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The Flu and Flu Vaccines

I was recently at a scientific conference where researchers from around the world were presenting on a range of topics relating to human health and disease. At one point in the talks, I had to step out for a short bit in order to work on an exam I was putting together for a class that I was running during the semester. In order to find some quiet, I moved into the dining area that was being prepared for a soon to be eaten complimentary meal that was provided to all attendees of the conference. While I was typing out exam questions, I noticed four members of the catering service walking around the room setting things in place for the onslaught that was to come in an hour or so, with talk of proper food arrangements and where and when lines would be likely to form. As they finished setting up the room, their talk turned in a different direction that caused my ears to perk up and listen in.

“Where's Carl today?” inquired one of the female caterers.

“He's out today, I think he has the flu of something” replied her colleague.

“Oh yeah, I had that last week, and I got the vaccine and everything” chimed in a third caterer.

“I never get the vaccine” the first woman said. “The vaccine is why flu is so bad. There used to only be one or two kinds of flu, but then they made the vaccine and now there is a different kind of flu each year that they don't even bother to protect us from. The only real way to not get the flu is to exercise and take lots of vitamins.”

“I exercise all the time and I've never had the flu, you're right…”

The conversation then trailed off as the caterers rounded a corner out of sight. At no point did I want to jump into their conversation and interfere, but in retrospect maybe I should have. There were so many misconceptions and nonsense rolled up into that conversation that it was clear that they did not have a grasp on the topic that they were discussing. They likely had little tidbits of knowledge that they had put together incorrectly to produce a biased and even harmful view of the flu as a result, and someone needs to inform them of the truth of the situation. The greatest issue I had with this topic is that they were saying these things mere meters away from a number of eminent flu researchers. In a way this seems to epitomize the divide between the research community and the general public - despite a wealth of scientific insight that is available if one chooses to seek it out, there is a basic failure to readily communicate this information to the public. The fault here no doubt falls in part on the general populace for not seeking it out, but it also falls on the research community for failing to find more accessible means to spread this information to any that might find value in it. This brings us to the main issue at hand: what is the flu, and the flu vaccine, and more importantly what aren't they?

The Virus

The flu is a very specific virus. It is not a broad term for a range of illnesses, which is how some people tend to use it in conversation. For example, people may claim to have a “stomach flu”, which is not a real thing. These people typically have food poisoning which comes from toxins found in some food that they ate due to bacterial contamination or, more rarely, due to a direct infection with something. This condition is very unfortunate, but it bears no real resemblance to a typical presentation of influenza, which may or may not cause any nausea depending on the person, but which will in most cases last much longer than any so called stomach flu. Likewise, people may believe that they have the flu when they have any of a number of upper respiratory infections such as a common cold, especially if it is more severe than normal. The flu does indeed often present itself as a more severe version of a common cold that lasts much longer, and as such these confusions are entirely excusable but do cause people to incorrectly believe that they have the flu when they are feeling under the weather.

Influenza A virus (there is also Influenza B virus, but this is less common and rarely a wisdespread threat) is an RNA virus that is made up of a very small bundle of proteins, lipids, and nucleic acids. On its surface, the virus is made up of a ball of lipids that are derived from the membranes of cells that it previously infected. Protruding from this lipid shell are surface proteins that are important for viral function - hemagglutinin and neuraminidase. Hemagglutinin is a receptor on the surface of the virus that allows it to bind to sialic acid, a compound present on the surface of many cells. The virus needs a functional hemagglutinin molecule to bind to cells, and if it does not have one then it cannot infect cells as it will never bind to them in the first place. Neuraminidase has a function that may seem odd considering the role played by hemagglutinin - it cleaves sialic acid on the surface of cells. Since the virus needs sialic acid to bind to and enter cells, this behavior may seem strange, but a basic understanding of the viral life cycle will help to understand the essential role of this protein. After a viral particle enters a cell, it begins to replicate and form new virus particles. Over time, these viruses are ready to leave the cell and they form bundles at the cell surface that begin to bud off and form new viral particles. Because these new viruses are convered in hemagglutinin, they will automatically bind to the cell they are budding from, and only neuraminidase can set them free from this surface. As such, virus particles need to have a balance between the activity of these two proteins.

