PDF(Pubmed)
Abstract：
Introducing new recombinant protein antigens to existing pediatric combination vaccines is important in improving coverage and affordability, especially in low- and middle-income countries (LMICs). This case-study highlights the analytical and formulation challenges encountered with three recombinant non-replicating rotavirus vaccine (NRRV) antigens (t-NRRV formulated with Alhydrogel® adjuvant, AH) combined with a mock multidose formulation of a pediatric pentavalent vaccine used in LMICs. This complex formulation contained (1) vaccine antigens (i.e., whole-cell pertussis (wP), diphtheria (D), tetanus (T), Haemophilus influenza (Hib), and hepatitis B (HepB), (2) a mixture of aluminum-salt adjuvants (AH and Adju-Phos®, AP), and (3) a preservative (thimerosal, TH). Selective, stability-indicating competitive immunoassays were developed to monitor binding of specific mAbs to each antigen, except wP which required the setup of a mouse immunogenicity assay. Simple mixing led to the desorption of t-NRRV antigens from AH and increased degradation during storage. These deleterious effects were caused by specific antigens, AP, and TH. An AH-only pentavalent formulation mitigated t-NRRV antigen desorption; however, the Hib antigen displayed previously reported AH-induced instability. The same rank-ordering of t-NRRV antigen stability (P[8] > P[4] > P[6]) was observed in mock pentavalent formulations and with various preservatives. The lessons learned are discussed to enable future multidose, combination vaccine formulation development with new vaccine candidates.
摘要：
在现有的儿科联合疫苗中引入新的重组蛋白抗原对于提高覆盖率和可负担性非常重要。特别是在低收入和中等收入国家（LMICs）。本案例研究强调了三种重组非复制轮状病毒疫苗（NRRV）抗原（用Alhydrogel®佐剂配制的t-NRRV，AH）与LMIC中使用的小儿五价疫苗的模拟多剂量制剂相结合。这种复杂的制剂含有(1)疫苗抗原(即，全细胞百日咳（wP），白喉（D），破伤风（T），流感嗜血杆菌（Hib），和乙型肝炎（HepB），（2）铝盐佐剂的混合物（AH和Adju-Phos®，AP),和(3)防腐剂(硫柳汞，TH).选择性,开发了指示稳定性的竞争性免疫测定来监测特异性单克隆抗体与每种抗原的结合，除了wP需要建立小鼠免疫原性测定。简单混合导致t-NRRV抗原从AH解吸并在储存期间增加降解。这些有害作用是由特异性抗原引起的，AP,和TH。仅AH的五价制剂减轻了t-NRRV抗原解吸;然而，Hib抗原显示先前报道的AH诱导的不稳定性。在模拟五价制剂和各种防腐剂中观察到t-NRRV抗原稳定性的相同排序(P[8]>P[4]>P[6])。讨论了吸取的教训，以实现未来的多剂量，新候选疫苗的联合疫苗制剂开发。
