PDF(Pubmed)
Abstract：
The identification of an appropriate animal model for use in the development of meningococcal vaccines has been a challenge as humans are the only natural host for Neisseria meningitidis. Small animal models have been developed and are widely used to study the efficacy or immunogenicity of vaccine formulations generated against various diseases. Here, we describe the development and optimization of a mouse model for assessing the immunogenicity of candidate tetravalent meningococcal polysaccharide (MenACYW-TT) protein conjugate vaccines. Three inbred (BALB/c [H-2d], C3H/HeN [H-2k], or C57BL/6 [H-2b]) and one outbred (ICR [H-2g7]) mouse strains were assessed using serial two-fold dose dilutions (from 2 µg to 0.03125 µg per dose of polysaccharide for each serogroup) of candidate meningococcal conjugate vaccines. Groups of 10 mice received two doses of the candidate vaccine 14 days apart with serum samples obtained 14 days after the last dose for the evaluation of serogroup-specific anti-polysaccharide IgG by ELISA and bactericidal antibody by serum bactericidal assay (SBA). C3H/HeN and ICR mice had a more dose-dependent antibody response to all four serogroups than BALB/c and C57Bl/6 mice. In general, ICR mice had the greatest antibody dose-response range (both anti-polysaccharide IgG and bactericidal antibodies) to all four serogroups and were chosen as the model of choice. The 0.25 µg per serogroup dose was chosen as optimal since this was in the dynamic range of the serogroup-specific dose-response curves in most of the mouse strains evaluated. We demonstrate that the optimized mouse immunogenicity model is sufficiently sensitive to differentiate between conjugated polysaccharides, against unconjugated free polysaccharides and, to degradation of the vaccine formulations. Following optimization, this optimized mouse immunogenicity model has been used to assess the impact of different conjugation chemistries on immunogenicity, and to screen and stratify various candidate meningococcal conjugate vaccines to identify those with the most desirable profile to progress to clinical trials.
摘要：
鉴定用于开发脑膜炎球菌疫苗的合适动物模型一直是一个挑战,因为人类是脑膜炎奈瑟菌的唯一天然宿主。已经开发了小动物模型并广泛用于研究针对各种疾病产生的疫苗制剂的功效或免疫原性。这里,我们描述了用于评估候选四价脑膜炎球菌多糖(MenACYW-TT)蛋白偶联疫苗免疫原性的小鼠模型的开发和优化.三个近交（BALB/c[H-2d]，C3H/HeN[H-2k]，或C57BL/6[H-2b]）和一个近交（ICR[H-2g7]）小鼠品系使用连续两倍剂量稀释（每个血清群每剂多糖2µg至0.03125µg）的候选脑膜炎球菌结合疫苗进行评估。10只小鼠的组间隔14天接受两剂候选疫苗，最后一次给药后14天获得血清样品，用于通过ELISA评估血清群特异性抗多糖IgG，并通过血清杀菌测定（SBA）评估杀菌抗体。与BALB/c和C57Bl/6小鼠相比,C3H/HeN和ICR小鼠对所有四个血清群具有更剂量依赖性的抗体应答。总的来说,ICR小鼠对所有四种血清群具有最大的抗体剂量-反应范围(抗多糖IgG和杀菌抗体),并选择作为选择的模型。选择每个血清群0.25μg剂量作为最佳剂量，因为这在大多数评估的小鼠品系中处于血清群特异性剂量反应曲线的动态范围内。我们证明，优化的小鼠免疫原性模型足够敏感，可以区分缀合的多糖，对抗未结合的游离多糖，疫苗制剂的降解。优化后,此优化的小鼠免疫原性模型已用于评估不同缀合化学对免疫原性的影响，并对各种候选脑膜炎球菌结合疫苗进行筛选和分层，以确定具有最理想特征的疫苗，以进行临床试验。
