Safety and Immunogenicity of a Heptavalent Pneumococcal Conjugate Vaccine in Infants With Human Immunodeficiency Virus Type 1 Infection
* Department of Pediatrics, State University of New York Health Science Center at Stony Brook, Stony Brook, New York
Department of Biostatistics, Harvard School of Public Health, Boston, Massachusetts
Department of Pediatrics, University of Maryland School of Medicine, Baltimore, Maryland
|| Department of Pediatrics, Harlem Hospital Center, Columbia University, New York, New York
¶ University of Texas Southwestern Medical Center, Dallas, Texas
# Department of Infectious Diseases, Children’s Hospital Oakland, Oakland, California
** Department of Pediatrics, Baylor College of Medicine, Texas Children’s Hospital, Houston, Texas
Pediatric Medicine Branch, Division of AIDS, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland
Pediatric, Adolescent, and Maternal AIDS Branch, National Institute of Child Health and Human Development, National Institutes of Health, Rockville, Maryland
|||| Statistical and Data Analysis Center, Frontier Science & Technology Research Foundation, Inc, Chestnut Hill, Massachusetts
¶¶ Pediatric ACTG Operations Center, Rockville, Maryland
## Statistical and Data Management Center, Frontier Science & Technology Research Center, Amherst, New York
*** University of Maryland at Baltimore, Baltimore, Maryland
San Francisco General Hospital, San Francisco, California
Pharmaceutical and Regulatory Affairs Branch, Division of AIDS, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland
|||||| Lederle-Praxis Biologicals, West Henrietta, New York
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ABSTRACT |
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Objective. Heptavalent pneumococcal conjugate vaccine (PCV) has been shown to be safe and effective in healthy infants and children. However, little is known about its use in children who have human immunodeficiency virus (HIV) infection and are known to be at increased risk of developing pneumococcal infections. This study was conducted to evaluate the safety and immunogenicity of heptavalent PCV in infants with HIV infection.
Methods. The Pediatric AIDS Clinical Trials Group Study 292 Team randomized infants with HIV infection 2:1 to receive heptavalent PCV or placebo in a double-blinded manner. Infants were vaccinated with 3 doses at 2-month intervals, starting at ages 56 to 180 days. A booster dose was given at 15 months of age. Immunogenicity was evaluated after the third dose of vaccine, before and after the booster dose, and at 24 months of age.
Results. Thirty infants with HIV infection received PCV, and 15 received placebo. No differences in baseline characteristics were found across arms. Five severe acute reactions were experienced by 4 subjects: 3 in the PCV arm and 1 in the placebo arm; all occurred among subjects with symptomatic disease at study entry. No differences were found in the 2 arms with respect to the number or timing of new diagnoses through 24 months of age, including diagnoses of otitis media. However, when symptomatic subjects were examined separately, the first new diagnosis occurred more rapidly among PCV recipients. Three deaths, all judged to be unrelated to study vaccine, occurred during follow-up: 2 in the PCV arm and 1 in the placebo arm. The primary immunogenicity measures were based on composites of 4-fold changes in serotype-specific immunoglobulin G titers from preimmunization levels. We found a highly significant difference between the vaccine and placebo arms, with the PCV arm showing higher rates of response. Asymptomatic and symptomatic subjects who received PCV had similar immunologic responses for all serotypes.
Conclusions. This study demonstrates that heptavalent PCV was well tolerated and not associated with vaccine-associated adverse reactions. Most important, this vaccine was immunogenic in the infant with HIV infection. However, additional studies of this vaccine (or others) must pay special attention to patients with symptomatic HIV disease, as they seem to be at higher risk for adverse events to any antigen.
