Age: 1.0
Sex: U
Vaccine: HEPA, MMRV, PNC
Symptoms: Febrile convulsion
Clinical narrative: It was reported in a published article, that this study compared the immunogenicity and assessed the reactogenicity of PRIORIX-TETRA kept under two storage conditions (refrigerated at 4 degrees C [GSK+4C] or frozen at -20 degrees C [GSK-20C] with PROQUAD (Merck) [Merck-20C], when each was co-administered with HAVRIX and PREVNAR. The two GSK MMRV formulations were evaluated to determine whether either or both could demonstrate non-inferiority of immune response compared to PROQUAD (Merck) which is freezer-stored. This phase 2, randomized, multicenter, observer-blind, parallel-group study was performed between November 2007 and March 2009 at 133 Centers. Eligible healthy male or female subjects were 12-14 months old and had received three PCV7 doses within the first year of life. Key exclusion criteria included: known exposure to, previous vaccination against, or history of measles, mumps, rubella or varicella zoster diseases; previous hepatitis A vaccination; administration of immunoglobulins, blood products or chronic immunomodulators more or equal to 6 months before study vaccination; administration of other vaccines (except influenza) less or equal to 30 days before study vaccination until Day 42; prior (less or equal to 30 days) or planned use of investigational products during the study; serious chronic illness or major congenital defects, immunosuppressive/immunodeficient conditions; history of allergic disease or reactions likely to be exacerbated by any component of the vaccines used in the study; neurologic disorders or seizures (except uncomplicated febrile convulsions); and acute disease at enrollment. Subjects were randomized 2:2:1 to receive one dose of [GSK-4C] or [GSK-20C] or [Merck-20C] on Day 0. All subjects concomitantly received a single dose of PCV7 and HAV. The study consisted of three scheduled visits at Day 0, Day 42, and Day 180, with blood samples collected on Day 0 (pre-immunization) and Day 42 for antibody determination. GSK+4C, GSK-20C or Merck-20C were injected subcutaneously into the right upper arm. HAV and PCV7 were administered by intramuscular injection into the left and right thighs, respectively. A second HAV dose was administered into the left thigh at Day 180. In total, 1600 evaluable subjects for the GSK+4C (n=640), GSK-20C (n=640), and Merck-20C (n=320) groups were required to meet the primary objectives for immunogenicity with an overall power >85%. The primary study objective was to demonstrate non-inferiority of GSK+4C and/or GSK-20C, as compared with Merck-20C with respect to seroresponse rates for antibodies to measles, mumps, rubella and VZV, and GMCs for antibodies to VZV, hepatitis A virus and PCV7 pneumococcal serotypes at Day 42 post-vaccination. A total of 1850 subjects were enrolled and 1783 subjects were vaccinated (TVC): 705 received GSK-4C, 689 received GSK-20C and 389 received Merck-20C. Of these, 1646 subjects completed Visit 3 (Day 180), and 137 were withdrawn. The ATP cohort for immunogenicity comprised 1621 subjects in total: GSK-4C (n=632), GSK-20C (n=636) and Merck-20C (353). Non-inferiority of GSK+4C and GSK-20C compared with Merck-20C was demonstrated for seroresponse rates for measles, mumps and rubella viruses according to their respective clinical margins. However, for VZV, seroresponse rates were lower in the GSK MMRV groups (GSK-4C: 57.1%; GSK-20C: 69.8%) than in the Merck-20C group (86.7%). Seroresponse rates for VZV did not meet criteria for non-inferiority versus Merck-20C for either GSK MMRV vaccine, as the lower limit of the 97.5% Cl for the group difference was below the -15% clinical margin in both cases. A total of 41 subjects experienced at least one Serious Adverse Events (SAEs) during Days 0-180. The incidence of SAEs among the three groups was 2.0%, 2.9%, and 1.8% for GSK-4C, GSK-20C, and Merck-20C, respectively. Febrile seizures occurring from days 0-42 were reported in 0.3% of subjects in each treatment group: 2 subjects in the GSK-4C group (Days 16 and 24), 2 in the GSK-20C group (Days 24 and 42), and 1 in the Merck-20C group (Day 6). No fatal events were reported. Merck MMRV vaccine has been associated with an increase in febrile seizures in 12-23 month olds compared to MMR and varicella vaccines administered separately at the same visit. Consequently, the current ACIP recommendation (2010) is that for the first dose of measles, mumps, rubella, and VZV vaccines at age 12-47 months, either MMR vaccine and VZV vaccine or MMRV may be used; however, families without a strong preference for MMRV should receive MMR and VZV vaccine separately. Similarly, the Academy of Pediatrics (2011) also recommends the use of either MMR or VZV vaccines separately or MMRV for the first dose at 12-47 months. They state that the benefits and risks of both options should be discussed with parents/caregivers and that separate MMR and VZV injections should be given in cases where the risk-benefit can not be clearly communicated. The recognized period of increased risk for febrile seizure after a first dose of MMRV is either 5-12 days or 7-10 days after vaccination, although four of the five cases of febrile seizure in the current study occurred outside of the 5-12 day window. The risk of febrile seizure after administration of GSK MMRV vaccine relative to separate co-administration of MMR and monovalent VZV vaccine has not been investigated in a clinical trial of adequate power but; based on the reported fever profiles of the GSK and Merck vaccines would be expected to be similar. In conclusion, this study provides evidence that GSK-4C and GSK-20C vaccines are comparable with Merck-20C in terms of immunogenicity, for three of the four vaccine components and have a clinically acceptable reactogenicity/safety profile when given concomitantly with HAV and PCV7. The clinical significance of the differences in anti-VZV, seroresponse following at first dose of GSK MMRV requires further investigation. Upon internal review, febrile seizure was considered to be other important medical event. Additional information has been requested.