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Safety and Immunogenicity of a Heptavalent Pneumococcal Conjugate Vaccine in Infants With Human Immunodeficiency Virus Type 1 Infection

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Safety and Immunogenicity of a Heptavalent Pneumococcal Conjugate

Vaccine in Infants With Human Immunodeficiency Virus Type 1

Infection

Sharon Nachman, MD*; Soyeon Kim, ScD‡; James King, MD§; Elaine J. Abrams, MD储; David Margolis, MD¶; Ann Petru, MD#; William Shearer, MD**; Elizabeth Smith, MD‡‡;

Jack Moye, MD§§; Suzette Blanchard, PhD储储; Elizabeth Hawkins¶¶; Pamela Bouquin##; Peter Vink, MD***; Mindy Benson, RN‡‡‡; Scharla Estep, MS, RPh§§§; and Frank Malinoski, MD, PhD储储储, for the Pediatric

AIDS Clinical Trials Group Study 292 Team

ABSTRACT. 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 in-fections. 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. Immunoge-nicity was evaluated after the third dose of vaccine, be-fore 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 sub-jects with symptomatic disease at study entry. No differ-ences were found in the 2 arms with respect to the num-ber 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 recip-ients. 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 mea-sures were based on composites of 4-fold changes in serotype-specific immunoglobulin G titers from preim-munization levels. We found a highly significant differ-ence between the vaccine and placebo arms, with the PCV arm showing higher rates of response. Asymptom-atic and symptomAsymptom-atic subjects who received PCV had similar immunologic responses for all serotypes.

Conclusions. This study demonstrates that heptava-lent 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 symp-tomatic HIV disease, as they seem to be at higher risk for adverse events to any antigen.Pediatrics2003;112:66 –73; heptavalent pneumococcal conjugate vaccine, Prevnar, safety, immunogenicity, HIV, pneumococcal polysaccha-ride vaccine.

ABBREVIATIONS. PCV, pneumococcal conjugate vaccine; HIV, human immunodeficiency virus; HAART, highly active antiretro-viral treatment; PACTG 292, Pediatric AIDS Clinical Trials Group Study 292; CDC, Centers for Disease Control and Prevention; IgG, immunoglobulin G; GMC, geometric mean concentration.

H

eptavalent pneumococcal conjugate vaccine (PCV) has been shown to be safe, immuno-genic, and efficacious for preventing inva-sive pneumococcal disease in healthy children.1–3 The American Academy of Pediatrics recently rec-ommended the routine administration of heptava-lent PCV concurrently with other childhood immu-nizations for all children 23 months and younger and to children 24 to 59 months of age who are at high

From the *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; §De-partment of Pediatrics, University of Maryland School of Medicine, Balti-more, Maryland;储Department of Pediatrics, Harlem Hospital Center, Co-lumbia 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, Hous-ton, Texas; ‡‡Pediatric Medicine Branch, Division of AIDS, National Insti-tute of Allergy and Infectious Diseases, National InstiInsti-tutes of Health, Be-thesda, Maryland; §§Pediatric, Adolescent, and Maternal AIDS Branch, National Institute of Child Health and Human Development, National Institutes of Health, Rockville, Maryland;储储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 Mary-land at Baltimore, Baltimore, MaryMary-land; ‡‡‡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; and储储储 Lederle-Praxis Biologicals, West Henrietta, New York.

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@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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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) era6and 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 sub-jects 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 dis-ease from 1997 to 2000 ranged from 322/100 000 to 310/100 000 people.10The 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.

METHODS Study Design

The Pediatric AIDS Clinical Trials Group Study 292 (PACTG 292) was a randomized, double-blind, placebo-controlled trial con-ducted at 18 medical centers throughout the United States. The Institutional Review Boards of all participating institutions ap-proved 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/mm3or clinical disease

category C according to current CDC HIV classification guide-lines. Originally, 60 infants were to be enrolled. However, study enrollment was prematurely curtailed after 48 subjects were ran-domized. This decrease in enrollment was related to the institu-tion of perinatal prophylaxis for preveninstitu-tion 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) admin-istration 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 un-blinded 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 immunogenic-ity 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 pneu-mococcal 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 ⬎10⫻N or SGOT

⬎10⫻N.