Key Words: heptavalent pneumococcal conjugate vaccine • Prevnar • safety • immunogenicity • HIV • pneumococcal polysaccharide vaccine
Abbreviations: PCV, pneumococcal conjugate vaccine • HIV, human immunodeficiency virus • HAART, highly active antiretroviral treatment • PACTG 292, Pediatric AIDS Clinical Trials Group Study 292 • CDC, Centers for Disease Control and Prevention • IgG, immunoglobulin G • GMC, geometric mean concentration
Heptavalent pneumococcal conjugate vaccine (PCV) has been shown to be safe, immunogenic, and efficacious for preventing invasive pneumococcal disease in healthy children.1–3 The American Academy of Pediatrics recently recommended the routine administration of heptavalent PCV concurrently with other childhood immunizations for all children 23 months and younger and to children 24 to 59 months of age who are at high risk for invasive pneumococcal infection, including children who have human immunodeficiency virus (HIV) infection.4,5
Data presented in children with HIV infection show the incidence of invasive pneumococcal events to be 11.1 per 100 patient-years in the pre-highly active antiretroviral treatment (HAART) era6 and 4.1 events per 100 patient years in the post-HAART era.7 These incidence rates of invasive disease are 2.8 to 12.6 times the rate among HIV-negative control subjects for children younger than 2 years and younger than 3 years, respectively.8,9 Among US children through 24 months of age, the rate of invasive disease from 1997 to 2000 ranged from 322/100 000 to 310/100 000 people.10 The purpose of this study was to assess the safety and immunogenicity of a 3-dose series of vaccination with heptavalent PCV in infants with HIV infection starting at ages ranging from 2 to 6 months followed by a booster dose at 15 months of age.
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METHODS |
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Study Design
The Pediatric AIDS Clinical Trials Group Study 292 (PACTG 292) was a randomized, double-blind, placebo-controlled trial conducted at 18 medical centers throughout the United States. The Institutional Review Boards of all participating institutions approved the study. Written informed consent was obtained from parents or legal guardians.
Infants who were presumed to HIV infection were randomized 2:1 to receive either heptavalent PCV or placebo using permuted blocks of size 3 with stratification by whether the infant was Centers for Disease Control and Prevention (CDC) immunologic category 3 with CD4 count <750 cells/mm3 or clinical disease category C according to current CDC HIV classification guidelines. Originally, 60 infants were to be enrolled. However, study enrollment was prematurely curtailed after 48 subjects were randomized. This decrease in enrollment was related to the institution of perinatal prophylaxis for prevention of HIV transmission resulting in a significant decrease in a population of infants with HIV infection in the United States.
Safety was monitored in a blinded manner by the study team. Acute reactions up to 48 hours subsequent to each blinded study vaccine and pneumococcal polysaccharide vaccine (PPV) administration were reviewed and assessed to be attributable to the study vaccine or not. Signs, symptoms, and new diagnoses were reviewed throughout the study period by the study team on a monthly basis until each child was 24 months of age. Two unblinded interim analyses for safety were conducted by the study statistician and discussed with the National Institute of Allergy and Infectious Diseases and National Institute of Child Health and Human Development medical officers in lieu of an independent monitoring committee. No interim monitoring for immunogenicity was conducted.
Population
Subjects enrolled had to be between 56 and 180 days of age and were presumed to have HIV infection. Presumed HIV infection was defined as a single positive test by positive co-culture for HIV, or DNA polymerase chain reaction, or HIV p24 antigen tests obtained after 1 month of age. A confirmatory HIV test was required, before or after enrollment, for the subject’s data to be analyzed. Co-enrollment on other therapeutic protocols but not in HIV vaccine trials was permitted. Recipients of blood products within 56 days before study vaccination or vaccination with pneumococcal vaccine of any type, measles vaccine within 1 month, or other routine vaccinations within 1 week before study vaccination were excluded. Children had to have a birth weight of at least 1800 g. Children with congenital immunoglobulin deficiency, SS or SC hemoglobinopathy, asplenia, hypogammaglobulinemia, or major congenital anomalies were excluded. Subjects with acute moderate to severe intercurrent illness or fever within 72 hours before randomization or with any of the following abnormal laboratory findings within 28 days before randomization were excluded: platelet count <50 000 cells/mm3, hemoglobin <7.0 g/dL, serum creatinine >1.5 mg/dL, SGPT >10xN or SGOT >10xN.
