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Vaccine for broad protection against influenza
The development of a nanoparticle vaccine for one subtype of influenza that completely protected mice and partially protected ferrets against a different subtype of influenza virus—thereby achieving so-called heterotypic protection—is described in a paper published online this week in Nature Medicine.
Variation in viruses as a result of the accumulation of mutations within the genes that code for antibody binding sites means that seasonal influenza vaccines need to be continually updated to protect against circulating strains of the infection. Seasonal vaccines also do not protect against unrelated subtypes that infect animals such as birds and pigs and can be transmitted to humans.
Gary Nabel, Barney Graham and colleagues report the creation of a nanoparticle vaccine that targets a particular part of the hemagglutinin (HA) glycoprotein on the surface of influenza viruses—the stem—that is subject to minimal mutation, and tested its efficacy on mice and ferrets. The results provide a proof of concept that a vaccine that elicits stem-binding antibodies can provide heterosubtypic protection.
To target the stem region of influenza HA, the authors generated a stable version of the stem from an HA from an H1N1 influenza virus. After linking it to nanoparticles and mixing it with an adjuvant (a substance designed to boost immune responses), they immunized mice and ferrets, and then challenged them with infection with a lethal dose of H5N1 influenza. Although antibodies elicited by vaccination did not neutralize the H5N1 strain, vaccination protected the majority of animals against H5N1 influenza-induced death. A majority of unvaccinated mice that were injected with antibodies from immunized mice also survived subsequent infection with a lethal dose of H5N1, confirming that these antibodies—although not neutralizing—nevertheless protected the animals.
Further work is needed to determine if the vaccine works with other adjuvants—especially those approved for use in humans—and to unravel the mechanism by which these antibodies protect the host against influenza.
Expert Reaction
These comments have been collated by the Science Media Centre to provide a variety of expert perspectives on this issue. Feel free to use these quotes in your stories. Views expressed are the personal opinions of the experts named. They do not represent the views of the SMC or any other organisation unless specifically stated.
Associate Professor Sanjaya Senanayake is a specialist in Infectious Diseases and Associate Professor of Medicine at The Australian National University
There are a variety of influenza viruses that affect humans. Most of them are H1, H2, H3. One challenge with immunising against these viruses is that they mutate regularly. The small changes are called 'antigenic drift' and the big ones are 'antigenic shifts'. To address these mutations, flu vaccines have to be given annually and have to be developed, usually with three strains of flu in them. The scientists in this paper used nanoparticles linked to a substance that boosts the immune response (an adjuvant) to target a part of the flu virus that is thought to not mutate much - the stem. They found that giving such a vaccine from a H1 virus protected mice and ferrets even from a H5 virus (the one associated with bird flu). In other words, even this one vaccine seems to have the potential to provide some immunity across a number of influenza viruses. Some limitations is that these are animal studies rather than human ones. Also, it is not clear how long the immunity will last from a dose of this novel vaccine.
Dr Garry Lynch is an Honorary Senior Lecturer at the Central Clinical School at the University of Sydney. He is an expert on conserved influenza antigens
These are exciting findings coming from a number of highly respected researchers known for their solid attention to detail. Importantly these studies now add the necessary solid evidence that antibodies that target a highly conserved region of Influenzas surface protein hemagglutinin (HA) can deliver broad protection across different stains of influenza, essentially here showing protection in animal models of infection. It supports earlier findings and predictions from our own group at the University of Sydney and collaborators at the CSIRO's AAHL, where we showed in cell culture experiments that antibodies from adult Australians could protect against the H5N1 strain of influenza, and our studies implicating that this protection was at least in part from antibodies that target the highly conserved stem region of HA and the centre point of this present study.
For truly universal protection - a more complete list of other different Influenza types needs now to be studied for their protection also.
Notably this study is not showing complete protection in ferrets, the closest animal model of human infection and disease, and therefore suggests that additional targets are needed. Both for antibodies that target other conserved proteins sites as well as for cell-mediated protection to other conserved regions. All of which occur in a whole body infection.
This shows some of the-short comings of standard in vitro laboratory tests that cannot measure this type of protection, which is ideally observed only in whole body human or animal infection.
Translating these findings here to likely relevance for such constructs as human vaccines is that we would predict an even greater protective antibody response would occur in humans. Because adults already have antibodies to this region, as our own studies have detected. This being the result of repeated exposures to that conserved HA stem region, from all the different influenzas over their life. Therefore in contrast to model animal subjects seeing this region for the very first time such a vaccine in normal adults would we believe be even more dramatic.
We expect wonderful further developments in this area so that a fully universal vaccine for influenza can truly be realized
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