Oral treatment for mucopolysaccharidosis VI: Outcomes of the first phase IIa study with odiparcil.

Mucopolysaccharidosis (MPS) disorders are a group of rare, progressive lysosomal storage diseases characterized by the accumulation of glycosaminoglycans (GAGs) and classified according to the deficient enzyme. Enzyme replacement therapy (ERT) of MPS VI has limited effects on ophthalmic, cardiovascular, and skeletal systems. Odiparcil is an orally available small molecule that results in the synthesis of odiparcil-linked GAGs facilitating their excretion and reducing cellular and tissue GAG accumulation. Improve MPS treatment was a Phase 2a study of the safety, pharmacokinetics/pharmacodynamics, and efficacy of two doses of odiparcil in patients with MPS VI. The core study was a 26-week, randomized, double-blind, placebo-controlled trial in patients receiving ERT and an open-label, noncomparative, single-dose cohort not receiving ERT. Patients aged ≥ 16 years receiving ERT were randomized to odiparcil 250 or 500 mg twice daily or placebo. Patients without ERT received odiparcil 500 mg twice daily. Of 20 patients enrolled, 13 (65.0%) completed the study. Odiparcil increased total urine GAGs (uGAGs), chondroitin sulfate, and dermatan sulfate concentrations. A linear increase in uGAG levels and odiparcil exposure occurred with increased odiparcil dose. Odiparcil demonstrated a good safety and tolerability profile. Individual analyses found more improvements in pain, corneal clouding, cardiac, vascular, and respiratory functions in the odiparcil groups vs placebo. This study confirmed the mechanism of action and established the safety of odiparcil with clinical beneficial effects after only a short treatment duration in an advanced stage of disease. Further assessment of odiparcil in younger patients is needed.

Persistence of Immune Responses Through 36 Months in Healthy Adults After Vaccination With a Novel Staphylococcus aureus 4-Antigen Vaccine (SA4Ag).

BACKGROUND: Staphylococcus aureus causes serious health care- and community-associated disease, requiring improved preventive measures such as vaccines. The investigational S. aureus 4-antigen vaccine (SA4Ag), comprising capsular polysaccharide serotypes 5 and 8 (CP5 and CP8) conjugated to CRM197, recombinant mutant clumping factor A (rmClfA), and recombinant manganese transporter protein C (rP305A or rMntC), was well tolerated, inducing robust functional immune responses to all 4 antigens through 12 months postvaccination. This is a serological extension study through 36 months postvaccination. METHODS: In 2 previous studies, healthy adults received SA4Ag, SA3Ag (without rMntC), or placebo; serology was also assessed at ~24 and ~36 months postvaccination. Functional immune responses (antibody responses that facilitate killing of S. aureus or neutralize S. aureus virulence mechanisms) were assessed with opsonophagocytic activity killing assays (CP5 or CP8) and a fibrinogen-binding inhibition assay (ClfA). A competitive Luminex immunoassay assessed ClfA and rMntC responses. Adverse events within 48 hours of blood draw were recorded. RESULTS: Four hundred forty subjects (18-64 years old, 255; 65-85 years old, 185) were enrolled. At 24 and 36 months postvaccination, subjects receiving SA4Ag had substantially higher geometric mean titers (GMTs) for CP5, CP8, and ClfA vs baseline; geometric mean fold rises (GMFRs) from baseline to month 36 were 2.7-8.1. For rMntC, 36-month GMTs declined from peak levels but remained above baseline for all SA4Ag groups; GMFRs from baseline to month 36 were 1.8 and 1.5 in the younger and older cohorts, respectively. CONCLUSIONS: Persistent functional immune responses to S. aureus antigens were observed through 36 months in healthy adults. CLINICALTRIALSGOV: NCT01643941 and NCT01364571.

Immunogenicity and safety of intramuscular versus subcutaneous administration of a combined measles, mumps, rubella, and varicella vaccine to children 12 to 18 months of age.

