From year to year, there are variations in the effectiveness of the flu vaccine, although getting the flu vaccine is infinitely better than contracting the flu and risking some of the major complications of the disease. A peer-reviewed paper has just been published that examines flu vaccine research and development impact on flu vaccine effectiveness. Interestingly, the study authors may have identified the most important reason for the variable effectiveness – because the virus is grown in chicken eggs.
I think it’s important that vaccine manufacturers start to examine methods on how to improve effectiveness, since the flu, despite the claims of the antivaccine world, is a serious and dangerous diseases. And some strains of flu, like the H1N1 can be harmful to young healthy adults.
There are a lot of reasons why the flu vaccine research and development gives us a final product that varies in effectiveness from year to year, and we are going to look into some of them.
Flu vaccine research – picking antigens
Without getting too complicated, the flu vaccine induces a systemic immune response to a part of the influenza virus called hemagglutinin, which is a glycoprotein found on the surface of influenza viruses. Both inactivated and live influenza vaccines induce virus-specific serum antibodies which can protect against infection with wild influenza virus possessing the same hemagglutinin antigen.
The reason that each flu season brings a new risk for contracting the disease is that the virus has frequent mutations of the hemagglutinin, so the immune system doesn’t recognize the virus anymore, and you get the flu. It doesn’t matter if you get the flu “naturally” or boost your immune system with a vaccine, you are generally susceptible to the newly mutated flu virus each year.
Of course, this makes it difficult to develop a flu vaccine every year, because national health organizations, like the US Centers for Disease Control and Prevention, have to scientifically predict which mutated viruses might be prevalent in the upcoming flu season.
Vaccine manufacturers require a six month lead time from choosing the virus to shipping the vaccine, scientists must quickly determine what the new mutated types might be.
The first step is that over 100 national influenza centers in 100 countries receive and test virus samples from patients in their countries. These centers then send samples of the most prevalent viruses to five World Health Organization (WHO) Collaborating Centers for Reference and Research on Influenza, which include the following research organizations:
- Atlanta, Georgia, USA (Centers for Disease Control and Prevention, CDC);
- London, United Kingdom (The Francis Crick Institute);
- Melbourne, Australia (Victoria Infectious Diseases Reference Laboratory);
- Tokyo, Japan (National Institute for Infectious Diseases); and
- Beijing, China (National Institute for Viral Disease Control and Prevention).
Twice a year, February for the Northern Hemisphere and September for the Southern Hemisphere, WHO gathers the five Collaborating Centers to meet and discuss which flu virus mutations are going to be prevalent.
The key scientists from each of these centers review the results of surveillance, laboratory, and clinical studies, and the availability of vaccine viruses and make recommendations on the composition of the upcoming season’s influenza vaccine. Generally, the group decides on three subtypes of the flu virus – H1N1 (a subtype of A flu), H3N2 (another subtype of A flu), and type B strains. Recently, a second subtype of the B type virus is included in the quadrivalent flu vaccines.
WHO recommends specific vaccine viruses for inclusion in influenza vaccines; however, each country reviews the data and may modify the viruses in the vaccines for their own country. For example, in the USA, the Food and Drug Administration (FDA) makes the final decision about vaccine viruses, with input from the CDC, that will be used in vaccines sold in the USA.
As opposed to some of the tropes of the anti-vaccine radicals, this isn’t random guessing, like throwing darts at influenza strains and say, “we’re including that one.” In fact, it is a logical, scientific process that includes some of the leading experts on the flu virus from across the world. Although the process is far from perfect, for example, it’s difficult to predict a new mutation that appears after the February or September meetings, it works well enough in most years.
In the 2016-17 flu season for the Northern Hemisphere, the CDC estimated that the overall effectiveness of the flu vaccine was around 48%. I realize that’s far from perfect, but given the significant complications and costs of a flu infection, even reducing the risk by half has an important benefit to humans. Furthermore, given the very low risks from getting the shot, the benefit to cost equation is overwhelmingly on the side of benefit.
Flu vaccine research – it’s the eggs
To produce the vaccine, the flu virus for the upcoming flu season is grown on fertilized chicken eggs. This process is antiquated – it was first invented in 1931, and it has stuck since (see Plotkin and Plotkin, pp 6-7). To make a flu vaccine, producers inject a “seed” virus strain into eggs and then incubate them as the virus grows. Then they purify the virus, and either weaken it or kill it to make a vaccine.
However, there is some movement from eggs to other methods of virus production. There a number of reasons why vaccine manufacturing is looking at different methods to produce the virus. Some flu viruses do not grow well in chicken eggs, so that constrains the supply of viruses for vaccines. Growing the virus in eggs is a slow and tricky process, one that takes weeks or months and that can go wrong easily.
