Published online October 15, 2007
PEDIATRICS Vol. 120 No. 5 November 2007, pp. e1190-e1202 (doi:10.1542/peds.2007-0729)
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ARTICLE

Pertussis Booster Vaccination in HIV-Infected Children Receiving Highly Active Antiretroviral Therapy

Mark J. Abzug, MDa, Lin-Ye Song, PhDb, Terence Fenton, EdDb, Sharon A. Nachman, MDc, Myron J. Levin, MDa, Howard M. Rosenblatt, MDd, Stephen I. Pelton, MDe, William Borkowsky, MDf, Kathryn M. Edwards, MDg, Jody Peters, MSg for the International Maternal Pediatric Adolescent AIDS Clinical Trials Group P1024 Protocol Team

a School of Medicine, University of Colorado and Children's Hospital, Denver, Colorado
b Statistical and Data Analysis Center, Harvard School of Public Health, Boston, Massachusetts
c School of Medicine, State University of New York, Stony Brook, New York
d School of Medicine, Baylor College of Medicine, and Texas Children's Hospital, Houston, Texas
e School of Medicine, Boston University, and Boston Medical Center, Boston, Massachusetts
f School of Medicine, New York University Medical Center, and Bellevue Hospital, New York, New York
g School of Medicine, Vanderbilt University, Nashville, Tennessee


   ABSTRACT
TOP
 ABSTRACT
PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 CONCLUSIONS
 REFERENCES
 
OBJECTIVE. Our goal was to evaluate the immunogenicity and safety of pertussis booster vaccination in children infected with HIV on highly active antiretroviral therapy (HAART).

PATIENTS AND METHODS. HIV-infected children on stable HAART for ≥3 months with plasma HIV-RNA concentrations of <30000 to 60000 copies per mL who previously received ≥4 doses of diphtheria-tetanus-pertussis (DTP)–containing vaccine were eligible. Diphtheria-tetanus-acellular pertussis (DTaP) vaccine was administered to subjects 2 to <7 years old who had 4 previous DTP-containing vaccines, subjects 2 to <7 years old who had ≥5 previous DTP-containing vaccines and negative tetanus antibody, and subjects ≥7 to ≤13 years old who had negative tetanus antibody. Pertussis toxin and filamentous hemagglutinin antibodies were measured before and 8, 24, and 72 weeks after DTaP vaccine.

RESULTS. Ninety-two subjects received DTaP vaccine and met criteria for analysis. Antibody concentrations were low at entry: pertussis toxin geometric mean concentration at 4.8 enzyme-linked immunosorbent assay units (EU) per mL and filamentous hemagglutinin geometric mean concentration at 4.1 EU/mL. Pertussis toxin and filamentous hemagglutinin geometric mean concentrations rose to 22.3 and 77.0 EU/mL, respectively, 8 weeks after the study DTaP vaccine. Antibody concentrations fell by 24 weeks after vaccination but remained higher than before vaccination. Predictors of response 8 weeks after DTaP vaccine included the concentration of homologous antibody, lower HIV-RNA level, and higher CD4 percentage at entry. One vaccinated subject experienced erythema and induration of ≥25 mm.

CONCLUSIONS. A DTaP vaccine booster was well tolerated by children on HAART and induced increases in antibodies. Antibody concentrations after vaccination were lower than those reported in populations uninfected by HIV. Although comparison among studies must be made with caution, these data suggest that children infected with HIV may be deficient in immunologic memory from previous DTP-containing vaccination and/or that immune reconstitution with HAART may be incomplete for pertussis antigens.

Key Words: pertussis • pertussis vaccine • Bordetella pertussis • HIV • highly active antiretroviral therapy

Abbreviations: HAART—highly active antiretroviral therapy, DTP—diphtheria-tetanus-pertussis • DTaP—diphtheria-tetanus-acellular pertussis • PT—pertussis toxin • FHA—filamentous hemagglutinin • ELISA—enzyme-linked immunosorbent assay • EU—enzyme-linked immunosorbent assay unit • GMC—geometric mean concentration • CI—confidence interval

Bordetella pertussis is a cause of acute and prolonged respiratory illness in children and adults infected with HIV.1–5 The degree to which children infected with HIV are protected by immunization with pertussis-containing vaccines in early childhood has not been determined. In a small study conducted before the widespread use of highly active antiretroviral therapy (HAART), children infected with HIV had reduced antibody responses to acellular pertussis vaccine.6 Although studies suggest that HAART is associated with improved responses to revaccination with a variety of immunogens, the response of children infected with HIV who are on HAART to pertussis vaccination has not been described.7 Several reports have shown that pertussis vaccination does not have adverse effects on the clinical course, CD4 lymphocyte counts, or plasma HIV-RNA concentrations of children infected with HIV.8,9 International Maternal Pediatric Adolescent AIDS Clinical Trials Group/Pediatric AIDS Clinical Trials Group P1024 is a multicenter study designed to evaluate the immunogenicity and safety of routine pediatric vaccines in children infected with HIV who are on HAART and to assess the impact of CD4 percentage and viral load on vaccine response. This report focuses on the immunogenicity and safety of pertussis vaccination.