Study Vaccine and Administration
The study vaccine has been described in detail previously.1 In brief, vaccine contains serotypes 4, 6B, 9V, 14, 18C, 19F, 23F, and CRM197 and aluminum phosphate. The placebo is composed of sterile saline with aluminum phosphate.
Vaccine or placebo was administered intramuscularly in the anterolateral thigh in a volume of 0.5 mL in a double-blinded manner at weeks, 0, 8, and 16 after enrollment, and a booster dose was administered at 15 months of age (at least 6 months after the third vaccination). A PPV, PNU-IMUNE 23 (Wyeth Lederle Vaccines), was given in a volume of 0.5 mL intramuscularly or subcutaneously at 24 months of age.
Safety Assessment
Several assessments of safety were used. After each injection, including the PPV vaccination, subjects were observed in the clinic and reactions were recorded after 30 minutes. The parents or guardians were provided with a diary card to aid in the collection of additional acute reaction data and were contacted at 24 and 72 hours to determine acute reactions in the 24 and 48 hours after vaccination, respectively. Acute reactions indicating severe erythema, induration, pain, fever, irritability, and allergic reactions were captured. Severe reactions were defined as erythema or induration 
25 mm (size of a US quarter-dollar coin), pain restricting leg movement, fever 103.0°F; irritable behavior including inconsolable crying 3 hours, unusually high-pitched screaming or seizures; or allergic reactions that include bronchospasms requiring therapy, urticaria, anaphylaxis, or angioedema. Subjects who experienced severe reactions were asked to return for a follow-up visit.
In addition, complete blood count and lymphocyte enumeration and quantitative immunoglobulins were performed at preimmunization, study week 20, and 15 months of age. Signs and symptoms, occurring after or increasing in grade after entry, and new diagnoses, irrespective of possible association with vaccine, were recorded during each study visit to capture occurrences throughout the study period through 24 months of age. Analyses of signs and symptoms excluded acute reactions described above and were graded as mild, moderate, severe, or life-threatening.
Serology
Blood for antibody assays was drawn immediately at entry before receiving the first dose (week 0), 4 weeks after the third dose (20 weeks after entry), immediately before and 1 month after the booster dose (ages 15 and 16 months, respectively), and immediately before receiving PPV at 24 months of age. Blood was sent to Wyeth-Lederle laboratories (West Henrietta, NY) for blinded analysis. Serum levels of immunoglobulin G (IgG) to each of the 7 serotypes contained in PCV were quantified as described elsewhere11 and converted to micrograms per milliliter IgG by use of standard reference serum 89SF.12 Any concentration below the lower limit of quantitation of 0.01 µg/mL was reported as 0.005 µg/mL.
Primary Immunogenicity Endpoints
For avoiding inflating the false-positive rate associated with testing for immunogenicity against each of 7 serotypes for the primary endpoints, 2 composite endpoints were prespecified in the protocol for assessing overall immunogenicity of the vaccine, based on epidemiologic and scientific criteria using 4-fold IgG antibody increases (responses) from preimmunization levels after the primary series (week 20). The epidemiologic criterion of response of >4-fold antibody responses in vaccine serotypes represented >50% of disease burden, assuming that serotypes 4, 6B, 9V, 14, 18C, 19F, and 23F cause 7%, 19%, 8%, 28%, 8%, 15%, and 6% of pneumococcal disease, respectively. These percentages were derived from 2 studies of children without HIV infection.13–16 The scientific criterion of response required 4-fold increase for 3 or more of the serotypes in the vaccine.
Secondary Immunogenicity Endpoints
Immunogenicity was investigated further with the use of serotype-specific rates of 4-fold antibody increases from preimmunization levels, geometric mean concentrations (GMCs) of antibody, mean fold changes, and rates of achieving type-specific antibody levels of 0.5 and 0.15 µg/mL at week 20. Booster rates compare serotype-specific GMC, 4-fold increases, and mean fold changes in IgG antibody levels 4 weeks after the booster dose to levels just before administration of the booster dose.
