogroup C combination vaccine administered to infants at 2, 4 and 12 months of age.

Pediatr Infect Dis J 2014 Dec;33(12):1246-54

From the *Association Française de Pédiatrie Ambulatoire, Essey les Nancy, France; †Vaccine Evaluation Center, British Columbia Children's Hospital, Vancouver, Canada; ‡Pediatric Office, Heiligenhaus, Germany; §GlaxoSmithKline Vaccines, Wavre, Belgium; and ¶GlaxoSmithKline Vaccines, King of Prussia, Pennsylvania.

Background: The immunogenicity and safety of the investigational diphtheria, tetanus, acellular pertussis, hepatitis B, poliomyelitis, Haemophilus influenzae type b (Hib) and meningococcal serogroup C (MenC) heptavalent combination vaccine were compared with those of licensed control vaccines.

Methods: In this open, phase II, randomized study (NCT01090453), 480 infants from Germany, France and Canada received the heptavalent vaccine (Hepta group) or hexavalent and monovalent MenC control vaccines (HexaMenC group) co-administered with a 13-valent pneumococcal conjugate vaccine at 2, 4 and 12 months of age. Immunogenicity was measured 1 month after the second primary dose, and before and 1 month after the booster dose. Safety and reactogenicity were also evaluated.

Results: Non-inferiority of immune responses to MenC and Hib induced by 2-dose primary vaccination with the heptavalent vaccine versus control vaccines was demonstrated. In exploratory analyses, postprimary and postbooster functional antibody geometric mean titers against MenC tended to be lower (1119.5 vs. 3200.5; 2653.8 vs. 6028.4) and antibody geometric mean concentrations against Hib higher (1.594 vs. 0.671 μg/mL; 17.678 vs. 13.737 μg/mL) in the Hepta versus the HexaMenC group. The heptavalent and control vaccines were immunogenic to all other antigens, although immune responses to poliovirus were lower than expected in both groups. No differences in safety and reactogenicity profiles were detected between groups.

Conclusions: The heptavalent vaccine induced non-inferior MenC and Hib responses compared with control vaccines. Both vaccination regimens, when administered at 2, 4 and 12 months of age, had comparable safety profiles and were immunogenic to all antigens, with lower-than-expected responses to poliomyelitis.
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http://dx.doi.org/10.1097/INF.0000000000000468DOI Listing
December 2014

Association of serum anti-rotavirus immunoglobulin A antibody seropositivity and protection against severe rotavirus gastroenteritis: analysis of clinical trials of human rotavirus vaccine.

Hum Vaccin Immunother 2014 13;10(2):505-11. Epub 2013 Nov 13.

GlaxoSmithKline Vaccines; Wavre, Belgium.

Clinical trials of the human rotavirus vaccine Rotarix™ (RV1) have demonstrated significant reductions in severe rotavirus gastroenteritis (RVGE) in children worldwide. However, no correlate of vaccine efficacy (VE) has yet been established. This paper presents 2 analyses which aimed to investigate whether serum anti-RV IgA measured by ELISA 1 or 2 mo post-vaccination can serve as a correlate of efficacy against RVGE: (1) In a large Phase III efficacy trial (Rota-037), the Prentice criteria for surrogate endpoints was applied to anti-RV IgA seropositivity 1 mo post-vaccination. These criteria determine whether a significant vaccine group effect can be predicted from the surrogate, namely seropositivity (anti-RV IgA concentration>20 U/mL); (2) Among other GSK-sponsored RV1 VE studies, 8 studies which assessed immunogenicity at 1 or 2 mo post-vaccination in all or a sub-cohort of enrolled subjects and had at least 10 RVGE episodes were included in a meta-analysis to measure the regression between clinical VE and VE predicted from immunogenicity (VE1). In Rota-037, anti-RV IgA seropositivity post-vaccination was associated with a lower incidence of any or severe RVGE, however, the proportion of vaccine group effect explained by seropositivity was only 43.6% and 32.7% respectively. This low proportion was due to the vaccine group effect observed in seronegative subjects. In the meta-analysis, the slope of the regression between clinical VE and VE1 was statistically significant. These two independent analyses support the hypothesis that post-vaccination anti-RV IgA seropositivity (antibody concentration ≥20 U/mL) may serve as a useful correlate of efficacy in clinical trials of RV1 vaccines.
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http://dx.doi.org/10.4161/hv.27097DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4185910PMC
January 2015

Persistence clinical studies: can you believe what you see?

