Comparison of the immunogenicity and safety of Cervarix and Gardasil human papillomavirus (HPV) cervical cancer vaccines in healthy women aged 18-45 years.

This observer-blind study compared the prophylactic human papillomavirus (HPV) vaccines, Cervarix (GlaxoSmithKline) and Gardasil (Merck), by assessing immunogenicity and safety through one month after completion of the three-dose vaccination course. Women (n = 1106) were stratified by age (18-26, 27-35, 36-45 years) and randomized (1:1) to receive Cervarix (Months 0, 1, 6) or Gardasil (Months 0, 2, 6). At Month 7 after first vaccination, all women in the according-to-protocol cohort who were seronegative/DNA negative before vaccination for the HPV type analyzed had seroconverted for HPV-16 and HPV-18 serum neutralizing antibodies, as measured by pseudovirion-based neutralization assay (PBNA), except for two women aged 27-35 years in the Gardasil group who did not seroconvert for HPV-18 (98%). Geometric mean titers of serum neutralizing antibodies ranged from 2.3-4.8-fold higher for HPV-16 and 6.8-9.1-fold higher for HPV-18 after vaccination with Cervarix compared with Gardasil, across all age strata. In the total vaccinated cohort (all women who received at least one vaccine dose, regardless of their serological and DNA status prior to vaccination), Cervarix induced significantly higher serum neutralizing antibody titers in all age strata (p < 0.0001). Positivity rates for anti-HPV-16 and -18 neutralizing antibodies in cervicovaginal secretions and circulating HPV-16 and -18 specific memory B-cell frequencies were also higher after vaccination with Cervarix compared with Gardasil. Both vaccines were generally well tolerated. The incidence of unsolicited adverse events was comparable between vaccinated groups. The incidence of solicited symptoms was generally higher after Cervarix, injection site reactions being most common. However, compliance rates with the three-dose schedules were similarly high (>or= 84%) for both vaccines. Although the importance of differences in magnitude of immune response between these vaccines is unknown, they may represent determinants of duration of protection against HPV-16/18. Long-term studies evaluating duration of efficacy after vaccination are needed for both vaccines.

Immunogenicity and safety of an inactivated hepatitis a vaccine administered concomitantly with a pneumococcal conjugate vaccine in healthy children 15 months of age.

The immunogenicity and safety of hepatitis A vaccine and pneumococcal conjugate vaccine, administered separately or concomitantly in children 15 months of age, were evaluated. After completed vaccinations, antihepatitis A and antipneumococcal geometric mean concentrations were similar across groups. Both vaccines were well-tolerated when given concomitantly during the second year of life.

Rapid and sustained immune response against hepatitis A and B achieved with combined vaccine using an accelerated administration schedule.

BACKGROUND: Combined hepatitis A and B vaccine administered on an accelerated schedule provides a rapid immune response against both hepatitis A and B viruses, which might be especially relevant for individuals who need protection quickly. METHODS: A prospective, open-label, randomized study to compare the immunogenicity and reactogenicity of the combined hepatitis A and B vaccine Twinrix (GlaxoSmithKline Biologicals, Rixensart, Belgium) (>or=720 EL.U/mL inactivated hepatitis A antigen and 20 microg/mL recombinant hepatitis B surface antigen [HBsAg]) administered at 0, 7, 21 to 30 days, and 12 months compared with concurrent administration of Havrix [GlaxoSmithKline Biologicals, Rixensart, Belgium (>or=1440 EL.U/mL inactivated hepatitis A antigen)] at 0 and 12 months, and Engerix-B [GlaxoSmithKline Biologicals, Rixensart, Belgium (20 microg/mL recombinant HBsAg)] at 0, 1, 2, and 12 months in seronegative healthy adults. RESULTS: At month 13, the anti-hepatitis B seroprotection rates (>10 mIU/mL) for the combined vaccine compared to the monovalent hepatitis B vaccine were 96.4% (95% CI: 92.7-98.5) and 93.4% (95% CI: 89.0-96.4), respectively. The anti-hepatitis A seroconversion rates were 100% in both groups (95% CI: 98.1-100). At day 37, the anti-hepatitis A seroconversion rates were similar in both groups (98.5% for combined vaccine, 98.6% for the monovalent vaccine group), but the combined vaccine resulted in a statistically significantly ( p < 0.001) better anti-hepatitis B seroprotection compared to monovalent hepatitis B vaccine, 63.2% versus 43.5%, respectively. The reactogenicity profile was similar in both study groups. CONCLUSIONS: The combined hepatitis A and B vaccine administered on an accelerated schedule was at least as immunogenic and as well tolerated as the corresponding monovalent vaccines.

