Boehm Gérard, Peyre Marisa, Sesardic Dorothea, Huskisson Rachel J, Mawas Fatme, Douglas Alexandra, Xing Dorothy, Merkle Hans P, Gander Bruno, Johansen Pål
Institute of Pharmaceutical Sciences, ETH Zurich, Switzerland.
Pharm Res. 2002 Sep;19(9):1330-6. doi: 10.1023/a:1020354809581.
With the aim of developing multivalent vaccines for single-injection, we examined the feasibility of combining antigens in biodegradable microspheres. Such vaccines are expected to improve vaccination coverage by reducing the number of vaccination sessions required to generate immunity.
Mono- and multivalent vaccines of Haemophilus influenzae type b (Hib) conjugate, diphtheria toxoid (DT), tetanus toxoid (TT), and pertussis toxin (PT) in poly (lactic acid) and poly(lactic-coglycolic acid) microspheres were prepared by spray drying, and the influence of coencapsulated antigens and excipients on antigen loading, release, and stability was examined. Two tetravalent formulations were tested in guinea pigs.
Monovalent Hib and PT vaccines showed loading efficiencies of 10% (Hib) and 30% (PT) in both polymers. The loading efficiencies increased upon addition of trehalose and, even more, when the antigens were coencapsulated in di- and trivalent combinations. Highest loading efficiencies (> 80%) were achieved with trivalent formulations (DT + PT + Hib) that also contained coencapsulated albumin. The percentage of antigen released during 24 h of incubation was typically 10-40% and decreased as loading efficiency increased. Enzyme-linked immunosorbent assay (ELISA) data revealed that TT, DT, and PT remained antigenic throughout the encapsulation and subsequent release processes. Finally, all antigens maintained their immunogenicity, since strong and sustained antibody responses were elicited after a single injection of tetravalent microsphere vaccines (DT + TT + PT + Hib) in guinea pigs.
This study reveals technologic benefit as well as an immunological potential of multivalent single-injection microsphere vaccines. The results support our hypothesis that coencapsulation of several antigens may intrinsically improve entrapment of antigenic and immunogenic antigen probably by virtue of increased protein concentration during microencapsulation leading to mutual stabilization of the components.
为研发单针注射用多价疫苗，我们研究了在可生物降解微球中组合抗原的可行性。此类疫苗有望通过减少产生免疫所需的接种次数来提高疫苗接种覆盖率。
通过喷雾干燥制备了聚乳酸和聚乳酸-乙醇酸共聚物微球中包含的b型流感嗜血杆菌（Hib）结合物、白喉类毒素（DT）、破伤风类毒素（TT）和百日咳毒素（PT）的单价及多价疫苗，并研究了共包封的抗原和辅料对抗原负载、释放及稳定性的影响。在豚鼠中测试了两种四价制剂。
单价Hib和PT疫苗在两种聚合物中的负载效率分别为10%（Hib）和30%（PT）。添加海藻糖后负载效率提高，当抗原以二价和三价组合共包封时提高得更多。含共包封白蛋白的三价制剂（DT + PT + Hib）实现了最高负载效率（> 80%）。孵育24小时期间释放的抗原百分比通常为10 - 40%，且随负载效率增加而降低。酶联免疫吸附测定（ELISA）数据显示，TT、DT和PT在整个包封及后续释放过程中均保持抗原性。最后，所有抗原均保持其免疫原性，因为在豚鼠单次注射四价微球疫苗（DT + TT + PT + Hib）后引发了强烈且持续的抗体反应。
本研究揭示了多价单针注射微球疫苗的技术优势及免疫潜力。结果支持了我们的假设，即几种抗原的共包封可能通过微囊化过程中蛋白质浓度增加导致各组分相互稳定，从而本质上改善抗原性和免疫原性抗原的包封。
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