Hum Vaccin Immunother 2013 Jun 7;9(6):1351-7. Epub 2013 Mar 7.

GlaxoSmithKline; Wavre, Belgium.

Long-term immunity, evaluated by the persistence of antibody titers, is important to assess duration of protection induced by vaccination. This paper aims at drawing awareness on the risk of misinterpreting persistence results in absence of adjustment for missing or left-censored data. Using simulations, the paper shows that repeated measurement models are an appropriate alternative to control the bias associated to unadjusted persistence results.
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http://dx.doi.org/10.4161/hv.24168DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3901829PMC
June 2013

Meta-analysis of pregnancy outcomes in pooled randomized trials on a prophylactic adjuvanted glycoprotein D subunit herpes simplex virus vaccine.

Vaccine 2013 Mar 10;31(13):1759-64. Epub 2013 Jan 10.

GlaxoSmithKline Vaccines, Wavre, Belgium.

The primary objective of this investigation was to assess whether the AS04-adjuvanted herpes simplex virus (HSV) glycoprotein D candidate prophylactic vaccine against genital herpes disease increases the risk of spontaneous abortion associated with pregnancy conceived within the vaccination exposure window (vaccine dose received within the period starting 60 days before and ending 20 weeks post-conception day). We performed a meta-analysis of studies designed as part of the clinical development program for this vaccine, to examine the relative risk of abortion (spontaneous or elective) associated with unintended vaccination exposure during pregnancy. Nineteen studies, completed before September 2010, were eligible; 5 matched the inclusion criteria for this analysis (presence of a control arm and at least one adverse pregnancy outcome reported). All vaccinated women (N=19,727) were included, of whom 660 reported a pregnancy during the study period. Overall, 13.3% of pregnancies in the HSV vaccine group and 11.0% in the control group resulted in spontaneous abortion; 24.2% and 20.0% resulted in elective abortion. Among 180 women with a first pregnancy conceived in the vaccination exposure window, 16.7% (HSV vaccine) and 9.5% (control) had a spontaneous abortion and 38.5% and 33.3%, elective abortion. The relative risk for spontaneous abortion associated with vaccine exposure during the risk period for abortion in the course of pregnancy was 1.7 (95% CI: 0.7-4.6). For all women receiving HSV vaccine, this relative risk was 1.3 (95% CI: 0.8-2.1). The corresponding relative risks for elective abortion were 1.2 (95% CI: 0.7-2.0) and 1.3 (95% CI: 0.9-1.8). There was no apparent relationship to dosing and no difference between groups in gestational age at the time of spontaneous or elective abortion. In conclusion there is no statistical evidence that the investigational HSV vaccine increased the risk of spontaneous or elective abortion.
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http://dx.doi.org/10.1016/j.vaccine.2013.01.002DOI Listing
March 2013

Horizontal transmission of a human rotavirus vaccine strain--a randomized, placebo-controlled study in twins.

Vaccine 2011 Nov 18;29(51):9508-13. Epub 2011 Oct 18.

Hospital Maternidad Nuestra Sra de la Altagracia, Santo Domingo, Dominican Republic.