In addition, the methods required to purify the viruses to remove all egg proteins and contaminants is substantial and quite expensive. The techniques are so powerful that the CDC has removed “allergy to eggs” from contraindications to the vaccine.
Because it is expensive and time-consuming to do, the flu vaccine research and clinical trials to get regulatory approval for a new method of manufacturing the virus, pharmaceutical companies have been reluctant to move on to more modern methods of virus production, like cell culture or recombinant technology. Just to scare away the world of the cross section between anti-vaccines and anti-GMOs, there is even an important research direction to produce the influenza virus in genetically modified plants.
But there may a more significant issue that will spur change from eggs to other methods of growing the flu virus. A recent article about flu vaccine research, published in the Proceedings of the National Academy of Sciences fo the United States of America (PNAS), showed that the methods of growing the virus in eggs may cause the virus to mutate more than normal. This means that the viruses used for the vaccines have mutations that make them different than the wild viruses.
Scientists are not surprised that eggs are an inefficient and problematic way to grow the viruses. Vaccine manufacturers, physicians, immunologists and other experts have known for years that the methods used to manufacture flu vaccines are slow, outdated, and prone to errors. All of this leads to issues in the effectiveness of the vaccine.
The researchers examined the H3N2 component of the 2016-17 vaccines, the component that made most people sick in the USA. When people were tested specifically for flu strains, the vacine reduced H3N2 disease by just 34%, compared with the overall 48% effectiveness of the season’s flu vaccine.
Interestingly, two vaccines sold in the USA do not use eggs for production. Flucelvax, which is grown in canine kidney cells, and FluBlok (now manufactured by Sanofi Pasteur), which uses an insect virus called a baculovirus grown in caterpillar cells. I know these statements will find their way into some bogus anti-vaccine meme, but just to be clear, there are undetectable levels of canine kidney or caterpillar cells, proteins, or DNA in the vaccine.
Purification methods are much more sophisticated than what anti-vaccine people believe – I am convinced that vaccine deniers believe that Sanofi Pasteur tosses a handful of caterpillars in a blender, then adds water, thimerosal, and MSG, puree it, put it in a syringe, and inject it into screaming babies.
Flu vaccine research is also moving in a new direction. They are trying to find the Holy Grail of a universal vaccine – one that would protect against all flu strains even as they mutate, and maybe that even wouldn’t have to be freshly given every year. In other words, it could give protection for several years.
Furthermore, a universal vaccine could be very important, because every 20 years or so, a new pandemic strain of flu emerges and kills many more people than usual. These pandemic strains get moving quickly because almost no one has any immunity against that strain, and it affects more people and causes more serious disease.
So that’s the real science behind flu vaccine research. It requires solid predictions of what mutated version of the flu virus will be circulating in six months, which is what is required to grow the virus and manufacture the vaccine.
There’s also an issue of extra mutations occurring in egg grown viruses, which may make the vaccine less successful than predicted. But real scientific flu vaccine research is finding new and better ways to produce flu viruses for vaccines.
And let me remind you one more time. Just because the flu vaccine isn’t 100% perfectly effective does not mean it’s useless. Reducing your risk to a dangerous flu outbreak by just 50% can mean fewer visits to the hospital. And yes, fewer deaths.
Vaccines save lives.
- Ghendon Y. The immune response to influenza vaccines. Acta Virol. 1990 May;34(3):295-304. Review. PubMed PMID: 1980401.
- Landry N, Ward BJ, Trépanier S, Montomoli E, Dargis M, Lapini G, Vézina LP. Preclinical and clinical development of plant-made virus-like particle vaccine against avian H5N1 influenza. PLoS One. 2010 Dec 22;5(12):e15559. doi: 10.1371/journal.pone.0015559. PubMed PMID: 21203523; PubMed Central PMCID: PMC3008737.
- Nobusawa E, Sato K. Comparison of the mutation rates of human influenza A and B viruses. J Virol. 2006 Apr;80(7):3675-8. PubMed PMID: 16537638; PubMed Central PMCID: PMC1440390.
- Plotkin, S.L. and Plotkin, S.A. “A short history of vaccination.” In: Vaccines, Stanley A. Plotkin, Walter A. Orenstein, Paul A. Offit, eds. Elsevier Health Sciences, 2008.
- Zost SJ, Parkhouse K, Gumina ME, Kim K, Diaz Perez S, Wilson PC, Treanor JJ, Sant AJ, Cobey S, Hensley SE. Contemporary H3N2 influenza viruses have a glycosylation site that alters binding of antibodies elicited by egg-adapted vaccine strains. Proc Natl Acad Sci U S A. 2017 Nov 6. pii: 201712377. doi: 10.1073/pnas.1712377114. [Epub ahead of print] PubMed PMID: 29109276.
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