Susan Partridge

Bordetella Pertussis Infections in Vaccinated and Unvaccinated Adolescents and Adults, as Assessed in a National Prospective Randomized Acellular Pertussis Vaccine Trial (APERT)

BACKGROUND Acellular pertussis (aP) booster immunizations have been recommended for adolescents and older persons to enhance long-term protection and to possibly reduce community transmission of infections. METHODS This was a multicenter, randomized, double-blind vaccine trial in which one-half of the subjects received aP vaccine and one-half received hepatitis A vaccine (control subjects). All subjects were observed for almost 2 years for cough illnesses, and all underwent microbiologic and serologic studies for detection of pertussis infection. Immunoglobulin G (IgG) and immunoglobulin A (IgA) antibodies to pertussis toxin, filamentous hemagglutinin, pertactin, and fimbriae 2/3 were measured by enzyme-linked immunosorbent assay in serum samples obtained 1 and 12 months after immunization. Infection rates were determined with a variety of serologic criteria for control and vaccinated subjects. The incidence of prolonged cough illness was ascertained for subjects with and subjects without serologic evidence of infection. RESULTS Infection rates among control subjects are particularly representative of those in nonimmunized adults. Among control subjects, 0.4%-2.7% had increases in pertussis antibody of various types and degrees over 1 year, and 20%-46% had prolonged cough illnesses during this interval. Pertussis toxin antibody had the greatest specificity for detecting increases in antibody levels. Asymptomatic infections were approximately 5 times more common than clinical illnesses that met a strict clinical and microbiologic case definition. Relative to control subjects, aP-immunized subjects may have fewer increases in the antibody level (i.e., infections), especially for antibodies to fimbriae 2/3 (an antigen not in the vaccine). CONCLUSIONS Pertussis infections in older persons are largely asymptomatic. aP boosters confer protection for adolescents and adults against symptomatic pertussis and likely confer protection against mild and asymptomatic infections, and use of boosters may reduce transmission to others, especially infants.

Prospective, randomized, placebo-controlled evaluation of the safety and immunogenicity of three lots of intranasal trivalent influenza vaccine among young children.

BACKGROUND Trivalent formulations of an experimental, cold-adapted, intranasal influenza (CAIV) vaccine have been shown to be safe, immunogenic and efficacious in young children. METHODS We evaluated the safety and immunogenicity of three consistency lots of CAIV in children 12 to 36 months of age randomized to one of five groups: Groups 1, 2 and 3 received separate lots containing A/Shenzhen/227/95 (H1N1), A/Wuhan/359/95(H3N2) and B/Harbin/7/94-like viral strains. Group 4 received an earlier efficacy trial lot which included a different H1N1 strain (A/Texas/36/91-like); and Group 5 received placebo. We performed strain-specific serum hemagglutination inhibition antibody levels against type A (H3N2 or H1N1) or type B as appropriate. RESULTS Overall 474 children received 2 doses, 2 months apart. Each lot was well-tolerated, and there were no significant group differences between consistency lots in the proportion of children with fever and local or systemic reactions after vaccination. The 3 consistency lots were not statistically different with regard to immunogenicity as measured by seroconversion or absolute geometric mean titer. Immune responses were more robust among initially seronegative children and for H3N2 and B strains than for H1N1 strains. After 2 doses of vaccine 97, 84 and 62% had hemagglutination inhibition titers > or = 1/32 against A/H3N2, B and H1N1 strains, respectively. For A/H3N2 only, immune responses after 1 dose of vaccine are similar to those seen after 2 doses. CONCLUSIONS Each consistency lot of CAIV is as or more immunogenic than a lot used in a large efficacy trial.

Safety and immunogenicity of a pentavalent diphtheria, tetanus, pertussis, hepatitis B and polio combination vaccine in infants.

