Simple interventions to Improve Rotavirus Vaccine Effectiveness (SIRVE)

描述（由申请人提供）：（SIRVE来自西班牙语servir，“服务”。"先生？"用作疑问句的意思是，"它有效吗？") 这项研究汇集了来自不同学科的研究人员团队，以解决低收入和中等收入国家（LMIC）轮状病毒疫苗性能低下的问题。虽然大多数轮状病毒导致的儿童死亡发生在低收入国家，但与高收入国家相比，目前获得许可的轮状病毒疫苗在低收入国家的有效性较低，保护期较短。越来越多的证据表明，LMIC婴儿对轮状病毒疫苗的免疫反应减弱;我们预计这种微弱的反应可能会在生命的第二年减弱到非保护性水平。免疫原性降低的一种新解释是母乳对口服轮状病毒疫苗的抑制作用。合作研究者江宝明提供的初步数据显示，来自LMIC母亲的母乳具有高轮状病毒特异性IgA，并且能够在体外抑制轮状病毒疫苗活性。这项拟议的研究通过评估战略性母乳喂养抑制干预对尼加拉瓜五价轮状病毒疫苗免疫原性的影响，将这一实验室发现转化为翻译领域。我们提出了一项随机对照试验的540哺乳期的母亲-婴儿对比较五价轮状病毒疫苗接种前11/2小时和接种后1小时停止母乳喂养（干预）和常规母乳喂养（对照）对婴儿免疫球蛋白A血清转换的影响。我们假设干预组婴儿的血清转换频率高于对照组婴儿。再加上试验，我们建议仔细评估母乳喂养模式或母亲对母乳喂养的态度的变化，作为干预的结果。如果发现干预措施有效，则有必要进行风险评价，以告知实施步骤。最后，我们计划解决轮状病毒疫苗保护持续时间短的问题，为将来加强剂量管理的临床试验做准备。我们将收集 并分析18个月大之前免疫儿童的血清，以描述五价轮状病毒疫苗的长期免疫原性动力学。这些数据将用于潜在证明和告知此类试验的加强剂量给药时间。另外，这些数据将使我们能够评估战略性母乳喂养抑制干预的长期影响。我们建议通过尼加拉瓜大学传染病研究中心在尼加拉瓜莱昂进行这项研究，合作者Felix Espinoza此前在尼加拉瓜协调了单价轮状病毒疫苗的田间试验。对80对母婴进行的一项试点研究证实了招募目标、社区随访和标本收集以及CDC病毒性胃肠炎实验室实验室分析的可行性。最后，在我们的CDC合作者的协助下，我们将通过与国际卫生政策机构的计划传播，最大限度地提高研究结果的公共卫生影响。

DESCRIPTION (provided by applicant): (SIRVE comes from the Spanish word servir, "to serve". "Sirve?" used as a question means, "Does it work?") This study brings together a team of investigators from diverse disciplines to address the problem of low rotavirus vaccine performance in low and middle income countries (LMICs). While the majority of the child deaths due to rotavirus occur in LMICs, currently-licensed rotavirus vaccines are less effective and have a shorter duration of protection in LMICs as compared to high income countries. A growing body of evidence shows that LMIC infants mount a blunted immune response to the rotavirus vaccines; we expect that this weak response may then wane to non-protective levels in the second year of life. One novel explanation for decreased immunogenicity is inhibition of the oral rotavirus vaccines by breast milk. Preliminary data provided by co-investigator, Baoming Jiang, show that breast milk from LMIC mothers has high rotavirus-specific IgA and is able to inhibit rotavirus vaccine activity in vitro. The propose study takes this laboratory finding to the translational realm by evaluating the effect of a strategic breastfeeding withholding intervention on immunogenicity to the pentavalent rotavirus vaccine in Nicaragua. We propose a randomized control trial of 540 lactating mother-infant pairs to compare the effect of withholding breastfeeding 11/2 hours before and 1 hour after pentavalent rotavirus vaccine administration (intervention) to routine breastfeeding (control) on the frequency of IgA seroconversion to the vaccine in infants. We hypothesize that intervention group infants will have a higher frequency of seroconversion as compared to control group infants. Coupled with the trial, we propose a careful evaluation of changes in breastfeeding patterns or maternal attitudes towards breastfeeding as a result of the intervention. This risk evaluation is necessary to inform the implementation step if the intervention is found to be efficacious. Finally, we plan to address the problem of short duration of rotavirus vaccine protection by preparing for a future clinical trial of booster dose administration. We will collect and analyze sera from immunized children until 18 months of age to describe the kinetics of long-term immunogenicity to the pentavalent rotavirus vaccine . These data will be used to potentially justify and inform the timing of booster dose administration for such a trial. Separately, these data will allow us to assess the long-term effect of the strategic breastfeeding withholding intervention. We propose to conduct the study in Leon, Nicaragua, through the Center for Infectious Disease Research at the University of Nicaragua, Leon, where collaborator Felix Espinoza previously coordinated the field trials of the monovalent rotavirus vaccine in Nicaragua. A pilot study conducted with 80 mother-infant pairs confirms the feasibility of recruitment goals, community follow-up and specimen collection, and laboratory analysis at the CDC's Viral Gastroenteritis Laboratory. Finally, with the assistance of our CDC collaborators, we will maximize the public health impact of the study findings through planned dissemination with international health policy agencies.