3 - The Influenza Vaccine (w/ Gavin Hennessy!)

3. The Influenza Vaccine

Many of us have experienced the flu: fever, cough, lethargy, fatigue, vomiting, so on. In today’s episode, we will discuss influenza and some subtleties of the flu vaccine. What is the flu? What is the vaccine and who designs it? Let’s learn to be scientifically conversational.


General Learning Concepts

1)    What is the flu?

a.    What it is: The influenza virus: a contagious respiratory illness. It’s a microorganism 80-120 nm in diameter (Examples: about 1,000 times larger than an atom; magnify a cell until it was the size of a basketball, a virus would still only be about the size of a single period on this page). The shell of the virus is covered in a lipid envelope (like vegetable oil – oil and water don’t mix)

i.    DNA supplies nearly each cell of the body with an instruction book on how to make tiny chemical machines. Known as proteins, these itty bitty widgets do all the work needed to help a cell survive. Some proteins carry in crucial supplies. Others take out the trash. Some send important messages. Some even fight off invaders.

ii.    Virus: an infective agent that typically consists of a nucleic acid molecule in a protein coat, is too small to be seen by light microscopy, and is able to multiply only within the living cells of a host

b.    Symptoms: Fever (chills), cough, sore throat, runny nose, body aches, headaches, fatigue, vomiting and diarrhea. More severe cases can lead to pneumonia from the flu alone or coinfection of bacteria (different domain of life). It can lead to death in severe cases, especially with children or the elderly (80,000 people died of flu in the 2017-2018 flu season according to the CDC, based on mathematical modeling).

c.     What it infects: Certain types of flu are zoonotic (that is, capable of infecting humans and many types of animals: pigs, birds, cattle, etc). Influenza A / B lead to seasonal epidemics (but A can lead to pandemics; B infects humans and seals).

d.    Where it is: All over! Comes with migration of birds, so Australia and the tropics tend to harbor many viruses.

e.    How it moves: Influenza is spread by airborne droplet from those who have high titer (levels of viral load) in nasal and throat secretions. Airborne droplets of the right size travel into the next victim.

f.      Changes by year: Flu viruses are constantly changing so formulations for the flu vaccine must be changed each season. Helen Branswell, an infectious disease and public health reporter, likens it to the immune system “being on guard against a man in a trench coat, [but] the resulting antibodies are looking for a man in a windbreaker”.


2)    How and who decide which viruses are used for the vaccine?

a.    What is the influenza vaccine? It’s a shot (or jet injection). As in all vaccines, the purpose is to generate antibodies that are capable of providing protection against infection from the viruses included. The most common influenza vaccines are inactivated viruses (killed viruses) which means there is no live virus and is incapable of giving the recipient the flu.

b.    Who: The World Health Organization (WHO) has two yearly meetings with directors of Collaborating Centers for Research on Influenza (Center for Disease Control and Prevention in Georgia, USA – The Francis Crick Institute in London, UK – Victoria Infectious Diseases Reference Laboratory in Melbourne, Australia – National Institute for Infectious Disease in Tokyo, Japan – National Institute for Viral Disease Control and Prevention, Beijing, China). Hundreds of national influenza centers in over 100 countries send viruses to those five collaborating centers. The WHO recommends viruses, but ultimately, it’s up to each country to make the decision.

c.     How: Scientists survey which viruses are circulating. These viruses must be similar to vaccine viruses that are available to make large supplies of viruses for vaccines: this is determined by antigenic characterization or by genetic characterization. Additionally, it will take at least six months to produce a stockpile of the vaccine.

i.    Antigenic: Structures on the surface of viruses are capable of being recognized by the human immune system and creating an immune response: this is an antigen. Antigen characterization may give indications of a flu vaccine’s ability to stimulate the immune system to respond to a circulating flu strain.

ii.    Genetic: The flu virus has a genome (provides instructions for making new viruses while using human machinery) that may be similar or dissimilar to other viruses. This allows scientists to track flu virus ‘ancestry’, see how flu viruses evolve, and might help single out specific bits of instructions that allow for more virulent viruses.

d.    Trivalent vs Tetra/quadvalent vaccine: Tetravalent vaccine contains two B strain viruses and 2 influenza A viruses (4 viruses). The trivalent contains 2 influenza A viruses (one H1N1, one H3N2) and 1 influenza B virus, and some contain about four times as many antigens for a stronger immune response -- tends to be for those who are 65 years old or above.

i.    “Our results [modeling] indicate that shifting from TIV to QIV is expected to reduce the health burden of influenza B over the next 20 years by 27.2% [in the US]” – de Boer and Dr. Postma, 2016, University of Groningen, The Netherlands


3)    How many people vaccinate and what are the reasons to vaccinate?

a.    How many people vaccinate? Roughly 40% of adults in the US, 40-60% of children since 2009-2010.

b.    Benefits of vaccination: Prevention of the flu (CDC estimates 5.3 million influenza illnesses were prevented). If the vaccine matches the circulating virus, doctors’ visits are reduced by 40-60%. Vaccination has helped prevent chronic conditions like cardiac events (those with heart disease). Reduces risk of acute respiratory infection in pregnant women by 40%. A scientific journal Pediatrics published a paper in 2017 that shows significant reduction of the risk of a child’s death from influenza.