   PATIENTS AND METHODS
TOP
 ABSTRACT
 PATIENTS AND METHODS
RESULTS
 DISCUSSION
 CONCLUSIONS
 REFERENCES
 
Study Population
Children infected with HIV who were 2 to <19 years of age at 39 sites were eligible for enrollment if they fit into 1 of the following immunologic strata: group 1, nadir CD4 percentage before HAART of <15% and CD4 percentage at study screening of <15%; group 2, pre-HAART nadir CD4 percentage of <15% and screening CD4 percentage of ≥15%; group 3, pre-HAART nadir CD4 percentage of 15% to ≤25% and screening CD4 percentage of ≥15%; and group 4, pre-HAART nadir CD4 percentage of ≥25% and screening CD4 percentage of ≥25%. Subjects in strata 2 to 4 were required to be perinatally infected, to have been on the same HAART regimen (≥3 antiretroviral agents from ≥2 therapeutic classes) for ≥6 months, and to have a plasma HIV-RNA polymerase chain reaction (Roche Amplicor Assay; Roche Diagnostics, Indianapolis, IN) of <30000 copies per mL. Subjects in stratum 1 were permitted to be infected via any route and were required to be receiving the same HAART regimen for ≥3 months and to have an HIV-RNA level of <60000 copies per mL. All of the subjects were required to have previously received ≥4 doses of diphtheria-tetanus-pertussis (DTP)–containing vaccines (acellular and/or whole-cell pertussis). Exclusion criteria included receipt of other vaccines within a prescribed period preceding entry; immune suppressive or immunomodulatory therapy; blood products within 6 months; other immune diseases; and having grade 2 or higher clinical toxicities that overlap with potential vaccine-associated toxicities. Target enrollment was 300, with 75 per stratum, with a maximum of 50 subjects at ≥7 or <7 years in each stratum.

Study Protocol
Informed consent was obtained, and human experimentation guidelines of the US Department of Health and Human Services and participating institutions were followed. The age for administration of a pediatric formulation of diphtheria-tetanus-acellular pertussis (DTaP) vaccine was extended to 13 years based on satisfactory experience in other populations.10 Tetanus seronegativity at entry was used as an adjunct to select subjects eligible to receive a DTaP booster based on experience in Pediatric AIDS Clinical Trials Group 377, in which children 2 to 9 years of age infected with HIV lacking protective antibody levels to tetanus tolerated DTaP revaccination.11 DTaP (diphtheria and tetanus toxoids and acellular pertussis vaccine adsorbed: Infanrix; 25 µg of pertussis toxin [PT], 25 µg of filamentous hemagglutinin [FHA], and 8 µg of pertactin; GlaxoSmithKline Pharmaceuticals, Research Triangle Park, NC; 0.5 mL intramuscularly) was administered at the 24-week study visit to the following subjects: those at age <7 years and with 4 previous DTP vaccines; those at age <7 years, ≥5 previous DTP vaccines, and negative tetanus antibody; and those at age ≥7 to ≤13 years and negative tetanus antibody. Subjects received other study vaccines at other visits; responses to these will be reported separately. Therapies included among exclusion criteria for study entry were also disallowed during the study vaccination period. Subjects were monitored for adverse events for 1 hour after vaccination and by telephone 3, 7, and 14 days later. Subjects grade-3 or higher adverse reactions were evaluated within 48 hours. Specimens for pertussis antibody determination were obtained at study entry and 8 weeks after DTaP vaccination (study week 32), 24 weeks after DTaP (study week 48), and 72 weeks after DTaP (study week 96) from DTaP recipients. Subjects who did not qualify to receive DTaP based on age, previous number of DTP doses, and tetanus serology criteria defined above ("nonrecipients") had serum for pertussis antibody measurement obtained at entry and at study weeks 48 and 96. HIV-RNA and lymphocyte subsets were determined at entry and at study weeks 24, 48, and 96.

Laboratory Assays
Tetanus immunoglobulin G was determined on duplicate serum aliquots by sandwich enzyme-linked immunosorbent assay (ELISA) (IBL-Hamburg, Hamburg, Germany). Diluted sera were incubated on plates followed by the sequential addition of enzyme-conjugated antihuman immunoglobulin G, tetramethylbenzidine substrate solution, and stop solution (0.5 mol/L of H2SO4). Absorbance at 450 nm was read, and titers were determined from standard curves generated in each run using defined standards. A titer of <0.1 IU/mL was considered negative.

Antibodies to PT and FHA were determined by ELISA using a previously reported methodology.12 The lower limit of detection was 2 ELISA units (EU)/mL for both PT and FHA. Values of <2 EU/mL were set at 1 EU/mL for analyses.