If you are somewhat familiar with the way flu viruses are identified (beyond the media classifications such as “Spanish flu”, “avian flu”, or “swine flu”) then you may have noticed that hemagglutinin and neuraminidase begin with the letters that are commonly used to classify flu viruses, H and N. Indeed, a typical flu virus strain will be designated based on its hemagglutinin and neuraminidase. There are many different forms of these proteins, and they can be present in different combinations on different strains of virus. For example, the recent “swine flu” virus was an H1N1 virus, meaning that its hemagglutinin structure is of the type designated “1” by lab tests, as is its neuraminidase. These numbers are arbitrary and are based on the order different forms were identified, and as such they do not correspond to the danger posed by the virus. Different isoforms of these proteins are more common in viruses of certain origins, so influenza that originates from birds will often have Hemagglutinin of type 5 (H5N*).

Similarly, if you follow the coverage of flu outbreaks in the mass media, you may have noticed that while flu is an infection we are most worried about in people, the strains you hear about most often are those that come from pigs and birds, but not other species. This is not by chance; pigs and migratory water birds are the two species besides humans that are most readily infected with influenza viruses, and viruses that can infect these animals can in rare cases make the leap into human hosts, that may not be well prepared for these infections. Influenza also has a somewhat peculiar trait among viruses - its genetic material is not a single loop or strand of DNA as in bacteria or mammalian cells. Instead, it is made up of 9 separate segments of RNA. As such, if two different influenza strains infect a single cell, the resulting viral particles may receive any mix of the RNA from either of the two infecting viruses, in the process generating entirely new viruses. For example, if a chicken is infected with both H1N1 and H2N2, it can produce four different types of virus - H1N1, H1N2, H2N1, and H2N2. As a result, these animals, especially migratory birds that travel to many areas, can pick up several strains of virus and in the process produce a new strain of influenza that may be harmless or that may have the potential to start a pandemic.

As an aside, the hemagglutinin and neuraminidase proteins are not the only proteins that determine how dangerous a given strain of flu is. Instead there are several different non-structural proteins that are produced by the flu genome, and these are responsible for many of the more pathogenic actions undertaken by the flu. As such, not all flu viruses are created equally such that the H1N1 that caused the infamous Spanish flu outbreak is far more pathogenic than another H1N1 virus, the so-called swine flu, despite them having the same surface markers. More in depth assessment of viral function by research staff is often needed to determine what proteins endow a given viral strain with its unique characteristics, and why they only do so in certain people.

This is why there is apprehension whenever a new strain of flu makes the leap from birds or pigs into humans - we don't know what it will do. There is always a risk that a new strain of virus will be extremely lethal in human hosts for any number of reasons, even if it is fairly innocuous in the animals from whence it originates. Often, the most dangerous strains of flu in humans are not well optimized for human to human transmission, which is why we do not have frequent pandemics, but epidemiologists must remain ever vigilant to identify viruses which have attained this person to person transmission as this can be a red flag. There has been some controversy in the field of scientific research about how easy it is to generate a virus that can be transmitted though the air. A pair of recent studies in 2011 showed that it could take as few as two mutations in the influenza genome in order to render a virus transmissible through the air, however these mutations also made the virus much less dangerous to the ferrets that were infected in the study, meaning that it is not clear as to how easy it is for a virus to maintain both high rates of transmission and lethality.

The Sickness

Fortunately, pandemic strains of influenza are incredibly uncommon, and the most prominent one in recent memory was the 1918 Spanish influenza outbreak, an H1N1 virus which decimated the population of Europe and much of the world. No flu pandemic has since reached such serious levels, but the concern is always present. During the start of the recent H1N1 swine flu outbreak there was fear that it would prove to be very dangerous, and there was even talk of quarantines, but ultimately it proved to be a relatively inocuous virus all things considered - it could still be lethal, but no more so than the normal seasonal influenza viruses that cyclically circle the world each year.

As suggested above, flu outbreaks typically happen in a seasonal manner. In the Northern hemisphere, flu season is from ~November - March, coinciding with the colder months of the year. This happens fairly regularly each year, with cases peaking in January-February and falling off again. Sometimes a second peak may occur in March, and the specific kinetics of an outbreak depend on the year. By contrast, pandemic strains of flu tend to arise out of season as in the case of the swine flu which arose in the summer months of 2009. The seasonal nature of the flu is not a coincidence, however the exact reasons for it are not entirely certain. Whether the cold allows the virus to better infect cells in not certain, but another train of thought is that the cold causes people to stay inside more often in crowded areas, increasing the ability of the virus to make the jump from person to person and thus spread more easily in the winter than in the summer months. This hypothesis needs to be rigorously tested, but is generally cited by many in the field as a probable explanation for this phenomena.