This randomized trial conducted in France compared intramuscular (IM) and subcutaneous (SC) administration of two doses of a measles, mumps, rubella, and varicella (MMRV) combination vaccine (ProQuad®) administered one month apart to 405 children 12-18 months of age (NCT00402831). The 2-dose regimen of MMRV administered IM was shown to be as immunogenic as the 2-dose regimen administered SC for all antigens 6 weeks post-vaccination for the subjects who were initially seronegative for measles, mumps, rubella, or varicella (lower bounds of the two-sided 95% CIs for the difference in response rates for all antigens greater than -10% [range -2.1 for varicella to -3.0 for mumps]). The antibody response rates for all vaccine antigens 6 weeks after the second dose of MMRV were > 99% in both the IM and SC groups. Fewer subjects in the IM group experienced injection-site AEs compared with the SC group (17.8% and 28.6% post-dose 1, and 20.4% and 29.5% post-dose 2, respectively). From Day 0 to Day 4 post-dose 2, fewer subjects reported erythema and swelling in the IM group than in the SC group (15.4% and 27.0%, and 6.0% and 12.5%, respectively). In both groups, most injection-site AEs started during the first four days after vaccination; their intensity was mainly mild or ≤2.5 cm. The rates of fever were comparable between the two groups after each dose of MMRV. In conclusion, two doses of the MMRV vaccine were highly immunogenic and well tolerated when administered either SC or IM. ClinicalTrials.gov Identifier: NCT00402831.

Immunogenicity and safety of a second administration of 13-valent pneumococcal conjugate vaccine 5 years after initial vaccination in adults 50 years and older.

BACKGROUND: Vaccination effectively reduces invasive disease and pneumonia caused by Streptococcus pneumoniae. However, waning antibody titers and the ability of revaccination to boost titers in older adults have been concerns. A study to describe antibody persistence after vaccination with 13-valent pneumococcal conjugate vaccine (PCV13) and response to revaccination 5 years after the initial dose was conducted. METHODS: Pneumococcal vaccine-naive subjects aged 50-59 years were randomized and vaccinated with PCV13 plus trivalent inactivated influenza vaccine concomitantly or 1 month apart, then revaccinated with PCV13 five years later. Antipneumococcal polysaccharide opsonophagocytic activity (OPA) geometric mean titers (GMTs) and immunoglobulin G (IgG) geometric mean concentrations (GMCs) were determined before and approximately 1 month after each vaccination. Targeted local reactions and systemic events were collected for 14 days, adverse events (AEs) for 1 month, and serious AEs (SAEs) for 6 months after each vaccination. RESULTS: Of 1116 randomized subjects, 727 were revaccinated at year 5. Between the time of initial vaccination and revaccination, OPA GMTs and IgG GMCs declined but remained higher than levels before initial vaccination for 12 of the 13 vaccine serotypes. One month after revaccination, OPA GMTs and IgG GMCs were comparable with, or higher than, levels observed 1 month after initial vaccination for most vaccine serotypes. Local reactions were mostly mild. AEs were reported by <5% and SAEs by <1% of subjects at 1 and 6 months after revaccination, respectively. No SAEs were vaccine-related. CONCLUSIONS: Revaccination of adults ≥50 years with PCV13 five years after primary vaccination was safe and immunogenic. Additionally, antibody titers were maintained for at least 5 years after vaccination. The vaccine stimulated a memory response as shown by enhanced responses that were maintained or enhanced by revaccination. CLINICALTRIALS. GOV REGISTRATION: NCT00521586.

13-valent pneumococcal conjugate vaccine (PCV13) is immunogenic and safe in children 6-17 years of age with sickle cell disease previously vaccinated with 23-valent pneumococcal polysaccharide vaccine (PPSV23): Results of a phase 3 study.