Statistical Analysis
Logarithms (base 10) of PT and FHA antibody concentrations were used to normalize data where appropriate, and antibody concentrations were described with geometric mean concentrations (GMCs). Only those DTaP recipients for whom results were available at entry and 8 ± 4 weeks after DTaP administration (study week 32 ± 4 weeks) were included in analyses of immunogenicity. Their 24-week postvaccination results were included if obtained within a window of ±4 weeks (study week 48 ± 4 weeks), and their 72-week postvaccination results were included if obtained within ±12 weeks of the appropriate time point (study week 96 ± 12 weeks). Similarly, antibody concentrations were examined for DTaP nonrecipients for whom entry and study week 48 ± 4 weeks results were available; their week-96 values were included if obtained within ±12 weeks of the appropriate time point.

Univariate linear regression analyses were performed to identify predictors of entry PT and FHA antibody concentration among DTaP recipients and nonrecipients combined and for the response to pertussis booster vaccination measured 8 weeks after DTaP among vaccine recipients. Categorical variables were represented by dummy variables, and for variables having >2 categories, Tukey-Kramer simulation-based adjusted P values were used for pairwise comparisons when F tests were significant. Variables identified as at least marginally significant (P < .1) predictors of antibody concentration 8 weeks after DTaP were included in multivariate regression analyses. The strength of association between PT and FHA antibody concentrations and between entry PT and FHA antibody concentrations and change in concentration from entry to 8 weeks after DTaP were assessed with Spearman rank order methods.


   RESULTS
TOP
 ABSTRACT
 PATIENTS AND METHODS
 RESULTS
DISCUSSION
 CONCLUSIONS
 REFERENCES
 
Study Population Characteristics
A total of 263 children were enrolled; 6 were omitted from analysis because of violations of inclusion and exclusion criteria. One hundred and nineteen were eligible to receive the DTaP vaccine per protocol criteria; of these, 113 actually received DTaP. Ninety two of these had sera obtained at baseline (study entry) and 8 ± 4 weeks after DTaP; these 92 subjects comprise the primary data set of DTaP recipients. A total of 138 subjects did not qualify to receive DTaP. Nine of these were inadvertently administered DTaP. Of the remaining 129 subjects who did not receive DTaP, 98 had baseline and week 48 ± 4-week sera obtained and are included in the primary data set of DTaP nonrecipients. Age, Centers for Disease Control and Prevention clinical classification, nadir CD4 percentage before HAART, CD4 percentage at study screening, and CD4 percentage at the study DTaP visit of the primary data set of DTaP recipients differed according to immunologic strata (Table 1). Low percentages of subjects in all of the strata had received DTaP in the 2 years before study entry. Characteristics of the DTaP nonrecipients in the primary data set were generally similar to those of the DTaP recipients, with comparable relationships between immunologic strata and age, clinical classification, and CD4 measures (data not shown). Moreover, the trend toward a lower HIV-RNA concentration with ascending immune stratum was statistically significant for DTaP nonrecipients (P = .004). Because enrollment in stratum 1 was low (2 DTaP recipients and 9 nonrecipients because of a limited pool of qualifying patients), these subjects were excluded from immunogenicity analyses. There were no significant differences between subjects excluded from the primary data set and those in the primary data set with respect to baseline characteristics.


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  		TABLE 1 Characteristics of DTaP Recipients Included in the Primary Data Set

 
Antibody Concentrations: Immunologic Strata Combined
PT GMCs at entry were 4.8 EU/mL (95% confidence interval [CI]: 3.7–6.3 EU/mL) and 6.5 EU/mL (95% CI: 5.0–8.6 EU/mL) in DTaP recipients and nonrecipients, respectively (excluding stratum 1), and FHA GMCs were 4.1 EU/mL (95% CI: 2.9–5.8 EU/mL) and 7.4 EU/mL (95% CI: 5.2–10.6 EU/mL), respectively (Fig 1 A and B; Table 2). Recipients of DTaP had a significant rise in PT and FHA antibody concentration 8 weeks after vaccination (study week 32), reaching GMCs of 22.3 EU/mL for PT (95% CI: 15.9–31.2 EU/mL) and 77.0 EU/mL (95% CI: 51.0–116.2 EU/mL) for FHA. Their antibody concentrations fell significantly by 24 weeks postvaccination (study week 48; decay: 55% and 57% for PT and FHA antibody, respectively), but remained higher for both FHA and PT than at entry (Table 2). A lesser but statistically significant decline in antibody concentrations occurred between weeks 24 and 72 postvaccination. The 72-week postvaccination (study week 96) GMC for FHA, but not PT, remained significantly higher than at entry. The overall decrement in antibody concentration was 70% and 65% for PT and FHA, respectively, from 8 to 72 weeks postvaccination. PT and FHA antibody concentrations among recipients of DTaP were weakly correlated at entry but were more highly correlated thereafter (Spearman correlation coefficients: 0.21 at entry [P = .05] and 0.58, 0.39, and 0.53 at 8, 24, and 72 weeks postvaccination, respectively [P ≤ .0004]).