You get the flu just as you get pretty much any other respiratory infection - by inhaling or otherwise ingesting viral particles, such as those coughed or sneezed out by a colleague at work, making hand washing an always important defense against the spread of the disease, as you might expect. Once you have taken up the flu virus, depending on how much virus was there (it likely takes thousands - millions of viral particles to make you sick, unless you are immunocompromised) you may start to develop symptoms in 2-7 days. Symptoms will begin like a common cold, with cough, congestion, sore throat, and fever. As time passes, the fever will often grow more severe and may even become dangerously high, and you will typically develop aching pain throughout your body. Lab tests are generally needed to confirm that you have the flu rather than any of a number of other respiratory infections, and body aches coupled with extensive duration are often two of the most common indicators that you may be sick with the flu. These symptoms will persist for several days, and it can take a week or more for the flu to fully resolve. Even after the initial infection resolves, it leaves your lungs damage making you more likely to catch a secondary bacterial infection in your lungs which can prolong your suffering.

They symptoms you associate with the flu are mostly caused by your body, rather than by the virus itself. Your body is able to detect that a flu virus has made its way into your cells, and your immune system is then tasked with eliminating that virus before it is able to replicate and kill you. If left uncheck, influenza will turn your lung cells into viral factories that produce lots of new virus, so your body will often seek to preemptively kill virally infected cells once it recognizes them. In addition, your body produces many different inflammatory compounds at the site of infection (your lungs) that serve to attract immune cells into the lungs to help in the clearance of virus. If your body responds robustly to the viral infection, then these inflammatory compounds may begin to diffuse throughout the bloodstream and into other parts of the body where they will cause you to develop a fever as well as the painful aches that help distinguish the flu from other respiratory infections. While the virus itself would eventually likely kill you in the absence of an immune response, it is the immune response that you are most likely to be feeling when you come down with the flu.

Like many diseases, the flu is often most severe in the very young and the very old segments of the population, in whom immune responses are not fully formed or have been altered by the aging process to dangerous and or nonfunctional states. As such, seasonal influenza can be a serious inconvenience for most of the population resulting in days of missed work and misery, but it is not likely to be lethal (except in those with preexisting conditions, such as severe asthma or the like). Pandemic influenza, on the other hand, can at times take an abnormal distribution of lethality, with the majority of deaths associated with pandemic strains of flu occuring in the young, otherwise healthy segment of the population in their 20's and 30's. The reason that this is believed to be the case is that our bodies respond more strongly to pandemic flu strains than to seasonal strains, and people with the most vigorous immune responses (who are typically in their 20's and 30's) can respond to an excessive degree that may prove deleterious. In these individuals, the severe inflammation can cause extensive death of lung cells and result in fluid leakage into the lungs, leading to pneumonia and death not because the virus itself was too powerful, but because the body's response to said virus was too powerful.

Even if young people are able to survive the initial onslaught brought on by influenza, their lungs will have suffered extensive cell death. These dead lung cells serve as ideal binding sites for a number of bacteria that normally reside in the upper respiratory tract, such as Staphylococcus aureus or Streptococcus pneumoniae. These bacteria can thus enter the lungs via post-nasal drip or other accidental aspiration, and once in the lungs they can begin to readily replicate, inducing more damage and inflammation, with the potential to cause a second round of pneumonia leading to death. Indeed, in the case of the 1918 Spanish flu, it is believed that up to 90% of victims likely died as a result of a bacterial infection that either coincided with or followed flu infection. As such, the initial flu infection is not the only cause for concern, and constant vigilance is necessary to promote the survival of those that are infected with this pathogen. Fortunately, most infections do not have pandemic potential, but even so this risk of bacterial infection is still present and must be addressed without the nonspecific use of antibiotics, which has other risks that can promote the development of drug resistant bacterial diseases such as MRSA.