Statistical Methods
The study was designed so that 60 subjects would provide 80% power to detect a difference of 
40% between the PCV and placebo arms on any individual serotype, after allowing for 20% attrition. The power of the global epidemiologic test and the scientific tests was 0.99 and 1.0, respectively.
Subjects without HIV infection status confirmation were excluded from all analyses unless otherwise specified. As prespecified in the protocol, subjects who received exogenous blood products before completing the primary series were excluded from the immunogenicity analyses. When subjects received exogenous blood products after the primary series, serology for 3 months subsequent was excluded.
Baseline characteristics were compared using 2-sided Fisher exact test; Exact test for R x C tables; or the Wilcoxon test for binary, categorical, and continuous characteristics, respectively. Acute reactions were compared using a 1-sided Fisher exact test. Time to first event data were compared using the log rank test. All safety measures, other than acute reactions, use 2-sided exact or log rank tests.
GMCs of IgG antibody to pneumococcal serotypes were determined for PCV and placebo arms at each time point, and 95% confidence intervals were calculated assuming normality of the data on the logarithmic scale and were antilogged for presentation. Baseline GMC comparisons were made using a 2-sided t test, whereas postimmunization comparisons were made using a 1-sided t test. Binary measures of immunogenicity were compared using a 1-sided Fisher exact test. Reverse cumulative distribution plots were used to display the percentage of subjects who achieved different concentrations of antibody to each of the 7 pneumococcal serotypes in the vaccine. Overall summary measures for immunogenicity using epidemiologic and scientific criteria are compared using 2-sided tests. Changes in antibody levels on the PCV after the primary series to just before the booster dose were tested against a null hypothesis of no change using a 2-sided t test.
Subgroup analyses were based on HIV clinical classification groups that were based on CDC guidelines. Asymptomatic is defined as category N, and symptomatic is defined as category A or B (mildly or moderately symptomatic). No subjects in this cohort were category C (severely symptomatic). Immune categories are based on 1994 CDC Morbidity and Mortality Weekly Reports groupings.
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RESULTS |
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A total of 48 subjects were randomized to the study between January 1996 and January 1998: 32 to the PCV arm and 16 to the placebo arm at a total of 18 sites. Of the 48 subjects randomized, 2 did not receive any blinded study vaccine: 1 subject who was randomized to the PCV arm did not show for clinic visits, and 1 subject who was randomized to the placebo arm had a fever contraindicating vaccination. These same 2 subjects were not followed during the study and were not included in any analyses. A third subject, randomized to the PCV arm, died of cytomegalovirus pneumonia 6 months after randomization without HIV status confirmation. Unless otherwise specified, this subject without HIV confirmation was also excluded from all analyses.
Of the remaining 45 subjects available for analysis, 5 prematurely discontinued vaccination schedule and study. On the PCV arm, 2 subjects died and the mother requested that 1 subject be withdrawn from study. On the placebo arm, 1 subject died and 1 subject was lost to follow-up. There was no statistically significant difference across the 2 arms in the percentage or the time to premature discontinuation.
Eight subjects received exogenous blood products, 4 during the primary series. The latter 4 subjects were excluded from the primary immunogenicity analyses. An additional 7 subjects did not have serology at preimmunization or week 20 as a result of death/dropout or missing data and are excluded from the primary immunogenicity analyses. A total of 24 subjects on PCV and 10 subjects on placebo are included in the primary immunogenicity analyses. Of interest is that only 71% of the subjects were on any antiretroviral therapy (11% on protease inhibitor containing regimen therapy) at the time of their initial vaccination. At the time of evaluating the immunogenicity of the vaccine, week 20, 82% were on antiretrovirals (18% on protease inhibitor containing regimens), and at the completion of the study, chronologically 24 months of age, 95% were on any antiretroviral (51% on a protease inhibitor containing regimens).
