When it comes to the flu, each year is a different story.  By all objective measures, the 2017-18 influenza season has definitely been a bad one (1).  The chief public health measure used to control influenza is wide-scale immunization.  And this season the chief – and valid – complaint about the flu vaccines is that they provided weak protection.    

Flu2018

Making Flu Vaccines – It’s Not So Simple

In an age of medical miracles, why can’t someone produce an effective flu vaccine?  The first problem is that influenza never attacks alone.  Every year several distinct types and multiple subtypes of flu viruses (2) will be in general circulation.  The seasonal flu vaccines are formulated to protect us against 3 or 4 viruses.  Unfortunately, it is not possible to cover all the existing viruses or new variant forms that inevitably crop up and spread during flu season.  Until someone devises a ‘universal’ flu vaccine (3) some gaps will remain. 

Another problem has to do with time requirements to produce vaccines and the fact that success hinges on making accurate predictions about an erratic foe.  Today vaccine components are mostly produced in embryonated chicken eggs.  The complete process is lengthy because it takes a great deal of time to orchestrate the egg supply and produce enough viral antigens.  That means if a vaccine does not perform well we are usually stuck with it for the season.  But there is an additional wrinkle to this problem.  Let’s imagine producers make a vaccine that provides perfect protection against the viruses creating havoc at that specific moment in time.  That does not mean influenza has been vanquished.  Because flu viruses evolve quickly and constantly, there is a high probability even a perfect vaccine will fail to provide full protection in only a few months.  Unlike other vaccines for disease agents such as measles or chickenpox, what worked last year may not – likely will not – work well for the next flu season.  The intrinsic variability and long vaccine production lead times forces vaccine manufacturers to decide (guess) 6 months or more in advance which flu viruses will create the biggest problems in the next flu season.  Incorrect assessments can leave us with vaccines that match up poorly against the viruses actually in circulation.  Remember, vaccine manufacturers are attempting to predict the future for up to 4 distinct and highly variable flu viruses – one mistake can ruin a lot of otherwise superb work.  In addition, during the extended time periods necessary to scale up flu vaccine manufacture, the viruses attacking humans will undergo continuous diversification.  These incessant changes virtually guarantee vaccines and flu viruses will generally have some degree of mismatch. 

There is another factor affecting vaccine success – influenza viruses grown in chicken eggs become acclimated to those unique environmental conditions.  To be a good vaccine stock for most production methods, the influenza viruses must grow avidly in chicken eggs.  Unfortunately, egg-adapted viruses may not be precise matches to the viruses being spread by respiratory infection of human beings.  New vaccine production methods employing cell cultures may shorten the time requirements for vaccine production and make mass-scale production easier.  In addition, claims have been made that the cell-based vaccine stocks yield viruses that do not sport mutations that often emerge in egg-cultured strains and are anticipated to match more reliably the forms in actual circulation (2).  However, these influenza vaccine strains are still grown in living cells which suggests some adaptation to the new host environment is inevitable.  This year the A H3N2 viruses were most problematic and it will be interesting to determine whether the products from cell cultures offered superior protection to those using traditional chicken egg methods.  Perhaps DNA-based vaccines (3) will solve both the adaptation and mass production problems for future influenza vaccine producers.

Fostering Problems

Influenza has been with us for a long time, but the human condition is changing in ways that may elevate the risk for pandemics.  Populations are growing and crowding into larger cities and megacities of 10 million or more inhabitants.  Massing so many persons in close proximity may promote the amplification and rapid spread of influenza as well as other diseases. 

Steadily expanding populations have placed accelerating demands on the food supply.  The adoption of large-scale production strategies provides high quality food at low costs, but analogous to the situation with megacities, efficient animal husbandry methods may pose enhanced infectious disease transmission threats.  Important food animals such as chickens and pigs are also reservoirs for influenza viruses, many not currently known to circulate in humans.  We are not going to eliminate the need for these animals which means we will have to be diligent about reducing risks for disease agent transmission between livestock, human caretakers and production workers.  For example, producers and government investigators devote a great deal of effort to detect and eliminate avian influenza viruses thought to possess potential to spark a pandemic as soon as they are discovered in food animals (4, 5). 

Jason Wiebers Farms 2

 

But what if exotic avian influenza viruses only kill some chickens?  Aside from the huge economic losses to producers and taxpayers, under the right circumstances the medical consequences could be devastating because many human vaccines are produced in chicken eggs.  An avian influenza outbreak in vaccine egg production facilities could mean that even an ‘average’ flu season would produce far more human deaths than normal.  In a situation like that it is unrealistic to believe manufacturers of anti-influenza drugs like Tamiflu would be able to keep up with the demand surge.   

Egg flu                                         

Forget About It

Influenza is in the news and public consciousness at the moment because this season has been long and tough.  The data suggests the U.S. epidemic has peaked (1) and soon the numbers of afflicted patients jamming Emergency Departments will decline quickly.  That’s when we will do what we always do with the flu – forget about it.  Most of us will probably think nothing more of influenza until next October when we receive reminders to get our seasonal flu vaccination.  Maybe we will heed them.

Flu2018 season

 

Influenza is not the only disease we ‘manage’ this way – severe, acute respiratory syndrome (SARS) and Ebola outbreaks consumed our attention and then faded away.  Unfortunately, declining public attention goes hand-in-hand with vanishing political will and resources necessary to prevent future outbreaks. 

Flu trends

The graph above confirms that flu outbreaks come at different times and exhibit different degrees of severity.  However, influenza remains completely predictable in one critical way – descendants of the viruses will return next year.  Apart from that it is nearly impossible to assert with confidence whether the next encounter will be mild or nasty.  Maybe one migrating duck will bring a new virus that devastates chickens or something dangerous will bubble out of a megacity, perhaps to unleash a pandemic as deadly as the 1918 killer flu.  We will know when it emerges. 

Researchers have developed several new types of influenza preventative vaccines to improve efficacy and coverage.  New vaccine production methods that may shorten lead times or yield superior products are being tested.  Public concern about the flu will naturally fade as cases and news coverage decline.  However, we will be wise to not forget about influenza completely and demand resources are available to improve our ability to combat this unrelenting threat to human health.  Ready or not, the flu will be back.  

 

(1) Donald G. McNeil, Jr.   This Flu Season is Now the Worst in Years. Here’s Why.  The New York Times, 18 January 2018 (updated 16 February 2018).  https://www.nytimes.com/2018/01/18/health/flu-season-facts.html

(2) Centers for Disease Control and Prevention. Frequently Asked Flu Questions for the 2017-2018 Influenza Season.   https://www.cdc.gov/flu/about/season/flu-season-2017-2018.htm

(3) Merika T. Koday et al.   Multigenic DNA Vaccine Induces Protective Cross-reactive T Cell Responses Against Heterologous Influenza Viruses in Nonhuman Primates.  PLoS One, 21 December 2017.  http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0189780

(4) Anne Trafton.   Tracking the Spread of Bird Flu.  MIT News, 17 March 2017.  http://news.mit.edu/2017/tracking-spread-bird-flu-alaska-north-america-0317

(5) Donald G. McNeil, Jr.   Bird Flu is Spreading in Asia, Experts (Quietly) Warn.  The New York Times, 17 November 2017.  https://www.nytimes.com/2017/11/17/health/bird-flu-asia.html

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