Transmission of excreted vaccine-derived infectious virus from vaccinated to unvaccinated individuals is possible within close contacts. This randomized (1:1), double-blind study evaluated the potential for transmission of human rotavirus vaccine strain, HRV (Rotarix™) from vaccine recipients to unvaccinated close contacts (twins). 100 pairs of healthy twins aged 6-14 weeks at the time of Dose 1 of HRV vaccine/placebo were enrolled and one randomly selected twin from each pair received two vaccine doses and the other received placebo doses (at 2 and 4 months of age). Presence of vaccine strain in the stool samples of placebo recipients was an indicator of transmission. Serial stool samples were tested for rotavirus using ELISA at pre-determined time points; rotavirus positive stool samples were tested with RT-PCR and reverse hybridization assay to identify G1P[8] vaccine strain. If G1P[8] vaccine strain was detected, the complete genome was sequenced to assess the similarity between viral isolates. Immunogenicity and safety of HRV vaccine in transmission cases was assessed. 15 transmission cases were reported in 80 evaluable twins who received placebo and the transmission rate was 18.8% (95% CI: 10.9-29.0%). None of the transmission cases was associated with gastroenteritis symptoms. Anti-rotavirus IgA seroconversion was 62.5% (95% CI: 51.0-73.1%) (HRV) and 21.3% (95% CI: 12.9-31.8%) (placebo) 7-weeks post-Dose 2; seroconversion in transmission cases was 26.7% (95% CI: 7.8-55.1%). Genetic variations or amino acid substitutions in transmission cases were similar to that seen in corresponding vaccine recipients. Transmission of HRV vaccine strain to unvaccinated twins living in close contact occurred, however, they were not associated with increased of gastroenteritis. Whether transmission leads to indirect protection among unvaccinated individuals remains unknown at this stage.
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http://dx.doi.org/10.1016/j.vaccine.2011.10.015DOI Listing
November 2011

Effect of human rotavirus vaccine on severe diarrhea in African infants.

N Engl J Med 2010 Jan;362(4):289-98

Department of Science and Technology/National Research Foundation: Vaccine Preventable Diseases, University of the Witwatersrand, Johannesburg, South Africa.

Background: Rotavirus is the most common cause of severe gastroenteritis among young children worldwide. Data are needed to assess the efficacy of the rotavirus vaccine in African children.

Methods: We conducted a randomized, placebo-controlled, multicenter trial in South Africa (3166 infants; 64.1% of the total) and Malawi (1773 infants; 35.9% of the total) to evaluate the efficacy of a live, oral rotavirus vaccine in preventing severe rotavirus gastroenteritis. Healthy infants were randomly assigned in a 1:1:1 ratio to receive two doses of vaccine (in addition to one dose of placebo) or three doses of vaccine--the pooled vaccine group--or three doses of placebo at 6, 10, and 14 weeks of age. Episodes of gastroenteritis caused by wild-type rotavirus during the first year of life were assessed through active follow-up surveillance and were graded with the use of the Vesikari scale.

Results: A total of 4939 infants were enrolled and randomly assigned to one of the three groups; 1647 infants received two doses of the vaccine, 1651 infants received three doses of the vaccine, and 1641 received placebo. Of the 4417 infants included in the per-protocol efficacy analysis, severe rotavirus gastroenteritis occurred in 4.9% of the infants in the placebo group and in 1.9% of those in the pooled vaccine group (vaccine efficacy, 61.2%; 95% confidence interval, 44.0 to 73.2). Vaccine efficacy was lower in Malawi than in South Africa (49.4% vs. 76.9%); however, the number of episodes of severe rotavirus gastroenteritis that were prevented was greater in Malawi than in South Africa (6.7 vs. 4.2 cases prevented per 100 infants vaccinated per year). Efficacy against all-cause severe gastroenteritis was 30.2%. At least one serious adverse event was reported in 9.7% of the infants in the pooled vaccine group and in 11.5% of the infants in the placebo group.

Conclusions: Human rotavirus vaccine significantly reduced the incidence of severe rotavirus gastroenteritis among African infants during the first year of life. (ClinicalTrials.gov number, NCT00241644.)
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http://dx.doi.org/10.1056/NEJMoa0904797DOI Listing
January 2010

Live attenuated human rotavirus vaccine, RIX4414, provides clinical protection in infants against rotavirus strains with and without shared G and P genotypes: integrated analysis of randomized controlled trials.

Pediatr Infect Dis J 2009 Apr;28(4):261-6

GlaxoSmithKline Biologicals, Rixensart, Belgium.