Baseline Characteristics
Table 1 shows the baseline characteristics of infants who were enrolled in the study, including age at vaccination, CD4 count and percentage, clinical classification, and baseline antiretroviral regimen. Generally, characteristics were evenly distributed across vaccination arms, with the exception of a marginal imbalance in gender (P = .053). In particular, CD4+ cell count, percentage of lymphocytes that are CD4+, CDC clinical classification and immune category, and baseline antiretroviral regimen were well balanced across vaccination arms.
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Safety
PCV
Of the infants with confirmed HIV infection, 30 who were randomized to PCV and 15 who were randomized to placebo are included in the analysis of reactogenicity. Four subjects experienced a total of 5 severe reactions to vaccine; 3 subjects were on the PCV arm, and 1 was on the placebo arm. The parents of 1 subject on the PCV arm reported severe induration, erythema, and limited leg movement after the first vaccination. The parents of another subject on the PCV arm reported limited leg movement and high-pitched crying after the first vaccination and limited leg movement after the second vaccination. Another PCV recipient had a fever of 103.6°F after the first vaccination. On the placebo arm, the parents of 1 subject reported a 103.1°F fever after the second vaccination. All adverse reactions resolved within 48 hours. No statistically significant differences in percentages of subjects who had reactions of any type were found after any vaccination with PCV (P = .59). All 4 severe reactions to vaccination occurred among subjects with symptomatic disease at baseline, ie, CDC clinical classification of A or B (n = 22), and the difference in severe acute reactions between asymptomatic and symptomatic groups was significant (P = .049). Comparisons of severe acute reactions among symptomatic subjects across vaccination arms were not statistically significant (P = .62).
Lowering our criterion to include all moderate or worse levels of reactogenicity and comparing vaccine and placebo arms, we did find significant differences. Differences occurred after the first and second doses (56.7% vs 20.0% [P = .02] and 53.3% vs 13.3% [P = .01], respectively). The moderate reactions included swelling, redness, pain, fever, and/or irritability.
PPV
Of the 40 subjects who remained on study to 24 months of age—27 and 13 on PCV and placebo arms, respectively—all were vaccinated with PPV. One subject on each of the PCV and placebo arms experienced a severe reaction to PPV. The subject on the PCV arm experienced pain restricting leg movement and irritability, and the subject on the placebo arm experienced erythema and induration >25 mm and pain restricting leg movement. There was no statistically significant difference across arms in overall rates of reactogenicity to vaccination (P = 1.0).
Hematology, Signs/Symptoms, and New Diagnoses
No differences in severe anemia or neutropenia were seen during study follow-up across study arms (P = 1.00, 1.00). Of the 30 and 15 subjects with HIV status confirmed on the PCV and placebo arms, 10 (33.3%) and 1 (6.7%) on the two arms, respectively, had severe signs and symptoms other than acute reactions to vaccination; these rates were statistically significantly different (P = .044). Signs and symptoms experienced included but are not restricted to fever, anemia, rash, diarrhea, hepatomegaly, splenomegaly, cough, wheezing, and apnea. There was also a marginally significant difference in the time to first abnormal sign or symptom with those on the PCV arm experiencing them quicker (P = .051). On the placebo arm, the 1 subject who experienced a grade 3 sign or symptom experienced it 190 days after the first injection. In contrast, by 6 months, 5 (17%) of subjects on the PCV arm had experienced a new grade 3 sign or symptom. These signs or symptoms occurred throughout the period, not just subsequent to receipt of a dose of vaccine. Comparing asymptomatic to symptomatic subjects, no significant difference in time to first grade 3 sign or symptom was observed (P = .19).