Study Vaccine and Administration

The study vaccine has been described in detail previously.1In

brief, vaccine contains serotypes 4, 6B, 9V, 14, 18C, 19F, 23F, and CRM197and 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 Vac-cines), was given in a volume of 0.5 mL intramuscularly or sub-cutaneously 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 ery-thema, induration, pain, fever, irritability, and allergic reactions were captured. Severe reactions were defined as erythema or indurationⱖ25 mm (size of a US quarter-dollar coin), pain re-stricting leg movement, feverⱖ103.0°F; irritable behavior includ-ing inconsolable cryinclud-ingⱖ3 hours, unusually high-pitched scream-ing 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 enumera-tion and quantitative immunoglobulins were performed at preim-munization, 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 im-mediately 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 elsewhere11and converted to micrograms per milliliter IgG by use

of standard reference serum 89SF.12Any concentration below the

lower limit of quantitation of 0.01␮g/mL was reported as 0.005 ␮g/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 re-sponse of⬎4-fold antibody responses in vaccine serotypes repre-sented⬎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 de-rived from 2 studies of children without HIV infection.13–16The

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Secondary Immunogenicity Endpoints

Immunogenicity was investigated further with the use of sero-type-specific rates of 4-fold antibody increases from preimmuni-zation levels, geometric mean concentrations (GMCs) of antibody, mean fold changes, and rates of achieving type-specific antibody levels of 0.5 and 0.15␮g/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 ex-cluded from all analyses unless otherwise specified. As prespeci-fied in the protocol, subjects who received exogenous blood prod-ucts 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⫻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 deter-mined 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 presenta-tion. Baseline GMC comparisons were made using a 2-sidedttest, whereas postimmunization comparisons were made using a 1-sidedttest. 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 mea-sures for immunogenicity using epidemiologic and scientific cri-teria 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

ttest.

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 catego-ries are based on 1994 CDC Morbidity and Mortality Weekly Reports groupings.

RESULTS

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 vaccina-tion. 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 random-ization without HIV status confirmation. Unless oth-erwise specified, this subject without HIV confirma-tion 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 statisti-cally 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

se-TABLE 1. Baseline Characteristics of Infants

Characteristic Total PCV Placebo P*

N 45 30 15

Median Age (d) 157 155 161 .72

Gender: % Male 33.3 43.3 13.3 .053

Race/ethnicity (%) 1.00

White non-Hispanic 17.8 16.7 20.0

Black non-Hispanic 64.4 63.3 66.7

Hispanic 15.6 16.7 13.3

American Indian/Alaskan Native

2.2 3.3 0.0

CDC clinical classification (%) 1.00

Asymptomatic (N) 51.1 50.0 53.3

Mildly symptomatic (A) 46.7 46.7 46.7

Moderately symptomatic (B) 2.2 3.3 0.0

Severely symptomatic (C) 0.0 0.0 0.0

Median CD4⫹count (/mm3) 1963 2457 1870 .44

Median CD4⫹percentage 36 36 37 .74

CDC immune category (%)† 1.00

No suppression 75.6 73.3 80.0

Moderate suppression 15.6 16.7 13.3

Severe suppression 8.9 10.0 6.7

Antiretroviral therapy (%) .24

None 28.9 30.0 26.7

Nonprotease regimen 60.0 53.3 73.3

Protease-containing regimen 11.1 16.7 0.0

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rology 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 ini-tial vaccination. At the time of evaluating the immu-nogenicity of the vaccine, week 20, 82% were on antiretrovirals (18% on protease inhibitor containing regimens), and at the completion of the study, chro-nologically 24 months of age, 95% were on any an-tiretroviral (51% on a protease inhibitor containing regimens).

Baseline Characteristics

Table 1 shows the baseline characteristics of in-fants 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 mar-ginal imbalance in gender (P ⫽ .053). In particular, CD4⫹cell count, percentage of lymphocytes that are CD4⫹, CDC clinical classification and immune cate-gory, and baseline antiretroviral regimen were well balanced across vaccination arms.