Background: : The 2-dose, oral live attenuated human G1P[8] rotavirus vaccine (RIX4414) is highly effective against rotavirus gastroenteritis caused by circulating G1 and non-G1 types. An integrated analysis on vaccine efficacy was undertaken to obtain more precise estimates of the overall protective effect of the RIX4414 vaccine against rotavirus gastroenteritis due to common rotavirus types (G1, G3, G4, G9, P[8]) and less commonly encountered strains such as G2P[4] across heterogenous settings.

Methods: : The studies used in the integrated analysis were all previously reported randomized, double-blind, placebo-controlled, phase II and III trials with at least 1 report of rotavirus gastroenteritis in the efficacy follow-up period (up to 1 year of age or end of first RV epidemic season after vaccination). The integrated analysis was performed for all circulating rotavirus strains sharing G and/or P genotype and not sharing G or P genotype with the vaccine strain. Vaccine efficacy was estimated as 1 minus rate of rotavirus gastroenteritis relative to placebo, using exact Poisson rate ratio stratified by study.

Results: : The integrated estimates for vaccine efficacy against severe rotavirus gastroenteritis were 87.43% (95% confidence interval [CI]: 78.89-92.86) for G1P[8] strains, 71.42% (95% CI: 20.12-91.11) for G2P[4] strains, 90.19% (95% CI: 55.51-98.94) for G3P[8] strains, 93.37% (95% CI: 51.50-99.85) for G4P[8] strains, and 83.76% (95% CI: 71.18-91.28) for G9P[8] strains. The integrated estimates for vaccine efficacies against rotavirus gastroenteritis of any severity were 82.57% (95% CI: 73.91-88.56) for G1P[8] strains, 81.04% (95% CI: 31.58-95.76) for G2P[4] strains, 87.66% (95% CI: 34.57-98.76) for G3P[8] strains, 84.86% (95% CI: 50.92-96.41) for G4P[8] strains, and 60.64% (95% CI: 38.15-74.96) for G9P[8] strains.

Conclusions: : Two doses of RIX4414 provide overall good clinical protection against all cases of rotavirus gastroenteritis and comparable, high clinical protection against severe rotavirus gastroenteritis caused by circulating rotavirus strains with and without G and P genotypes shared with the vaccine strain, such as G2P[4].
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http://dx.doi.org/10.1097/INF.0b013e3181907177DOI Listing
April 2009

The human rotavirus vaccine RIX4414 in infants: a review of safety and tolerability.

Pediatr Infect Dis J 2009 Mar;28(3):225-32

GlaxoSmithKline Biologicals, Rixensart, Belgium.

Background: An oral, live attenuated human rotavirus vaccine, RIX4414 has been developed to prevent rotavirus gastroenteritis. An integrated safety summary of 8 randomized, placebo-controlled, double-blind phase II and III trials of vaccine at potency licensed for use worldwide was performed.

Methods: Healthy 1- to 18-week-old infants (N = 71209) were enrolled to receive 2 doses of RIX4414/placebo according to 0, 1 or 0, 2 month schedules. Solicited (fever, fussiness/irritability, loss of appetite, vomiting, diarrhea, cough/rhinorrhea) and unsolicited adverse events (AEs) were recorded for 8 days and 31 days, respectively, after each dose. Serious adverse events (SAEs) including intussusception and death were collected throughout the entire study periods. Potential imbalances were defined as the 95% confidence interval (CI) for the relative risk (RR) stratified by trials excluding "1."

Results: Solicited AEs were evaluated in 3286 RIX4414 vaccinees and 2015 placebo recipients. Among solicited AEs, no imbalance was noted between groups. SAEs, including death and intussusception, were evaluated in 36755 RIX4414 and 34454 placebo recipients. Within 31 days after each dose, no imbalances were noted between the groups for all SAEs (RR = 0.9; 95% CI: 0.81, 1.01), deaths (RR = 1.64; 95% CI: 0.92, 3.02), and intussusception (RR 1.23; 95% CI: 0.41, 3.90). SAEs because of gastrointestinal diseases including diarrhea, gastroenteritis (all cause and due to rotavirus), dehydration, and intestinal ileus occurred significantly less often in RIX4414 than placebo recipients.