c.     Herd immunity: Immunocompromised individuals, children, and the elderly have weakened immune systems that can be more easily thwarted by infections. Those people may not be able to handle a vaccination (not usually true with flu) or may benefit from less spreading flu in a population. Those who are resistant or immune to flu strains will not pass them on to others, which allows for herd immunity.

d.    Effectiveness of the vaccine: Varies by flu type and subtype. Vaccine effectiveness is usually measured by the CDC as a point estimate called vaccine effectiveness or VE. These ratings have varied from a high of 60% in the 2010-2011 season and a low of 10% in the 2004-2005 season when the VE measurements began to be taken.

e.    Criticism: Some scientists do not believe in the overall effectiveness of a year-by-year approach for immunity and think the moving target is a universal vaccine. Michael Osterholm, director of the University of Minnesota’s Center for Infectious Diseases Research and Policy, has been attributed to saying that the influenza vaccine is a sales pitch and is “overpromoted” … though he still does recommend getting the vaccine.


4)    Fun Tidbits

a.    Why does my being allergic to eggs get mentioned when getting the flu shot? The flu vaccine strains are grown in embryonated eggs to high titer (concentration of virus). Those will egg allergies are still encouraged to take the flu shot, no matter how severe the allergy (maybe at an inpatient/outpatient facility). Vaccine flu strains are now also being grown in human cells for FDA approval and boast a 20% increase in effectiveness preventing the flu.

b.    Why don’t I get nasal flu vaccinations anymore? You might! They’re still available, but for a number of years the nasal flu vaccine wasn’t sufficient at triggering an immune response versus the A strain influenza viruses. This is interesting because the nasal spray is an attenuated (weakened live) virus entering through a physiologically relevant entry site. In a bioRxiv preprint from the Fred Hutchinson Cancer Research Center in Seattle, WA just this year, the authors allude that the reasons for the LAIV failing are still unclear.

c.     Why is flu season in the Winter? People spend more time indoors in non-circulating environments. Our immune systems could be compromised from a lack of production of vitamin D and melatonin due to lack of sunlight. The influenza virus itself may be more stable in cold weather.

d.    Why are there separate seasonal influenza vaccines for the North and South hemispheres? If you live in the Northern hemisphere you may be used to getting your flu vaccine in the Fall. The winter for the north and south hemispheres comes at different times; beyond this, some tropical municipalities have influenza viruses whose seasonality is yearlong.

i.    Every year, the composition of influenza vaccines is modified separately for the northern and southern hemispheres. Since the antigenic changes in circulating influenza viruses can occur abruptly and at different times of the year, there may be significant differences between prevailing influenza strains in the northern and southern hemispheres.


5)    Famous examples of flu

a.    1918 Spanish Influenza (The Spanish Flu, though a common argument is that it originated in the Midwest of the United States): One of the deadliest outbreaks in recorded human history. Estimates put 1/3 of world’s population as being infected, 50 million deaths worldwide, 675k in the USA. Fueled by World War I (close quarters, movement worldwide). Viruses had not yet been characterized. Cross reactive immunity kept older (>30 years old) populations alive longer. Viral genome was assembled from formalin-fixed, paraffin-embedded lung tissue from 1918 influenza victims and from the lungs of a 1918 influenza victim buried in Alaska's permafrost. The fully reconstructed 1918 influenza virus proved to be highly pathogenic in mice, ferrets, and macaques.

b.    2009 Swine Flu: The virus genes were a combination of genes most closely related to North American swine-lineage H1N1 and Eurasian lineage swine-origin H1N1 influenza viruses. It reached pandemic proportions, spurred the development of a direct vaccine, and an improved modeling approach resulted in an estimated range of deaths from between 151,700 and 575,400.


6)    Solicited Naïve Questions

a.    As we vaccinate more and more people, do we [humans] create more chances of evolving more and more resistant flu strains?

i.    Andrew Read, Evan Pugh University Professor of Biology and Entomology at University Park, published a controversial paper that showed a viral infection in chickens (Marek’s disease) gives rise to deadlier pathogens with imperfect or leaky vaccines.

ii.    When the birds weren't vaccinated, infection with highly virulent strains killed them so fast that they shed very little virus—orders of magnitude less than when they were infected with less virulent strains. But in vaccinated birds, the opposite was true: Those infected with the most virulent strains shed more virus than birds infected with the least virulent strain.

iii.    Many argue this supports Read’s point but does not prove them: circumstances are specialized, chickens are not humans, human vaccines do not tend to be leaky.

iv.    Even Read says that “even if a human vaccine is ever shown to cause dangerous evolution of the pathogen, that wouldn't be a reason not to vaccinate”

b.    How are the flu strains chosen each year?

i.    Answered above.

c.     Do flu viruses mutate the same geographically?

i.    Answered above.

d.    What is done with flu vaccine surplus?

i.    Most influenza vaccine has a June 30th expiration date and is donated to other countries or stored: however, frozen vaccine is not to be used under most circumstances.

Calvin YeagerComment