Carter DM, Darby CA, Johnson SK, Carlock MA, et al. Elicitation of protective antibodies against a broad panel of H1N1 viruses in ferrets pre-immune to historical H1N1 influenza viruses. J Virol 2017 Oct 4
Most pre-clinical animal studies test influenza vaccines in immunologically na?ve animal models, even though the results of vaccination may not accurately reflect the effectiveness of vaccine candidates in humans that have pre-existing immunity to influenza. In this study, novel, broadly-reactive influenza vaccine candidates were assessed in pre-immune 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 HA antigens (COBRA) for H1N1 isolates. Vaccinating ferrets with virus-like particle (VLP) vaccines expressing COBRA HA proteins elicited antibodies with 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 11-14 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 pre-immune ferrets had superior breadth of hemagglutination-inhibition (HAI) activity following vaccination with COBRA HA VLP vaccines than COBRA pre-immune ferrets vaccinated with VLP vaccines expressing wild-type HA proteins. Overall, priming na?ve ferrets with COBRA HA based viruses or using COBRA HA based vaccines to boost pre-existing 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 pre-immune ferret model.IMPORTANCE: 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 na?ve animal models that do not have anti-influenza Immune responses, however, humans have pre-existing immunity to influenza viral antigens, particularly antibodies to the HA and NA glycoproteins. Therefore, this study investigated how pre-existing antibodies to historical influenza viruses influenced HAI-specific antibodies and protective efficacy using a broadly protective vaccine candidate.
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