Tag Archives: flu

Fighting the Flu

Unless you have been living as a hermit in a cave* for the past week you will be aware that the world’s medical services are on high alert following the emergence of swine flu in Mexico, a new strain of the Influenza A/H1N1 virus that has now killed more than 160 people. While there is now evidence that swine flu may not lead to the number of deaths worldwide that were initially feared, this is still a serious situation and it is only right that governments and the UN are taking all necessary precautions.

Swine Flu

This is a good time to see how animal research contributes to the development of treatments and vaccines that are vital tools in ongoing efforts to control the damage that this virus can do. On Wednesday the US Centers for Disease Control and Prevention (CDC) announced the welcome news that swine flu is sensitive to the neuraminidase inhibitor antiviral medications zanamivir (Relenza) and oseltamivir (Tamiflu), so these drugs will be effective in treating swine flu infection. These anti-virals work by binding to and blocking the activity of the enzyme neuraminidase (the N in H1N1) that is found on the surface of the flu virus and whose activity is required for the virus to infect cells. This news is doubly pleasing since there had been concern that swine flu might have evolved resistance to Tamiflu (but not to Relenza), but so far it appears that this has not happened and it is still a good treatment.

Animal research played an important role in the development of both Relenza and Tamiflu. In particular they were key during the later stages of the process as candidate neuraminidase inhibitors that had performed well in in vitro anti-viral tests were evaluated for their ability to kill the virus in vivo, and for their pharmacokinetic profile and toxicity, before being modified and then re-evaluated until two neuraminidase inhibitors were produced that had the right properties to justify evaluation in human clinical trials (1,2). In the case of Tamiflu the animal stuidies lead to the development of a prodrug that is metabolized in the body to produce the active anti-viral, while with Relenza the scientists identified a modification to the drug that greatly enhanced its anti-viral activity while also slowing down its breakdown in the body. In addition to rodent models of flu infection some of these studies also involved ferrets, animals that are naturally prone to infection with many of the influenza viruses that humans suffer from and in which the course of the virus is almost identical, making them a very valuable model for studying the disease and developing new treatments.

Of course in the longer term it would be better to develop a vaccine against swine flu, and efforts to do so are already underway at research laboratories in the US and UK. This will probably take months, but the vaccine will hopefully be completed in time to reduce the impact of a pandemic. The time required to develop a vaccine with the currently available flu vaccine technology , the same that is used to develop the vaccines against seasonal flu that you will probably be familiar with, is a consequence of the fact that they only provide protection against one strain of the virus. This is because these vaccines direct the immune system to target the haemagglutinin (the H in H1N1) and neuraminidase proteins on the surface of the virus, but these proteins frequently mutate and can become invisble to the immune system again, so a new vaccine corresponding to the new version of haemagglutinin or neuraminidase must be developed.

Consequently several groups of scientists around the world are now working on “universal” influenza vaccines that it is hoped will provide protection against a wide range on influenza strains. Last year there were reports on the successful completion of early clinical trials of one such vaccine developed by Acambis, a vaccine that directs the immune system to target a protein in the virus envelope named matrix protein 2 (M2e) whose structure is highly conserved across different strains of the influenza A virus. Studies on mice were crucial to the initial development and optimization of this vaccine and to the later demonstration that it could provide protection against a range of influenza A strains (3,4), leading to the decision to test it in human clinical trials. It’s clear that animal research has made important contributions to both the treatments that are available to fight swine flu now, and to ongoing efforts to produce new vaccines that will hopefully help us to avoid flu pandemics in the future. As to the wider situation we are pleased to see that President Obama has appointed the leading cancer biologist and Nobel Prize laureat Harold Varmus and the human geneticist and former leader of the mouse genome sequencing project Eric Lander to the President’s Council of Advisors on Science and Technology (PCAST). The advice provided by these two scientists, both of whom fully appreciate the great importance of animal research to medical progress, will no doubt be of great value to the President over the coming months, as the President himself said “our capacity to deal with a public health challenge of this sort rests heavily on the work of our scientific and medical community”. His is a view that we are happy to share.

* Though if you believe some of the more alarmist newspaper reports hiding in a cave might not be such a bad idea.