Figure 1
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  		FIGURE 1 A and B, PT and FHA GMCs, immunologic groups 2 to 4 combined. C and D, PT and FHA GMCs of DTaP recipients divided among immunologic groups; DTaP given at study week 24 and antibody measured at entry and 8, 24, 72 weeks postvaccination (study weeks 0, 32, 48, and 96). E and F, PT and FHA GMCs of DTaP nonrecipients divided among immunologic groups; antibody measured at study weeks 0, 48, and 96. Error bars indicate 95% CIs. GMCs were compared with F tests (general linear models procedure); immunologic group 1 is presented in C through F but was not included in comparisons.

 

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  		TABLE 2 GMCs of PT and FHA Antibody in Recipients of DTaP and Nonrecipients at Each Study Visit

 
Among nonrecipients of DTaP, PT and FHA antibody concentrations were relatively unchanged over the 96-week study period; a slight decline in PT antibody and a rise in FHA antibody from week 0 to week 48 were statistically significant, however, and the week-96 PT antibody concentration was lower than at week 0 (Fig 1 A and B; Table 2).

Comparison of Antibody Concentrations Among Immunologic Strata
Baseline PT and FHA antibody concentrations were similar among immune strata for recipients of DTaP. Postvaccination, strata 3 and 4 had similar PT antibody concentration profiles, with higher concentrations than those of stratum 2, although differences were not significant. A similar trend was not apparent for FHA antibody (Fig 1 C and D). Among nonrecipients of DTaP, FHA GMCs, but not PT GMCs, were directly related to immune stratum, although these findings were not significant (Fig 1 E and F).

Antibody Concentrations and HIV-RNA Level
PT and FHA antibody concentrations at baseline were generally similar among recipients of DTaP regardless of plasma HIV viral load (Fig 2 A–D). After vaccination, PT and FHA antibody concentrations varied inversely with baseline viral load (Fig 2 A and B). Although similar patterns were evident when the HIV-RNA level at the time of DTaP administration (study week 24) was substituted for baseline viral load, especially with respect to the association of lower antibody levels with viral load of >5000 copies per mL, the relationship between viral load and antibody concentrations was not as consistent (Fig 2 C and D). This reflected some shifting of subjects among the viral load categories during the study, although total numbers of subjects in each category remained relatively stable. Among nonrecipients of DTaP, PT GMC did not vary significantly with viral load, whereas an inverse relationship between FHA GMC and baseline viral load was observed (Fig 2 E and F). The latter relationship was less consistent when the study week-24 viral load was used, although viral load of >5000 copies per mL remained associated with lower FHA GMCs (Fig 2 G and H).


Figure 2
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  		FIGURE 2 A–D, PT and FHA GMCs of DTaP recipients according to HIV-RNA concentration at baseline and at DTaP visit (study week 24); antibody measured at entry and 8, 24, 72 weeks postvaccination (study weeks 0, 32, 48, and 96). E–H, PT and FHA GMCs of DTaP nonrecipients according to viral load at baseline and at week 24; antibody measured at study weeks 0, 48, 96. Error bars indicate 95% CIs. GMCs were compared with F tests (general linear models procedure); immunologic group 1 was not included in graphs or comparisons.

 
Predictors of Entry Antibody Concentration
Univariate analyses of baseline antibody concentrations among recipients of DTaP and nonrecipients combined (excluding an outlier with an extreme elevation of PT but not FHA antibody at entry) demonstrated an inverse relationship between FHA antibody and the interval between the last previous pertussis vaccination and study entry (P = .04), a higher PT GMC in boys (P = .03), a higher PT GMC in subjects 2 to <7 years of age (P = .05), a higher FHA GMC in the subjects who did not qualify to receive study DTaP (P = .02), and a direct relationship between baseline PT and FHA antibody concentrations (Spearman correlation coefficient: 0.40; P < .0001). A direct relationship between baseline FHA antibody concentration and entry CD4 percentage was also observed (Spearman correlation coefficient: 0.20; P = .006). The entry FHA GMC of subjects whose viral load closest to the most recent previous pertussis vaccination was >5000 copies per mL was lower than the GMC of subjects with viral loads of >400 to ≤5000 copies per mL (3.5 vs 21.1 EU/mL; P = .002) and marginally lower than that of subjects with viral loads of ≤400 copies per mL (3.5 vs 8.8 EU/mL; P = .06), although these viral load data were lacking for ≥50% of subjects. Neither baseline PT nor FHA antibody concentrations correlated with race, nadir CD4 percentage before HAART, lowest CD4 percentage ever, CD4 percentage at initiation of HAART, duration of the entry HAART regimen, CD4 percentage nearest to the most recent previous pertussis vaccination, or entry lymphocyte count, CD19%, immune stratum, or viral load.