Prospective clinical trial of hepatitis B vaccination in adults with and without type-2 diabetes mellitus.

Objective: Patients with diabetes mellitus are at increased risk for hepatitis B virus (HBV) infection and its complications. HBV vaccination is recommended for adults with diabetes in the United States and other countries. However, few studies have assessed safety and immunogenicity of hepatitis B vaccine in such patients. We assessed the safety and immunogenicity of recombinant hepatitis B vaccine in subjects with and without diabetes mellitus. METHODS: Prospective, multi-country controlled study in 21 centers ( www.clinicaltrials.gov NCT01627340). Four hundred and sixteen participants with Type-2 diabetes and 258 controls matched for age and body mass index (BMI) (2:1 ratio) received 3-doses of HBV vaccine (Engerix-B™, GSK Vaccines, Belgium) according to a 0, 1, 6 months schedule. Antibodies were measured against HBV surface antigen and expressed as seroprotection rates (anti-HBs ≥10mIU/mL) and geometric mean concentration (GMC). RESULTS: The median age and BMI in patients with diabetes and controls (according-to-protocol cohort) were 54 y and 32.1 kg/m2, and 53 y and 30.8 kg/m2, respectively. Seroprotection rates (GMCs) one month post-dose-3 were 75.4% (147.6 mIU/mL) and 82.0% (384.2 mIU/mL) in patients with diabetes and controls, respectively. Age-stratified seroprotection rates for patients with diabetes were 88.5% (20-39 years), 81.2% (40-49 years), 83.2% (50-59 years), and 58.2% (≥60 years). The overall safety profile of hepatitis B vaccine was similar between groups. CONCLUSIONS: Hepatitis B vaccine is immunogenic in patients with diabetes and has a similar safety profile to vaccination in healthy controls. Because increasing age was generally associated with a reduction in seroprotection rates, hepatitis B vaccine should be administered as soon as possible after the diagnosis of diabetes.

Immunogenicity of AS03-adjuvanted and non-adjuvanted trivalent inactivated influenza vaccines in elderly adults: A Phase 3, randomized trial and post-hoc correlate of protection analysis.

In this study we describe the immunogenicity results from a subset of older people (N = 5187) who participated in a Phase 3 randomized, observer-blinded trial of AS03-TIV versus TIV (Fluarix™) (ClinicalTrials.gov, NCT00753272). Participants received one dose of AS03-TIV or TIV in each study year and antibody titers against the vaccine strains were assessed using hemagglutination-inhibition (HI) assay at 21 d and 180 d post-vaccination in each vaccine group in the 2008/09 (Year 1) and 2009/10 (Year 2) influenza seasons. Manufacturing consistency of 3 lots of AS03-TIV for HI antibody responses in Year 1 was a co-primary objective. In a post-hoc analysis, a statistical regression model included 4830 subjects in whom immunogenicity and laboratory-confirmed attack rate data were available; the analysis was performed to assess HI antibody titers against A/H3N2 as a correlate of protection for laboratory-confirmed A/H3N2 influenza. AS03-TIV and TIV elicited strong HI antibody responses against each vaccine strain 21 d post-vaccination in both years. The manufacturing consistency of 3 lots of AS03-TIV was demonstrated. In both years and each vaccine group, HI antibody responses were lower for A/H1N1 than the other vaccine strains. Day 180 seroconversion rates (proportion with ≥4-fold increase in titer compared with pre-vaccination titer) in Year 1 in the AS03-TIV and TIV groups, respectively, were 87.7% and 74.1% for A/H3N2, 69.7% and 59.6% for influenza B, and 58.3% and 47.4% for A/H1N1. The post-hoc statistical model based on A/H3N2 attack rates and HI antibody titers estimated that a 4-fold increase in post-vaccination titers against A/H3N2 was associated with a 2-fold decrease in the odds of A/H3N2 infection.

AS03-adjuvanted versus non-adjuvanted inactivated trivalent influenza vaccine against seasonal influenza in elderly people: a phase 3 randomised trial.

