Research Areas:

Respiratory Viruses

Influenza (flu) is a contagious respiratory disease caused by influenza viruses. It can cause mild to severe illness. Every year over half a million people die of seasonal influenza. Many different influenza viruses are found around the globe and these viruses easily mutate to new virus variants.

In addition, there is the constant threat of a new pandemic influenza virus. A ‘new’ virus that may be formed after recombination between bird-influenza viruses and pig-influenza viruses, and that is able cause serious disease in humans. A scenario similar to the Spanish flu in 1918 which killed over 50 million people.

Ideally, an influenza vaccine would provide protection against a broad spectrum of seasonal influenza, as well as pandemic influenza viruses. However, current influenza vaccines afford only limited protection against seasonal as well as pandemic influenza. Therefore, new and improved vaccine-strategies are required. This involves new vaccine concepts as well as improved vaccine production technologies.

At BPRC we use influenza infection models in monkeys to evaluate the protective capacity of several novel vaccine strategies.

Experimental animal models for universal influenza vaccines

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BPRC was partner in a collaborative European consortium: Educate Influenza Vaccine (EduFluVac). As part of this network a workshop was organized. During this workshop a diversity of models to evaluate universal influenza vaccines were discussed. The program covered well-established and publicly accepted animal models, newly developed animal models as well as ex-vivo approaches and human models. The audience concluded that, depending on vaccine approach and the type of immune response, different models are required. As safety is the main concern for transition to clinical development, influenza vaccine associated enhancement of disease was specifically emphasized. An efficient animal model to evaluate this aspect of safety still needs to be identified. Working with animal models requires ethical compliance and consideration of the 3R principles. Development of alternative approaches such as ex-vivo techniques is progressing but is still at an early stage. These methods are not yet suitable for broader application for vaccine evaluation. The human challenge is the ultimate model to assess influenza vaccines. However, this model is expensive and not largely applicable. The currently used pre-clinical models are not yet specifically focused on studying unique aspects of a universal influenza vaccine. Further collaboration, communication and effective networking are needed for success to establish harmonized and standardized pre-clinical models for evaluation of new influenza vaccines.

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Needle-free influenza vaccine protects rhesus macaques against H1N1 influenza

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The production of conventional influenza vaccines is a complicated and time consuming process. By contrast DNA vaccines can be rapidly produced and offers tailor-made flexibility to efficiently counter newly emerging influenza virus strains. However, a drawback of DNA vaccines is their generally low immunogenicity in non-human primates and humans. Norwegian scientists have developed a novel DNA influenza vaccine strategy that induced good immune responses in ferrets and pigs. BPRC evaluated this vaccine in rhesus macaques. The vaccine, a DNA vaccine encoding for a bivalent fusion protein that targets influenza virus hemagglutinin (HA) to Mamu class II molecules, was intradermally administered by pain- and needle-free jet injections. The vaccine induced neutralizing antibodies and antigen-specific T cells and protected against a challenge with influenza virus. This type of needle free DNA vaccination may become an effective way to rapidly and efficiently protect people to emerging seasonal or pandemic influenza virus strains. The information of this study will be published in 2019.

 

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Mini-hemagglutinin vaccination induces cross-reactive antibodies in pre-exposed NHP that protect mice against lethal influenza challenge

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By the age of 6 years, virtually all people have detectable influenza-specific antibodies. However, these antibodies are only effective if the next influenza infection occurs with a virus variant that strongly resembles the previous one. In the light of yearly vaccinations to seasonal influenza it is important to know if antibody responses can be broadened by vaccination.

In 2015 we conducted a study in collaboration with Crucell Vaccine Institute. This work was published in Science (Impagliazzo, A. et al. Science, 2015) and described a successful influenza vaccine approach with the so-called ‘mini-HA’ in our monkeys. In 2017 blood samples from these animals were used to investigate the protective capacity of the antibodies in the blood of the animals. This was done by adoptive transfer in mice. Mice that were inoculated with antibodies from monkeys that received the influenza vaccine after they were exposed to influenza virus were better protected from influenza infection compared to mice that received antibodies from animals that were only exposed to the virus. This study suggests yearly vaccination may broaden the influenza-specific humoral immune responses in humans.

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New in vitro assays

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At BPRC we are constantly developing and optimizing in vitro laboratory assays to analyze the anti-viral immunity. We use these tests to study immune responses after influenza vaccination or infection in monkeys. In 2018 the focus was on the implementation of new assays that visualize antibody mediated cellular processes in our animals. For instance, killing of virally infected cells and the elimination of infected cells through phagocytosis. These assays will improve our understanding about what is required for achieving broad protection against influenza infection.

 

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PhD student influenza specific antibody responses

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Protection from influenza infection relies on good antibody responses. In collaboration with the Amsterdam Medical Centre we are currently training a PhD student to study the plasticity of antibody producing B-cells. For this project we use in vitro models and blood samples from previously vaccinated rhesus macaques. The results of the project will lead to better understanding of antibodies after influenza-vaccination.

 

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