Uh Oh…. Predicting the Efficacy of the 2018-19 Flu Vaccine


If you get an egg-based flu vaccine and the A H3N2 strain happens to be prevailing, don’t be optimistic that the vaccine will be effective.

Background:
The seasonal flu attacks ~5-10% of people around the world, and as high as 20-30% of children. The CDC recommends that everybody age 6 months and up get vaccinated (unless they have a contraindication).

Influenza (the flu) is a major upper respiratory virus that can induce complications like pneumonia, organ diseases (such as myocarditis or encephalitis), kidney and respiratory failure. It can also lead to muscle tissue damage (myositis and rhabdomyolysis).  The high mutation rate of the seasonal influenza viruses, coupled with the ability to quickly infect and replicate, leads to the production of many different strains because of the rearrangement (and combination) of genes. While most of these mutations are insignificant, some are major and allow a particular strain to withstand environmental stressors most of its counterparts couldn’t. All it takes is 1 of these “daughter” strains that has a selective advantage to grow exponentially - possibly causing a pandemic.

There are 4 types of influenza viruses: A, B, C and D. The seasonal influenza virus vaccine only includes Type A and Type B, as these are the most prevalent for humans.

Most types of influenza originate in southeast, east and southern Asia, where they will continuously evolve due to the combination of having a very large number of people (half the world’s population) and tropical, temperate climates. However, of the various strains, influenza Type A has more potential to quickly spread throughout the world due to its association with birds.  Generally Type A influenza has the strains that the CDC is most concerned about. The reason flu vaccine is administered in the fall in the United States is because our immune systems weaken in the winter.

How effective is the flu vaccine?
Lately, not very good (there is a trend towards declining efficacy). The Fitzpatrick team analyzed the overall influenza vaccine effectiveness (VE) published over the past 24 years (see graph below).  The whole determination of effectiveness is nebulous, so rather than have us err on our interpretation, we pulled the “Overall Vaccine Effectiveness” stats right from the CDC and/or other credible sources. In seasons where we were unable to find “U.S. Overall Vaccine Effectiveness”, we applied data from Scotland as surrogates. We used an 8 and 6-point grouped analysis (r² = 0.31 and r² = 0.44 respectively shows correlation).


Going back two years, the overall 2016-17 flu vaccine efficacy was 43% The overall 2017-18 flu vaccine efficacy was 40%. Note that there were 155.3 million doses distributed for the 2017-18 season. The definition of overall flu vaccine efficacy is a composite measure of the vaccine’s ability to prevent both A and B strains.

We do not yet know the number of influenza vaccines shipped for 2018-19, but manufacturer projections are 163-165 million doses, which would be up to 10 million more doses than any other year. We do not know how many of these will get returned. At some point in the future, there may be more convergence between flu vaccine efficacy and doses administered.

A Rice University study is predicting the 2018-19 flu vaccine H3N2 (A) strain to AGAIN be a very poor match with predicted efficacy of only 19% in egg-based vaccines. The Rice University’s flu prediction model is called “pEpitope”, and flu vaccine strains have been analyzed over the past 40 years. The model measures critical differences in the genetic sequences of flu strains. The authors state that if a vaccine provided a perfect H3N2 match, it would at best yield a 47% efficacy. They theorize that mutations in 2 amino acids (out of >300) in the hemagglutinin protein were enough to drop efficacy to the 19% level they predicted for the 2017-18 vaccine (which is almost identical to the CDC’s 20% efficacy for the H3N2 strain last year). The Rice University authors said “it is apparent over the last 10 years that egg adaptions have affected the efficacy of flu vaccines”. 

How well the flu vaccine works (or its ability to prevent flu illness) can range widely from season to season and by geography. Vaccine effectiveness can also vary depending on who is being vaccinated. The following factors play an important role in determining the likelihood that a flu vaccine will protect a person from flu illness:

  1. A person’s age

  2. A person’s health

  3. The similarity or "match" between the flu viruses and the flu vaccine

  4. The severity of the season

  5. Other miscellaneous factors (Even in good-match years, the benefits of vaccinations will vary across the population depending on characteristics of the person being vaccinated and even, potentially, which vaccine was used. Vaccine effectiveness can vary significantly by age cohort and health status.)