BACKGROUND: A large population of older children with sickle cell disease (SCD) is currently vaccinated with only 23-valent pneumococcal polysaccharide vaccine (PPSV23). In immunocompetent adults, PPSV23 vaccination reduces immune responses to subsequent vaccination with a pneumococcal vaccine. The 13-valent pneumococcal conjugate vaccine (PCV13), which addresses this limitation, may offer an advantage to this population at high risk of pneumococcal disease. PROCEDURE: Children with SCD 6-17 years of age previously vaccinated with PPSV23 at least 6 months before study enrollment received two doses of PCV13 6 months apart. Anti-pneumococcal polysaccharide immunoglobulin G (IgG) geometric mean concentrations (GMCs) and opsonophagocytic activity (OPA) geometric mean titers (GMTs) were measured before, 1 month after each administration, and 1 year after the second administration. RESULTS: Following each PCV13 administration, IgG GMCs and OPA GMTs significantly increased, and antibody levels after doses 1 and 2 were generally comparable. Antibody levels declined over the year following dose 2. At 1 year after the second administration, OPA GMTs for all and IgG GMCs for most serotypes remained above pre-vaccination levels. Most adverse events were due to vaso-occlusive crises, a characteristic of the underlying condition of SCD. CONCLUSIONS: Children with SCD who were previously vaccinated with PPSV23 responded well to 1 PCV13 dose, and a second dose did not increase antibody response. PCV13 antibodies persisted above pre-vaccination levels for all serotypes 1 year after dose 2. Children with SCD may benefit from at least one dose of PCV13.

Immunogenicity and safety of a live attenuated shingles (herpes zoster) vaccine (Zostavax®) in individuals aged ≥ 70 years: a randomized study of a single dose vs. two different two-dose schedules.

Disease protection provided by herpes zoster (HZ) vaccination tends to reduce as age increases. This study was designed to ascertain whether a second dose of the HZ vaccine, Zostavax(®), would increase varicella zoster virus (VZV)-specific immune response among individuals aged ≥ 70 y. Individuals aged ≥ 70 y were randomized to receive HZ vaccine in one of three schedules: a single dose (0.65 mL), two doses at 0 and 1 mo, or two doses at 0 and 3 mo. VZV antibody titers were measured at baseline, 4 weeks after each vaccine dose, and 12 mo after the last dose. In total, 759 participants (mean age 76.1 y) were randomized to receive vaccination. Antibody responses were similar after a single dose or two doses of HZ vaccine [post-dose 2/post-dose 1 geometric mean titer (GMT) ratios for the 1-mo or 3-mo schedules were 1.11, 95% confidence interval (CI) 1.02-1.22 and 0.78, 95% CI 0.73-0.85], respectively). The 12-mo post-dose 2/12-mo post-dose 1 GMT ratio was similar for the 1-mo schedule and for the 3-mo schedule (1.06, 95% CI 0.96-1.17 and 1.08, 95% CI 0.98-1.19, respectively). Similar immune responses were observed in participants aged 70-79 y and those aged ≥ 80 y. HZ vaccine was generally well tolerated, with no evidence of increased adverse event incidence after the second dose with either schedule. Compared with a single-dose regimen, two-dose vaccination did not increase VZV antibody responses among individuals aged ≥ 70 y. Antibody persistence after 12 mo was similar with all three schedules.

Challenge with a hepatitis B vaccine in two cohorts of 4-7-year-old children primed with hexavalent vaccines: an open-label, randomised trial in Italy.

BACKGROUND AND AIMS: The anamnestic response to a challenge dose of vaccine can assess immune memory and protection against hepatitis B infection. This study investigated responses to a challenge dose of monovalent hepatitis B vaccine in children immunised with three doses of either Hexavac or Infanrix-Hexa during infancy. METHODS: This open-label, randomised, controlled, four-arm study enrolled 410 healthy children aged 4-7 years who had received either Hexavac (n=201) or Infanrix-Hexa (n=209) at 3, 5 and 11 months of life. Children received a single intramuscular challenge dose of either hepatitis B vaccine, HBVaxPro (Hexavac, n=34; Infanrix-Hexa, n=28) or Engerix-B (Hexavac, n=167; Infanrix-Hexa, n=181). Hepatitis B surface antibody (anti-HBs) concentrations were measured before and 1 month after the challenge vaccine dose. The analysis was descriptive and no formal hypothesis was tested. RESULTS: One month post-challenge, 91.2% of children in the Hexavac group (95% confidence interval [CI] 86.3, 94.8) and 98.0% (95% CI 94.9, 99.4) in the Infanrix-Hexa group had anti-HBs concentrations ≥10 mIU/ml (primary endpoint). In a post hoc analysis, most children with pre-challenge anti-HBs concentration <10 mIU/ml achieved anti-HBs concentrations ≥10 mIU/ml (Hexavac group, 85.3% [95% CI 77.6, 91.2]; Infanrix-Hexa group, 91.9% [95% CI 78.1, 98.3]). Both challenge vaccines were well tolerated. CONCLUSIONS: These data suggest that immune memory persists for long-term (5 years) after a primary vaccination in infancy with a hexavalent vaccine (Hexavac or Infanrix-Hexa).

