Phase I evaluation of intranasal trivalent inactivated influenza vaccine with nontoxigenic Escherichia coli enterotoxin and novel biovector as mucosal adjuvants, using adult volunteers
Phase I evaluation of intranasal trivalent inactivated influenza vaccine with nontoxigenic Escherichia coli enterotoxin and novel biovector as mucosal adjuvants, using adult volunteers
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DOI：
10.1128/jvi.80.10.4962-4970.2006
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发表时间：
2006-05-01
影响因子：
5.4
通讯作者：
Nicholson, Karl G.
中科院分区：
文献类型：
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作者：
Stephenson, Iain;Zambon, Maria C.;Nicholson, Karl G.
在一项随机、对照、剂量范围的I期研究中，使用了A/鸭/新加坡（H5N3）、A/巴拿马（H3N2）和B/广东三价流感病毒疫苗制剂。该疫苗由高纯度的血凝素和神经氨酸酶制备而成，这些血凝素和神经氨酸酶是从在胚鸡蛋中繁殖的流感病毒中提取出来的，并用甲醛灭活。我们将100名参与者分配到六个疫苗组，如下所示。三个鼻内接种组分别用3、10或30吉热不稳定的大肠杆菌肠毒素（LTK63）和990吉超分子生物载体分别接种7.5 μ g剂量的每个病毒株的血凝素；一个鼻内接种组给予7.5 μ g剂量的血凝素和30 μ g不含生物载体的LTK63；另一组鼻内接种疫苗的人接受生理盐水溶液作为安慰剂。最后一组用MF59佐剂注射含有每株15 μ g血凝素的肌内疫苗。用针筒滴入双鼻孔、间隔1周的两剂鼻内注射与隔3周肌内注射两剂的免疫原性比较。肌内和鼻内疫苗制剂都具有免疫原性，但刺激的是不同肢体的免疫系统。循环抗体的最大增加发生在肌肉注射疫苗的反应中；最大的粘膜免疫球蛋白A （IgA）反应发生在粘膜疫苗接种反应中。目前欧盟的流感疫苗许可标准满足于A/Panama和B/广东血凝素与MF59佐剂一起注射，以及B/广东血凝素与最高剂量LTK63和生物载体一起鼻内给药的血清血凝抑制反应。通过血凝抑制和微量中和作用，肌肉注射疫苗接种者在3周和6周时每种病毒株的几何平均血清抗体滴度显著高于鼻内疫苗接种者。鼻内注射的实验性疫苗的免疫原性因流感病毒株而异。与安慰剂组相比，给予30 jig LTK63生物载体的受试者对A/Duck/Singapore （H5N3）、A/Panama （H3N2）和B/Guandong的粘膜IgA反应最高，分别发生在7/15 （47%,P = 0.0103）、8/15 （53%,P = 0.0362）和14/15 （93%,P = 0.0033）。在含有30 μ g LTK63的疫苗中添加该生物载体可增强对A/Duck/Singapore (H5N3) （P = 0.0491）和B/Guandong （P = 0.0028）的黏膜IgA反应，但对A/Panama （H3N2）没有作用。所有疫苗均具有良好的耐受性。
Trivalent influenza virus A/Duck/Singapore (H5N3), A/Panama (H3N2), and B/Guandong vaccine preparations were used in a randomized, controlled, dose-ranging phase I study. The vaccines were prepared from highly purified hemagglutinin and neuraminidase from influenza viruses propagated in embryonated chicken eggs and inactivated with formaldehyde. We assigned 100 participants to six vaccine groups, as follows. Three intranasally vaccinated groups received 7.5-mu g doses of hemagglutinin from each virus strain with either 3, 10, or 30 jig of heat-labile Escherichia coli enterotoxin (LTK63) and 990 jig of a supramolecular biovector; one intranasally vaccinated group was given 7.5-mu g doses of hemagglutinin with 30 mu g of LTK63 without the biovector; and another intranasally vaccinated group received saline solution as a placebo. The final group received an intramuscular vaccine containing 15 mu g hemagglutinin from each strain with MF59 adjuvant. The immunogenicity of two intranasal doses, delivered by syringe as drops into both nostrils with an interval of I week between, was compared with that of two inoculations by intramuscular delivery 3 weeks apart. The intramuscular and intranasal vaccine formulations were both immunogenic but stimulated different limbs of the immune system. The largest increase in circulating antibodies occurred in response to intramuscular vaccination; the largest mucosal immunoglobulin A (IgA) response occurred in response to mucosal vaccination. Current licensing criteria for influenza vaccines in the European Union were satisfied by serum hemagglutination inhibition responses to A/Panama and B/Guandong hemagglutinins given with MF59 adjuvant by injection and to B/Guandong hemagglutinin given intranasally with the highest dose of LTK63 and the biovector. Geometric mean serum antibody titers by hemagglutination inhibition and microneutralization were significantly higher for each virus strain at 3 and 6 weeks in recipients of the intramuscular vaccine than in recipients of the intranasal vaccine. The immunogenicity of the intranasally delivered experimental vaccine varied by influenza virus strain. Mucosal IgA responses to A/Duck/Singapore (H5N3), A/Panama (H3N2), and B/Guandong were highest in participants given 30 jig LTK63 with the biovector, occurring in 7/15 (47%; P = 0.0103), 8/15 (53%; P = 0.0362), and 14/15 (93%; P = 0.0033) participants, respectively, compared to the placebo group. The addition of the biovector to the vaccine given with 30 mu g LTK63 enhanced mucosal IgA responses to A/Duck/Singapore (H5N3) (P = 0.0491) and B/Guandong (P = 0.0028) but not to A/Panama (H3N2). All vaccines were well tolerated.