Fries L F, Gordon D M, Richards R L, Egan J E, Hollingdale M R, Gross M, Silverman C, Alving C R
Center for Immunization Research, School of Hygiene and Public Health, The Johns Hopkins University, Baltimore, MD 21205.
Proc Natl Acad Sci U S A. 1992 Jan 1;89(1):358-62. doi: 10.1073/pnas.89.1.358.
This study describes the safety and immunogenicity of a liposome-based vaccine injected into human subjects. Thirty healthy adult male volunteers were immunized with a liposome-encapsulated recombinant protein (R32NS181) containing epitopes from the repeat region of the circumsporozoite protein of Plasmodium falciparum. This antigen had previously been found to be poorly immunogenic in humans when it was adsorbed with Al(OH)3. In the present study, R32NS181 was encapsulated in liposomes containing monophosphoryl lipid A that were subsequently adsorbed to Al(OH)3. Increasing doses of liposomes containing antigen and monophosphoryl lipid A were used, but the liposomes were always adsorbed to the same dose of Al(OH)3. R32-specific serum IgG antibody responses to liposome-encapsulated R32NS181 were much higher than levels attained previously in humans with R32NS181 adsorbed to Al(OH)3. Geometric mean specific IgG levels after three doses ranged from 14 to 33 micrograms/ml. Sera from volunteers receiving the two highest doses inhibited P. falciparum sporozoite invasion of cultured hepatoma cells by an average of 92%, a result that was again superior to previously reported vaccines. Moderate but acceptable transient local reactogenicity was noted at high doses of the vaccine formulation, but little or no systemic toxicity was seen despite liposomal monophosphoryl lipid A doses up to 2200 micrograms. We conclude that encapsulation of poorly immunogenic circumsporozoite protein repeat peptides in monophosphoryl lipid A-containing liposomes is a successful adjuvant strategy in humans for inducing high levels of specific antibody production.
本研究描述了一种注射到人体受试者体内的脂质体疫苗的安全性和免疫原性。30名健康成年男性志愿者用一种脂质体包裹的重组蛋白（R32NS181）进行免疫，该重组蛋白包含恶性疟原虫环子孢子蛋白重复区域的表位。此前发现，当这种抗原与氢氧化铝吸附时，在人体中的免疫原性较差。在本研究中，R32NS181被包裹在含有单磷酰脂质A的脂质体中，随后吸附到氢氧化铝上。使用了含抗原和单磷酰脂质A的脂质体递增剂量，但脂质体始终吸附到相同剂量的氢氧化铝上。对脂质体包裹的R32NS181的R32特异性血清IgG抗体反应远高于此前人体中R32NS181与氢氧化铝吸附时所达到的水平。三剂后的几何平均特异性IgG水平在14至33微克/毫升之间。接受最高两剂的志愿者血清平均抑制恶性疟原虫子孢子对培养的肝癌细胞的侵袭达92%，这一结果同样优于此前报道的疫苗。在高剂量疫苗制剂时观察到中度但可接受的短暂局部反应原性，尽管脂质体单磷酰脂质A剂量高达2200微克，但几乎未见全身毒性。我们得出结论，将免疫原性差的环子孢子蛋白重复肽包裹在含单磷酰脂质A的脂质体中，是在人体中诱导高水平特异性抗体产生的一种成功的佐剂策略。
