IMMUNOGENICITY OF HEPTAVALENT PNEUMOCOCCAL CONJUGATE VACCINE IN VLBW INFANTS

本子项目是利用由NIH/NCRR资助的中心赠款提供的资源的众多研究子项目之一。子项目和研究者（PI）可能已经从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。列出的机构是中心的，不一定是研究者的机构。我们假设，在极低出生体重儿（VLBW）中，七价肺炎球菌- crm197结合疫苗（PCV-7）的免疫原性与出生体重直接相关，PCV-7可以有效预防侵袭性肺炎球菌疾病。在美国，肺炎链球菌导致的肺炎约占所有肺炎的10-25%，每年造成约40,000人死亡。随着美国引入结合疫苗，乙型流感嗜血杆菌（Hib）疾病实际上已被根除，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个月的儿童中发病率最高，为235/100,000。肺炎球菌脑膜炎比Hib或脑膜炎奈瑟菌引起的死亡（15%）或神经系统后遗症（12-28%）的风险更高。早产儿面临着各种病原体引起的疾病发病率增加的风险，如果受到感染，疾病的严重程度也会增加。在最近一项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<2500克的婴儿中，侵袭性肺炎球菌疾病的发病率增加2.6倍。虽然只有133名出生体重低于1500克的婴儿被纳入研究，但出生体重在1000-1500克之间未接种疫苗的婴儿的发病率比足月婴儿高出6.7倍。美国儿科学会（AAP）建议“早产婴儿，包括出生体重低的婴儿，在大多数情况下应该在正常的实际年龄接种疫苗。”然而，美国儿科学会也警告说，“一些研究表明，按常规接种计划接种的VLBW婴儿（<1500克）的免疫反应降低。”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婴儿的反应不同。虽然早产儿通常对与足月出生婴儿相同出生年龄的疫苗反应正常，但据几位调查人员报道，对Hib、脊髓灰质炎和乙型肝炎的抗体滴度较低。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，婴儿在产生对多糖抗原免疫所需的t细胞非依赖性反应方面相对较差。通过将多糖抗原与免疫原性蛋白结合，将这种反应转化为t细胞依赖性反应，可以对多糖产生成功的免疫反应。这一策略已成功地用于几种疫苗的生产，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引起了早产儿的特别关注。使用多种结合疫苗，来自几项研究的数据表明，即使是结合疫苗在生病或极度早产儿中也可能具有较低的免疫原性。PCV-7，这项研究中评估的七价结合肺炎球菌疫苗是由惠氏-莱德勒疫苗和儿科（罗切斯特，纽约州）开发的。在人类婴儿的试验中，它已被证明是安全的、免疫原性的和有效的。PCV-7是由制造商、美国儿科学会（AAP）、疾病控制中心（CDC）和预防免疫实践咨询委员会（ACIP）推荐给2、4、6和12-15个月大的婴儿普遍接种的疫苗。指南中没有提到针对早产儿的具体建议。目前早产儿的护理标准是遵循同样的时间表。本研究旨在评估PCV-7在其普遍使用历史中的相对早期，目的是根据具体数据而不是根据足月出生婴儿的研究推断，建立早产儿使用指南。方法要求家长在给药1、2、3次后填写日记卡，记录任何反应。(在某些情况下，剂量1将在婴儿出院回家之前给予。在这些情况下，医疗记录将用于记录对疫苗的任何反应。)出生体重低于1500克的婴儿通常在18-22.5个月大时在婴儿发育诊所（IDC）进行神经发育评估。当参加本研究的婴儿在IDC进行18个月的访问时，父母将被问及间隔病史，以筛查可能的侵袭性细菌感染和不良事件。神经发育结局数据将从出生体重为1000克及以下的入选婴儿的图表中收集。

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.