Safety of a 2-dose regimen of a combined measles, mumps, rubella and varicella live vaccine manufactured with recombinant human albumin.

BACKGROUND: ProQuad, a vaccine containing antigens from M-M-RVAXPRO (measles, mumps and rubella vaccine) and VARIVAX (varicella vaccine), is indicated for simultaneous vaccination against measles, mumps, rubella and varicella (MMRV) in individuals from 12 months of age. To eliminate blood-derived products of human origin from the manufacturing process of the MMRV vaccine, recombinant human albumin was selected as a replacement for human serum albumin. METHODS: This open-label, multicenter clinical trial (clinicaltrials.gov identifier NCT00560755) was designed to describe the safety profile of a 2-dose schedule of the MMRV vaccine at a 1-month interval in healthy children aged 12-22 months. RESULTS: In total, 3388 children received at least 1 dose of the MMRV vaccine. Overall, 3376 (99.65%) children were included in the post-dose 1 safety analysis and 3342 (98.64%) in the post-dose 2 safety analysis. After doses 1 and 2, the frequencies of children experiencing solicited injection-site reactions (post-dose 1: erythema 14.31%; swelling 5.57% and pain 10.31%; post-dose 2: erythema 30.46%; swelling 13.23% and pain 11.49%), rashes of interest (post-dose 1: 11.4%; post-dose 2: 2.78%), vaccine-related nonserious systemic adverse events (post-dose 1: 34.86%; post-dose 2: 13.4%) and temperature ≥39.4 °C (post-dose 1: 25.24%; post-dose 2: 12.06%) were consistent with those observed in previous studies of the MMRV vaccine manufactured with human serum albumin. Neither serious allergic-type adverse events nor anaphylactic reactions were reported. CONCLUSION: The results confirm the good safety profiles of MMRV and of measles, mumps and rubella vaccines manufactured with recombinant human albumin.

Immunogenicity and safety of a two-dose regimen of a combined measles, mumps, rubella and varicella live vaccine (ProQuad(®)) in infants from 9 months of age.

Vaccination against measles, mumps, rubella and varicella (MMRV) is currently recommended in developed countries for infants from 12 months of age. However, measles vaccination at 9 months of age is recommended by the WHO in the Expanded Program on Immunization (EPI) schedule and it is therefore possible that MMR or MMRV vaccines might also be given at this age. This open-label, randomised, comparative study evaluated the immunogenicity and safety of a 2-dose schedule of ProQuad(®) (MMRV vaccine) given at a 3-month interval in healthy infants aged ≥9 months. For measles, the non-inferiority of the response rate post-Dose 2 was reached when Dose 1 was administered at 11 months (98%) compared with 12 months (99%) but was not reached when Dose 1 was administered at 9 months (95%). The response rate to measles post-Dose 1 increased with age, from 73% to 88% and 90% at 9, 11 and 12 months, respectively. For mumps, rubella and varicella, response rates were not different after Dose 1 (>95%) or Dose 2 (>99%) regardless of whether Dose 1 was administered at 9, 11 or 12 months of age. In conclusion, the age of administration of the first of a two-dose regimen of ProQuad may be lowered to 11 months. Dose 1 may be administered at 9 months if early protection is required, but it should be recognised that a second dose is required promptly with a minimum of 3-month interval between doses.

Immunogenicity and safety of ZOSTAVAX(®) approaching expiry potency in individuals aged ≥50 years.

