This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH source,and thus could be represented in other CRISP entries. The institution listed isfor the Center, which is not necessarily the institution for the investigator.ABSTRACT The recent approval by the FDA of the quadrivalent meningococcal conjugate vaccine (MCV4) has led to a recommendation to vaccinate 11-12 year-old individuals at a pre-adolescent visit, individuals entering high school (approximately 15 years of age) and incoming college freshman living in dormitories, in recognition of the increased meningococcal disease risk during adolescence. As the majority of children with perinatally acquired HIV infection have aged into adolescence, and the majority of new pediatric HIV infections in the US are occurring in the adolescent age group, the new age-based recommendations for meningococcal immunization patients will lead to most HIV-infected youth being age-eligible for a vaccine for which there are no safety or immunogenicity data available from HIV-infected populations. This phase I/II study will evaluate the safety and immunogenicity of MCV-4 in 296 HIV-infected youth between =11 and <25 years of age. This study is also designed to answer several important questions related to immunization of HIV-infected youth including both short-term and long-term immunogenicity. The primary objectives are: To compare the immunogenicity of the MCV4 in HIV-1 infected youth at 28 weeks between a single-dose regimen vs. a two-dose regimen, where an immunogenic response is defined as a 4-fold or greater increase in serum bactericidal antibody titers; To estimate the short-term (4 and 24 weeks) immunogenicity of the MCV4 vaccine in HIV-1 infected youth for those in Group 1 (CD4% >15); To estimate the long-term (at 72 weeks) immunogenicity of the MCV4 vaccine in HIV-1 infected youth; To evaluate the safety of the MCV4 vaccine in HIV-1 infected youth, including short-term local and systemic reactions following administration of the vaccine.HYPOTHESIS MCV-4 immunization in HIV-infected youth will be safe and the vaccine will be immunogenic in a single dose regimen for youth who have CD4% >15 but two doses will be required for immunogenicity in youth who have CD4%<15.
SPECIFIC AIMS Primary To compare the immunogenicity of the quadrivalent meningococcal conjugate vaccine (MCV4) in HIV-1 infected youth at 28 weeks between a single-dose regimen vs. a two-dose regimen, where an immunogenic response is defined as a 4-fold or greater increase in serum bactericidal antibody titers;To estimate the short-term (4 and 24 weeks) immunogenicity of the MCV4 vaccine in HIV-1 infected youth for those in Group 1 (CD4% >15);To estimate the long-term (at 72 weeks) immunogenicity of the MCV4 vaccine in HIV-1 infected youth;To evaluate the safety of the MCV4 vaccine in HIV-1 infected youth, including short-term local and systemic reactions following administration of the vaccine.Secondary To examine whether the short and long-term immunogenicity of the MCV4 in HIV-1 infected youth varies as a function of the study subjects' immune status at the time of vaccination; To compare the long-term immunogenicity (at 72 weeks) of the MCV4 in HIV-1 infected youth between a 1-dose vs. 2-dose regimen for those in Group 1 (CD4% > 15);To evaluate whether the safety of the MCV4 vaccine varies by immune status based on CD4% at the time of vaccination;To evaluate whether, in subjects with CD4% < 15%, 2 doses of MCV4 can produce an immunogenic response (defined as a 4-fold or greater increase in serum bactericidal antibody titers reaching at least 1:8);To identify host genetic determinants of immunity that may affect the response to MCV4.BACKGROUND AND SIGNIFICANCE Meningococcal disease in HIV-infected patientsHIV infection can lead to T-cell dependent B-cell dysfunction, which increases the risk of invasive disease due to encapsulated organisms, such as pneumococcus. This immune dysfunction may increase the risk of invasive meningococcal disease in HIV-infected patients as well, but few cases have been reported. In a case-control study during a meningococcal A outbreak in Uganda, the prevalence of HIV infection was no more common among meningococcal cases than a cohort of pregnant women selected as controls. In a retrospective cohort study of a population of 2900 HIV-infected patients followed over 10 years in London , only two cases of invasive meningococcal disease were identified, but this annualized rate of 6.9/100,000 was substantially higher than population-based studies of meningococcal disease in similar areas. In a population-based study of invasive meningococcal disease in Atlanta, Georgia, there was, as expected, a higher annual rate of disease among 18-24 years old (1.17 per 100,000) compared to that of all adults (0.5 per 100,000), but the estimated annual rate among HIV-infected adults was substantially higher (11.2 per 100,000). These data are suggestive but not definitive of an increased risk of invasive meningococcal disease in HIV-infected populations.Meningococcal conjugate vaccineThe tetravalent meningococcal polysaccharide-protein conjugate vaccine (MCV4) is a meningococcal polysaccharide diphtheria toxoid conjugate vaccine. The vaccine contains Neisseria meningitidis serogroup A, C, Y, and W-135 capsular polysaccharide antigens individually conjugated to diphtheria toxoid protein. The vaccine is administered intramuscularly. The four meningococcal components, present as individual serogroup-specific glycoconjugates, compose the final formulated vaccine. No preservative or adjuvant is added during the manufacturing process. The vaccine is manufactured as a sterile, clear to slightly turbid liquid. Each 0.5 mL dose of vaccine is formulated in sodium phosphate buffered isotonic sodium chloride solution to contain 4 g each of meningococcal A, C, Y, and W-135 polysaccharides conjugated to approximately 48 g of diphtheria toxoid protein carrier. MCV4 is available only in single-dose vials. The vaccine was approved by the FDA on January 18, 2005. The meningococcal work group of the ACIP has made a recommendation that adolescents 11-12 years of age receive the vaccine at their preadolescent physician visit. ACIP's final recommendations also included vaccination of adolescents at approximately 15 years of age (high-school entry), and incoming college freshmen living in dormitories. By 2008, ACIP's goal will be routine vaccination with MCV4 of all adolescents beginning at age 11 years. Correlates of protection against invasive meningococcal diseaseWhile the reference standard for evidence of protection against invasive meningococcal disease caused by serogroup C was demonstration of titers =4 using a serum bactericidal antibody assay in which human sera are used as the exogenous complement source (hSBA), limited availability of human sera for the assay has led to substitution of baby rabbit sera as the exogenous complement source (rSBA). rSBA is considered the standard correlate of clinical protection against serogroup C meningococcal disease by the World Health Organization, and rSBA titers of < 8 have been proposed to be predictive of susceptibility to invasive meningococcal disease. rSBA titers =1:128 have been found to be highly predictive of protection, but the range of 1:8-1:64 were equivocal. Based on additional analyses, rSBA titers of = 8 have been proposed to correlate with short-term protection. During an outbreak of serogroup C infection in a university setting, for instance, all infected students had rSBA titers of <4. A fourfold rise in rSBA titers pre- to post-vaccination has been proposed as a correlate of protection, particularly for those cases in which rSBA titer falls in the equivocal range of 1:8-1:64. This four-fold rise in rSBA was the principal immunogenicity outcome measure used for the trial of MCV4 in healthy 11-18 year olds, used as the basis for licensure of MCV4 in the US for this age group [see below]. No direct efficacy measures of this vaccine were used for the basis of licensure. Monovalent (serogroup C) meningococcal conjugate vaccines (MenC) were first licensed in the United Kingdom on the basis of their ability to induce serum bactericidal activity as a correlate of efficacy without explicit efficacy data. A reduction in the incidence of bacterial meningitis caused by serogroup C was observed in the United Kingdom after immunization campaigns with MenC were introduced. Based on these data, we would propose using 4-fold rise in rSBA titers to serogroup C as the primary measure upon which sample size for studying immunogenicity should be calculated.
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