Adapting Group Sequential Methods to Observational Postlicensure Vaccine Safety Surveillance: Results of a Pentavalent Combination DTaP-IPV-Hib Vaccine Safety Study

Abstract

To address gaps in traditional postlicensure vaccine safety surveillance and to promote rapid signal identification, new prospective monitoring systems using large health-care database cohorts have been developed. We newly adapted clinical trial group sequential methods to this observational setting in an original safety study of a combination diphtheria and tetanus toxoids and acellular pertussis adsorbed (DTaP), inactivated poliovirus (IPV), and Haemophilus influenzae type b (Hib) conjugate vaccine (DTaP-IPV-Hib) among children within the Vaccine Safety Datalink population. For each prespecified outcome, we conducted 11 sequential Poisson-based likelihood ratio tests during September 2008-January 2011 to compare DTaP-IPV-Hib vaccinees with historical recipients of other DTaP-containing vaccines. No increased risk was detected among 149,337 DTaP-IPV-Hib vaccinees versus historical comparators for any outcome, including medically attended fever, seizure, meningitis/encephalitis/myelitis, nonanaphylactic serious allergic reaction, anaphylaxis, Guillain-Barré syndrome, or invasive Hib disease. In end-of-study prespecified subgroup analyses, risk of medically attended fever was elevated among 1- to 2-year-olds who received DTaP-IPV-Hib vaccine versus historical comparators (relative risk = 1.83, 95% confidence interval: 1.34, 2.50) but not among infants under 1 year old (relative risk = 0.83, 95% confidence interval: 0.73, 0.94). Findings were similar in analyses with concurrent comparators who received other DTaP-containing vaccines during the study period. Although lack of a controlled experiment presents numerous challenges, implementation of group sequential monitoring methods in observational safety surveillance studies is promising and warrants further investigation.

Timely Versus Delayed Early Childhood Vaccination and Seizures

“…17,18 There is no evidence that the acellular DTaP vaccines in use since the late 1990s are associated with seizures in the United States. 31 Other infant vaccines currently in use, for instance the DTaP, inactivated poliovirus, and Haemophilus influenza type B combined vaccine (DTaP-IPV-HIB), have not been associated with seizures in the United States, 32 although DTaP-IPV-HIB has been linked with increased febrile seizures in Denmark. 24 Other early childhood vaccines that have been associated with febrile seizures in the United States include inactivated influenza vaccine, but only in some influenza seasons, such as 2010-2011, and the 13-valent pneumococcal conjugate vaccine.…”

Safety Analysis for Pentavaccine Used in Premature Infants: Family Vaccination Centre’s Experiment

“…Вак-цина включена в графики вакцинации детей различных стран мира (как на первом году жизни для первичной вакцинации, так и для ревакцинации на втором году). В многоцентровых исследованиях свойств пентавакци-ны доказана безопасность [5], хорошая переносимость и высокая иммуногенность препарата в отношении всех антигенов, включенных в его состав, при использовании разных графиков вакцинации [6,7].…”

Combined Vaccine Is an Effective and Safe Protection From Five Controllable Infections

“…1); however, tolerance to the drug and vaccination with separate monocomponent vaccines depending on frequency of administration thereof (tb. 2) and generation of specific antibodies has been compared [6][7][8][9]. General safety of the pentavalent vaccine with acellular pertussis component has been evaluated in comparison with whole cell vaccine.…”

“…Comparative studies of tolerance to the pentavalent vaccine in combination with a recombinant hepatitis B vaccine and to vaccination with inactivated poliovirus, acellular pertussis-diphtheria-tetanus vaccine and conjugate Hib vaccine (Hib) demonstrated equivalent tolerance to the immunization. Several studies [6,7,9] demonstrated immunogenicity of the pentavalent vaccine: protective antibody titer against diphtheria and tetanus (more than 0.01 IU/ml) developed in 92.2-100% of children after the primary vaccination, against type 1, 2 and 3 poliomyelitis -in 99.6-100% of children. Type b Haemophilus influenzae antibodies could be observed 1 month after the third administration of the vaccine in 92-100% of cases (according to different authors) [6][7][8][9].…”

“…Several studies [6,7,9] demonstrated immunogenicity of the pentavalent vaccine: protective antibody titer against diphtheria and tetanus (more than 0.01 IU/ml) developed in 92.2-100% of children after the primary vaccination, against type 1, 2 and 3 poliomyelitis -in 99.6-100% of children. Type b Haemophilus influenzae antibodies could be observed 1 month after the third administration of the vaccine in 92-100% of cases (according to different authors) [6][7][8][9]. Studies of seroconversion to filamentous hemagglutinin and pertactin in Sweden demonstrated that the protective antibody titer against pertactin developed in 97% of the children, who had been administered 3 vaccinal doses, to filamentous hemagglutinin -in 89.1%.…”