Predictors of Response to Study Vaccination
Univariate analyses demonstrated that PT and FHA antibody concentrations 8 weeks after DTaP booster (study week 32) were directly related to the concentration of the homologous antibody at entry (Tables 3 and 4). The change in concentration of FHA but not PT antibody from baseline to 8 weeks postvaccination was also positively related to the homologous antibody concentration at entry (Spearman correlation coefficient: 0.45; P < .0001). Eight weeks after vaccination, GMCs were not significantly related to immunologic stratum, lowest CD4 percentage before initiation of the first HAART regimen, or lowest CD4 percentage ever. However, PT antibody was directly related to CD4 percentage at entry and at the time of study DTaP administration. Both PT and FHA GMCs 8 weeks after DTaP were inversely related to baseline viral load (Table 3); pairwise comparisons demonstrated significant differences in PT and FHA antibodies between subjects with viral loads of ≤400 copies per mL versus subjects with viral loads of >5000 copies per mL (P ≤ .05). Although similar trends were observed in relation to the viral load at the time of DTaP administration (study week 24), they did not approach significance. Scatter plots of the logarithm of the 8-week postvaccination PT and FHA antibody concentrations versus the logarithm of viral load at baseline or at the DTaP visit for subjects with viral loads of >400 copies per mL suggested negative slopes but with considerable scatter and no HIV-RNA thresholds predictive of greatly diminished responses (data not shown).


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  		TABLE 3 Univariate Regression Analyses of Predictors of PT and FHA Antibody Concentrations 8 Weeks After Booster Vaccine (Study Week 32) in Recipients of DTaP: Categorical Variables

 

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  		TABLE 4 Univariate Regression Analyses of Predictors of PT and FHA Antibody Concentrations 8 Weeks After Booster Vaccine (Study Week 32) in Recipients of DTaP: Continuous Variables

 
In multivariate analyses with antibody concentration 8 weeks after vaccination as the outcome and predictors consisting of the concentration of homologous antibody at entry and baseline viral load, the former predictor remained highly significant (P ≤ .0001), whereas entry HIV-RNA concentration was only marginally related (P = .09) for both PT and FHA antibodies. In a second multivariate analysis, PT antibody 8 weeks after vaccination was significantly associated with baseline PT antibody concentration (P < .0001) and CD4 percentage at the time of study DTaP administration (P = .03) but not with race (P = .2) or baseline viral load (P = .3).

Safety
One subject had a grade-3 event, localized erythema and induration (≥25 mm but <50% of involved extremity), judged related to DTaP. This represented 1 (0.8%) of 122 subjects who received study DTaP; 1 (2.4%) of 41 subjects in stratum 2 who received study DTaP; and 1 (10%) of 10 subjects <7 years of age who had received ≥5 doses of DTaP before entry, had negative tetanus titers, and received study DTaP. None of the 9 subjects who did not qualify to receive DTaP but were inadvertently administered vaccine suffered a grade-3 reaction. There were no grade-4 events related to study vaccinations, and no life-threatening adverse events or deaths occurred. There was no significant change during the study in the percentage of recipients of DTaP with plasma HIV-RNA levels of ≤400 copies per mL (60%–61% at each visit) or in the mean CD4 percentage after DTaP administration (33%–34% at each visit).


   DISCUSSION
TOP
 ABSTRACT
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
CONCLUSIONS
 REFERENCES
 
Interpretation of serologic responses to pertussis vaccination is challenging, because correlates of protection have not been established, there probably are contributions of multiple antibodies and cellular immunity to protection, and standardized functional assays are not available. Although antibody concentrations to antigens such as PT or to a combination of antigens correlated with clinical protection in some studies, they did not in others.13–17 Nevertheless, several conclusions can be drawn by comparing the antibody levels that we observed with levels in HIV-uninfected populations. Baseline antibody concentrations in our cohort were low, similar to or lower than concentrations in 15- to 20-month-olds who had received a 3-dose primary series of acellular pertussis vaccines in infancy,18 4- to 6-year-olds who had received a primary series in infancy and a booster dose at 12 to 18 months,16,17 and adolescents and adults tested before receiving a booster dose19–21 (PT GMCs = 2–14 EU/mL and FHA GMCs = 0–62 EU/mL after various vaccine formulations). The low baseline antibody concentrations in our population, despite ≥4 previous pertussis vaccinations, were also consistent with low levels found in a cross-sectional analysis of 10- to 49-year-olds in the Third National Health and Nutrition Examination Survey. In this large serosurvey of a nationally representative sample of adolescents and adults remote from vaccination whose specimens were tested in the same laboratory used in the present study, PT antibody concentrations were <1 EU/mL in 16% and <20 EU/mL in 85%, and FHA antibody concentrations were <1 EU/mL in 1% and <20 EU/mL in 58%.12