Regards

Paul Browne

1) Eisenberg E.J. et al. “Penetration of GS4071, a novel influenza neuraminidase inhibitor, into rat bronchoalveolar lining fluid following oral administration of the prodrug GS4104.” Antimicrob Agents Chemother. Volume 41(9), Pages 1949-1952 (1997) PubMed Central: PMC164042

2) von Itzstein M. et al. “Rational design of potent sialidase-based inhibitors of influenza virus replication” Nature. Volume 363(6428), Pages 418-23 (1993) PubMed: 8502295

3) Neirynck S. et al. “A universal influenza A vaccine based on the extracellular domain of the M2 protein.” Nature Med. Volume 5(10), Pages 1157-1163 (1999) PubMed: 10502819

4) De Filette M. et al. “Universal influenza A vaccine: optimization of M2-based constructs” Virology Volume 337(1), Pages 149-161 (2005) PubMed: 15914228

A passive defence against the flu?

Influenza is a disease that kills hundreds of thousands of people every year, and periodically causes global pandemics that kill many millions.  There are three major types, A, B and C that can infect humans, although the A is responsible for the most cases and deaths. Within influenza A virus there are two major groups, 1 and 2, each of which includes several subtypes, and finally within each subtype there are many strains. Currently available vaccines can only protect against a narrow range of strains, sometimes only one, and as a consequence every year the World Health Organization (WHO) has to try to predict which strains will cause problems over the following year and make vaccines to protect vulnerable people from them, and naturally they can’t always get the prediction right. More worryingly it takes several months to develop each vaccine so in the event that a new pandemic strain arises a vaccine to protect against it may not become available before it has spread widely. For this reason scientists are working to develop vaccines that will protect against a broad range of influenza strains and subtypes, while at the same time others are developing improved treatments for those who do become infected.

In an exciting paper published online in Nature Structural & Molecular Biology (1) a team led by Wayne Marasco of the Dana-Farber Cancer Institute, Robert Liddington of the Burnham Institute for Medical Research, and Ruben Donis of the Centers for Disease Control and Prevention (CDC) have used an in vitro screening method to identify human antibodies that bind to a protein called hemagglutinin (the “H” in H5N1) that is found on the surface of the virus and is required for the virus to enter a cell once it has bound to it.  As described in in Nature news the antibodies they identified using an in vitro phage display screening method bind to a portion of hemagglutinin known as the stem that varies little between different subtypes of group 1  influenza A virus and stop the virus entering the cell. Having proved that the antibodies could block virus entry into cells in vitro the scientists then tested if clinically realistic doses of antibody could protect animals from an otherwise lethal influenza A infection. They found that when these antibodies were given to mice that had previously been infected with highly pathogenic strains of the H5N1 and H1N1 virus subtypes the mice remained healthy and the spread of the virus through their organs greatly reduced, while mice that were not given the antibodies died. While H5N1 and H1N1 are both group 1 subtypes of  influenza A currently available vaccines against one do not protect against the other, so this result taken with the in vitro data demonstrated that the antibodies provide broad protection against group 1 influenza A viruses.  This protection was even observed when the antibodies were given 3 days after infection, indicating that these antibodies are suitable for a passive immunization approach to the treatment of influenza following infection, which would be a very valuable addition to the limited range of treatments currently available. Their research also indicated that their screening technique can be used to identify antibodies that can be used to protect against other groups of influenza virus.

But what of “classic” vaccines that stop people acquiring the flu in the first place? Well, the authors of this study suggests that by designing vaccines that direct the immune system to target the conserved stem region of hemagglutinin, rather than the more variable portions of hemagglutinin as is now the case, it may be possible to have vaccines that confer protection against a broad range of influenza subtypes. A combination of only a few such vaccines could yield a “universal” flu vaccine, which is certainly an exciting prospect, though since flu is also found in many wild and domesticated animal populations which can transmit it to us we will probably never be possible to control it as thoroughly we have controlled polio.

Regards

Paul Browne
1) Sui J. et al “Structural and functional bases for broad-spectrum neutralization of avian and human influenza A viruses” Nat. Struct. Mol. Biol. Advanced Online Publication , 22 February 2009, doi:10.1038/nsmb.1566