BACKGROUND: We aimed to compare AS03-adjuvanted inactivated trivalent influenza vaccine (TIV) with non-adjuvanted TIV for seasonal influenza prevention in elderly people. METHODS: We did a randomised trial in 15 countries worldwide during the 2008-09 (year 1) and 2009-10 (year 2) influenza seasons. Eligible participants aged at least 65 years who were not in hospital or bedridden and were without acute illness were randomly assigned (1:1) to receive either AS03-adjuvanted TIV or non-adjuvanted TIV. Randomisation was done in an internet-based system, with a blocking scheme and stratification by age (65-74 years and 75 years or older). Participants were scheduled to receive one vaccine in each year, and remained in the same group in years 1 and 2. Unmasked personnel prepared and gave the vaccines, but participants and individuals assessing any study endpoint were masked. The coprimary objectives were to assess the relative efficacy of the vaccines and lot-to-lot consistency of the AS03-adjuvanted TIV (to be reported elsewhere). For the first objective, the primary endpoint was relative efficacy of the vaccines for prevention of influenza A (excluding A H1N1 pdm09) or B, or both, that was confirmed by PCR analysis in year 1 (lower limit of two-sided 95% CI had to be greater than zero to establish superiority). From Nov 15, to April 30, in both years, participants were monitored by telephone or site contact and home visits every week or 2 weeks to identify cases of influenza-like illness. After onset of suspected cases, we obtained nasal and throat swabs to identify influenza RNA with real-time PCR. Efficacy analyses were done per protocol. This trial is registered with ClinicalTrials.gov, number NCT00753272. FINDINGS: We enrolled 43 802 participants, of whom 21 893 were assigned to and received the AS03-adjuvanted TIV and 21 802 the non-adjuvanted TIV in year 1. In the year 1 efficacy cohort, fewer participants given AS03-adjuvanted than non-adjuvanted TIV were infected with influenza A or B, or both (274 [1·27%, 95% CI 1·12-1·43] of 21 573 vs 310 [1·44%, 1·29-1·61] of 21 482; relative efficacy 12·11%, 95% CI -3·40 to 25·29; superiority not established). Fewer participants in the year 1 efficacy cohort given AS03-adjuvanted TIV than non-adjuvanted TIV were infected with influenza A (224 [1·04%, 95% CI 0·91-1·18] vs 270 [1·26, 1·11-1·41]; relative efficacy 17·53%, 95% CI 1·55-30·92) and influenza A H3N2 (170 [0·79, 0·67-0·92] vs 205 [0·95, 0·83-1·09]; post-hoc analysis relative efficacy 22·0%, 95% CI 5·68-35·49). INTERPRETATION: AS03-adjuvanted TIV has a higher efficacy for prevention of some subtypes of influenza than does a non-adjuvanted TIV. Future influenza vaccine studies in elderly people should be based on subtype or lineage-specific endpoints. FUNDING: GlaxoSmithKline Biologicals SA.

Immunogenicity and safety of an inactivated hepatitis A vaccine when coadministered with measles-mumps-rubella and varicella vaccines in children less than 2 years of age.

BACKGROUND: Hepatitis A vaccination in early childhood has reduced hepatitis A transmission. Coadministration of hepatitis A vaccine with other childhood vaccines may assist completion of the age-appropriate immunization schedule. We assessed the immunogenicity and safety of an inactivated hepatitis A virus vaccine when coadministered with measles-mumps-rubella (MMR) and varicella vaccines in children less than 2 years of age. METHODS: In this open-label, randomized, multicenter study, 3 groups of healthy children 15 months of age received either 2 doses of hepatitis A vaccine 6 to 9 months apart (n = 324), hepatitis A vaccine coadministered with MMR and varicella vaccines and a second dose of hepatitis A vaccine 6 to 9 months later (n = 462), or MMR and varicella vaccines followed 6 weeks later by 2 doses of hepatitis A vaccine 6 to 9 months apart (n = 455). Immune responses were evaluated at baseline, 31 days after the second dose of hepatitis A vaccine, and 42 days after MMR and varicella vaccine administration. Solicited, unsolicited, and serious adverse events were collected. RESULTS: After 2 doses of hepatitis A vaccine, nearly all subjects in all groups were seropositive (≥99%). Coadministration of hepatitis A vaccine with MMR and varicella vaccines did not impact the immunogenicity of any of the vaccines and was well tolerated. CONCLUSIONS: The immune response to hepatitis A vaccine and US-licensed MMR and varicella vaccines is not adversely affected when coadministered in children 15 months of age.

