All New This Flu Season: Strain, Vaccines, and (Potentially) Treatments

March 14, 2010 — In April of last year, influenza A H1N1, or “swine flu,” led the news.  People watched attentively as the number of confirmed cases and affected countries grew, with the spread deemed particularly newsworthy since this strain of influenza had not circulated before in humans; it was a new flu.  In June, the World Health Organization (WHO) declared influenza A H1N1 a pandemic¹.  Following the announcement, governments released stockpiles of antiviral drugs and researchers increased efforts to prepare a vaccine.  In October, the vaccine for influenza A H1N1 became available in the United States², the United Kingdom³, France⁴, and Canada⁵, among many other countries.  After initial shortages, vaccine production expanded.  By the end of 2009, more than 85 million doses were available in the United States².  However not all countries were able to quickly produce vaccines.  WHO called for an international effort to allow equal access to vaccines and received about 200 million doses of donated vaccines which will go to 95 countries requesting aide⁶.  By February, WHO planned to have distributed vaccines to 14 countries; but only two, Mongolia and Azerbaijan, have received them.  WHO officials note such distributions present considerable logistical challenges; still the efforts continue⁷. 

How an Influenza Vaccine Establishes Immunity

Vaccines work by exposing the body to a weakened or killed form of the disease-causing organism, in this case influenza.  This exposure does not cause this disease but rather induces the immune system to produce antibodies to neutralize the organism.  Immunity develops in the weeks following vaccination and lasts for years, even a person’s whole life.  This type of immunity is known as active immunity and is also acquired by contracting the disease.  It should be noted that the antibodies which confer immunity are very specific.  This specificity is relevant to the influenza vaccines because the influenza A H1N1 vaccine only provides immunity to the version of the flu caused by this exact strain influenza.  Since a given influenza vaccine provides immunity only to specific strains of influenza, a new vaccine is needed when additional strains emerge.  

When It’s Too Late for the Vaccine 

For individuals who contract the flu, treatment may include a prescription for an antiviral medication such as oseltamivir (Tamiflu®) or zanamivir (Relenza®).  These drugs do not cure influenza but rather reduce the speed at which the influenza virus reproduces in the body.  Taking the drug can decrease the duration of illness by one or two days and can also prevent complications.  The drugs work best when within 48 hours of the first symptoms⁸.  

However, there have been reports of resistance to oseltamivir, meaning the virus reproduces at normal speed even when the drug is present.  In November, the Associated Press reported four patients at Duke University Medical Center with oseltamivir-resistant influenza A H1N1, adding to the approximately 50 cases reported worldwide since April 2009⁹.  The National Public Health Service (NPHS) for Wales also reported five oseltamivir-resistant cases.  The NPHS discouraged panic, noting that the resistant form does not appear any more severe than the susceptible A H1N1 strain and that oseltamivir remains effective for treating most people¹⁰.

New Antiviral Drugs:  The Search Is On!  

Despite the general effectiveness of oseltamivir and zanamivir, the search is on for new antiviral drugs.  One approach involves studying how existing antiviral drugs delay viral replication at a molecular level.  Such information would allow the development of drugs which more specifically target the proteins needed for replication.  A recent article in Nature determined how the antiviral drug amantadine interacts with the M2 protein of the influenza virus¹¹.  In the 1960s, amantadine was reported as inhibiting replication of influenza A12.  Researchers have long used amantadine to study the function of the M2 protein.  The M2 protein is a channel connecting the inside of the virus with the host cell.  Protons are pumped through this channel into the virus to increase its acidity, thereby activating the virus to infect the cell^13,14.  Amantadine blocks proton passage through the channel¹³, as illustrated in the figure below.  Multiple strains of influenza, including the current A HIN1 strain, have developed resistance to amantadine, meaning the virus is still able to pump proteins through the channel when amantadine is present.  

