May 22, 2013

expert reaction to new research into a new type of influenza vaccine

A study in Nature suggested a new type of influenza vaccine, utilising a new type of nanoparticle, outperformed commercial equivalents in animal tests.

Dr Mike Skinner, Senior Lecturer in Virology, Imperial College London, said:

“There is an acute need for novel influenza vaccines that will be effective against seasonal influenza and can be produced rapidly to combat a future pandemic.

“In some ways this approach follows on from other GM (recombinant) vaccines, such as Hepatitis B (the first, produced in 1986 in the early days of the technology) and the more recent HPV vaccines against cervical cancer (Gardasil & Cervarix), all of which involve production in yeast or insect cells of virus proteins that assemble into non-infectious, virus-like particles, which are potent immune stimulators.

“It also follows on from the approach of fusing the virus protein to a different carrier protein (such as the protein from the tetanus vaccine) that is a potent immune stimulator.

“The elegance of the new influenza vaccine is that is grounded in basic structural biology and methodical design of the optimal structure of a recombinant vaccine.

“The problem facing the scientists was that the influenza protein (HA) has to be assembled into a closely-bound, triangular complex (a trimer). From its molecular structure, they identified the iron transport protein, ferritin, as the ideal candidate for a carrier protein. 24 ferritin molecules assemble into a near-spherical particle (a nanoparticle, of similar size to a small virus), with symmetry such that it had 8 summits displaying the required triangular (three-fold) symmetry. Moreover, the spacing of the ferritin subunits at the summits is the same as that between the individual subunits of the HA trimer.

“The scientists produced recombinant HA fused to ferritin, by culturing modified mammalian cells, purified it and allowed it to assemble into nanoparticles (HA-np). When the NP were injected into mice or ferrets, they stimulated production of antibodies that could protect the mice against infection with influenza. Importantly, the mice were protected not only against the strain of influenza from which the HA was derived but against a broader range of strains. Apparently, they stimulate production of antibodies that target parts of the HA that are conserved between strains.

“This is a thoughtful and really promising development. It would avoid the need to grow vaccine virus in eggs or cell culture, which currently poses technical and safety issues and can be a bottle-neck to rapid, large scale production. It should be noted that optimal protection with HA-np required the use of adjuvants to enhance the immune response, so some time might be required to identify the optimal combination of HA-np and adjuvant for use in humans.

“In the normal run of events, it would take several years for this candidate to progress through clinical trials and regulatory hurdles before it sees widespread use. Although it might be more broadly effective than the current vaccines, it is too early to tell how easily or how frequently resistant viruses would arise in the future, given that candidate pandemic viruses are continually being produced in wild birds.”

Professor Wendy Barclay, Chair in Influenza Virology, Imperial College London, said:

“Influenzas viruses are difficult to vaccinate against because they vary their target antigen HA (haemagglutinin) so effectively that vaccines rapidly become out of date as the virus evolves. This paper explores a soft underbelly of the virus that might help us overcome this troublesome issue.

“Around 4 years ago, a landmark discovery found that some antibodies could target many different HAs and gave a glimmer of hope that the specificity issues for flu vaccine could be potentially overcome. The problem is that the cross reactive antibodies are extremely rare in human sera. One group of the cross reactive antibodies see an epitope on the stem of the HA protein that might be relatively inaccessible both to B cell receptors and to corresponding antibodies. So the big question in flu vaccinology is how to persuade the human immune system to make more of these cross reactive antibodies?  In this latest stab at the problem, Gary Nabel’s group have engineered a synthetic antigen based on HA which seems to stimulate a much higher proportion of these cross reactive antibodies and thus gives a much broader immune protection than the usual inactivated flu vaccine. They did it by fusing HA to ferritin, a bacterial protein that then self assembles into nanoparticles smaller than the virus itself, but with a different arrangement of the HA molecules. This may be why some of the antibodies induced are directed against parts of HA that might be otherwise obscured on the whole virus or in conventional vaccine preparations. The electron micrographs of these nanoparticles provided in the paper show beautiful little stars; it would be very informative to compare these structures side by side with a typical prep of inactivated flu vaccine to see if we could understand why they apparently present their epitopes so differently.

“In short this paper takes us a step closer to believing that a universal flu vaccine is possible, by thinking outside of the box in terms of how to synthesize and manufacture flu vaccines. What’s more this route could be faster, cheaper and safer than the one we usually use. I think the important question to explore in the field now is, if we all get this vaccine and start directing the majority of our antibodies against these universal epitopes, will the virus be able to escape by ‘drift’ like it does each year to our natural antibody response, or can it be ‘pinned in’ by the immune response induced by this new era of vaccines?”

Professor Sarah Gilbert, Professor of Vaccinology, University of Oxford, said:

“Overall, the study shows that it is possible to achieve broader immunity to influenza than that obtained with licensed influenza vaccines, which is an important step in the right direction, but there is a long way to go before this will make a difference to protecting people against influenza.

“Regarding safety, it’s potentially safer to manufacture, because live flu virus is not involved. But there is no information on safety of the vaccine in vaccine recipients yet and it’s important not to get those things confused.

“It’s a recombinant HA (haemagglutinin) vaccine, and Protein Sciences already have a licensed recombinant HA flu vaccine (Flublok, licensed in the US). The novelty here is that the vaccine is assembled into a small protein particle, and particulate proteins are generally more immunogenic than soluble proteins. The idea of making a protein into a particle to improve immunogenicity is not novel, but I think it’s the first time that it has been done in precisely this way, using ferritin to form particles.

“The ‘diverse strains’ that were neutralised were all of the H1 subtype. This is clear in the paper but not the press release. The results show better neutralisation of other strains (within the H1 subtype) than using a conventional inactivated vaccine and this could be useful for seasonal flu vaccines because at present, if there is not a good match between the strain in the vaccine and the strain that is infecting people, vaccine efficacy can be notably reduced. If the new type of vaccine was to work as well in people, the requirement for very close matching of vaccine strain and the circulating virus might disappear. That could possibly also mean that there could be a stockpile of e.g. an H5 vaccine made in advance of a pandemic, which could still be used once the pandemic starts even though the HA sequence in the virus and the vaccine were not identical.  However there would probably still need to be a different vaccine for each HA subtype, so we’d need to stockpile one for H7 as well, maybe also H9.

“There’s no indication as to whether any clinical trials are planned, and since this is a new type of vaccine it might be some time before they could start. I suspect that the process used to produce the particles would need to be modified before material to use in clinical trials could be produced, then there are toxicology studies to complete. So at the moment it’s an interesting development in the lab, with some novel aspects, but definitely not a universal influenza vaccine and it needs to be tested in clinical trials before we get too excited.”

Professor Adam Finn, Professor of Paediatrics, University of Bristol Medical School, said:

“This is a very encouraging study of a new approach to making vaccines and shows very clearly that this works very well in protecting ferrets against different strains of flu. The ferret is an animal that can be infected with flu viruses that also infect humans. Further studies will be needed to find out whether humans get similar protection and these are likely to take several years. This approach could probably be used to make vaccines against other infections as well and, like several vaccines already in use, the components are made in the lab without have to grow the bug that causes the infection. This makes manufacture more straightforward and reduces any risk of any traces of anything else getting into it.”

‘Self-assembling influenza nanoparticle vaccines elicit broadly neutralizing H1N1 antibodies’ by M Kanekiyo et al. published in Nature on Wednesday 22^nd May 2013