IMMUNOGENICITY OF HEPTAVALENT PNEUMOCOCCAL CONJUGATE VACCINE IN VLBW INFANTS

这个子项目是利用由NIH/NCRR资助的中心拨款提供的资源的许多研究子项目之一。子项目和调查员(PI)可能从另一个NIH来源获得了主要资金，因此可能会出现在其他CRISE条目中。列出的机构是针对中心的，而不一定是针对调查员的机构。我们推测，能有效预防侵袭性肺炎球菌疾病的七价肺炎球菌-CRM197结合疫苗(PCV-7)的免疫原性将与极低出生体重儿(VLBW)的出生体重直接相关。目标肺炎链球菌引起的肺炎约占美国肺炎总数的10%-25%，每年造成约4万人死亡。在引入结合疫苗后，随着b型流感嗜血杆菌(Hib)在美国的实际根除，肺炎链球菌已成为婴儿菌血症和脑膜炎的主要原因。侵袭性肺炎球菌病在6-11个月大的儿童中发病率最高，为235/100,000。肺炎球菌脑膜炎的死亡风险(15%)或神经后遗症(12%-28%)高于Hib或奈瑟氏菌脑膜炎。早产儿面临由各种病原体引起的疾病发病率增加的风险，如果他们受到感染，疾病的严重性也会增加。最近在一种结合肺炎球菌疫苗的疗效试验中收集的流行病学信息表明，在出生体重为2500克的婴儿中，侵袭性肺炎球菌疾病的发病率增加了2.6倍。尽管只有133名出生体重低于1500克的婴儿被包括在内，但出生体重在1000-1500克之间的未接种疫苗的婴儿的发病率表明，与足月婴儿相比，风险增加了6.7倍。美国儿科学会(AAP)建议，“在大多数情况下，早产儿，包括低出生体重儿，应该在正常的年龄接种疫苗。”然而，美国儿科学会也警告说，“一些研究表明，按常规计划免疫的极低出生体重儿(1500克)的免疫反应会降低。”早产儿对当前一代儿童疫苗的反应在某些重要方面与足月出生的婴儿的反应不同。尽管早产儿通常在与足月出生的婴儿相同的出生后年龄接种疫苗时正常反应，但一些研究人员报告说，针对Hib、脊髓灰质炎和乙肝的抗体效价较低。对于免疫原性最低的疫苗，抗体反应不足的可能性似乎最大。一般来说，婴儿在提高对多糖类抗原的免疫力所需的T细胞非依赖性反应方面相对较差。通过将多糖抗原结合到免疫原蛋白上，将这种反应转化为依赖T细胞的反应，可以成功地产生对多糖的免疫反应。这一策略已经成功地用于生产几种疫苗，包括针对Hib和肺炎链球菌的疫苗。然而，目前针对肺炎链球菌的结合疫苗对早产儿提出了特殊的关注。使用各种结合疫苗，来自几项研究的数据表明，即使是结合疫苗在患病或极早产儿中的免疫原性也可能较低。PCV-7是由Wyeth-Lederle疫苗和儿科公司(Rochester，NY)开发的将在本研究中进行评估的七价结合肺炎球菌疫苗。在人类婴儿的试验中，它被证明是安全的、免疫原性的和有效的。PCV-7是由制造商AAP、疾病控制中心(CDC)和预防免疫实践咨询委员会(ACIP)推荐的，用于2、4、6和12-15个月大的婴儿的普遍接种。指南中没有提到针对早产儿的具体建议。目前对早产儿的护理标准是遵循相同的时间表。这项研究旨在评估PCV-7在其普遍使用历史上相对较早的情况，目的是根据具体数据而不是根据对足月出生婴儿的研究推断，建立早产儿使用指南。方法在接种1、2和3剂后，家长将被要求填写一张日记卡，以记录任何反应。(在某些情况下，将在婴儿出院回家之前给予第一剂。在这些情况下，医疗记录将被用于记录对疫苗的任何反应。)出生体重低于1500克的婴儿通常会在18-22.5个月大的时候在婴儿发育诊所(IDC)接受神经发育评估。当参加这项研究的婴儿在IDC进行18个月的探视时，父母将被问及间隔多长时间的病史，以筛查可能的侵袭性细菌感染和不良事件。神经发育结果数据将从出生体重在1000克及以下的登记婴儿的图表中收集。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. We hypothesize that the immunogenicity of heptavalent pneumococcal-CRM197 conjugate vaccine (PCV-7), which effectively prevents invasive pneumococcal disease, will vary directly with birth weight in very low birth weight infants (VLBW). Goals Streptococcus pneumoniae causes an estimated 10-25% of all pneumonias in the United States, and is responsible for some 40,000 deaths each year. With the virtual eradication of Haemophilus influenzae type b (Hib) disease in the United States following the introduction of conjugate vaccines, S. pneumoniae has emerged as a leading cause of bacteremia and meningitis in infants. Invasive pneumococcal disease has a peak incidence of 235/100,000 among children aged 6-11 months. Pneumococcal meningitis carries a higher risk of death (15%) or neurologic sequelae (12-28%) than that caused by Hib or Neisseria meningitides. Premature infants are at risk for increased incidence of disease from a variety of pathogens, and for an increased severity of disease if they become infected. Epidemiological information gathered during a recent efficacy trial of a conjugated pneumococcal vaccine suggested that a 2.6-fold increase in invasive pneumococcal disease among infants with birth weights <2500 grams. Although only 133 infants with birth weights less than 1500 grams were included, the rate of disease among unimmunized infants born weighing 1000-1500 grams suggested a 6.7-fold increase in risk over full term infants. The American Academy of Pediatrics (AAP) recommends that "prematurely born