Influenza Virus
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, the so-called ‘antigenic drift’.
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. This is called ‘antigenic shift’.
Ideally, an influenza vaccine provides 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 and improved vaccine production technologies.
At BPRC we use influenza infection models in monkeys to evaluate the protective capacity of novel vaccine strategies.
Experimental animal models for universal influenza vaccines
Non-human primate animal models are important to determine whether novel vaccines against influenza can provide a good and broad protection against influenza virus and are safe to use. To measure protection, it is necessary to experimentally expose animals to influenza virus. This is usually done by applying an amount of virus in the nose, mouth and directly in the lungs. However, infection in humans is mainly caused by exposure to aerosols or droplets that enter the airways either via respiration, inhalation, or via contact with contaminated surfaces. To better mimic this typical human way of exposure, a non-human primate model was developed that could be infected by virus in aerosols. Although the animals became infected, the reaction of the body differed from what was observed when the virus was directly injected into the lungs. Infection by aerosols gave lower levels of inflammation and may therefore be more typical of a mild infection in humans. Instead, direct injection in the lungs gave more pronounced inflammatory response, typical of the more severe infection that develops in some humans. These findings can contribute to using the correct animal model for testing of vaccines for use in humans and better prediction of the effect that a vaccine will have in humans. This work is published in Journal of General Virology.
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Experimental animal models for bird flu
The name bird flu, or avian influenza, is misleading as bird flu virus not only infects birds but occasionally also humans. Bird flu virus infection of humans is rare, but if it happens often fatal i.e 455 deaths in a total of 861 cases for so called H5 viruses. Like for seasonal flu, it is crucial to have an animal model to test vaccines.
In 2020 we used various techniques to expose macaques to H5N1 bird flu virus. The results of that work are now prepared for publishing.
Vaccines and antiviral drugs
In 2022 we started a study to investigate a new vaccination regimen against Flu and RSV (Respiratory Syncytial Virus). RSV is the commonest cause of lower respiratory tract infection in children. Worldwide an estimated 34 million children fall ill due to RSV each year and over 3 million children have to be taken to a hospital and 66,000–199,000 children die. We tested whether vaccination via a spray on the tonsils could induce more long-lasting protection against infection with RSV as well as influenza. In addition, we tested whether this vaccine strategy could provide broader protection against influenza, which is needed because of the continuous formation of new virus variants (see above). After an initial intramuscular injection with vaccine, two boosters were administered to the respiratory tract as a spray. Animals were then experimentally infected with RSV. The vaccine strategy proved to result in lower levels of virus replication in the nose, throat, and lungs. In 2023 there will follow an experimental infection with influenza to test whether the vaccine also protects against this virus. When proven effective this new vaccine regimen may also be applied for other respiratory viruses (e.g. SARS-CoV-2).
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PhD student influenza specific antibody responses
Protection from influenza infection relies on good antibody responses. As part of a PhD project and in collaboration with the Amsterdam Medical Center novel influenza proteins were designed by a BPRC PhD student, to identify precisely which antibody-producing B-cells are induced by vaccination or influenza virus infection
This work describes the method to characterize the diversity of antibody responses against influenza. It will be applied on frozen materials from previously performed animal studies to identify protein specific B cells and antibodies with unknown specificities that could be relevant for vaccine design.
The novel influenza proteins were used to study how B cell responses against influenza are formed during a first infection. This aspect is difficult to study in humans, because the first infection always occurs early in life and adults have already encountered several different viruses. However, it is important to understand how a first response is formed as the first response is thought to determine how one responds to subsequent viral infections. To study a first response frozen materials from previously performed influenza infection studies in macaques were used.
It is known that after influenza infection most of the antibodies that are formed are directed against the hemagglutinin molecule. Hemagglutinin is present on the outside of the virus particle and is necessary for the virus to bind to its target cells and to infect these cells. Hemagglutinin is composed of a highly variable head domain and a much more constant stem domain. The head domain is needed for the binding to the target cell. It is at this site that most of the mutations occur, leading to new virus variants that are no longer recognized by the antibodies that were formed during a previous infection or vaccination. This is why people need to be vaccinated with a new vaccine every year. The stem domain is much more constant and is needed for virus entry into the target cell. Antibodies directed against this part of the hemagglutinin protein are able to recognize different virus variants, but they are less efficient in blocking the virus than the anti-head antibodies. How to induce these types of antibodies via vaccination is one of the key-questions in influenza vaccine development. We have shown that such antibodies are formed after the first infection with influenza virus. However, we found that they strongly decrease in time, while the anti-head antibodies gradually increase and come to dominate the antibody response. These results were recently published. Further research will be directed at understanding what the effect is of vaccination on these types of anti-stem antibodies.
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