Where is the efficacy data published?
Researchers at the World Health Organization, CDC, DHHS and state health offices are responsible for gathering and publishing continuous influenza surveillance and vaccination information. There is no shortage of literature accessible from a variety of government-sponsored sites that share important, up-to-date information on prevailing strains. Sadly, the seasonal influenza vaccine effectiveness is following a dangerous downward trend. The perception that the influenza vaccine is highly effective in preventing seasonal flu is becoming less true. Has this virus advanced to the point where we are unable to adapt to it? Looking at the coefficient of determination plotting out 24 years, the r² value = 0.15:


Year
Reference
Overall match
1994-1995
62%
1995-1996
66%
1996-1997
66%
1997-1998
50%
1998-1999
86%
1999-2000
54%d
2000-2001
NIH f
22%
2001-2002
Euro b
77%
2002-2003
Euro b
68%
2003-2004
Euro b
49%
2004-2005
NIH c, CDC e
10%
2005-2006
NIH, CDC e
21%
2006-2007
CDC e, CDC
52%
2007-2008
CDC e, CDC
37%
2008-2009
CDC e, CDC
10%
2009-2010
CDC a, CDC e
56%
2010-2011
CDC e, CDC
60%
2011-2012
47%
2012-2013
CDC e, CDC
49%
2013-2014
CDC e, CDC
52%
2014-2015
CDC e, CDC
19%
2015-2016
CDC e
47%
2016-2017
43%
2017-2018
40%


Summary:
The vast majority of the 2018-19 influenza virus vaccine will still be made using 70+ year-old technology that uses an egg-based manufacturing process. The CDC or WHO provides approved manufacturers with the candidate vaccine viruses that are grown into fertilized hens’ eggs and incubated for several days to allow the viruses to replicate. The virus-containing fluid is then harvested from the eggs.  

The 2017-18 flu season was very severe and extended from November and into March (lasting 19 weeks). Up to 7.7% of the US had an influenza-like illness.  Interestingly, although the 2017-18 egg-based flu vaccine had poor efficacy (40%), the CDC still claims that the vaccine was a good match. Normally, a “good match” would translate to an “effective vaccine,” but not last year. Some experts say that the antibody serums used to make the vaccine work had errors last year. So, the vaccine strains were very similar to the circulating virus, but not close enough. Some experts suggest that in the egg-based vaccine, the vaccine virus acquires amino acid changes to the hemagglutinin protein that mediates the receptor binding. 

Fortunately, there are new influenza virus vaccines that are egg-free. These include:
  • Cell-based flu vaccines (instead of viruses growing in fertilized hens’ eggs, they are grown in mammalian cells)

  • Recombinant flu vaccines – first launched in 2013, the virus is mixed with insect cells where it replicates and is then harvested and purified. 

NOTE: Except for the CDC’s Overall VE data for 2005-2017, there is no single repository for identifying prior year’s efficacy; the authors are including the most appropriate references.

a 2009-10 the vaccine effectiveness could not be estimated; pandemic year, Monovalent vaccine was created.
b Data from Simpson, et al. Scotland data. This is not U.S. data, however the vaccines are the same northern hemisphere trivalent.
c Manufacturing problems resulted in a loss of nearly half of the US vaccine supply for the 2004-2005 season
d Overall vaccine effectiveness data was not published, however the match by strain was. 
e 2005 – 2017 also had a single reference for Overall Vaccine Effectiveness (VE)
f Maglani MJ, et al. JAMA Ped. 2004;158(1):65-73. Note that vaccine efficacy is limited to children aged 2.5 – 18 and only included the TIAV vaccine.


Kevin Fitzpatrick, MBA is president of Fitzpatrick Translational Science www.fitzpatricktranslationalscience.com and has written or co-designed >300 evidence-based health tools. 

Brock Fitzpatrick is a senior at the University of Wisconsin, College of Letters and Science

André Sheats, Mechanical Designer, Graphic/Website Designer and all around spreadsheet & math geek

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