Analytical Sciences, R&D Sanofi Pasteur, Swiftwater, PA, United States.
Sanofi Medical Affairs, Sanofi Pasteur, Swiftwater, PA, United States.
Front Immunol. 2022 Jan 20;13:814088. doi: 10.3389/fimmu.2022.814088. eCollection 2022.
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 . 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.
为开发脑膜炎球菌疫苗，合适的动物模型的鉴定一直是个挑战，因为人类是唯一的天然宿主。已开发出小型动物模型，并广泛用于研究针对各种疾病的疫苗制剂的功效或免疫原性。在这里，我们描述了一种评估候选四价脑膜炎球菌多糖（MenACYW-TT）蛋白结合疫苗免疫原性的小鼠模型的开发和优化。使用三种近交系（BALB/c [H-2d]、C3H/HeN [H-2k] 或 C57BL/6 [H-2b]）和一种远交系（ICR [H-2g7]）小鼠品系，通过候选脑膜炎球菌结合疫苗的连续两倍剂量稀释（每组血清型多糖剂量从 2 µg 至 0.03125 µg）进行评估。每组 10 只小鼠接受两次候选疫苗接种，间隔 14 天，最后一次接种后 14 天采集血清样本，通过 ELISA 评估血清型特异性抗多糖 IgG ，通过血清杀菌试验（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型的抗体反应更具剂量依赖性。一般来说，ICR 小鼠对所有四个血清型的抗体剂量反应范围（抗多糖 IgG 和杀菌抗体）最大，因此被选为首选模型。选择每个血清型 0.25 µg 的剂量是最优的，因为这在大多数评估的小鼠品系的血清型特异性剂量反应曲线的动态范围内。我们证明，优化后的小鼠免疫原性模型足够灵敏，可区分结合多糖、未结合游离多糖和疫苗制剂的降解。优化后，该优化的小鼠免疫原性模型已用于评估不同结合化学对免疫原性的影响，并筛选和分层各种候选脑膜炎球菌结合疫苗，以确定具有最理想特征以进入临床试验的疫苗。