All but 1 subject on the PCV arm and all subjects on the placebo arm experienced at least 1 new diagnosis with an average of >8 new diagnoses per subject. Diagnoses included but are not limited to episodes of otitis media, upper respiratory infection, pneumonia, thrush, candidiasis (other than thrush), bacteremia, and conjunctivitis. We found no difference across arms in the time to first diagnosis (P = .24). We also found no difference across asymptomatic and symptomatic groups in time to first new diagnosis (P = .16). Among subjects who were symptomatic at baseline, there was a significant difference across vaccination arms in the time to first new diagnosis (P = .002); 14 (93%) of 15 on the PCV arm and 2 (29%) of 7 on the placebo arm had received at least 1 new diagnosis by week 16.
Three deaths occurred during study follow-up; 2 were on the PCV arm, and 1 was on the placebo arm. The time to death was similar in the 2 arms (P = .96). An additional death on the PCV arm was excluded as a result of our inability to confirm his or her HIV status. If we were to include this infant, then we still would not have evidence of difference across vaccination arms (P = .69).
Immunogenicity
Preimmunization GMC on the PCV and placebo arms ranged between 0.02 and 0.10 µg/mL for the 7 vaccine serotypes. The differences across arms were not statistically significant for any serotype (all P > .30).
For the primary epidemiologic endpoint, we required coverage of 50% of pneumococcal disease present in young children from the 7 serotypes in the vaccine as measured by 4-fold increases from preimmunization to postdose 3. We found that 22 of 24 subjects on the PCV arm and 0 of 10 subjects on the placebo arm met this criterion of response. For the scientific criterion, we required 4-fold increases to 3 or more serotypes in the vaccine, and we also found that the same 22 of 24 subjects on the PCV arm and 0 of 10 subjects on the placebo arm met this criterion of response. Both 2-sided comparisons were highly significant (P < .001).
Serotype-specific analyses based on GMC, mean fold rises, and rates of 4-fold rise after the primary series are shown in Table 2. For all vaccine serotypes, GMC and mean fold rises were statistically significantly higher for the PCV arm than for the placebo arm (P < .001). Rates of achieving 4-fold rises in IgG levels from preimmunization ranged from 88% to 100% for the PCV arm depending on serotype and from 0% to 20% for the placebo arm depending on serotype. All differences in rates of achieving 4-fold rises were highly statistically significant (all P < .001). Figure 1 shows reverse cumulative distributions for PCV and placebo arms for each of the 7 serotypes. More than 95% of PCV recipients achieved levels of 0.15 µg/mL after the primary series, and at least 80% achieved levels of 0.5 µg/mL. In contrast, for placebo recipients, 100% of subjects who received placebo have antibody levels below 0.5 µg/mL, and at least 80% are below 0.15 µg/mL for all serotypes. All serotype-specific comparisons of rates of achieving levels of 0.15 or 0.5 µg/mL show highly significant differences across vaccination arms (P < .001).
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Serotype-specific responses to the booster dose are also shown in Table 2. After the primary series, there were significant declines in antibody levels to just before the booster dose on the PCV arm for all serotypes (all P < .001). After the booster dose, booster rates as measured by 4-fold increases ranged from 30% to 72% depending on serotype. The difference in booster rates across serotypes was significantly higher for the PCV arm compared with the placebo arm for all serotypes except 14 (P = .12), which had high prebooster GMC. However, mean fold changes on the PCV arm ranged from 3.9 to 9.1 depending on serotype, and comparisons across PCV and placebo arms all were highly significant (all P < .001). Subjects who were enrolled on PCV arm experienced significant waning of serotype-specific IgG GMC to 24 months of age, although they remained well above preimmunization levels.
