Quadrivalent Flu Vaccine

3-D representation of influenza virion, CDC/Doug Jordan. Photo credit Dan HigginsIt has been a little more than 100 years since the discovery of viruses by Martinus Beijerinck. In that time, more than 5,000 different viruses have been discovered and studied. One of those viruses, influenza, has been a scourge to humanity even before we knew it existed. Influenza has caused local epidemics and worldwide pandemics since well before it was discovered.[1] Between 1918 and 1919, influenza killed between 20 and 40 million people worldwide, more than the World War occurring at the time.[2] At the time of the 1918 pandemic, it was believed that the disease was caused by other agents, like the bacteria Haemophilus influenzae. It wasn’t until the 1930’s that the influenza virus was discovered and grown in chicken eggs. In the 1940s, an influenza vaccine was developed and used widely on soldiers during World War II.[3]

Today, we know that influenza circulates during the colder months of the year. In the Southern Hemisphere, influenza peaks between June and September, when that part of the world experiences winter. In the Northern Hemisphere, where the United States is located, influenza peaks between October and May.[4] We also know that three types of influenza exist: type A, type B, and type C. Of those three, types A and B are the ones that cause the overwhelming majority of disease each year. Type C influenza is not known to cause widespread outbreaks, so the current influenza vaccine only protects against types A and B.[5] In fact, the current flu vaccines used in the United States protect against two strains of type A influenza and one strain of type B influenza. The decision on which exact strains to include in the vaccine is made each year based on the known spread and infectivity (epidemiology) of influenza from observations made at disease surveillance sites around the world.

That strategy of immunizing the population against two type A strains and one type B with a “trivalent” (triple variation of the same virus) vaccine has been used since the 1940’s.[6] Because type A viruses spread among birds, pigs, and humans, priority was given to covering the major strains of that virus type, including the H1 and H3 strains since 1978.[7] On the other hand, type B influenza spreads only between humans and some marine mammals, limiting its ability to cause widespread epidemics. Yet type B influenza does cause localized outbreaks and serious disease.[8] Like type A influenza, type B influenza also changes its genetic traits, albeit at a slower rate. Those changes (mutations) help the virus evade the immune system by changing its outer coating enough to prevent antibodies from attacking it. So vaccination with a vaccine containing the circulating strain is necessary each season.

Unfortunately, the matching of circulating strains to strains included in the vaccine has not always been perfect. There have been times, as we just learned in April 2009, when a new variant of influenza appears and causes disease in the human population. While type B influenza mutates at a slower rate and has a limited range of natural hosts compared to type A influenza, a type B strain different than the one in the vaccine may become predominant during any particular season. This leaves those who received the trivalent vaccine with a mismatched strain of type B flu somewhat unprotected. (“Somewhat unprotected” because there are other measures that can be taken to prevent influenza.)

For example, during the 2007-2008 influenza season in the United States, only 2% of the type B influenza viruses detected by surveillance testing matched the vaccine strain (called the “Victoria” strain) for that year. The following season, 2008-2009, only 17% of type B influenza detected matched the vaccine strain. That season, the “Yamagata” strain was used. In the 2009-2010 season, the “Victoria” strain was used again in the vaccine, and it was a good match to the circulating strain, with 88% of type B viruses detected matching the vaccine strain. The matching of type B influenza  was even better in the 2010-11 season, when 94% of type B viruses detected by surveillance matched the vaccine strain. However, during the current flu season, 2011-2012, only 42% of type B viruses detected so far have matched the strain in the vaccine. As you can see, type B viruses of a strain different than the vaccine can and do circulate, causing disease. Of the last 5 flu seasons, including the current 2011-12 season, there has been a mismatch on the type B strain on 3 of those seasons.

To address this type B mismatching, vaccine manufacturers have been working on a “quadrivalent” vaccine that contains four strains of influenza: two type A strains and two type B strains. (If necessary, as would have been the case during the 2009 pandemic, the vaccine could have three type A strains and one type B.) The first quadrivalent vaccine licensed by the FDA was MedImmune’s nasal spray vaccne, FluMist ® Quadrivalent (quadrivalent formulation of the Influenza Vaccine, Live, Intranasal).[9] Soon after that, Sanofi Pasteur announced the results of its Phase II and Phase III clinical trials of their injectable quadrivalent flu vaccine.[10] Phase III trials are the last step before FDA licensure for use, so Sanofi’s vaccine will be on the market soon if it is approved.

According to the Centers for Disease Control and Prevention, between 3,000 and 49,000 people in the United States die each year from influenza and its complications, depending on the severity and geographic spread of the disease.[11] According to the World Health Organization, between 25 and 50 million cases of influenza occur in the United States, with over 150,000 hospitalizations.[12] Influenza also costs billions of dollars to the economy in loss of productivity and hospitalization costs.[13] While vaccine researchers continue to work on a universal flu vaccine that could spell the end to the seasonal epidemics of influenza, the development of quadrivalent influenza vaccines is an important step in reducing the burden of influenza on the population.

Additional Reading

“Influenza (Flu) Viruses” Centers for Disease Control and Prevention. Available at: http://www.cdc.gov/flu/about/viruses/

“The rationale for quadrivalent influenza vaccines” Landes Bioscience. Available at: http://www.landesbioscience.com/journals/13/article/17623/

“Research May Provide New Possibilities For Universal Influenza Vaccine” History of Vaccines. Available at: http://www.historyofvaccines.org/content/blog/research-may-provide-new-possibilities-universal-influenza-vaccine



[1] “A Brief History of: Flu Pandemics” TIME Magazine online http://www.time.com/time/magazine/article/0,9171,1894950,00.html

[2] “The Influenza Pandemic of 1918” Stanford University http://virus.stanford.edu/uda/

[3] “The Flu Vaccine” TIME Magazine online http://www.time.com/time/nation/article/0,8599,1864920,00.html

[4] “Seasonal Influenza: Flu Basics” Centers for Disease Control and Prevention http://www.cdc.gov/flu/about/disease/index.htm

[5] “Influenza (Seasonal)” World Health Organization http://www.who.int/mediacentre/factsheets/fs211/en/index.html

[6] “Epidemiology and Prevention of Vaccine-Preventable Diseases: Influenza” Centers for Disease Control and Prevention http://www.cdc.gov/vaccines/pubs/pinkbook/flu.html

[7] Personal communication with CDC influenza surveillance staff

[8] “Microbiology and Immunology Online: Influenza Virus” University of South Carolina School of Medicine http://pathmicro.med.sc.edu/mhunt/flu.htm

[11] “Estimating Seasonal Influenza-Associated Deaths in the United States” Centers for Disease Control and Prevention http://www.cdc.gov/flu/about/disease/us_flu-related_deaths.htm

[12] “Influenza” World Health Organization http://www.who.int/immunization/topics/influenza/en/index.html

[13] “The annual impact of seasonal influenza in the US: measuring disease burdens and costs” Vaccine. 2007 Jun 28;25(27):5086-96. Epub 2007 Apr 20. http://www.ncbi.nlm.nih.gov/pubmed/17544181

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