Multiple researchers already study how amantadine blocks proton passage through the channel, although previous results have been contradictory.  Stouffer and colleagues reported that amantadine acts at a single site inside the channel to physically block the passage of protons¹⁵.  Schnell and colleagues, however, reported the drug acts on four sites on the outside of the protein, thereby changing the conformation of the channel.  In this new conformation, protons cannot pass through the channel¹⁶.  

In the most recent (February 2010) article on the subject, Sarah Cady of Iowa State University and colleagues there and at the University of Pennsylvania conclude that amantadine acts at both locations.  At the first location, inside the channel, amantadine has a stronger interaction with the protein.  The second location, on the outside of the protein, is used only when amantadine is present in large amounts¹¹.  Therefore, amantadine works predominantly by physically blocking the M2 proton channel. With this information, researchers can now develop new drugs to block the proton channel.  Hopefully, such new drugs will be treatments in future flu seasons.  

References:

1. “World now at the start of 2009 influenza pandemic.” Statement by Dr Margaret Chan, Director-General of the World Health Organization. 6 June 2009. http://www.who.int/mediacentre/news/statements/2009/h1n1_pandemic_phase6_20090611/en/index.html
2. “Swine Flu (H1N1) Vaccine” Times Topics. New York Times. http://www.nytimes.com/info/swine-flu-h1n1-vaccine/?inline=nyt-classifier
3. “Swine Flu” National Health Service. http://www.nhs.uk/Conditions/Pandemic-flu/Pages/Vaccine.aspx
4. “Début de la vaccination contre la grippe A(H1N1)” Le monde. 20 October 2009. 
5. “Swine flu vaccine approved in Canada” Canadian Broadcasting Corporation. 21 October 2009. http://www.cbc.ca/canada/story/2009/10/21/flu-vaccine-h1n1-approval-canada.html
6. “Production and availability of pandemic (H1N1) 2009 vaccines.” World Health Organization. 31 October 2009. http://www.who.int/csr/disease/swineflu/frequently_asked_questions/vaccine_preparedness/production_availability/en/index.html
7. McNeil Jr., Donald. “Progress Is Slow on Moving Surplus Swine Flu Vaccine to Countries That Need It.” New York Times. 1 February 2010. http://www.nytimes.com/2010/02/02/health/02flu.html?scp=2&sq=swine%20flu&st=cse
8. “2009 H1N1 and Seasonal Flu: What You Should Know About Flu Antiviral Drugs” Centers for Disease Control and Prevention. http://www.cdc.gov/h1n1flu/antivirals/geninfo.htm
9. Stobbe, Mike. “Tamiflu-Resistant Swine Flu Cluster Reported in NC.” Associated Press. 20 November 2009. http://abcnews.go.com/Health/wireStory?id=9138659
10. Person to person spread of swine flu resistant to Tamiflu” National Public Health Service of Wales. http://www.wales.nhs.uk/sites3/news.cfm?orgid=719&contentid=13713
11. Cady, S et al. Structure of the amantadine binding site of influenza M2 proton channels in lipid bilayers. Nature 463, 689-693 (2010).
12. Davies et al. Antiviral activity of 1-adaamantanamine (amantadine). Science 144, 862-863 (1964).
13. Cady, S. et al. Structure and function of the influenza M2 proton channel. Biochemistry 48, 7356–7364 (2009).
14. Pinto, L. H. & Lamb, R. A. The M2 proton channels of influenza A and B viruses. J. Biol. Chem. 281, 8997–9000 (2006).
15. Stouffer, A. L. et al. Structural basis for the function and inhibition of an influenza virus proton channel. Nature 451, 596–599 (2008).
16. Schnell, J. R. & Chou, J. J. Structure and mechanism of the M2 proton channel of influenza A virus. Nature 451, 591–595 (2008). Keywords:  Microbiology, Molecular Biology, Swine Flu, Influenza, A H1N1, Vaccine, Antibodies, Amantadine, M2 Proton Channel, Oseltamivir, Zanamivir, Tamiflu, Relenza