After booster vaccination, our subjects had significant increases in PT and FHA antibody concentrations, although levels achieved were generally less than in children uninfected with HIV after a primary series of acellular pertussis vaccines in infancy,22–24 after a first booster dose of DTaP at 12 to 28 months of age preceded by primary vaccination in infancy,16,25 and after a second booster dose of DTaP at 4 to 6 years16 (PT GMCs: 51–137 EU/mL and FHA GMCs: 103–650 EU/mL after Infanrix or different vaccine formulations containing the same concentrations of PT and FHA antigens). The antibody concentrations our cohort attained were also lower than postvaccination antibody concentrations reported for acellular pertussis vaccines containing approximately one third the amount of PT and FHA antigens (ie, 8 µg of PT and 8 µg of FHA) in HIV-uninfected 10- to 18-year-olds20 and adults21,26,27 (PT GMCs: 38–140 EU/mL and FHA GMCs: 354–906 EU/mL). Direct comparison among studies must be done with caution because of differences in populations, vaccines, study design, and serologic assays.17 For example, a limitation of the present study is that serologic response was assessed 2 months after vaccination (range: 1–3 months) rather than 1 month postvaccination as was done in most comparator studies. In addition, we did not measure the antibody to pertactin because this assay was not included in the assay standardization reported for the laboratory used in the present study.12 Despite these limitations, previously described populations uninfected with HIV seemed to mount higher antibody responses after boosting than did our subjects infected with HIV. Our use of tetanus seronegativity as a screen for administering DTaP to subjects <7 years of age who had previously received ≥5 DTP vaccines and for subjects 7 to 13 years of age may have biased the vaccinated group in favor of a less immune-competent subset. However, the similar profiles of subjects who did and did not qualify to receive DTaP argue against significant bias. On the other hand, this selection strategy may have contributed to the low rate of adverse events that we observed with pediatric DTaP in children infected with HIV up to 13 years of age. This low reactogenicity was similar to that observed with primary vaccination in infants28 and contrasts with rates of moderate-severe erythema, swelling, and pain of ≥26% in 4- to 6-year-old children uninfected with HIV who were receiving a fifth dose of Infanrix.29

The rapid rates of antibody decay were similar to rates of decline after pertussis vaccination in infants and young children (>50% in 6 months12,15; 85%–98% over 4 years16) and adolescents and adults (42%–58% between 1 and 6 months postvaccination; 61%–73% between 1 and 18 months postvaccination; and 80%–86% over 3 years postvaccination) uninfected with HIV.19 Reported rates of decay of PT antibody in the year after vaccination of 52% to 78% mirror the decrement in cell-mediated immune responses after vaccination and the fall in titers in the year after natural B pertussis infection (66% for PT and 19% for FHA).19,21,30 Despite waning antibody titers, subjects uninfected with HIV rapidly develop high PT and FHA antibody levels after booster vaccination, consistent with an anamnestic response and immunologic memory.16 Whether this is true of HIV-infected populations is unknown.

De Martino et al6 demonstrated that 9 of 12 children infected with HIV receiving monotherapy (zidovudine or didanosine) who were given 3 doses of acellular pertussis vaccine had a fourfold or more rise in antibody to ≥1 of PT, FHA, or pertactin. Antibody titers 2 months after the third dose were significantly lower than those of control subjects uninfected with HIV: PT GMC was 30 vs 106 EU/mL, and FHA GMC was 26 vs 760 EU/mL. Although our study did not directly compare immune responses in children infected with HIV on HAART with children uninfected by HIV, postbooster GMCs attained by our population were more similar to the postvaccination titers of subjects infected with HIV who were on monotherapy than the HIV-uninfected control subjects in the study by De Martino et al.6 This may reflect a deficiency of immunologic memory induced by previous DTP vaccination and absence of an anamnestic response to boosting. Alternatively, the low pertussis antibody response, which contrasts with ELISA antibody responses to a pneumococcal conjugate plus polysaccharide vaccine series that were quite similar to those of children uninfected with HIV,31 may be indicative of immunogen-specific variability in the degree of immune reconstitution that accompanies HAART. Deficient pathogen-specific immune responses have been documented in patients infected with HIV who were on HAART.32–35 Similarly, although small studies of children treated with HAART demonstrated improved antibody responses to measles, mumps, rubella, tetanus, and Haemophilus influenzae type b vaccines, other reports found that children and adults infected with HIV and on HAART have limited antibody and cellular responses to hepatitis A and tetanus vaccines.7,11,36–39 Whether additional doses of DTaP or higher doses of pertussis antigens while on HAART would stimulate antibody levels similar to those seen in children uninfected with HIV remains to be tested.39

Antibody concentration at entry was a strong predictor of response to booster vaccine, and entry FHA antibody concentration correlated with change in FHA antibody concentration from before to after booster vaccination, despite the bias in the negative direction of regression toward the mean. This is similar to observations in an adolescent and adult acellular pertussis vaccine study21 and in our study of pneumococcal conjugate and polysaccharide vaccines in children infected with HIV.31 It suggests that baseline antibody concentration may be a marker of immune competence, perhaps reflecting genetic factors that influence vaccine responsiveness.40–43 Baseline PT antibody concentration did not correlate significantly with change in PT antibody concentration after booster vaccine, possibly because the magnitude of PT antibody responses was less robust overall.