Immunogenicity and safety of an inactivated hepatitis A vaccine when coadministered with Diphtheria-tetanus-acellular pertussis and haemophilus influenzae type B vaccines in children 15 months of age.

BACKGROUND: This study (NCT00197236) evaluated the safety and immunogenicity of a hepatitis A virus (HAV) vaccine when coadministered with diphtheria-tetanus-acellular pertussis (DTaP) and Haemophilus influenzae type b (Hib) vaccines in children 15 months of age. METHODS: This was an open-labeled, multicenter study with healthy subjects enrolled and randomized (1:1:1) into 3 treatment groups. A total of 394 subjects received the first study vaccinations at 15 months of age. Group HAV (N = 135) received 2 doses of HAV vaccine 6 to 9 months apart. Group HAV+DTaP+Hib (N = 127) received HAV vaccine coadministered with DTaP and Hib vaccines and the second dose of HAV vaccine, 6 to 9 months later. Group DTaP+Hib→HAV (N = 132) received the DTaP and Hib vaccines at 15 months of age, followed by HAV vaccine 30 days later and the second dose of HAV vaccine 7 to 10 months after the DTaP+Hib vaccines. Immune responses were evaluated before the first study vaccination and 30 days after each vaccine dose. Solicited, unsolicited, and serious adverse events were collected. RESULTS: After 2 doses of the HAV vaccine, all subjects in the 3 groups were seropositive. The geometric mean concentration of anti-HAV antibodies ranged between 1625.1 and 1904.4 mIU/mL. Coadministration of the 3 vaccines did not impact immunogenicity of the HAV, DTaP, or Hib vaccines. Vaccines were well tolerated in all groups. CONCLUSIONS: A 2-dose schedule of HAV vaccine was well tolerated and immunogenic when administered to children starting at 15 months of age. Immune responses to the DTaP or Hib vaccines were similar whether they were administered alone or were coadministered with the HAV vaccine.

Immunogenicity and safety of an inactivated hepatitis A vaccine administered concomitantly with diphtheria-tetanus-acellular pertussis and haemophilus influenzae type B vaccines to children less than 2 years of age.

OBJECTIVE: The availability of a hepatitis A virus vaccine for infant and early childhood immunization could reduce the transmission of hepatitis A virus in the United States. This study evaluated the immunogenicity and safety of a hepatitis A virus vaccine (Havrix, GlaxoSmithKline Biologicals, Rixensart, Belgium) administered concomitantly with diphtheria-tetanus-acellular pertussis and Haemophilus influenzae type b vaccines to children < 2 years. METHODS: In this open, comparative, multicenter study, 1084 healthy children aged 11 to 25 months were allocated (4:4:3:3:4 ratio) to 5 treatment groups based on age and previous vaccination history. Subjects 11 to 13 months of age received 2 doses of hepatitis A virus vaccine 6 months apart (N = 243). Subjects aged 15 to 18 months received 2 doses of hepatitis A virus vaccine 6 months apart (N = 241); or hepatitis A virus vaccine, diphtheria-tetanus-acellular pertussis, and H influenzae type b at month 0 and the second dose of hepatitis A virus vaccine 6 months later (N = 183); or diphtheria-tetanus-acellular pertussis and H influenzae type b at month 0 and hepatitis A virus vaccine at months 1 and 7 (N = 175). Subjects 23 to 25 months of age received hepatitis A virus vaccine at months 0 and 6 (N = 242). Immune responses were measured at baseline and 30 days after vaccine doses, and solicited and unsolicited adverse events were collected. RESULTS: After 2 doses of hepatitis A virus vaccine, all of the subjects in all of the groups were seropositive. Coadministration of hepatitis A virus vaccine with diphtheria-tetanus-acellular pertussis and H influenzae type b vaccines did not impact the immunogenicity of the 3 vaccines, except for the antipertussis toxoid vaccine response, which was slightly decreased. Hepatitis A virus vaccine was well tolerated in children 11 to 25 months of age. CONCLUSION: The administration of 2 doses of hepatitis A virus vaccine on a 0- and 6-month schedule starting at 11 to 13 months of age or at 15 to 18 months of age was as immunogenic and well tolerated as the administration of 2 doses in children 2 years of age. Immune responses to diphtheria-tetanus-acellular pertussis and H influenzae type b either given alone or coadministered with hepatitis A virus vaccine were similar except for antipertussis toxoid response.