BACKGROUND: Age is a major risk factor for herpes zoster (HZ) and its potential long-term complication post-herpetic neuralgia (PHN). Due to the significant burden of HZ and PHN on patients' quality of life, it is vital that effective and well-tolerated vaccines are available to prevent HZ in older adults. ZOSTAVAX(®) vaccine was developed to prevent HZ and PHN in individuals ≥50 years (y) of age, and its clinical efficacy and safety have been demonstrated. AIMS AND METHODS: This phase 4, open-label, multicenter study was undertaken to assess the immunogenicity and safety of a single dose of ZOSTAVAX (refrigerator-stable formulation) given within 6 mo of its expiry date in individuals ≥50 y of age. The geometric mean fold rise (GMFR) from pre-vaccination to 4 weeks post-vaccination in varicella zoster virus (VZV) antibody titers was calculated. An acceptable antibody response was defined as a lower 95% confidence interval (CI) of GMFR > 1.4. Solicited and unsolicited injection-site reactions and systemic adverse events were recorded. RESULTS: The GMFR in VZV antibody titers was 3.1 (95% CI: 2.6, 3.8), satisfying the criterion for an acceptable VZV antibody response to ZOSTAVAX (minimum requirement: 1.4 GMFR). An acceptable rise in VZV antibody titers was observed in individuals of 50-59 y of age (GMFR 3.9; 95% CI: 2.9, 5.1) and in those ≥60 y of age (GMFR 2.5; 95% CI: 1.9, 3.2). ZOSTAVAX was well tolerated; no serious adverse events were reported. CONCLUSION: ZOSTAVAX elicits an acceptable immune response in immunocompetent individuals ≥50 y of age when stored as directed and administered during the 6 mo prior to expiration.

Immunogenicity and safety of combined adsorbed low-dose diphtheria, tetanus and inactivated poliovirus vaccine (REVAXIS (®)) versus combined diphtheria, tetanus and inactivated poliovirus vaccine (DT Polio (®)) given as a booster dose at 6 years of age.

This randomized, comparative, phase-IIIb study conducted in France aimed to demonstrate whether seroprotection against diphtheria, tetanus and poliomyelitis 1 month after a single dose of REVAXIS (low-dose diphtheria) is non-inferior to seroprotection 1 month after a single dose of DT Polio (standard-dose diphtheria), both vaccines being given as a second booster to healthy children at 6 years of age. Children were randomly assigned to receive a single intramuscular dose of REVAXIS or DT Polio. Primary endpoints were the 1-month post-booster seroprotection rates for diphtheria, tetanus and poliovirus type-1, -2 and -3 antigens. Secondary endpoints were immunogenicity and safety observations. Of 788 children screened, 760 were randomized: REVAXIS group, 384 children; DT Polio group, 376 children. No relevant difference in demographic characteristics at baseline was observed between REVAXIS and DT Polio groups. Non-inferiority of REVAXIS compared with DT Polio for seroprotection was demonstrated against diphtheria (respectively 98.6% and 99.3%), tetanus (respectively 99.6% and 100%), and poliovirus antigens (100% for each types in both groups). No allergic reactions to REVAXIS were reported. A benefit/risk ratio in favor of REVAXIS was suggested by the trend towards a better tolerability of REVAXIS compared with DT Polio regarding the rate of severe solicited injection-site reactions. The results support the use of REVAXIS as a booster at 6 years of age in infants who previously received a three-dose primary series within the first 6 months of life and a first booster including diphtheria, tetanus and poliovirus vaccine(s) given before 2 years of age.

Results from a randomized clinical trial of coadministration of RotaTeq, a pentavalent rotavirus vaccine, and NeisVac-C, a meningococcal serogroup C conjugate vaccine.

RotaTeq (Merck & Co. Inc./Sanofi Pasteur MSD) is a three-dose, oral pentavalent rotavirus vaccine for the immunization of infants from 6 weeks of age for the prevention of rotavirus gastroenteritis. The primary objective of the present trial was to demonstrate that RotaTeq can be coadministered with meningococcal serogroup C conjugate vaccine (MenCC; NeisVac-C; Baxter Healthcare) to healthy infants without impairing the protective immune responses to MenCC. This was an open-label, randomized, comparative study conducted in Finland. The study was designed to assess concomitant versus sequential administration of RotaTeq and MenCC on the immune response to both vaccines. Healthy infants (n = 247), aged 6 to 7 weeks, were recruited. Coadministration of MenCC with RotaTeq was noninferior to sequential administration for the seroprotection rate against meningococcal serogroup C (the proportion of infants with a serum bactericidal antibody titer using baby rabbit complement of ≥ 8 was 100% in both groups). The other responses to MenCC (titer of ≥ 1:128, ≥ 4-fold increase in titer, and geometric mean titers [GMTs]) and the responses to RotaTeq (IgA and SNA response to G1 to G4 and P1A[8], GMTs, and ≥ 3-fold increase in titer) were comparable between groups, including a ≥ 3-fold IgA increase in >96% of the infants in both groups. Concomitant administration of the first doses of MenCC, diphtheria and tetanus toxoids and acellular pertussis vaccine, inactivated poliovirus vaccine, and Haemophilus influenzae type b conjugate vaccine (DTaP-IPV-Hib), and RotaTeq was associated with a higher rate of vomiting and diarrhea than concomitant administration of MenCC and DTaP-IPV-Hib, but that was not observed after the second concomitant administration. The convenience of concomitant administration of RotaTeq and MenCC may, however, outweigh the additive effect of mostly mild adverse events reported after the individual administration of each vaccine. These results support the coadministration of RotaTeq and MenCC.