PT antibody response correlated with the CD4 percentage at study entry and at the time that the booster DTaP dose was administered but not with the nadir CD4 percentage before HAART. This is consistent with other studies in HIV-infected populations that showed direct relationships between the CD4 percentage and response to a variety of vaccines, including pertussis-containing vaccine.6,37,44–50 It suggests that changes in the CD4 percentage in response to HAART are more predictive of vaccine response than the CD4 percentage before initiation of HAART, as we observed with pneumococcal vaccination.31 PT and FHA antibody responses were inversely related to HIV-RNA level, also similar to our findings with pneumococcal vaccination31 and to observations with measles and varicella vaccines.38,51 Whether ongoing HIV replication in the face of HAART reflects antiretroviral resistance, medication nonadherence, or pharmacologic factors, these findings are consistent with observed HIV-induced impairment of B-cell–CD4-cell interactions.52


   CONCLUSIONS
TOP
 ABSTRACT
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 CONCLUSIONS
REFERENCES
 
The relatively low pertussis antibody responses to boosting in children infected with HIV suggest that a single booster dose of pertussis vaccine, even in the context of HAART, may be insufficient to induce an immune response comparable to that of children, adolescents, and adults who are uninfected with HIV. Although minimum protective levels of antibody to pertussis antigens have not been defined, these findings further suggest that immunologic memory from previous pertussis vaccination may be lacking in children infected with HIV and/or that immune reconstitution with HAART may be incomplete with respect to pertussis antigens. Further investigation is needed to define the optimal approach to preventing pertussis infection in children infected with HIV and to better understand the immunologic deficits that may be present in children infected with HIV despite treatment with HAART.


   ACKNOWLEDGMENTS
 
This work was supported in part by the International Maternal Pediatric Adolescent AIDS Clinical Trials Group of the National Institute of Allergy and Infectious Disease (NIAID) and the Pediatric/Perinatal HIV Clinical Trials Network of the National Institute of Child Health and Human Development (NICHD) (NIAID sites were supported by NIAID grant U01 AI068632, and NICHD sites were supported by NICHD contract N01-HD-3-3345). This work was also supported in part by the General Clinical Research Center Units, funded by the National Center for Research Resources, National Institutes of Health. GlaxoSmithKline Pharmaceuticals provided study vaccine.

Additional members of the P1024 Protocol Team include Shirley Jankelevich, MD (Pediatric Medicine Branch, National Institute of Allergy and Infectious Diseases, Bethesda, MD), Jennifer Read, MD (Pediatric, Adolescent, and Maternal AIDS Branch, National Institute of Child Health and Human Development, Bethesda, MD), Victoria Hadhazy, MA (International Maternal Pediatric Adolescent AIDS Clinical Trials Group/Pediatric AIDS Clinical Trials Group Operations Office (Rockville, MD), Alison Robbins, MA (International Maternal Pediatric Adolescent AIDS Clinical Trials Group/Pediatric AIDS Clinical Trials Group Operations Office, Rockville, MD), Jane C. Lindsey, ScD (Statistical and Data Analysis Center, Harvard School of Public Health, Boston, MA), Janice Hodge, RN, BS (Frontier Science and Technology Research Foundation, Amherst, NY), Dorothy Smith, MS, CPNP (University of Massachusetts Memorial Medical Center, Worcester, MA), Paul Tran, RPh (Pharmaceutical Affairs Branch, National Institute of Allergy and Infectious Diseases, Bethesda, MD), Grace Aldrovandi, MD (Children's Hospital of Los Angeles, Los Angeles, CA), Rachel Barrett, BS (University of Colorado School of Medicine, Denver, CO), William Kabat, BS (Chicago Children's Memorial Hospital, Chicago, IL), Velma Keeley, BS (Wyeth-Ayerst Global Pharmaceuticals, St Davis, PA), Paul Willems, MD (GlaxoSmithKline Pharmaceuticals, Collegeville, PA), and Carol Gore (Panorama Village, TX).

