Cleland J L, Powell M F, Lim A, Barrón L, Berman P W, Eastman D J, Nunberg J H, Wrin T, Vennari J C
Department of Pharmaceutical Research and Development, Genentech, Inc., South San Francisco, California 94080.
AIDS Res Hum Retroviruses. 1994;10 Suppl 2:S21-6.
The successful development of an AIDS vaccine will require formulations that not only invoke the desired immunological response, but also are stable and easy to administer. A single shot MN rgp120 vaccine formulation comprised of MN rgp120 encapsulated in poly (lactic-coglycolic) acid (PLGA) microspheres was developed to provide an in vivo autoboost of antigen. These formulations were designed to yield an in vivo autoboost at 1, 2, 3 or 4-6 months. In addition, PLGA microspheres containing the adjuvant, QS21, were also prepared to provide an in vivo autoboost concomitant with antigen. In guinea pigs, these formulations yielded higher anti-MN rgp120 and anti-V3 loop antibody titers than alum formulations that were administered at higher antigen doses. Different doses of encapsulated MN rgp120 provided a clear and well-defined dose response curve for both anti-MN rgp120 and anti-V3 loop antibody titers. When soluble QS21 was mixed with the encapsulated MN rgp120, the antibody titers were increased by a factor of 5 over the titers with encapsulated MN rgp120 alone. An additional fivefold increase in antibody titers was observed for guinea pigs immunized with encapsulated MN rgp120 and QS21 on the same microspheres. These results suggest that the adjuvant properties of QS21 can be increased by microencapsulation in PLGA. Furthermore, antibodies induced by these preparations neutralized the MN strain of HIV-1. The neutralization titers for sera from animals immunized with MN rgp120-PLGA and soluble QS21 were greater than the titers obtained from guinea pigs that were treated with MN rgp120 and soluble QS21 at the same dose. Overall, these studies validate the in vivo autoboost concept, reveal a method for improving the adjuvant properties of QS21, and indicate the potential of future single shot vaccine formulations.
不仅能引发预期的免疫反应，而且稳定且易于给药。研发了一种单次注射的MN rgp120疫苗制剂，其由包裹在聚（乳酸-乙醇酸）（PLGA）微球中的MN rgp120组成，以在体内实现抗原的自身增强。这些制剂设计为在1、2、3或4 - 6个月时在体内实现自身增强。此外，还制备了含有佐剂QS21的PLGA微球，以在体内实现与抗原相伴的自身增强。在豚鼠中，这些制剂产生的抗MN rgp120和抗V3环抗体滴度高于以更高抗原剂量给药的明矾制剂。不同剂量的包裹MN rgp120为抗MN rgp120和抗V3环抗体滴度提供了清晰且明确的剂量反应曲线。当将可溶性QS21与包裹的MN rgp120混合时，抗体滴度比单独使用包裹的MN rgp120时提高了5倍。在用相同微球上的包裹MN rgp120和QS21免疫的豚鼠中，观察到抗体滴度又额外提高了5倍。这些结果表明，通过在PLGA中进行微囊化可增强QS21的佐剂特性。此外，这些制剂诱导产生的抗体可中和HIV - 1的MN毒株。用MN rgp120 - PLGA和可溶性QS21免疫的动物血清的中和滴度高于以相同剂量用MN rgp120和可溶性QS21处理的豚鼠所获得的滴度。总体而言，这些研究验证了体内自身增强概念，揭示了一种改善QS21佐剂特性的方法，并表明了未来单次注射疫苗制剂的潜力。