Evaluation of non-inferiority of intradermal versus adjuvanted seasonal influenza vaccine using two serological techniques: a randomised comparative study.

BACKGROUND: Although seasonal influenza vaccine is effective in the elderly, immune responses to vaccination are lower in the elderly than in younger adults. Strategies to optimise responses to vaccination in the elderly include using an adjuvanted vaccine or using an intradermal vaccination route. The immunogenicity of an intradermal seasonal influenza vaccine was compared with that of an adjuvanted vaccine in the elderly. METHODS: Elderly volunteers (age > or = 65 years) were randomised to receive a single dose of trivalent seasonal influenza vaccine: either a split-virion vaccine containing 15 microg haemagglutinin [HA]/strain/0.1-ml dose administered intradermally, or a subunit vaccine (15 microg HA/strain/0.5-ml dose) adjuvanted with MF59C.1 and administered intramuscularly. Blood samples were taken before and 21 +/- 3 days post-vaccination. Anti-HA antibody titres were assessed using haemagglutination inhibition (HI) and single radial haemolysis (SRH) methods. We aimed to show that the intradermal vaccine was non-inferior to the adjuvanted vaccine. RESULTS: A total of 795 participants were enrolled (intradermal vaccine n = 398; adjuvanted vaccine n = 397). Non-inferiority of the intradermal vaccine was demonstrated for the A/H1N1 and B strains, but not for the A/H3N2 strain (upper bound of the 95% CI = 1.53) using the HI method, and for all three strains by the SRH method. A post-hoc analysis of covariance to adjust for baseline antibody titres demonstrated the non-inferiority of the intradermal vaccine by HI and SRH methods for all three strains. Both vaccines were, in general, well tolerated; the incidence of injection-site reactions was higher for the intradermal (70.1%) than the adjuvanted vaccine (33.8%) but these reactions were mild and of short duration. CONCLUSIONS: The immunogenicity and safety of the intradermal seasonal influenza vaccine in the elderly was comparable with that of the adjuvanted vaccine. Intradermal vaccination to target the immune properties of the skin appears to be an appropriate strategy to address the challenge of declining immune responses in the elderly. TRIAL REGISTRATION: ClinicalTrials.gov: NCT00554333.

Antibody persistence in UK pre-school children following primary series with an acellular pertussis-containing pentavalent vaccine given concomitantly with meningococcal group C conjugate vaccine, and response to a booster dose of an acellular pertussis-containing quadrivalent vaccine.

This open-label, randomised, controlled study examined antibody persistence following infant vaccination at 2, 3 and 4 months of age with either an acellular pertussis, diphtheria, tetanus, inactivated poliovirus, Haemophilus influenzae type b (DT(5)aP-IPV-Hib; Pediacel) or a whole-cell pertussis (DTwP//Hib+oral poliomyelitis vaccine [OPV]) combination vaccine, given concomitantly with meningococcal serogroup C conjugate (MCC) vaccine, followed by a Hib booster at approximately 15 months of age. Immune responses were sustained to 3.5-4.5 years of age for all antigens contained in Pediacel. Administration of an acellular pertussis-containing quadrivalent pre-school booster (Td(5)ap-IPV; Repevax), with or without measles, mumps and rubella (M-M-RII) vaccine, induced robust antibody responses indicative of protection, regardless of the vaccine used for the primary series. Reactogenicity of Repevax was acceptable and consistent with previous experience.