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 indura-tion, 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 per-centages 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 asymp-tomatic and sympasymp-tomatic 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 vac-cine and placebo arms, we did find significant dif-ferences. Differences occurred after the first and sec-ond doses (56.7% vs 20.0% [P ⫽ .02] and 53.3% vs 13.3% [P ⫽ .01], respectively). The moderate reac-tions 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 expe-rienced 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 statis-tically 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 symp-toms experienced included but are not restricted to fever, anemia, rash, diarrhea, hepatomegaly, spleno-megaly, cough, wheezing, and apnea. There was also TABLE 2. GMC and Fold Rises of Pneumococcal Antibody in Recipients of PCV and Placebo

Serotype Prevaccination Postdose 3

GMC (␮g/mL) GMC (␮g/mL) Mean Fold Rise PCV (N⫽24)

4-Fold RiseN(%) PCV

(N⫽24)

Placebo (N⫽12)

PCV (N⫽24)

Placebo (N⫽10)

PCV (N⫽24)

Placebo (N⫽10) 4 0.02 (0.02–0.03) 0.02 (0.01–0.03) 2.8 (1.9–4.3) 0.01 (0.01–0.02) 122.1 (69.1–215.6) 24 (100) 1 (10) 6B 0.05 (0.03–0.10) 0.06 (0.04–0.11) 5.4 (2.6–11.1) 0.06 (0.03–0.10) 99.5 (39.0–253.5) 21 (88) 2 (20) 9V 0.03 (0.02–0.06) 0.03 (0.02–0.05) 1.6 (1.0–2.7) 0.04 (0.03–0.06) 50.2 (23.0–109.4) 21 (88) 2 (20) 14 0.05 (0.03–0.10) 0.07 (0.03–0.15) 8.5 (5.1–14.2) 0.02 (0.01–0.03) 155.5 (68.2–354.7) 22 (92) 0 (0) 18C 0.03 (0.02–0.05) 0.03 (0.02–0.05) 2.6 (1.7–3.9) 0.02 (0.02–0.04) 84.9 (44.2–163.3) 24 (100) 1 (10) 19F 0.07 (0.04–0.12) 0.10 (0.07–0.14) 4.7 (3.0–7.3) 0.06 (0.03–0.13) 67.9 (33.7–136.7) 22 (92) 0 (0) 23F 0.03 (0.02–0.05) 0.04 (0.03–0.06) 3.3 (1.8–5.9) 0.03 (0.02–0.04) 101.9 (48.7–212.9) 22 (92) 0 (0) 95% confidence intervals are calculated on the log scale and transformed to the original scale for display.

*N⫽11 for serotype 6B.

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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 asymp-tomatic to sympasymp-tomatic subjects, no significant dif-ference 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 diag-nosis with an average of⬎8 new diagnoses per sub-ject. Diagnoses included but are not limited to epi-sodes of otitis media, upper respiratory infection, pneumonia, thrush, candidiasis (other than thrush), bacteremia, and conjunctivitis. We found no differ-ence across arms in the time to first diagnosis (P⫽ .24). We also found no difference across asymptom-atic and symptomasymptom-atic groups in time to first new diagnosis (P⫽.16). Among subjects who were symp-tomatic at baseline, there was a significant difference across vaccination arms in the time to first new di-agnosis (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 vacci-nation arms (P⫽ .69).

Immunogenicity

Preimmunization GMC on the PCV and placebo arms ranged between 0.02 and 0.10␮g/mL for the 7 vaccine serotypes. The differences across arms were not statistically significant for any serotype (allP⬎ .30).

For the primary epidemiologic endpoint, we re-quired coverage of 50% of pneumococcal disease present in young children from the 7 serotypes in the vaccine as measured by 4-fold increases from preim-munization 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 signifi-cantly 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 distribu-tions for PCV and placebo arms for each of the 7 serotypes. More than 95% of PCV recipients achieved levels of 0.15␮g/mL after the primary series, and at least 80% achieved levels of 0.5␮g/mL. In contrast, for placebo recipients, 100% of subjects who received placebo have antibody levels below 0.5␮g/mL, and at least 80% are below 0.15␮g/mL for all serotypes. All serotype-specific comparisons of rates of achiev-ing levels of 0.15 or 0.5␮g/mL show highly signifi-cant differences across vaccination arms (P⬍ .001).

