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Peters, Vicki B. M.D.; Sood, Sunil K. M.D.

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The Pediatric Infectious Disease Journal: July 1997 - Volume 16 - Issue 7 - p 711-713
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Haemophilus influenzae type b (Hib) was a major cause of serious infections in children until the introduction of Hib vaccines. Despite the decline of disease in the vaccine era, cases of invasive disease continue to be reported.1 Thus maintenance of immunity to Hib should remain an important goal, especially in the immunocompromised host.

We previously showed that among children infected with HIV who were vaccinated with the recommended single dose of a Hib vaccine at ≥15 months of age, immunity to Hib was uncommon at a mean time of 38 months after vaccination regardless of the Hib vaccine type and the HIV disease severity.2 Only 16% had anticapsular antibody (ACA) concentrations associated with long term protective immunity, i.e. ACA ≥1 μg/ml. The purpose of this study was to evaluate immunity to Hib after reimmunization with a Hib conjugate vaccine in a group of HIV-infected children who lacked long term protective immunity to Hib. Our findings suggest a predominant T cell-independent type response to reimmunization in most of these children.

Methods. We routinely evaluate children with HIV infection for immunity to childhood vaccines for the purpose of determining protective immunity and as a measure of immune function. Among 24 children immunized with a single dose of a Hib vaccine, at a mean time of 37 months later, 19 (79%) had <1 μg/ml, including 12 with <0.15 μg/ml. Five of the 19 children died, 1 moved and the remaining 13 children were enrolled in the present study between May, 1993, and October, 1995. Eleven children were from the previous study.2 Study children were reimmunized with a dose of Hib oligosaccharide CRM197 conjugate vaccine (HbOC, HibTI-TER®; Lederle-Praxis Biologics, Inc.).

Total serum ACA concentrations were assayed by radioantigen binding assay (Farr assay) as previously described.3 The lower limit of detection was a concentration of 0.09 μg/ml and the upper limit was 40 μg/ml. For statistical analysis a value of 0.05 μg/ml was assigned to sera with an ACA concentration below the lower limit of detection and 40 μg/ml to sera above the upper limit of detection. Geometric mean antibody concentrations (GM) and 95% confidence intervals were derived from log10 transformed data.

The two-tailed Fisher's exact test was used to evaluate differences between proportions. The two-tailed Mann-Whitney U test was used to evaluate differences between median values. The two-tailed paired t test was used to evaluate differences between mean values.

Results. Eleven children acquired HIV infection by maternal transmission and 2 children from neonatal blood transfusions. Eleven children had received a single dose of a Hib conjugate vaccine (7 oligosaccharide CRM197 conjugate vaccine, 3 polyribosylribitol phosphate-diphtheria toxoid vaccine, 1 child a conjugate vaccine that was not specified) and 2 a polysaccharide vaccine at a mean age of 22 months (range, 15 to 33 months). The first ACA determination was at a mean age of 58 months (range, 26 to 118 months), a mean of 37 months (range, 10 to 85 months) after vaccination. The GM ACA for the 13 children was 0.11 μg/ml (95% confidence interval (CI), 0.06 to 0.21 μg/ml; range, <0.09 to 0.60 μg/ml). Seven children had no detectable ACA. There was no correlation between the ACA level and the time from immunization.

The second Hib vaccine, i.e. HbOC, was administered at a mean age of 72 months (range, 38 to 126 months). Six children had asymptomatic or mildly symptomatic HIV disease (CDC Disease Class N/A) and 7 had moderately or severely symptomatic HIV disease (Class B/C).4 All children were receiving antiretroviral therapy. None had received intravenous immunoglobulin at any time during the study.

At a mean of 3.3 months (range, 1 to 6 months) after reimmunization with HbOC, the GM for the 13 children was 4.15 μg/ml (95% CI, 1.01 to 16.98; range, <0.09 to >40 μg/ml). The GM was significantly higher than the GM of the first ACA determination (P = 0.007). Ten children (77%) had ACA ≥1 μg/ml. Only one child had no detectable ACA. The one child whose ACA determination was 6 months after reimmunization had >40 μg/ml of ACA.