The Treatment

As with most viral diseases, there is no cure for the flu, and it must generally be allowed to run its course once an infection has been diagnosed, with care being provided primarily to prevent excessive inflammation and fever, and to reduce the risk of a secondary infection. Unlike some viruses such as the common cold, however, there are certain drugs that may be able to reduce the duration of an influenza infection. The most prominent of these drugs are the neuraminidase inhibitors, and in particular Tamiflu. As mentioned previously, the flu virus needs neuraminidase in order to escape from a cell and infect another cell. As such, inhibiting neuraminidase activity can reduce the amount of active virus particles in your body thus reducing the severity of the disease.

Unfortunately, Tamiflu is only likely to be effective if administered within the first 12-24 hours of being infected with the flu, even though symptoms will likely not begin to appear for days. This is because the viral particle levels in the body will begin to peak within 2-4 days of infection, while the immune response will peak several days later at the time when symptoms are most severe. This means that Tamiflu and other neuraminidase inhibitors are only useful if you believe you have been infected with the flu recently due to contact with someone known or suspected to be infected. As a result, Tamiflu may be prescribed to elderly or other at risk individuals in order to reduce their risk of getting a severe case of the flu. The drug does not completely prevent infection, instead it reduces the duration and severity to a degree which may make it a promising means of reducing the economic and phyical demands caused by the flu, in a addition to reducing the ensuing lung damage and consequences thereof.

Many strains of flu are resistant to the activity of Tamiflu and other neuraminidase inhibitors. This is because the drugs only interfere with the activity of neuraminidase that is in a particular chemical conformation on the surface of viral particles. As a result, a single mutation in neuraminidase at the right location can make the protein resistant to the action of these drugs while still allowing the virus to replicate as normal. This is the case in several recent strains of flu that have appeared, and may be a result of unintentional selection for resistant viral particles due to widespread use of the drug. Other attempts to develop drugs to treat influenza are being constantly considered, however no other classes of drugs have been effectively brought to market at this point in time.

Of course, the best way to avoid a serious influenza infection is by getting the flu vaccine. Unlike most vaccines, the flu vaccine needs to be taken annually, and there are multiple reasons for this. For one, protection provided by the vaccine does not last for a long time, and within a few years it will likely wear off entirely, unlike if you had been infected with the actual disease in which case you would receive long lasting immunity. Unfortunately, in either case immunity to flu is strain specific, such that immunity to an H1N1 virus will not provide immunity to an H5N2 virus, nor in all likelihood to another distinct H1N1 strain of the virus. This means that each year scientists and epidemiologists need to predict what strains of virus people are most likely to encounter that year, so that they can put those strains in the vaccine.

The flu vaccine typically contains 4 strains of flu - one influenza B strain (lower risk flu viruses that often just circulate locally) and three influenza A strains, the type discussed at length in this article. Predicting which strains will circulate in a given year is no small feat, especially considering the predictions need to be made almost a full year before that flu season in order to allow sufficient time to develop and bring that year's vaccine to market. Epidemiologists consult a number of predictions and mathematical models in order to divine the strains to combat that year, with mixed results. For example, in 2012-2013 the flu vaccine did not contain the strain of flu that was most widespread in the USA that year meaning that the vaccine provided little to no protection. For the 2013-2014 season, however, the vaccine contained the 2009 H1N1 swine flu virus which proved to be the most widespread flu strain of the season, making the vaccine the most efficacious possible considering the circumstances. As such it is essential that the makers of the vaccines always be planning far into the future, which can make it very difficult to deal with an unexpected pandemic strain that appears out of season when no vaccine is readily available.

Unfortunately, even if the vaccine makers are able to plan perfectly and pick the correct flu strains to immunize people against in a given year the vaccine may not work well. As far as vaccines go the flu vaccine is not particularly effective, yielding only an estimated 60-80% protection against severe infection, with rates being even lower in the elderly who are already more susceptible to infection. Obviously, this protection represents a huge victory and saves countless lives and man-hours of work every year, but compared to polio or MMR vaccines that have greater than 95% rates of protection the flu vaccine is not very powerful. The reasons for this are not immediately clear, and are a result of the state of the vaccine development field - much work still needs to be done in order to determine how the body recognized and promotes immunity to the flu, and only once this process is fully understood will we likely be able to exploit natural immune responses to generate long-lived and complete immune protection.