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 sero-types (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 (allP⬍ .001). Sub-jects 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 pri-mary epidemiologic and scientific measures compar-TABLE 2. GMC and Fold Rises of Pneumococcal Antibody in Recipients of PCV and Placebo—Continued

Prebooster Postbooster

GMC (␮g/mL) GMC (␮g/mL) Mean Fold

Rise PCV (N⫽19)†

4-Fold RiseN(%) PCV

(N⫽21)

Placebo (N⫽12)*

PCV (N⫽19)

Placebo (N⫽10)

PCV (N⫽18)

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ing PCV and placebo recipients were significant (bothP⬍.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

DISCUSSION

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 random-ized, double-blind, placebo-controlled trial, was in-stituted 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 anti-biotic prophylaxis.7

A total of 48 subjects were randomized to this study, and data were available on 45 of them. Base-line characteristics were evenly distributed across the vaccination arms. Few infants were on protease in-hibitors 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 al3also 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 pla-cebo arms, respectively, suggest that this may be more of a function of their response to any vaccina-tion rather than their response to this specific vacci-nation. No events of anaphylaxis were observed, but the sample size was small to observe rare events.

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were related to disease progression, vaccination, or antiretroviral therapies as this study did not control for treatment or change in HAART therapy. Periph-eral blood HIV RNA polymerase chain reaction was not examined systematically in this cohort of chil-dren; 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

rep-lication in this group of infants with HIV infection and were unrelated to study vaccine.

The vaccine was immunogenic in this study pop-ulation, despite the lack of standardized antiretrovi-ral therapy. Subjects had GMC preimmunization pneumococcal IgG titers of 0.10␮g/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 recipi-ents 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) pa-Fig 2. GMCs of antibody to each vaccine serotype for recipients of PCV and placebo with results from HIV-1–negative volunteers1

(8)

tients. 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.

CONCLUSIONS

This study demonstrates the safety and impressive immunogenicity profile of this vaccine in infants and young children with HIV infection. A limited num-ber 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 re-actions occurred in symptomatic patients. Any addi-tional 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 out-side the United States where HAART therapy is not in common usage. Despite the lack of HAART ther-apy, vaccine recipients mounted a significant im-mune 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 re-sponse to this vaccine. Ideally, additional studies of this type and population should include several years of follow-up.

ACKNOWLEDGMENTS

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.). Pharmaceu-tical 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, Colum-bia 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 Hos-pital, Houston, TX); Ram Yogev, MD, Amy Talsky, RN, CPNP, Deborah Cloutier, RN, BSN (Children’s Memorial Hospital, Chi-cago, IL); Charles Mitchell, MD, Gwendolyn B. Scott, MD, Char-lotte 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, Jack-sonville, FL); Stuart E. Starr, MD, Carol A. Vincent, CRNP, MSN, Richard M. Rutstein, MD (The Children’s Hospital of Philadel-phia, PhiladelPhiladel-phia, 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

Kora´nyi, 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 Fran-cisco, CA); Rosemary Johann-Liang, MD (The New York Hospi-tal–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).

REFERENCES

1. Rennels MB, Edwards KM, Keyserling HL, et al. Safety and immuno-genicity of heptavalent pneumococcal vaccine conjugated to CRM197 in United States infants.Pediatrics. 1998;101:604 – 611

2. Shinefield HR, Black S, Ray P, et al. Safety and immunogenicity of heptavalent pneumococcal CRM197 conjugate vaccine ininfants and toddlers.Pediatr Infect Dis J. 1999;18:757–763

3. Black S, Shinefield H, Fireman B, et al. Efficacy, safety and immunoge-nicity of heptavalent pneumococcal conjugate vaccine in children. Pe-diatr Infect Dis J. 2000;19:183–186

4. American Academy of Pediatrics, Committee on Infectious Diseases. Policy statement: recommendation for the prevention of pneumococcal infections, including the use of pneumococcal conjugate vaccine (Prev-nar), pneumococcal polysaccharide vaccine, and antibiotic prophylaxis.

