Sunday, April 28, 2013

Is the flu shot worth it?

Have you ever received a flu shot (thinking you'd get through flu season unscathed), only to come down with the characteristic fever, sore throat, and lethargy along with everyone else? Why did you still get the flu? Or, has your doctor ever recommended the flu shot with the disclaimer that this season's flu shot may only serve to lessen symptoms, and that you shouldn't count on being fully immune? Don't blame the doctors, and don't blame the scientists: as it turns out, we are in an ever 'one-step-behind' race with influenza.

The ability of the flu to rapidly mutate is the reason behind our inability to eliminate the occasional but consistent flu pandemic; with a high error rate due to RNA polymerase's lack of endonuclease proofreading ability (the flu is an RNA virus), everything in the flu genome mutates at rates higher than our own DNA, and many other viruses (1). For a similar host immune-evasion reason, HIV has proven extremely difficult to eradicate. While HIV antiretroviral treatments have successfully targeted the virus at a multitude of steps in its replication cycle (2), virtually indefinitely preventing progression to AIDS, it is a latent virus, and so cessation of medication leads to resumption of particle manufacture. Thankfully, influenza is an acute virus, and so as quickly as it comes, it goes. However, symptoms of the flu can be very taxing on the human body, ranging from high fevers to nasal discharge/sneezing/general respiratory problems (3) to sometimes unrecoverable weight loss (at least in ferret models); in some cases, vulnerable groups may even die if infected. We would hope that the vaccines that we create to protect ourselves from this ravaging bug would be highly successful in attenuating the severity of these symptoms, and even better, prevent us from acquiring the virus altogether. However, the ability of the flu to evade our immune systems through mutation of its immunogenic properties makes creation of the perfect flu shot, a long shot.

Influenza has two surface proteins, hemagglutinin (HA) and neuraminidase (NA) (3); flu strains are classified according to the specific combination of these surface molecules. For example, the H1N1 strain contains H1 and N1 isotypes of HA and NA respectively. Since HA has been shown to play an important role in the flu virus's ability to enter a cell, a hosts ability to create antibodies against a specific HA molecule often correlates positively with immunity to that specific strain (or homologous strains). Thus, in creating a vaccine, it is reasonable to use an attenuated, recent flu strain isolate in an attempt to stimulate host HA antibody production for immunity against similar/future strains. However, rapid mutation of the virus quickly out-dates our vaccines, and sometimes we are just unable to keep up.

Via experiments conducted by Huang et al., a comparison study between historical and contemporary flu strains provides evidence for reasons of vaccine failures and wild outbreaks of the disease. Essentially, the group compared the clinical signatures of a variety of flu strains between 1918 and 2009 in ferrets, a model organism for studying the flu as they relate to humans. What they found was that each strain caused a unique clinical response in the ferret; supporting this were concordant records of symptoms and symptom severity of the same strain in the human population it affected. Thus, each new flu strain should be viewed as its own unique bug, and that vaccinations prepared from past strains may not be as successful in providing protection against new strains. Following from this, they showed that antibodies produced against one type of HA can react to (and thus stimulate an immune response against) a different flu strain, with the stipulation that the HAs between the two strains have similar enough amino acid sequences. They determined that antibodies created against HA were also effective against the HAs of other flu strains that were chronologically nearby (which makes sense, since strains further away, chronologically, have had more time to mutate away from the original strain). Another relevant result showed that strain Marton/43 (year 1943) did not produce antibodies against HA that reacted with the HA of FM/47 flu virus, which emerged only four years afterwards in 1947. This complimented the observance of the historical ineffectiveness of the vaccine used in '47, which was prepared using strains from years 1943, 1940, and 1934. This suggests that mutations in HA can be very volatile and can mean the difference between a super-effective vaccine, and one that completely fails.

This study was one that emphasized the importance of the evolution of the flu, particularly the mutational path taken by the HA gene, and its implications for creating an effective vaccine. As is probably quite obvious, understanding the evolutionary intricacies of the flu will help us to better prepare ourselves as a human population and create highly efficient preventative measures. The difficulty lies within being able to keep up with the mutational capabilities of influenza, and creating vaccines accordingly. Often, the flu vaccine should do a good job of protecting us from falling to the bug. However, every so often, the mutations in HA may be just enough to render utilization of past strains completely ineffective in vaccine preparation (amino acid sequence differences may result in a new antigenic site; this would mean antibodies created against HA for past strains would do nothing against the new strain), leading to high rates of infection within the population. Since this can be so hard to predict, though, your doctor or everyday virologist might sometimes get it wrong. Ultimately, one should be confident more often than not that the flu vaccine will do its job...and when it doesn't, that the next season's formula will likely do the trick.

Primary article:

Huang, S.S.H. et al. Immunity toward H1N1 influenza hemagglutinin of historical and contemporary strains suggests protection and vaccine failure. Sci. Rep. 3, 1698; DOI:10.1038/srep01698 (2013).

Find it here

Secondary articles:

1) Love, Jamie. ""Flu" - Recombinant Genes on the Loose!" Science Explained. N.p., n.d. Web. <http://www.synapses.co.uk/science/fluvirus.html>.

2) UNAIDS. N.p.: World Health Organization, 1009. Print.

3) Clancey, Suzanne. "Genetics of the Influenza Virus." Nature Education (2008): n. pag. Scitable. Web.

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