Immunogenicity and safety of PNEUMOVAX II manufactured by a new process in older adults.

In response to increased demand for the 23-valent pneumococcal vaccine PNEUMOVAX II, a new manufacturing process has been implemented that improves the consistency and increases the scale of production. This double-blind, randomized, clinical study compared the immunogenicity and safety profiles of the new-process PNEUMOVAX II (n = 111) formulated with all 23 new process polysaccharides to the former-process PNEUMOVAX II (n = 109) formulation in adults aged > or =50 years. The primary aim of the study was to compare the post-vaccination geometric mean of antibody titres (GMT) to pneumococcal serotypes 3 and 8 in recipients of new- and former-process PNEUMOVAX II. The post-vaccination GMTs for serotypes 3 and 8 elicited by the new-process PNEUMOVAX II [1.40 (95% confidence interval, 1.21-1.63) and 10.78 (95% CI, 9.10-12.77), respectively] were non-inferior to those elicited by the former-process PNEUMOVAX II [1.24 (95% CI, 1.07-1.43) and 9.72 (95% CI, 8.22-11.50), respectively]. Both PNEUMOVAX II formulations were well tolerated; there were no vaccine-related serious adverse events. A total of 74 (66.7%) subjects in the new-process group and 66 (60.6%) in the former-process group had at least one injection-site reaction or vaccine-related systemic event within 14 days following vaccination. There was a trend for higher incidence of two solicited injection-site reactions (erythmea and induration) and three solicited systemic events (asthenia, chills and body aches) with the new- versus former-process PNEUMOVAX II, but these were mainly of mild intensity and short duration. The new-process PNEUMOVAX(R II thus showed similar immunogenicity to the former-process vaccine for pneumococcal serotypes 3 and 8 and both vaccines were well tolerated in older subjects.

Immunogenicity and safety of concomitant administration of a measles, mumps and rubella vaccine (M-M-RvaxPro) and a varicella vaccine (VARIVAX) by intramuscular or subcutaneous routes at separate injection sites: a randomised clinical trial.

BACKGROUND: When this trial was initiated, the combined measles, mumps and rubella (MMR) vaccine was licensed for subcutaneous administration in all European countries and for intramuscular administration in some countries, whereas varicella vaccine was licensed only for subcutaneous administration. This study evaluated the intramuscular administration of an MMR vaccine (M-M-RvaxPro) and a varicella vaccine (VARIVAX) compared with the subcutaneous route. METHODS: An open-label randomised trial was performed in France and Germany. Healthy children, aged 12 to 18 months, received single injections of M-M-RvaxPro and VARIVAX concomitantly at separate injection sites. Both vaccines were administered either intramuscularly (IM group, n = 374) or subcutaneously (SC group, n = 378). Immunogenicity was assessed before vaccination and 42 days after vaccination. Injection-site erythema, swelling and pain were recorded from days 0 to 4 after vaccination. Body temperature was monitored daily between 0 and 42 days after vaccination. Other adverse events were recorded up to 42 days after vaccination and serious adverse events until the second study visit. RESULTS: Antibody response rates at day 42 in the per-protocol set of children initially seronegative to measles, mumps, rubella or varicella were similar between the IM and SC groups for all four antigens. Response rates were 94 to 96% for measles, 98% for both mumps and rubella and 86 to 88% for varicella. For children initially seronegative to varicella, 99% achieved the seroconversion threshold (antibody concentrations of >or= 1.25 gpELISA units/ml). Erythema and swelling were the most frequently reported injection-site reactions for both vaccines. Most injection-site reactions were of mild intensity or small size (

Safety of a refrigerator-stable varicella vaccine (VARIVAX) in healthy 12- to 15-month-old children: A randomized, double-blind, cross-over study.