Participating sites and site personnel include Chicago Children's Memorial Hospital (Ram Yogev, MD), University of Medicine and Dentistry of New Jersey-New Jersey Medical School (Barry Dashefsky, MD, Linda Bettica, RN, and Paul Palumbo, MD), Harlem Hospital (Elaine Abrams, MD, Maxine Frere, RN, and Lisa Gaye Robinson, MD), Metropolitan Hospital Center (Mahrukh Bamji, MD), Long Beach Memorial Hospital (Audra Deveikis, Susan Marks, Karen Elkins, and Lisa Melton), San Juan City Hospital (Eleanor Jimenez, MD), Los Angeles County Medical Center (James Homans, MD, Ana Melendez, RN, and Andrea Kovacs, MD), University of Florida-Jacksonville (Mobeen H. Rathore, MD, Ana Alvarez, MD, Ayesha Mirza, MD, and Thomas Chiu, MD), University of California-San Diego (Stephen A. Spector, MD, Rolando Viani, MD, MTP, Mary Caffery, RN, MSN, and Lisa Stangl, CPNP), State University of New York at Stony Brook (Denise Ferraro, RN, Silvia Muniz, and Michell Davi, NP), University of Colorado School of Medicine and the Children's Hospital (Jody Maes, MD, Carol Salbenblatt, RN, Suzanne Paul, BSN, MSN, FNP, and Emily Barr, CPNP, CNM, MSN [grant M01 RR00069, General Clinical Research Centers Program, National Center for Research Resources, National Institutes of Health]), University of Chicago Children's Hospital, Schneider Children's Hospital of North Shore-Long Island Jewish Health System (Vincent R. Bonagura, MD, Susan J. Schuval, MD, and Connie Colter, MS, CPNP), Children's Hospital of Oakland (Ann Petru, MD, Teresa Courville, RN, MN, Karen Gold, RN, FNP, and Lauren Poole, RN, FNP), St Christopher's Hospital for Children and Drexel University College of Medicine (Janet S. Chen, MD, Jill A. Foster, MD, Daniel H. Conway, MD, and Gary Koutsoubis), Boston Medical Center and Boston University School of Medicine (Ann Marie Regan, PNP), State University of New York Downstate (H. Jack Moallem, MD, Edward Handelsman, MD, Denise Swindell, and Jean Kaye, RN), Ramon Ruiz Arnau University (Wanda Figueroa, MD), Bronx Lebanon Hospital Center (Mavis Dummitt, RN, Anantha Kallury, BPharm, Murli Purswani, MD, and Saroj Bakshi, MD), St Lukes/Roosevelt Hospital Center (Emma Stuard, MD, and Steven Arpadi, MD), University of Massachusetts Medical Center (Katherine Luzuriaga, MD, and Dottie Smith), Children's Hospital of Boston (Sandra Burchett, MD, MS, Lynne Lewis, RN, MS, CPNP, and Catherine Kneut, RN, MS, CPNP), North Broward Hospital District (Amy Inman, BS, Linh Tran, PharmD, Guillermo Talero, MD, and Ann Puga, MD), University of Maryland (John Farley, MD, and Mary MacFadden), University of California-San Francisco Moffitt Hospital (Diane Wara, MD), New York University School of Medicine (Siham Akleh, RN, Aditya Kaul, MD, Sulachni Chandwani, MD, and Thomas Hastings, RN), University of Rochester Medical Center (Geoffrey A. Weinberg, MD, Susan Laverty, RN, Barbra Murante, MS, RN, PNP, and Francis Gigliotti, MD), Yale University School of Medicine (Warren A. Andiman, MD, Leslie Hurst, MS, and Sostena Romano, APRN), University of Puerto Rico and University Children's Hospital (Irma Rodriguez, MD), University of Connecticut Health Center/Connecticut Children's Medical Center (Juan C. Salazar, MD, MPH, Gail Karas, RN, and Lorraine Wells, RN), Texas Children's Hospital and Baylor University (William Shearer, MD), Cook County Hospital (Jaime Martinez, MD), Cornell University-New York Presbyterian Hospital (Joseph Stavola, MD), Children's Hospital National Medical Center (Hans Spiegel, MD), University of Florida-Gainesville (Robert Lawrence, MD), Tulane University and Charity Hospital of New Orleans (Russell Van Dyke, MD, Cheryl Borne, RN, and Margaret Cowie, BS), and University of Alabama at Birmingham (Robert Pass, MD, Marilyn Crain, MD, and Newana Beatty).

We appreciate the participation of patients and families in this study, the assistance of research personnel at the study sites, and the performance of tetanus antibody assays by Carmen White, BS, and Patricia Defechereux, PhD.


   FOOTNOTES
 
Accepted May 3, 2007.

Address correspondence to Mark J. Abzug, MD, Pediatric Infectious Diseases, Children's Hospital, 13123 E 16th Ave, Aurora, CO 80045. E-mail: abzug.mark{at}tchden.org

Financial Disclosure: Dr Nachman is a consultant for Medimmune, Inc, Merck & Co, Inc, and Sanofi Pasteur; Dr Levin received research funding from GlaxoSmithKline Pharmaceuticals (for herpes simplex virus vaccine and human papillomavirus vaccine); Dr Pelton is on the vaccine advisory boards of GlaxoSmithKline Pharmaceuticals (pneumococcal and meningococcal), Wyeth Pharmaceuticals (pneumococcal), and Sanofi Pasteur (meningococcal, tetanus, diphtheria, pertussis, poliovirus, and Haemophilus influenzae B) and received research funding from Wyeth Pharmaceuticals and Sanofi Pasteur; Dr Borkowsky received research funding from GlaxoSmithKline Pharmaceuticals (fosamprenavir); and Dr Edwards received research funding from Sanofi Pasteur, Medimmune, Inc, Vaxgen, Inc, Merck & Co, Centers for Disease Control and Prevention, and National Institutes of Health. The other authors have indicated they have no financial relationships relevant to this article to disclose.

The content of this article is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute of Allergy and Infectious Diseases or the National Institutes of Health.

This trial has been registered at www.clinicaltrials.gov (identifier NCT00013871).


   REFERENCES
TOP
 ABSTRACT
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 CONCLUSIONS
 REFERENCES
 

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