Children with ACA ≥1 μg/ml after reimmunization with HbOC were more likely than children with ACA <1 μg/ml to have higher CD4 cell counts and less symptomatic HIV disease (Table 1). The GM correlated with the HIV disease severity as defined by CDC clinical and immunologic criteria.4 The seven children with mild HIV disease (Classes N1, N2, A2, B1) had a significantly higher GM than the six children with advanced HIV disease (classes B2, B3, C3): 23.39 μg/ml (95% CI, 11.83 to 46.24) vs. 0.55 μg/ml (95% CI, 0.08 to 3.73) (P = 0.001).

Clinical and immunologic characteristics according to ACA concentrations achieved after reimmunization with HbOC

Discussion. Our previous finding that most HIV-infected children immunized with a single dose of a Hib vaccine lack long term "protective" ACA concentrations2 is in contrast to healthy children who maintain ACA concentrations ≥1 μg/ml several years after vaccination.5-7 Because ACA determinations had not been made before and after vaccination, we were unable to determine whether our patients had a primary lack of an immune response to the Hib capsule, or, if we presume that an initial response occurred, a secondary failure of persistence of antibody. The findings of Gibb et al.8 support the latter hypothesis. They showed that although 88% of a group of HIV-infected children had ACA levels ≥1 μg/ml 1 month after immunization with a single dose of a Hib conjugate vaccine, only 57% had ≥1 μg/ml 1 year later.

In another study we showed that the majority of 18 HIV-infected infants developed ACA at a mean of 4 months after immunization with the complete HbOC vaccine series.9 However, their GM of 0.82 μg/ml contrasts with the GMs reported for healthy infants similarly immunized. Infants with immunity had significantly higher CD4 cell counts than the infants lacking immunity. A booster effect between the third and fourth vaccine doses was infrequent, suggesting a B cell memory defect.

The majority of the children in the present study, including children with advanced HIV infection, developed ACA ≥1 μg/ml after reimmunization with HbOC. However, the magnitude of the response correlated with HIV disease severity. All children with mild HIV disease developed ACA and had significantly higher ACA concentrations than children with more advanced HIV disease.

Our finding that persistence of immunity to Hib is uncommon yet immunity develops after reimmunization suggests that the response to reimmunization may occur by a thymus-independent mechanism. T cell-independent antigens can induce protective levels of antibody even in the absence of memory B cells generated by T cell cooperation. Perhaps no response to polysaccharide antigens is strictly T cell-independent,10 so that as HIV disease progresses we may expect the response to be further impaired.

In HIV-infected individuals the potential benefits of developing protective vaccine immunity should be weighed against the possibility of increasing HIV viral loads. Indeed studies in both HIV-infected adults and children showed that increases in HIV viral load can occur after immunization. However, they were transient and did not correlate with changes in CD4 cell counts.11-13 Although this study did not evaluate for changes in HIV viral load in relationship to reimmunization, there were no significant differences in CD4 cell counts recorded before and after immunization (data not shown).

Our findings are relevant to HIV-infected children who were ≥15 months of age in October, 1990, when the recommendation to immunize infants with a conjugate Hib vaccine was made. These children would have received a single dose of vaccine. Older HIV-infected children with inadequate protective immunity may remain at risk for Hib infections because the risk is inversely correlated with the serum concentration of protective ACA. In HIV-infected children not immunized in the first year of life, a second dose of a Hib vaccine appears to be necessary to develop protective concentrations of ACA. Similarly HIV-infected children immunized with the complete vaccine series in infancy may be unable to maintain adequate protective ACA levels and will require reimmunization in childhood. In fact periodic reimmunization may be necessary if the pattern of response is of a thymus-independent type. This novel finding, that protective antibody can be induced in a "T cell-independent" manner, could have implications for the design of future schedules to immunize HIV-infected children against another encapsulated bacterium, Streptococcus pneumoniae.

