COMPARISON OF ACELLULAR PERTUSSIS-DIPHTHERIA-TETANUS TOXOIDS AND HAEMOPHILUS INFLUENZAE TYPE B VACCINES ADMINISTERED SEPARATELYVS. COMBINED IN YOUNGER VS. OLDER TODDLERS

Abstract

Three acellular pertussis vaccines combined with diphtheria and tetanus toxoids (DTaP) have been approved by the Food and Drug Administration for all doses, and the licensure of others is anticipated.1, 2 None of these vaccines have been licensed in the US as a combination with Haemophilus influenzae type b for the infant series, and at this point only one of these three DTaP vaccines has been approved for use combined with H. influenzae type b for the fourth booster dose.3 The physical mixing of vaccines can result in deceased immunogenicity of one or more of the vaccine components, necessitating clinical evaluation of every vaccine combination in each age group intended to receive it.4, 5 Another limitation on the use of DTaP vaccines is that they are approved for the fourth toddler dose only at 15 months of age or older. The only reason for this age restriction is lack of data in younger toddlers. A comparison of the safety and immunogenicity of the Lederle Takeda four-component DTaP and the Lederle HbOC [polyribosylribitol phosphate (PRP) conjugated to CRM197] vaccine administered separately,vs. combined, in children 12 to <15 months of age, vs. 15 to <19 months of age, is reported herein. Methods. Healthy toddlers ages 12 to <19 months were enrolled from their primary health care settings in Maryland, North Carolina and Pennsylvania. Children were eligible if they had received three doses of HbOC and whole cell pertussis combined with diphtheria and tetanus toxoids vaccine for their primary infant series of vaccines. The study was approved by the institutional review boards of each institution, and written informed consent was obtained from a parent or guardian. Children were stratified into two age groups, 12 to <15 and 15 to <19 months. Within each age group children were equally randomized to receive Lederle DTaP and HbOC, either concurrently in opposite thighs or as an investigational combined vaccine (liquid premixed, 0.5 ml/dose). There are 10 μg of PRP in a dose of the HbOC vaccine, and the per dose content of the DTaP vaccine are: pertussis toxoid (PT), 3.5 μg; filamentous hemagglutinin(FHA), 35 μg; fimbriae (FIM), 0.8 μg; pertactin (PRN), 2 μg; diphtheria toxoid, 9 limit of flocculation units (Lf); and tetanus toxoid, 5 Lf. Prophylactic antipyretic medication was not given. Parents were blinded as to which vaccine was injected into which thigh. Evening rectal temperatures were taken and parents maintained a diary of local reactions (erythema, induration, tenderness) at each injection site and of systemic symptoms (fussiness, sleepiness, decreased appetite). Blood for serology was drawn pre- and 1 month postvaccination. Standard enzyme-linked immunosorbent assay (ELISA) methods6 were used to measure serum IgG to the following antigens: PRP; tetanus toxoid; diphtheria toxoid; PT; FHA; PRN; and serotype 2 FIM. FDA or Wyeth-Lederle Laboratories reference sera were used to convert ELISA units to micrograms per ml (anti-PRP), units/ml (PT, FHA, PRN, FIM) or International Units (diphtheria, tetanus toxoid). Geometric mean antibody concentration (GMC) was obtained by averaging the logged antibody concentrations, then exponentiating the average. The t distribution with (n − 1) degrees of freedom was used to calculate 95% confidence intervals on each GMC. The primary analysis of the postvaccination titers used analysis of covariance with the prevaccination antibody titer as a covariate. Children were considered to have experienced a seroresponse of antibody to PT, FHA and PRN if their postvaccination antibody level was twice that of the prevaccination value and twice the limit of quantitation for the respective assay. The definition of a seroresponse to FIM was met if there was a 3-fold rise in antibody concentration that was 3 times the limit of quantitation for the assay. Results. Of 235 toddlers enrolled, 126 were 12 to <15 months of age and 109 were 15 to <19 months old. Sixty-five of the younger children received combined vaccine, and 61 were given DTaP and HbOC in opposite thighs. Among the older group 55 and 54 received combined and separate vaccines, respectively. The mean ages of the 4 groups were: younger separate group, 13.1 months; older separate group, 15.9 months; younger combined group, 12.8 months; and older combined group, 16.0 months. Twenty-five of the combined and 23 of the separate subjects were considered inevaluable for the strict per protocol analysis. Antibody results of the evaluable children are presented. There were 8 inevaluable children for whom paired sera were available; an intent-to-treat analysis including these children showed no significant differences from the evaluable subjects. The only significant differences observed in rates of local and systemic reactions among groups was in the proportion of children experiencing local reactions. Induration was observed in 11 of 106 (10.4%) of the older toddlers compared with 2 of 126 (1.6%) of the younger children (P = 0.007). The occurrence of any local reaction was more common in children receiving the 2 separate injections, 26 of 112 (23.2%) vs. 15 of 120 (12.5%), P = 0.39. No clinically severe local reactions, as judged by the investigator, were observed. Fussiness, anorexia and/or drowsiness was reported to have been experienced by 45 of 112 (40.2%) recipients of the separate vaccines and 52 of 120 (43.3%) recipients of the combined vaccine and by 54 of 125 (43.2%) and 43 of 107 (40.2%) of the younger and older children, respectively. There were no differences in the frequency or height of fevers (temperature ≥38°C among any of the groups. However, there was a trend toward a higher incidence of fever in the older toddlers (24 of 98, 24.5%) than in the younger group (18 of 120, 15%), P = 0.086. Antibody responses are shown in Table 1. Postvaccination GMC of ELISA IgG antibody to PRP varied from 37.92 to 50.18 μg/ml among the four vaccine groups. There were no significant differences in the GMC of antibody between treatment groups or between age groups. All children in all groups had post-anti-PRP concentrations of >0.15 μg/ml, and a concentration of >1 μg/ml of antibody was achieved by ≥95.8% of subjects. The highest GMC to PT, 148.8 units/ml, was achieved by the younger recipients of the separate vaccines, and the lowest was seen in the younger combined vaccine group (52.2 units/ml, P < 0.05). This difference was the only postvaccination seroresponse to pertussis antigens that was significantly different among all of the groups. The greatest difference in the percentage of children showing seroresponse to PT also was between the younger combined group (84.8%) vs. the younger separate groups (93%), but significance was not reached. Postvaccination GMC to FHA in younger and older separate groups and younger and older combined groups were 67.7, 47.5, 58.0 and 58.2 units/ml, respectively. There were no significant differences between treatments or between age groups. Seroresponse rates to FHA varied from a low of 80.4% in the younger combined group to 95.4% in the younger separate group; this difference was marginally significant (P= 0.051). Antibody concentrations to PRN after vaccination ranged from 190.6 units/ml in the younger combined group to 233.4 in the older combined group, and seroresponse rates varied from 94 to 100%. The antibody responses to FIM were also similar among the groups; the GMCs postvaccination were 10.5 to 15 units/ml, and seroresponse occurred in 63 to 73% of children. There were no significant differences among the age or treatment groups in GMCs, or seroresponse rates, to PRN or FIM. The younger combined group had the lowest postvaccination GMC of antibody to diphtheria, and analysis indicated that age groups were significantly different but treatment groups were not. However, 100% of all children achieved greater than the protective concentration of 0.01 IU, and all but one child had 10-fold that amount of antibody to diphtheria postvaccination antibody. The postvaccination GMC of antibody to tetanus was lowest in the younger combined vaccine group; however, there were no significant differences among groups. All vaccinees had protective concentrations of tetanus antitoxin (>0.1 IU).TABLE 1: Seroresponses Discussion. United States children currently receive up to 15 injections of vaccine before 2 years of age. Combinations of vaccines and flexibility in timing of vaccinations are clearly needed. The results of this study indicate that the fourth dose of the Lederle DTaP vaccine is safe and immunogenic when given to children as early as 12 months of age. These encouraging data are the first available on giving a DTaP booster vaccine beginning at 12 months of age. The other important result of this study is that there was no significant immune interference, as measured by serum ELISA IgG antibody, when the Lederle HbOC and DTaP were combined in one syringe and administered to toddlers 15 to <19 months of age. There was significantly diminished antibody to PT in the younger age group given the combined vaccine; the clinical relevance of this observation is unclear because serologic correlates of protection against pertussis are yet to be defined. Children in this study were primed with whole cell pertussis combined with diphtheria and tetanus toxoids vaccine, and there is evidence that children primed with DTaP respond to boosting with lower antibody concentrations.7 Reality and practicality dictate that decisions must be made now about the timing of administration of the fourth booster dose of DTaP and the feasibility of administering DTaP vaccines combined with H. influenzae type b vaccines. Although it must be understood that making assumptions about the efficacy of pertussis vaccines based on serum antibody levels may be erroneous, there is currently no practical alternative. Some small risk of reduced protection may have to be taken to make vaccine delivery more acceptable. The data reported herein indicate that the fourth dose of the Lederle DTaP vaccine was safe and immunogenic when given to children as young as 12 months of age and that there was no significant diminution in antibody responses among 15- to 19-month-old toddlers when the Lederle DTaP and HbOC were given as a combined vaccine. Acknowledgments. We acknowledge and express appreciation to the participating children and parents and to the following nurses and pediatricians who made this trial possible: Linda Wadsworth, R.N.; Nancy Wymer, R.N.; Lynn Regina, R.N.; Carol Miller, L.P.N.; Sue Simmons, L.P.N.; David Bromberg, M.D., and his colleagues; Dwight Fortier, M.D., and his colleagues. Joseph Severs of Wyeth-Lederle Vaccine and Pediatrics performed the statistical analyses. This study was funded by Wyeth-Lederle Vaccines and Pediatrics. Margaret B. Rennels, M.D. Matthew J. Hohenboken, M.D., Ph.D. Keith S. Reisinger, M.D., M.P.H. Dennis A. Clements, M.D., Ph.D. Emmanuel B. Walter Jr., M.D., M.P.H. Mark M. Blatter, M.D. Jean Nonenmacher, B.S. Jill G. Hackell, M.D. Department of Pediatrics and Center for Vaccine Development; University of Maryland School of Medicine; Baltimore, MD (MBR) Wyeth-Lederle Vaccines and Pediatrics; Pearl River, NY (MJH, JN, JGH) Pittsburgh Pediatric Research; Pittsburgh, PA (KSR, MMB) Department of Pediatrics; Duke University; Durham, NC (DAC, EBW)