de Vries J J C, Bungener L, Ter Veer W, van Alphen L, van der Ley P, Wilschut J, Huckriede A
Department of Medical Microbiology, University Medical Center Groningen and University of Groningen, Groningen, The Netherlands.
Vaccine. 2009 Feb 5;27(6):947-55. doi: 10.1016/j.vaccine.2008.11.046. Epub 2008 Dec 4.
The increasing number of human influenza H5N1 infections accentuates the need for the development of H5N1 vaccine candidates to prevent a potential influenza pandemic. The use of adjuvants in such vaccines can contribute significantly to antigen dose-sparing. In this study, we evaluated the capacity of the non-toxic Neisseria meningitidis lipopolysaccharide analog LpxL1 to function as an adjuvant for an influenza H5N1 virosomal vaccine. Inactivated influenza H5N1 virus (NIBRG-14) was used to construct virosomes (reconstituted virus envelopes) with LpxL1 incorporated in the virosomal membrane thus combining the influenza hemagglutinin (HA) antigen and the adjuvant in the same particle. Mice were immunized in a one- or two-dose immunization regimen with H5N1 virosomes with or without incorporated LpxL1. After a single immunization, H5N1 virosomes with incorporated LpxL1 induced significantly enhanced H5N1-specific total IgG titers as compared to non-adjuvanted virosomes but hemagglutination inhibition (HI) titers remained low. In the two-dose immunization regimen, LpxL1-modified H5N1 virosomes induced HI titers above 40 which were significantly higher than those obtained with non-adjuvanted virosomes. Incorporation of LpxL1 had little effect on virosome-induced IgG1 levels, but significantly increased IgG2a levels in both the one- and two-dose immunization regimen. Compared to non-adjuvanted virosomes, LpxL1-modified virosomes induced similar numbers of IFNgamma-producing T cells but decreased numbers of IL-4-producing T cells irrespective of the number of immunizations. We conclude that LpxL1 incorporated in H5N1 influenza virosomes has the capacity to function as a potent adjuvant particularly stimulating Th1-type immune reactions.
人类感染H5N1型流感病毒的病例日益增多，这凸显了研发H5N1候选疫苗以预防潜在流感大流行的必要性。在此类疫苗中使用佐剂可显著有助于节省抗原剂量。在本研究中，我们评估了无毒的脑膜炎奈瑟菌脂多糖类似物LpxL1作为H5N1流感病毒体疫苗佐剂的功能。使用灭活的H5N1流感病毒（NIBRG - 14）构建病毒体（重组病毒包膜），将LpxL1掺入病毒体膜中，从而在同一颗粒中结合流感血凝素（HA）抗原和佐剂。用含或不含LpxL1的H5N1病毒体，以单剂量或双剂量免疫方案对小鼠进行免疫。单次免疫后，与未添加佐剂的病毒体相比，掺入LpxL1的H5N1病毒体诱导的H5N1特异性总IgG滴度显著提高，但血凝抑制（HI）滴度仍然较低。在双剂量免疫方案中，LpxL1修饰的H5N1病毒体诱导的HI滴度高于40，显著高于未添加佐剂的病毒体。掺入LpxL1对病毒体诱导的IgG1水平影响不大，但在单剂量和双剂量免疫方案中均显著提高了IgG2a水平。与未添加佐剂的病毒体相比，无论免疫次数如何，LpxL1修饰的病毒体诱导产生IFNγ的T细胞数量相似，但产生IL - 4的T细胞数量减少。我们得出结论，掺入H5N1流感病毒体中的LpxL1有能力作为一种强效佐剂，尤其能刺激Th1型免疫反应。