Conclusions: Across the phase II and III clinical trials, the reactogenicity and safety profile between RIX4414 and placebo was similar, in particular with no increased risk of intussusception.
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http://dx.doi.org/10.1097/INF.0b013e31819715faDOI Listing
March 2009

Immunogenicity and safety of a combination diphtheria, tetanus toxoid, acellular pertussis, hepatitis B, and inactivated poliovirus vaccine coadministered with a 7-valent pneumococcal conjugate vaccine and a Haemophilus influenzae type b conjugate vaccine.

J Pediatr 2007 Jul;151(1):43-9, 49.e1-2

University of Rochester Medical Center, Rochester, New York 14642, USA.

Objective: To evaluate the immunogenicity and safety of a diphtheria and tetanus toxoids, acellular pertussis, hepatitis B, and inactivated poliovirus-containing vaccine (DTaP-HepB-IPV) coadministered with pneumococcal 7-valent conjugate vaccine (PCV-7) and Haemophilus influenzae type b vaccine (Hib), with separate vaccines concurrently, or staggered (delayed) administration of PCV-7.

Study Design: At 2, 4, and 6 months of age, infants received either DTaP-HepB-IPV plus PCV-7 and Hib (n = 199), separate vaccines (n = 188), or DTaP-HepB-IPV plus Hib with PCV-7 administered 2 weeks later (n = 188). Blood was drawn before and after vaccination. Parents reported symptoms for 4 days after each dose and adverse events throughout the entire study.

Results: Immunogenicity in the Combination Vaccine Group was noninferior to that of the Separate and Staggered Vaccine Groups with respect to seroprotective rates for diphtheria, tetanus, and poliovirus and to geometric mean concentrations for pertussis. Seroprotective rates for HepB and Hib were not different between groups. Seropositivity for PCV-7 was high in all groups. Administration of combination vaccine appeared to be associated with higher rates of irritability, fever > or = 100.4 degrees F (38.0 degrees C) and some local symptoms compared with separate vaccines (exploratory P < .05). No group differences were observed in rates of symptoms for which parents sought medical advice.

Conclusions: DTaP-HepB-IPV was highly immunogenic and well tolerated when coadministered with Hib and PCV-7 at 2, 4, and 6 months of age.
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http://dx.doi.org/10.1016/j.jpeds.2007.02.013DOI Listing
July 2007

Safety of a combination diphtheria, tetanus toxoid, acellular pertussis, hepatitis B, and inactivated polio vaccine coadministered with a 7-valent pneumococcal conjugate vaccine and a Haemophilus influenzae type b conjugate vaccine.

Vaccine 2007 Feb 21;25(10):1806-13. Epub 2006 Nov 21.

UCLA School of Medicine, 1124 W Carson Street, LIU Research Bldg, Torrance, CA 90502, USA.

The safety of DTaP-HepB-IPV vaccine coadministered with PCV and Hib was compared with separate administration of DTaP, HepB, IPV, Hib, and PCV at 2, 4, and 6 months of age. Healthy 2-month-old infants (N=1008) were randomized to the two groups. Following dose 1, there was no significant difference between the groups in the incidence of fever >101.3 degrees F. After each dose, the incidence of any fever (> or =100.4 degrees F) was significantly higher in the Combination Vaccine Group. The rate of fever >103.1 degrees F was < or =1.4% in both groups after any of the doses. Medical advice visits for fever were infrequent in both groups (< or =1.2%). DTaP-HepB-IPV was safe and well tolerated when coadministered with PCV and Hib.
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http://dx.doi.org/10.1016/j.vaccine.2006.11.008DOI Listing
February 2007

Safety and efficacy of an attenuated vaccine against severe rotavirus gastroenteritis.

N Engl J Med 2006 Jan;354(1):11-22

Instituto Nacional de Ciencas Medicas y Nutricion, México Distrito Federal, Mexico.

Background: The safety and efficacy of an attenuated G1P[8] human rotavirus (HRV) vaccine were tested in a randomized, double-blind, phase 3 trial.

