Carter Donald M, Darby Christopher A, Johnson Scott K, Carlock Michael A, Kirchenbaum Greg A, Allen James D, Vogel Thorsten U, Delagrave Simon, DiNapoli Joshua, Kleanthous Harold, Ross Ted M
Center for Vaccines and Immunology, University of Georgia, Athens, Georgia, USA.
Department of Infectious Diseases, University of Georgia, Athens, Georgia, USA.
J Virol. 2017 Nov 30;91(24). doi: 10.1128/JVI.01283-17. Print 2017 Dec 15.
Most preclinical animal studies test influenza vaccines in immunologically naive animal models, even though the results of vaccination may not accurately reflect the effectiveness of vaccine candidates in humans that have preexisting immunity to influenza. In this study, novel, broadly reactive influenza vaccine candidates were assessed in preimmune ferrets. These animals were infected with different H1N1 isolates before being vaccinated or infected with another influenza virus. Previously, our group has described the design and characterization of computationally optimized broadly reactive hemagglutinin (HA) antigens (COBRA) for H1N1 isolates. Vaccinating ferrets with virus-like particle (VLP) vaccines expressing COBRA HA proteins elicited antibodies with hemagglutination inhibition (HAI) activity against more H1N1 viruses in the panel than VLP vaccines expressing wild-type HA proteins. Specifically, ferrets infected with the 1986 virus and vaccinated with a single dose of the COBRA HA VLP vaccines elicited antibodies with HAI activity against 11 to 14 of the 15 H1N1 viruses isolated between 1934 and 2013. A subset of ferrets was infected with influenza viruses expressing the COBRA HA antigens. These COBRA preimmune ferrets had superior breadth of HAI activity after vaccination with COBRA HA VLP vaccines than COBRA preimmune ferrets vaccinated with VLP vaccines expressing wild-type HA proteins. Overall, priming naive ferrets with COBRA HA based viruses or using COBRA HA based vaccines to boost preexisting antibodies induced by wild-type H1N1 viruses, COBRA HA antigens elicited sera with the broadest HAI reactivity against multiple antigenic H1N1 viral variants. This is the first report demonstrating the effectiveness of a broadly reactive or universal influenza vaccine in a preimmune ferret model. Currently, many groups are testing influenza vaccine candidates to meet the challenge of developing a vaccine that elicits broadly reactive and long-lasting protective immune responses. The goal of these vaccines is to stimulate immune responses that react against most, if not all, circulating influenza strains, over a long period of time in all populations of people. Commonly, these experimental vaccines are tested in naive animal models that do not have anti-influenza immune responses; however, humans have preexisting immunity to influenza viral antigens, particularly antibodies to the HA and NA glycoproteins. Therefore, this study investigated how preexisting antibodies to historical influenza viruses influenced HAI-specific antibodies and protective efficacy using a broadly protective vaccine candidate.
大多数临床前动物研究在免疫未成熟的动物模型中测试流感疫苗，尽管疫苗接种结果可能无法准确反映候选疫苗在对流感已有免疫力的人类中的有效性。在本研究中，在免疫前的雪貂中评估了新型的、具有广泛反应性的流感候选疫苗。这些动物在接种疫苗或感染另一种流感病毒之前，先感染了不同的H1N1分离株。此前，我们团队已经描述了针对H1N1分离株的通过计算优化的具有广泛反应性的血凝素（HA）抗原（COBRA）的设计和特性。用表达COBRA HA蛋白的病毒样颗粒（VLP）疫苗接种雪貂，与表达野生型HA蛋白的VLP疫苗相比，诱导出的抗体对更多组中的H1N1病毒具有血凝抑制（HAI）活性。具体而言，感染1986年病毒并接种单剂量COBRA HA VLP疫苗的雪貂，其诱导出的抗体对1934年至2013年间分离的15种H1N1病毒中的11至14种具有HAI活性。一部分雪貂感染了表达COBRA HA抗原的流感病毒。与接种表达野生型HA蛋白的VLP疫苗的COBRA免疫前雪貂相比，这些COBRA免疫前雪貂在用COBRA HA VLP疫苗接种后具有更高的HAI活性广度。总体而言，用基于COBRA HA的病毒对未免疫的雪貂进行初免，或使用基于COBRA HA的疫苗增强由野生型H1N1病毒诱导的已有抗体，COBRA HA抗原诱导的血清对多种抗原性H1N1病毒变体具有最广泛的HAI反应性。这是第一份证明在免疫前雪貂模型中具有广泛反应性或通用流感疫苗有效性的报告。目前，许多团队正在测试流感候选疫苗，以应对开发一种能引发广泛反应性和持久保护性免疫反应的疫苗的挑战。这些疫苗的目标是在所有人群中长时间刺激针对大多数（如果不是全部）流行流感毒株产生反应的免疫反应。通常，这些实验性疫苗在没有抗流感免疫反应的未免疫动物模型中进行测试；然而，人类对流感病毒抗原有已有免疫力，特别是对HA和NA糖蛋白的抗体。因此，本研究使用一种具有广泛保护性的候选疫苗，研究了针对历史流感病毒的已有抗体如何影响HAI特异性抗体和保护效力。
