Center for Vaccines and Immunology, University of Georgia, Athens, Georgia, USA.
Sanofi Pasteur, Cambridge, Massachusetts, USA.
J Virol. 2019 Jan 17;93(3). doi: 10.1128/JVI.00946-18. Print 2019 Feb 1.
The vast majority of people already have preexisting immune responses to influenza viruses from one or more subtypes. However, almost all preclinical studies evaluate new influenza vaccine candidates in immunologically naive animals. Recently, our group demonstrated that priming naive ferrets with broadly reactive H1 COBRA HA-based vaccines boosted preexisting antibodies induced by wild-type H1N1 virus infections. These H1 COBRA hemagglutinin (HA) antigens induced antibodies with HAI activity against multiple antigenically different H1N1 viral variants. In this study, ferrets, preimmune to historical H3N2 viruses, were vaccinated with virus-like particle (VLP) vaccines expressing either an HA from a wild-type H3 influenza virus or a COBRA H3 HA antigen (T6, T7, T10, or T11). The elicited antisera had the ability to neutralize virus infection against either a panel of viruses representing vaccine strains selected by the World Health Organization or a set of viral variants that cocirculated during the same time period. Preimmune animals vaccinated with H3 COBRA T10 HA antigen elicited sera with higher hemagglutination inhibition (HAI) antibody titers than antisera elicited by VLP vaccines with wild-type HA VLPs in preimmune ferrets. However, while the T11 COBRA vaccine did not elicit HAI activity, the elicited antibodies did neutralize antigenically distinct H3N2 influenza viruses. Overall, H3 COBRA-based HA vaccines were able to neutralize both historical H3 and contemporary, as well as future, H3N2 viruses with higher titers than vaccines with wild-type H3 HA antigens. This is the first report demonstrating the effectiveness of a broadly reactive H3N3 vaccine in a preimmune ferret model. After exposure to influenza virus, the host generates neutralizing anti-hemagglutinin (anti-HA) antibodies against that specific infecting influenza strain. These antibodies can also neutralize some, but not all, cocirculating strains. The goal of next-generation influenza vaccines, such as HA head-based COBRA, is to stimulate broadly protective neutralizing antibodies against all strains circulating within a subtype, in particular those that persist over multiple influenza seasons, without requiring an update to the vaccine. To mimic the human condition, COBRA HA virus-like particle vaccines were tested in ferrets that were previously exposed to historical H3N2 influenza viruses. In this model, these vaccines elicited broadly protective antibodies that neutralized cocirculating H3N2 influenza viruses isolated over a 20-year period. This is the first study to show the effectiveness of H3N3 COBRA HA vaccines in a host with preexisting immunity to influenza.
绝大多数人已经对一种或多种亚型的流感病毒产生了预先存在的免疫反应。然而，几乎所有的临床前研究都在免疫原性未成熟的动物中评估新的流感疫苗候选物。最近，我们的研究小组表明，用广泛反应的 H1 COBRA 血凝素（HA）疫苗对无反应的雪貂进行初步免疫，可以增强野生型 H1N1 病毒感染引起的预先存在的抗体。这些 H1 COBRA 血凝素（HA）抗原诱导的抗体具有针对多种抗原不同的 H1N1 病毒变异体的血凝抑制（HAI）活性。在这项研究中，对历史 H3N2 病毒无反应的雪貂用表达野生型 H3 流感病毒或 COBRA H3 HA 抗原（T6、T7、T10 或 T11）的病毒样颗粒（VLP）疫苗进行了疫苗接种。诱导的血清能够中和针对一组代表世界卫生组织选择的疫苗株的病毒或同一时期共同循环的一组病毒变体的病毒感染。用 H3 COBRA T10 HA 抗原免疫的无反应动物比用无反应的雪貂中的野生型 HA VLP 疫苗免疫的动物产生更高的血凝抑制（HAI）抗体滴度的血清。然而，虽然 T11 COBRA 疫苗没有诱导 HAI 活性，但诱导的抗体确实能够中和抗原不同的 H3N2 流感病毒。总体而言，基于 H3 COBRA 的 HA 疫苗能够中和具有更高滴度的历史 H3 和当代以及未来的 H3N2 病毒，比具有野生型 H3 HA 抗原的疫苗更有效。这是第一个证明广泛反应性 H3N3 疫苗在无反应的雪貂模型中有效的报告。在接触流感病毒后，宿主会针对该特定感染流感株产生针对血凝素（抗-HA）的中和抗体。这些抗体还可以中和一些，但不是全部，共同循环的菌株。下一代流感疫苗（如基于 HA 头部的 COBRA）的目标是刺激针对亚组内所有循环株的广泛保护性中和抗体，特别是那些在多个流感季节持续存在的抗体，而无需对疫苗进行更新。为了模拟人类的情况，用以前接触过历史 H3N2 流感病毒的雪貂测试了 COBRA HA 病毒样颗粒疫苗。在该模型中，这些疫苗诱导了广泛保护性的抗体，可中和 20 年来分离的共同循环的 H3N2 流感病毒。这是第一项表明 H3N3 COBRA HA 疫苗在预先存在对流感免疫力的宿主中有效的研究。