There are two types of flu vaccine: the shot, and a nasal spray known commonly as Flu mist. The influenza vaccine shot is injected into your upper arm, where it will likely cause localized pain and swelling as a result of a localized inflammatory immune response that generates short lived protection to the innoculated strains of flu in many people. This form of the vaccine contains inactive viral proteins (hemagglutinin and neuraminidase again), and contains no other parts of the virus. The Flu mist, on the other hand, is a spray given in the nose, and it contains live viral particles. These live viral particles are severely weakened such that they cannot cause significant disease, but your body will still be able to recognize them as viruses and respond appropriately in a way that causes limited inflammation but decent protection. Indeed, there is some evidence to suggest that the Flu mist vaccine may be modestly more effective than the traditional injected vaccine, at least in younger children. The reason for this is believed to be that your body is better able to recognize and respond to a replicating virus, and the Flu mist virus is present in your respiratory tract which is normally where the influenza virus is present whereas the injected vaccine is only present in your arm where such viral particles never appear. Because Flu mist better mimics the site and nature of a live flu infection, it is thus able to better engage your body's defenses to promote a productive response.

If the vaccine takes successfully, then your body will begin to produce antibodies and specialized immune cells that can recognize the flu strains that you were immunized against but not strains that you were not given. If these flu strains ever enter your body while your protective responses persist, then they will be cleared before they can gain a robust foothold, thereby preventing a serious flu infection from taking place and thus preventing you from spreading the disease to those around you. For this reason, it is essential that everyone who is able to get the flu vaccine every year do so. It will not only provide a reduced chance of getting the disease yourself, it will also reduce your ability to put those around you at risk of getting the disease because you will not be able to spread it to them. Contrary to the opinion of the aforementioned caterers, exercise is not a reliable means to avoid getting the flu, nor are vitamin supplements. It is true that keeping one's body in a healthy state will likely improve your immune responses, however as we have seen earlier, this is not always for the best in the case of flu (though of course it is a good idea for everyone to incorporate exercise into their daily routine). Vaccines are at present the only reliable way to prevent flu infection, aside from the basic tips of constant hand washing and covering one's mouth when one sneezes or coughs.

The Future

At this point, I think it should be quite clear as to why what the caterers had to say made me want to butt into their conversation or band my head on the table in dismay. For one, the vaccine is not why there are multiple strains of flu. These variations appear naturally, and are the result of millenia of mutations couples with constant reassortment of viral RNA in the cells of infected pigs and birds. The strains of flu that circle the world each year are not the result of the vaccine, and indeed the vaccine is a vague attempt made to predict what these strains will be which is not always a successful venture. The vaccine is also the only way to prevent the flu aside from basic hygiene, and claims that other things such as exercise or vitamins can actively prevent disease are vastly overblown if not outright false. Furthermore, the term “flu” is tossed around too casually by the general public. It is important that people realize that not all respiratory infections are in fact the flu, and no stomach bugs are any form of the flu. Proper terminology can hopefully in the long run promote a better understanding of what the flu is and how we as a society can respond to it.

There are still many challenges that we will need to face in the future before we can eliminate influenza as one of the chief causes of infections morbidity and mortality in the world each year. More drugs that can better treat people who are already infected with the flu would greatly help reduce the dangers posed by the disease. Similarly, research seeking to identify risk factors associated with age or rate of bacterial secondary infection will no doubt eventually yield preventative treatments that will save thousands of lives annually. Better vaccine development techniques can also provide a better means to prevent disease. Current efforts are working to find alternative sources for viral particles, which are classically grown in eggs meaning that people with egg allergies cannot receive the vaccine. In the long term, scientists hope to develop a universal flu vaccine that protects against all strains of the flu and not just certain structural hemagglutinin and neuraminidase motifs present on the viral surface. This, coupled with long term protection in >90% of people, would likely significant reduce the hold that the flu has on the public consciousness each year.

Thus, through education and ongoing research efforts, scientists can hope to better interface with the public about what the flu is and what can be done to treat it. An important aspect of this approach relies on the public to seek information about the flu each year beyond the occasional fear mongering stories in the news about some new potentially dangerous avian flu strain in China or Vietnam. Information of current flu strains and the annual flu season can be found on the sites of the CDC and the WHO (see below), and visiting these sites can be the best way to keep yourself informed about the dangers currently posed to you and the area in which you live by the flu. Get yourself vaccinated against the flu, and encourage those you know to do the same. In this way, we will be able to work together in a cogent fashion to defeat this insidious disease that currently kills scores of people annually.

References

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