Wong Terianne M, Allen James D, Bebin-Blackwell Anne-Gaelle, Carter Donald M, Alefantis Timothy, 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.01581-17. Print 2017 Dec 15.
Each influenza season, a set of wild-type viruses, representing one H1N1, one H3N2, and one to two influenza B isolates, are selected for inclusion in the annual seasonal influenza vaccine. In order to develop broadly reactive subtype-specific influenza vaccines, a methodology called computationally optimized broadly reactive antigens (COBRA) was used to design novel hemagglutinin (HA) vaccine immunogens. COBRA technology was effectively used to design HA immunogens that elicited antibodies that neutralized H5N1 and H1N1 isolates. In this report, the development and characterization of 17 prototype H3N2 COBRA HA proteins were screened in mice and ferrets for the elicitation of antibodies with HA inhibition (HAI) activity against human seasonal H3N2 viruses that were isolated over the last 48 years. The most effective COBRA HA vaccine regimens elicited antibodies with broader HAI activity against a panel of H3N2 viruses than wild-type H3 HA vaccines. The top leading COBRA HA candidates were tested against cocirculating variants. These variants were not efficiently detected by antibodies elicited by the wild-type HA from viruses selected as the vaccine candidates. The T-11 COBRA HA vaccine elicited antibodies with HAI and neutralization activity against all cocirculating variants from 2004 to 2007. This is the first report demonstrating broader breadth of vaccine-induced antibodies against cocirculating H3N2 strains compared to the wild-type HA antigens that were represented in commercial influenza vaccines. There is a need for an improved influenza vaccine that elicits immune responses that recognize a broader number of influenza virus strains to prevent infection and transmission. Using the COBRA approach, a set of vaccines against influenza viruses in the H3N2 subtype was tested for the ability to elicit antibodies that neutralize virus infection against not only historical vaccine strains of H3N2 but also a set of cocirculating variants that circulated between 2004 and 2007. Three of the H3N2 COBRA vaccines recognized all of the cocirculating strains during this era, but the chosen wild-type vaccine strains were not able to elicit antibodies with HAI activity against these cocirculating strains. Therefore, the COBRA vaccines have the ability to elicit protective antibodies against not only the dominant vaccine strains but also minor circulating strains that can evolve into the dominant vaccine strains in the future.
每个流感季节，都会挑选一组野生型病毒，包括一株H1N1、一株H3N2以及一到两株乙型流感病毒分离株，用于制备年度季节性流感疫苗。为了研发具有广泛反应性的亚型特异性流感疫苗，一种名为计算优化广泛反应性抗原（COBRA）的方法被用于设计新型血凝素（HA）疫苗免疫原。COBRA技术有效地用于设计能引发中和H5N1和H1N1分离株抗体的HA免疫原。在本报告中，对17种H3N2 COBRA HA蛋白原型进行了研发和特性分析，并在小鼠和雪貂中进行筛选，以检测其是否能引发针对过去48年中分离出的人类季节性H3N2病毒具有血凝素抑制（HAI）活性的抗体。与野生型H3 HA疫苗相比，最有效的COBRA HA疫苗方案能引发针对一组H3N2病毒具有更广泛HAI活性的抗体。对排名靠前的COBRA HA候选疫苗进行了针对同时流行变体的测试。野生型HA从被选为疫苗候选株的病毒中引发的抗体无法有效检测到这些变体。T-11 COBRA HA疫苗能引发针对2004年至2007年所有同时流行变体具有HAI和中和活性的抗体。这是第一份报告，表明与商业流感疫苗中所代表的野生型HA抗原相比，疫苗诱导的抗体对同时流行的H3N2毒株具有更广泛的广度。需要一种改进的流感疫苗，能引发识别更多流感病毒株的免疫反应，以预防感染和传播。使用COBRA方法，对一组针对H3N2亚型流感病毒的疫苗进行了测试，检测其引发不仅能中和H3N2历史疫苗株而且能中和2004年至2007年期间同时流行的一组变体病毒感染的抗体的能力。三种H3N2 COBRA疫苗能识别这一时期所有同时流行的毒株，但所选的野生型疫苗株无法引发针对这些同时流行毒株具有HAI活性的抗体。因此，COBRA疫苗不仅能够引发针对主要疫苗株的保护性抗体，还能引发针对未来可能演变成主要疫苗株的次要流行株的保护性抗体。