Acknowledgments. We thank Porter Anderson, M.D., University of Rochester, for providing us with tritiated polyribosylribitol phosphate antigen; Gary Dorante and Kenneth Lown, P.N.P., for technical assistance; and David Hodes, M.D., for referring children. This study was supported in part by Grant 1U01-AI27667 from the National Institute of Allergy and Infectious Diseases and was presented in part at the 35th Interscience Conference on Antimicrobial Agents and Chemotherapy.14

Vicki B. Peters, M.D.

Sunil K. Sood, M.D.

Department of Pediatrics; Mount Sinai School of Medicine; New York, NY (VBP)

Department of Pediatrics; Schneider Children's Hospital of Long Island; Jewish Medical Center; The Long Island Campus for the Albert; Einstein College of Medicine; New Hyde Park, NY (SKS)

1. Centers for Disease Control and Prevention. Final 1995 reports of notifiable diseases. MMWR 1996;45:742-54.
2. Peters VB, Sood SK. Immunity to Haemophilus influenzae type b polysaccharide capsule in children with human immunodeficiency virus infection immunized with a single dose of a Haemophilus vaccine. J Pediatr 1994;125:74-7.
3. Sood SK, Schreiber JR, Siber GR, Daum RS. Postvaccination susceptibility to invasive Haemophilus influenzae type b disease in infant rats. J Pediatr 1988;113:814-9.
4. Centers for Disease Control and Prevention. 1994 revised classification system for human immunodeficiency virus infection in children under 13 years of age. MMWR 1994;43(RR-12):1-10.
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6. Claesson BA, Schneerson R, Trollfors B, Lagergard T, Taranger J, Robbins JB. Duration of serum antibodies elicited by Haemophilus influenzae type b capsular polysaccharide alone or conjugated to tetanus toxoid in 18- to 23-month-old children. J Pediatr 1990;116:929-31.
7. Rothstein EP, Pennridge Pediatric Associates Members, Madore DV, Long SS. Antibody persistence four years after primary immunization with Haemophilus influenzae type b CRM197 conjugate vaccine. J Pediatr 1991;119:655-7.
8. Gibb D, Giacomelli A, Masters J, et al. Persistence of antibody response to Haemophilus influenzae type b conjugate vaccine in children with vertically acquired HIV infection. Pediatr Infect Dis J 1996;15:1097-101.
9. Peters VB, Sood SK. Immunity to Haemophilus influenzae type b polysaccharide capsule after vaccination with the complete series of oligosaccharide CRM197 conjugate vaccine in infants with human immunodeficiency virus infection. J Pediatr 1996;128:363-5.
10. Baker PJ. T cell regulation of the antibody response to bacterial polysaccharide antigens: an examination of some general characteristics and their implications. J Infect Dis 1992;165(Suppl 1):S44-8.
11. Jackson CR, Vavro CL, Valentine ME, et al. Effect of influenza immunization on immunologic and virologic characteristics of pediatric patients infected with human immunodeficiency virus. Pediatr Infect Dis J 1997;16:200-4.
12. Ramillo O, Hicks PJ, Borvak J, et al. T cell activation and human immunodeficiency virus replication after influenza immunization of infected children. Pediatr Infect Dis J 1996;15:197-203.
13. Stanley SK, Ostrowski MA, Justement JS, et al. Effect of immunization with a common recall antigen on viral expression in patients infected with human immunodeficiency virus type 1. N Engl J Med 1996;334:1222-30.
14. Peters VB, Dorante G, Hodes G, Sood S. Antibody response to a booster dose of Haemophilus influenzae type b after reimmunization with oligosaccharide CRM197 conjugate vaccine in HIV-infected children [Abstract I149]. Presented at the 35th Interscience Conference on Antimicrobial Agents and Chemotherapy, San Francisco, CA, September 17 to 20, 1995.

Human immunodeficiency virus-infected children; Haemophilus influenzae type b oligosaccharide CRM197 conjugate vaccine; anticapsular antibody

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