Immunogenicity was demonstrated among both asymptomatic and symptomatic subjects. The primary epidemiologic and scientific measures comparing PCV and placebo recipients were significant (both P < .008) in both subgroups. Serotype-specific response differences comparing PCV and placebo recipients was observed among both asymptomatic and symptomatic subjects for all measures, with PCV recipients having higher responses compared with placebo recipients. Figure 2 shows serotype-specific GMC during the study by CDC clinical classification group, illustrating the similarity of responses for the 2 groups as well as for healthy subjects studied by Rennels et al.1
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DISCUSSION |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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The safety and immunogenicity of PCV has been studied extensively in well infants and toddlers. Data on its use in adults with HIV infection suggested an acceptable safety profile.17 PACTG 292, a randomized, double-blind, placebo-controlled trial, was instituted to study the safety and immunogenicity of a heptavalent PCV in infants with HIV infection. This vaccine takes on special importance in view of the continued high incidence of invasive pneumococcal disease in children who have HIV infection and are immune reconstituted and have stopped their antibiotic prophylaxis.7
A total of 48 subjects were randomized to this study, and data were available on 45 of them. Baseline characteristics were evenly distributed across the vaccination arms. Few infants were on protease inhibitors at initiation of study. Despite this lack of treatments that are helpful in immune reconstitution and proven efficacious protease inhibitor therapy, infants developed excellent titers to both the primary and booster dose of this heptavalent PCV.
Although limited sample size is available to assess safety, PCV seemed to be very well tolerated by these infants with HIV infection (doses 1–3) and toddlers (dose 4). All of the severe local reactions appeared in the group with symptomatic HIV infection. More moderate or worse acute reactions were seen after doses 1 and 2. Black et al3 also observed more low-grade acute reactions after earlier doses. Unlike them, we did not find higher rates of high-grade fevers after dose 2, but this could be attributable to the limited sample size. Of these local reactions, all were resolved within 48 hours. Similar frequencies of response of symptomatic subjects in PCV and placebo arms, respectively, suggest that this may be more of a function of their response to any vaccination rather than their response to this specific vaccination. No events of anaphylaxis were observed, but the sample size was small to observe rare events.
Severe signs and symptoms were more frequent among PCV recipients (P = .044). Differences across vaccination arms occurred in both the asymptomatic and the symptomatic groups, although the latter no longer reached statistical significance. Small sample sizes limited the power of subgroup analyses. These signs and symptoms included such disparate symptoms as diarrhea, rash, fever, and anemia. It is difficult to ascertain whether these signs and symptoms were related to disease progression, vaccination, or antiretroviral therapies as this study did not control for treatment or change in HAART therapy. Peripheral blood HIV RNA polymerase chain reaction was not examined systematically in this cohort of children; thus, we are unable to verify whether indeed those children with earlier or more events did in fact have a higher viral load.
There were 3 deaths in this study cohort, with no difference across vaccination arms in the number of deaths or time to death. We believe that these deaths are a reflection of the illness stage of the cohort and the undocumented lack of control of HIV viral replication in this group of infants with HIV infection and were unrelated to study vaccine.
The vaccine was immunogenic in this study population, despite the lack of standardized antiretroviral therapy. Subjects had GMC preimmunization pneumococcal IgG titers of 0.10 µg/mL or lower for all 7 serotypes included in the vaccine. All PCV study subjects had a significant rise in titer after the primary series, whereas none of the placebo recipients did. This was again seen after receipt of the booster vaccine. The noted drop in titer prebooster and rise postbooster seen in these patients mimics that seen in normal (nonimmunocompromised) patients. Although the number of subjects studied was small, it was encouraging to see the immunologic response to both the primary vaccine series and the booster in children with HIV infection.
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CONCLUSIONS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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This study demonstrates the safety and impressive immunogenicity profile of this vaccine in infants and young children with HIV infection. A limited number of subjects were studied, so we have low power to compare safety measures across arms, including severe acute reactions; death; or rare sign, symptoms, or diagnoses. We observed that all severe acute reactions occurred in symptomatic patients. Any additional studies of this vaccine (or others) must pay special attention to this group of patients, as they seem to be at higher risk for adverse reactions.
The majority of subjects were not receiving HAART therapy at initiation of the study, and only 51% were receiving HAART at the end of study, which may extend its applicability to countries outside the United States where HAART therapy is not in common usage. Despite the lack of HAART therapy, vaccine recipients mounted a significant immune response to both the primary and the booster dose of vaccine.