Methods: We studied 63,225 healthy infants from 11 Latin American countries and Finland who received two oral doses of either the HRV vaccine (31,673 infants) or placebo (31,552 infants) at approximately two months and four months of age. Severe gastroenteritis episodes were identified by active surveillance. The severity of disease was graded with the use of the 20-point Vesikari scale. Vaccine efficacy was evaluated in a subgroup of 20,169 infants (10,159 vaccinees and 10,010 placebo recipients).

Results: The efficacy of the vaccine against severe rotavirus gastroenteritis and against rotavirus-associated hospitalization was 85 percent (P<0.001 for the comparison with placebo) and reached 100 percent against more severe rotavirus gastroenteritis. Hospitalization for diarrhea of any cause was reduced by 42 percent (95 percent confidence interval, 29 to 53 percent; P<0.001). During the 31-day window after each dose, six vaccine recipients and seven placebo recipients had definite intussusception (difference in risk, -0.32 per 10,000 infants; 95 percent confidence interval, -2.91 to 2.18; P=0.78).

Conclusions: Two oral doses of the live attenuated G1P[8] HRV vaccine were highly efficacious in protecting infants against severe rotavirus gastroenteritis, significantly reduced the rate of severe gastroenteritis from any cause, and were not associated with an increased risk of intussusception. (ClinicalTrials.gov numbers, NCT00139347 and NCT00263666.)
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http://dx.doi.org/10.1056/NEJMoa052434DOI Listing
January 2006

Anti-diphtheria antibody seroprotection rates are similar 10 years after vaccination with dTpa or DTPa using a mathematical model.

Vaccine 2004 Dec;23(3):336-42

GlaxoSmithKline Biologicals, Rue de l'Institut 89, B-1330 Rixensart, Belgium.

The reduced antigen content diphtheria, tetanus and pertussis (dTpa) vaccine (Boostrixtrade mark) has been shown to induce a strong booster response to all the vaccine components in 4-6 year olds. However, anti-diphtheria antibody levels were observed to be lower when compared to the "full strength" paediatric DTPa vaccine. To assess the impact of this difference on long-term protection, a mathematical model was developed to predict diphtheria antibody decay over time. The model was based on a linear decrease in log-transformed antibody concentrations after the first year post-vaccination. When applied to data collected 3.5 years after vaccination of 4-6 year olds with either DTPa or dTpa, the model predicted that 10 years post-vaccination, 98.6% of subjects vaccinated with dTpa were likely to remain seroprotected against diphtheria, compared to 99.6% vaccinated with DTPa. Therefore, the difference observed in diphtheria antibody geometric mean concentrations 1 month after booster vaccination at 4-6 years with dTpa or DTPa is unlikely to be of clinical relevance 10 years later at the time of the adolescent booster.
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http://dx.doi.org/10.1016/j.vaccine.2004.06.012DOI Listing
December 2004

Statistical approaches to establishing vaccine safety.

Stat Med 2002 Mar;21(6):877-93

Research Statistics Unit, Biomedical Data Sciences, GlaxoSmithKline, 1250 S. Collegeville Road, Collegeville, PA 19426-0989, U.S.A.

In a vaccine safety trial, the primary interest is to demonstrate that the vaccine is sufficiently safe, rejecting the null hypothesis that the relative risk of an adverse event attributable to the new vaccine is above a prespecified value, greater than one. We evaluate the exact probability of type I error of the likelihood score test, with sample size determined by normal approximation, by enumeration of the binomial outcomes in the rejection region and show that it exceeds the nominal level. In the case of rare adverse events, we recommend the Poisson approximation as an alternative and develop the corresponding conditional and unconditional tests. We give sample size and power calculations for these tests. We also propose optimal randomization strategies which either (i) minimize the total number of adverse cases or (ii) minimize the expected number of subjects when the vaccine is unsafe. We illustrate the proposed methods using a hypothetical vaccine safety study.
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http://dx.doi.org/10.1002/sim.1039DOI Listing
March 2002