The safety of a single injection of the refrigerator-stable formulation of varicella vaccine VARIVAX was assessed in a blind, randomized, cross-over trial. Five hundred seven healthy children aged 12 to 15 months received subcutaneous injections of VARIVAX on day 0 and the measles, mumps and rubella vaccine (M-M-R II) on day 42 or M-M-R II on day 0 and VARIVAX on day 42. To maintain blinding, injections were given by a study nurse not involved in safety assessments. M-M-R II acted as a reference to validate the safety assessment, as its safety profile is well known in this age range. Parents or legal guardians recorded adverse events for 42 days following each injection. Solicited injection-site reactions (erythema, swelling, pain) were recorded on days 0 to 4. Other injection-site reactions, daily temperature, rashes and systemic adverse events were recorded on days 0 to 42, and serious adverse events until the final study visit. The safety profile of M-M-R II was consistent with previous reports. Following VARIVAX administration, 47.7% of children had at least one vaccine-related adverse event. Solicited injection-site reactions were reported in 13.0% of children, and 17.2% had at least one other injection-site reaction between days 0 and 42. Most reactions were small (

Safety of Tdap-IPV given one month after Td-IPV booster in healthy young adults: a placebo-controlled trial.

BACKGROUND: In France, the only vaccines available for use as a pertussis booster in adults are combined vaccines containing adsorbed tetanus, diphtheria (adult formulation), acellular pertussis and inactivated poliovirus (Tdap-IPV). Adults may require a pertussis booster relatively soon after having received vaccines containing tetanus-diptheria antigens (Td) (occupational or familial circumstances such as new job, childbirth in recent past or future), although the safety of Tdap-IPV when administered soon after vaccination with Td is undocumented. METHODS: In this randomized, double-blind, multi-centre study, we assessed the safety of Tdap-IPV administered one month after vaccination with tetanus, diphtheria (adult formulation), inactivated poliovirus vaccination (Td-IPV) in healthy adults vaccinated according to the French vaccination calendar (seven tetanus-diphtheria vaccinations by age 18 years). Subjects received either Td-IPV (n = 249) or placebo (n = 251) followed 1 month later by Tdap-IPV. Any adverse events (AEs) were recorded. RESULTS: The safety of Tdap-IPV was similar when Tdap-IPV vaccine was administered one month after either Td-IPV or placebo: at seven days, 85.1% versus 93.4% subjects reported at least one reaction at the injection site, mainly pain (82.6% versus 92.1%); 40.5% versus 45.0%, at least one systemic AE (mainly headache: 26.4% versus 26.0%); fever concerned 1.7% of both groups. No serious vaccine-related AEs were reported. Both safety profiles corresponded to documented product characteristics. CONCLUSIONS: Tdap-IPV may be administered to adults one month after Td-IPV without exacerbating post-vaccination side-effects.

Fever as a marker of reactogenicity of an acellular pertussis-containing hexavalent vaccine (HEXAVAC) in a large-scale, open, randomized safety study in healthy French infants.

OBJECTIVE: New multivalent vaccines simplify childhood immunisation schedules and can increase vaccination coverage. However, they must have a reactogenicity profile which is acceptable and comparable with that of previously available vaccines. The objective of this trial was to assess the incidence of fever of 40.0 degrees C or higher following vaccination with HEXAVAC or concomitant PENTACOQ and HBVAXPRO. STUDY DESIGN: This was an open, randomized, pragmatic, post-licensure multicenter trial performed in France. Infants were randomly assigned to receive either a single injection of a hexavalent, aP-containing vaccine (HEXAVAC) or separate injections of a pentavalent, wP-containing vaccine (PENTACOQ) and Hepatitis B vaccine (HBVAXPRO) at 2, 3 and 4 months of age. Both groups received a HEXAVAC booster at 12-18 months of age. RESULTS AND DISCUSSION: 7151 infants were enrolled in 389 centers. During the combined three-day periods following the primary series injections, the incidence of fever of 40.0 degrees C or higher with HEXAVAC was not greater than with [PENTACOQ and HBVAXPRO]. The incidence of fever at thresholds of 38.0 degrees C, 38.5 degrees C, 39.0 degrees C and 39.5 degrees C was significantly lower in the HEXAVAC group. The vaccine attributable risk for fever of 40.0 degrees C following the booster injection with HEXAVAC was statistically acceptable. CONCLUSION: The incidence of fever of 40.0 degrees C or higher in this study was very low and similar in both groups (HEXAVAC or [PENTACOQ + HBVAXPRO] as a three-dose primary series). Fever > or =38.0 degrees C and < or =39.5 degrees C was significantly less frequent following administration of HEXAVAC. The incidence of fever of 40.0 degrees C or higher following a HEXAVAC booster dose was low in all infants studied.