Introduction. The objectives of this study were to evaluate the safety and immunogenicity of a new combination vaccine (DTaP-HB-IPV) containing diphtheria, tetanus, acellular pertussis and hepatitis B (HB) and a new inactivated poliovirus vaccine (IPV) manufactured by GlaxoSmithKline (GSK). This vaccine was given in an all IPV or sequential IPV and oral polio vaccine (OPV) schedule. Another combination vaccine, DTaP-HB (GSK), was similarly evaluated given with OPV or IPV. Methods. Four hundred infants were randomized into one of four study groups and immunized at 2, 4 and 6 months of age. Group A received three doses of DTaP-HB-IPV; Group B received DTaP-HB-IPV at 2 and 4 months and DTaP-HB with OPV (Orimune) at 6 months; Group C received three doses of DTaP-HB with licensed IPV (IPOL) administered separately; Group D received separate doses of OPV, DTaP (Infanrix; GSK) and HB (Engerix; GSK). All subjects received conjugate Haemophilus influenzae type b vaccine (Hib) (OmniHIB) at 2, 4 and 6 months of age given at a separate injection site. Subjects who returned at 12 to 18 months of age (229) received booster immunization with DTaP and Hib. Safety was evaluated after each vaccine dose. Blood was drawn before the first dose and one month after the third dose as well as before and after the booster dose. Results. There were no vaccine-related serious adverse events in any group after any vaccine dose. Minor systemic and local adverse events were also not significantly different among the four groups after any dose. There were no differences in the immune response rates for Hib, HB, polio (types 1, 2 and 3), diphtheria, tetanus or pertussis antigens (pertussis toxin, filamentous hemagglutinin, pertactin) among groups, although there were some quantitative differences in specific antibody titers among groups. DTaP-HB-IPV and DTaP-HB combination vaccines had safety and immunogenicity equivalent to those of standard individually administered vaccines. The new IPV was not inferior to IPOL. Conclusion. Use of the pentavalent combination vaccine would greatly reduce the number of required injections during the first 2 years of life, thereby simplifying the immunization schedule, enhancing compliance and facilitating acceptance of additional injections engendered by introduction of newer vaccines.

Enhanced antibody responses in infants given different sequences of heterogeneous Haemophilus influenzae type b conjugate vaccines

To evaluate the safety and immunogenicity of differing sequences of heterogeneous Haemophilus influenzae type b (Hib) conjugate vaccines, we randomly assigned 300 infants to one of six vaccination schedules. At 2, 4, and 6 months of age, subjects were given single or heterogeneous vaccines: Hib polysaccharide (PRP) conjugated to mutant diphtheria toxin (HbOC), PRP conjugated to outer-membrane protein of Neisseria meningitidis (PRP-OMP), or PRP conjugated to tetanus toxoid (PRP-T). No serious reactions were attributable to immunization with heterogeneous vaccines, and there were few significant differences in the rates of minor adverse reactions among groups. PRP-OMP was the only vaccine that induced an antibody response after the first dose, but significant booster responses were not seen after the second and third doses. Subjects given PRP-T vaccine responded well after two doses, but three doses of HbOC vaccine were needed for an equivalent antibody response. All the Hib vaccine schedules evaluated were immunogenic, and schedules initiated by PRP-OMP vaccine at 2 months of age, followed by two doses of either HbOC or PRP-T vaccine at 4 and 6 months of age, induced the highest antibody levels after each dose. Such schedules may be the best for protecting infants and children who are at greatest risk of having invasive Hib disease, such as American Indian children.

Comparative safety and immunogenicity of two recombinant hepatitis B vaccines given to infants at two, four and six months of age

OBJECTIVES To evaluate the relative safety and immunogenicity of the two recombinant hepatitis B vaccines licensed in the United States with doses recommended for routine immunization of low risk infants and a schedule that corresponds with routine pediatric visits. METHODS Healthy infants were immunized at 2, 4 and 6 months of age with hepatitis B vaccine manufactured by either SmithKline Beecham (Engerix-B, 10 micrograms/dose, n = 228) or Merck and Co. (Recombivax HB, 2.5 micrograms/dose, n = 200). Adverse reactions were ascertained by parental reports and interviews and by review of medical records. Antibody concentrations to hepatitis B surface antigen (anti-HBs) were measured in sequential serum specimens by enzyme immunoassay. RESULTS Adverse reactions were mild and the rates were not significantly different between the two groups. After the first and second doses the rates of seropositivity (> or = 10 mIU/ml) and seroprotection (> or = 10 mIU/ml) were significantly higher in infants given SmithKline Beecham vaccine (P < 0.01). After the second and third doses infants given SmithKline Beecham vaccine also had significantly higher geometric mean anti-HBs concentrations compared with those given Merck vaccine (348.0 mIU/ml vs. 66.9 and 1914.8 mIU/ml vs. 514.8 mIU/ml, respectively, P < 0.001). Nevertheless after the third dose 99% of infants in both vaccine groups achieved seroprotective antibody concentrations. CONCLUSIONS Both recombinant hepatitis B vaccines were safe and immunogenic when administered concurrently with other pediatric vaccines at 2, 4 and 6 months of age, but earlier protective responses were observed with the SmithKline Beecham vaccine than with the Merck vaccine.