Unfortunately, this study does not provide for any long-term data on the longevity of the immune response to this vaccine. Ideally, additional studies of this type and population should include several years of follow-up.
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ACKNOWLEDGMENTS |
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Support for this research came from the Pediatric AIDS Clinical Trials Group under NIAID grant AI-41110 and the Statistical and Data Analysis Center Grant of the Pediatric AIDS Clinical Trials group NIAID cooperative agreement AI-41110 (S.K.). Pharmaceutical support was provided by Lederle-Praxis Biologicals.
We thank the patients and their caregivers for participation.
List of Participants: Peter E. Vink, MD, John J. Farley, MD, MPH, Susan B. Lovelace, RN, CPNP (University of Maryland School of Medicine, Baltimore, MD); Elaine J. Abrams, MD, Delia Calo, CCRC, Maxine Frere, RN (Harlem Hospital Center, Columbia University, New York, NY); Ann Petru, MD, Karen Gold, RN, MA, Teresa Courville, RN, MN (Children’s Hospital and Research Center at Oakland, Oakland, CA); Sharon Nachman, MD, Michell Davi, RN, CPNP, Debra Hickey, RN, CPNP (SUNY Health Science Center at Stony Brook, Stony Brook, NY); William T. Shearer, MD, PhD, Mary E. Paul, MD, Alice Harris, RN (Texas Children’s Hospital, Houston, TX); Ram Yogev, MD, Amy Talsky, RN, CPNP, Deborah Cloutier, RN, BSN (Children’s Memorial Hospital, Chicago, IL); Charles Mitchell, MD, Gwendolyn B. Scott, MD, Charlotte Goldberg, RN (University of Miami School of Medicine, Miami, FL); Mobeen Rathore, MD, Melissa Scites, RN, Michelle Eagle, PA-C (University of Florida Health Science Center, Jacksonville, FL); Stuart E. Starr, MD, Carol A. Vincent, CRNP, MSN, Richard M. Rutstein, MD (The Children’s Hospital of Philadelphia, Philadelphia, PA); Paul Palumbo, MD, Arry Dieudonne, MD, Richard Stephens, PhD (New Jersey Medical School, Newark, NJ); Kenneth M. Boyer, MD, Cynthia Booth, RN (Cook County Children’s Hospital, Chicago, IL); Sunanda Gaur, MD, Silvia Callejas, RN, Lisa Cerrachio, RN (UMDNJ Robert Wood Johnson Medical School, New Brunswick, NJ); Michael Brady, MD, Katalin Korányi, MD, Jane Hunkler, RN (Children’s Hospital, Columbus, OH); Russell B. Van Dyke, MD, Margarita Silio, MD, Margaret L. Cowie, CCRC (Tulane University Medical School, New Orleans, LA); Diane W. Wara, MD (University of San Francisco, San Francisco, CA); Rosemary Johann-Liang, MD (The New York Hospital–Cornell University Medical College, New York, NY); Andrea Kovacs, MD (University of Southern California Medical Center, Los Angeles, CA); Saroj Bakshi, MD (Bronx-Lebanon Hospital Center, Bronx, NY).
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FOOTNOTES |
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Received for publication Jun 12, 2002; Accepted Dec 13, 2002.
Reprint requests to (S.N.) Department of Pediatrics, State University of New York Health Science Center at Stony Brook, Stony Brook, NY 11794. E-mail: sharon.nachman{at}stonybrook.edu
Financial disclosures: Dr Frank Malinoski is employed by and has a direct financial interest in Wyeth Pharmaceuticals, the company that has licensed and markets Prevnar, the heptavalent pneumococcal conjugate vaccine that is evaluated in this article. Dr Sharon Nachman serves as a consultant for Abbott Laboratories, Bristol-Myers Squibb, Glaxo–SmithKline Beecham, Wyeth Pharmaceuticals, Boehringer Ingelheim, and Pfizer Inc.
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REFERENCES |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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