Pediatrics.2000;106:362–366

5. Centers for Disease Control and Prevention. Preventing pneumococcal disease among infants and young children. Recommendations of the advisory committee on immunization practices (ACIP). MMWR Recomm Rep.2000;49:1–38

6. Dankner WM, Lindsey JC, Levin MJ. CD4 correlates of opportunistic infections in children infected with the human immunodeficiency virus managed before highly active antiretroviral therapy.Pediatr Infect Dis J. 2001;20:40 – 48

7. Danker W, Levin M, Nachman S, et al. Rates of opportunistic infections in HIV-infected children on Pediatric AIDS Clinical Trials Group treat-ment protocols in the post-protease inhibitor era. PACTG meetings, July 2001

8. Farley JJ, King JC, Nair P, et al. Invasive pneumococcal disease among infected and uninfected children of mothers with human immunodefi-ciency virus infection.J Pediatr. 1994;124:853– 858

9. Andiman WA, Mezger J, Shapiro E. Invasive bacterial infections in children born to women infected with human immunodeficiency virus type 1.J Pediatr. 1994;124:846 – 852

10. Centers for Disease Control and Prevention. Active bacterial core sur-veillance (ABCs) report, emerging infections program network, Strep-tococcus Pneumoniae.1997–2000. Available at: www.cdc.gov/ncidod/ dbmd/abcs

11. Quataert SA, Kirch CS, Wiedle LJ, et al. Assignment of weight-based antibody units to a human anti-pneumococci standard reference serum, lot 89-S.Clin Diagn Lab Immunol. 1995;2:590 –597

12. Quataert S, Martin D, Anderson P, et al. A multi-laboratory evaluation of an enzyme-linked immunoassay quantitating human antibodies to

Streptococcus pneumoniae polysaccharides. Immunol Invest. 2001;30: 191–297

13. Orange M, Gray B. Pneumococcal serotypes causing disease in children in Alabama.Pediatr Infect Dis J. 1993;12:244 –245

14. Ahman H, Kayhty H, Tamminen P, et al. Pentavalent pneumococcal oligosaccharide conjugate vaccine PncCRM is well-tolerated and able to induce an antibody response in infants.Pediatr Infect Dis. 1996;2:134 –139 15. Eskola J. Immunogenicity of pneumococcal conjugate vaccine.Pediatr

Infect Dis J. 2000;19:388 –393

16. Hausdorff WP, Bryant J, Paradiso PR, et al. Which pneumococcal sero-groups cause the most invasive disease: implications for conjugate vaccine formulation and use, part I.Clin Infect Dis. 2000;30:100 –121 17. Feikin D, Elie C, Goetz M, et al. Immunologic and virologic response to

a 7-valent pneumococcal conjugate vaccine and/or 23-valent polysac-charide vaccine among HIV-infected adults [abstract 48].Abstracts of the 40th Interscience Conference on Antimicrobial Agents and Chemotherapy.

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DOI: 10.1542/peds.112.1.66

2003;112;66

Pediatrics

Malinoski

Hawkins, Pamela Bouquin, Peter Vink, Mindy Benson, Scharla Estep and Frank

Petru, William Shearer, Elizabeth Smith, Jack Moye, Suzette Blanchard, Elizabeth

Sharon Nachman, Soyeon Kim, James King, Elaine J. Abrams, David Margolis, Ann

in Infants With Human Immunodeficiency Virus Type 1 Infection

Safety and Immunogenicity of a Heptavalent Pneumococcal Conjugate Vaccine

Services

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DOI: 10.1542/peds.112.1.66

2003;112;66

Pediatrics

Malinoski

Hawkins, Pamela Bouquin, Peter Vink, Mindy Benson, Scharla Estep and Frank

Petru, William Shearer, Elizabeth Smith, Jack Moye, Suzette Blanchard, Elizabeth

Sharon Nachman, Soyeon Kim, James King, Elaine J. Abrams, David Margolis, Ann

in Infants With Human Immunodeficiency Virus Type 1 Infection

Safety and Immunogenicity of a Heptavalent Pneumococcal Conjugate Vaccine

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Figure

TABLE 1.Baseline Characteristics of Infants
TABLE 2.GMC and Fold Rises of Pneumococcal Antibody in Recipients of PCV and Placebo
TABLE 2.GMC and Fold Rises of Pneumococcal Antibody in Recipients of PCV and Placebo—Continued
Fig 1. Reverse cumulative distribution curves of postdose 3 antibody concentrations for PCV and placebo arms.
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