Kinetics of maternal hepatitis a antibody decay in infants: implications for vaccine use.

We conducted a seroepidemiologic study to evaluate the kinetics of maternal hepatitis A antibody decay in infants. Serum samples obtained from 200 infants at 2 and 4 months of age were tested for hepatitis A antibody. Seventy-six infants (38%) were hepatitis A antibody-positive with a geometric mean antibody titer of 2634 mIU/ml. Samples collected at 4, 6 and/or 12 months of age showed seropositivity rates of 100, 95 and 39%, respectively. These data indicate that maternal antibody levels remained high through the first 6 months of life but decayed significantly by 12 months of age.

Immunogenicity of a Haemophilus influenzae type b-tetanus toxoid conjugate vaccine when mixed with a diphtheria-tetanus-acellular pertussis-hepatitis B combination vaccine.

BACKGROUND Combination vaccines are urgently needed to reduce the number of injections given to young children. The aim of the study was to evaluate the safety and immunogenicity of a combination vaccine that contains diphtheria and tetanus toxoids and acellular pertussis antigens (DTaP), recombinant hepatitis B surface antigen (HepB) and Haemophilus influenzae type b (Hib) polysaccharide conjugated to tetanus toxoid (PRP-T). METHODS Four hundred five infants were randomized equally to three groups and immunized at 2, 4 and 6 months of age with: (1) DTaP/HepB vaccine used to reconstitute lyophilized PRP-T vaccine and administered as a single injection; (2) DTaP/HepB vaccine and PRP-T vaccine administered as two separate injections; or (3) DTaP, HepB and PRP-T vaccines administered as three separate injections. Safety was closely monitored, and blood specimens were obtained to assess antibody responses to each vaccine antigen. RESULTS All study vaccines were well-tolerated, and the rates of systemic and injection site reactions were similar between groups. After the third dose the geometric mean antibody concentrations to Hib were significantly lower in subjects in Group 1 (1.63 microg/ml) compared with subjects in Groups 2 and 3 (6.26 and 6.15 microg/ml, respectively; P < 0.0001). Subjects with antibody concentrations <1.0 microg/ml after the third dose responded well to a booster dose of Hib conjugate vaccine given at 11 to 15 months of age (41 of 44 with anti-PRP > or = 1.0 microg/ml). Differences between groups for antibody responses to the other vaccine components were not clinically significant. CONCLUSIONS Infants given a combined DTaP/ HepB/PRP-T vaccine experienced a significantly lower antibody response to the PRP-T component than infants given PRP-T vaccine as a separate injection. However, the immune response to a booster dose of Hib conjugate vaccine indicated the presence of immunologic memory.

A Randomized Study of the Safety and Immunogenicity of DTPa-HB-IPV Vaccine Administered as Three Doses or in a Sequential IPV/OPV Schedule at 2, 4, and 6 Months of Age ♦ 933

A Randomized Study of the Safety and Immunogenicity of DTPa-HB-IPV Vaccine Administered as Three Doses or in a Sequential IPV/OPV Schedule at 2, 4, and 6 Months of Age ♦ 933

Factors Influencing the Immunogenicity of a Pneumococcal Conjugate Vaccine in Infants † 709

Factors Influencing the Immunogenicity of a Pneumococcal Conjugate Vaccine in Infants † 709

EVALUATION OF A HEPATITIS A VACCINE IN INFANTS: INFLUENCE OF MATERNAL ANTIBODY AND DOSE ON THE ANTIBODY RESPONSE. 1048

Hepatitis A vaccines have been extensively evaluated in adults and children> 2 years of age, but there have been few studies in infants. Although hepatitis A infections are usually asymptomatic in infants, immunization of infants may be desirable. Infected infants and children are often the source of infection for adults, and about 30% of reported cases occur in persons < 14 years of age. However, preliminary studies suggest that maternal antibodies may interfere with the response. We compared 3 dosages of Mercks hepatitis A vaccine (VAQTA) to determine if higher dosages might overcome this interference. Healthy 2-month-olds were randomized to 1 of 3 groups and given 2 doses (4 months apart) of either a 13 unit (U) (n=79), 25U (n=81), or 50U(n=80) dosage of vaccine. Safety data after the 1st dose are shown:Table Vaccination was well tolerated; the highest dose did not result in increased rates of local or systemic reactions. Local reactions were generally mild and nearly all had resolved by the 2nd day after vaccination. Results of antibody data will be presented. Funded by Merck & Co.