infants, including infants of low birth weight, should be immunized at the usual chronological age in most cases." However, the AAP also cautions that "some studies suggest a reduced immune response in VLBW infants (<1500 grams) immunized by the usual schedule." The responses of premature infants to the current generation of childhood vaccines differ in some important aspects from the responses of infants born at term. Although preterm infants generally respond normally to vaccines given at the same postnatal ages as infants born at term, antibody titers to Hib, polio, and hepatitis B have been reported to be lower by several investigators. The potential for inadequate antibody responses seems to be greatest for the least immunogenic vaccines. In general, infants are relatively poor at mounting the T-cell-independent responses needed to produce immunity to polysaccharide antigens. The conversion of this response to a T-cell-dependent one by conjugating a polysaccharide antigen to an immunogenic protein can produce a successful immune response to the polysaccharide. This strategy has been successfully employed in the production of several vaccines including those against Hib and S. pneumoniae. However, the current conjugate vaccines against S. pneumoniae raise specific concerns for premature infants. Using a variety of conjugate vaccines, data from several studies suggest that even conjugate vaccines may be less immunogenic among sick or extremely premature infants. PCV-7, the heptavalent, conjugate pneumococcal vaccine to be evaluated in this study was developed by Wyeth-Lederle Vaccines and Pediatrics (Rochester, NY). It has been shown to be safe, immunogenic and effective in trials among human infants. PCV-7 is recommended by the manufacturer, the AAP, and the Centers for Disease Control (CDC) and Prevention's Advisory Committee on Immunization Practices (ACIP) for universal administration to infants at 2, 4, 6, and 12-15 months of age. Specific recommendations for premature infants are not mentioned in the guidelines. The current standard of care for preterm infants is to follow the same timetable. This study is designed to evaluate PCV-7 relatively early in the history of its general use with the goal of establishing guidelines for use in premature infants based on specific data rather than extrapolation from studies of infants born at term. Methods Parents will be asked to complete a diary card after doses 1, 2, and 3 to document any reactions. (In some cases, dose 1 will be given before the infant is discharged to home. In those cases the medical record will be used to document any reactions to the vaccine.) Infants with birth weights less than 1500 grams are routinely seen for neurodevelopmental assessment at 18-22.5 months of age in the Infant Development Clinic (IDC). When infants who are enrolled in this study are in the IDC for their 18 month visit, the parents will be asked about the interval medical history to screen for possible invasive bacterial infections and adverse events. Neurodevelopmental outcome data will be collected from the charts of enrolled infants with birth weights of 1000 grams and lower.