You may have heard that this season’s influenza vaccines are only about 10 percent effective against the flu viruses circulating in the United States and wondered: What the heck? How can such a low level of effectiveness be the best that the world’s “best and the brightest” can produce? Why did expert immunologists fare so poorly with the 2017-2018 flu vaccines?

Clearly, a mismatch has occurred between the influenza virus strains that the current vaccines target (and immunize people from) and the influenza virus strains that are infecting people.

How did this mismatch happen? Can “we” stop it from happening again?

I can answer the first question. The probable answer to the second question is: Not yet.

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VIRUS STRAINS

An influenza strain is a genetic variant of the virus, which, lest there be any confusion, is a microorganism. All influenza viruses and their strains have their own genomes, which are essentially genetic instructions for life.

There are three types of human influenza viruses, known as A, B, and C. C is of little concern because it doesn’t cause severe illness. Influenza A and B bring on the seasonal outbreaks with which we’re familiar, with type A being the more common of the two.

Influenza A has subtypes that are named after the two proteins on the surface of the virus, hemagglutinin (H) and neuraminidase (N). The World Health Organization’s influenza A nomenclature includes combinations of H1 through H18 and N1 through N11. These subtypes, in turn, may have subtypes of their own.

Influenza B has no subtypes, but it is broken down by lineages and strains. (For more on the virus nomenclature, see below.)

Influenza A subtype H3N2—or A(H3N2)—has been predominant in recent years. But scores of influenza virus strains exist, and they are constantly changing.

Influenza vaccines are either trivalent, meaning they contain two strains of type A and one strain of type B; or quadrivalent, meaning they contain two strains of each. The quadrivalent vaccine is newly available this year.

The influenza vaccines do not contain live virus, so they cannot give you the flu.

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INFLUENZA ILLNESS

Influenza viruses infect your nose, throat, and lungs, causing a contagious respiratory illness. Flu symptoms usually start suddenly, not gradually, and include:

–Fever, sometimes with chills

–Cough

–Sore throat

–Runny or stuffy nose

–Muscle or body aches

–Headaches

–Fatigue*

As the viral infection increases, your body’s immune system responds to fight it by producing antibodies.

Within two weeks of receiving an influenza vaccine, your body will develop protective flu-virus-specific antibodies in the absence of a viral infection. If you are subsequently infected with a flu strain for which you were not vaccinated, the antibodies you developed may nonetheless help you. You may not become as ill as you would have become without the vaccination.

Influenza spreads from person to person, through respiratory droplets expelled by an infected person when he or she coughs, sneezes, or talks. You, therefore, should give a flu-infected person a wide berth, standing more than 6 feet away.

According to the WHO, seasonal flu epidemics cause 3 million to 5 million severe cases and 300,000 to 500,000 deaths globally each year. In the United States, the U.S. Centers for Disease Control and Prevention (CDC) reports, 140,000 to 170,000 influenza-related hospitalizations and 12,000 to 56,000 flu-related deaths occur each year, with the heaviest burden falling upon the very young, the very old, and people with coexisting medical conditions. These are people with immune systems that are not strong enough or competent enough to combat the viral invaders.

Adolescence and the onset of puberty generate substantial changes in the immune response of individuals and their intrinsic resistance to influenza-induced inflammation and death. Not only do children lack a resistant innate immune system, they have not lived long enough to have been exposed to influenza virus strains and to have developed antibodies to them.

A pandemic on the order of the 1918 influenza outbreak is the fear of every infectious disease specialist I’ve ever heard speak about emerging diseases. (See below for more about pandemics.) Despite the overall ineffectiveness of a particular season’s vaccines, all U.S. public-health agencies recommend that everyone over the age of six months be vaccinated.

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FLU VACCINES

According to the timely and informative article, “Chasing Seasonal Influenza—The Need for a Universal Influenza Vaccine,” in last week’s issue of The New England Journal of Medicine:

“The cornerstone of influenza prevention and epidemic control is strain-specific- vaccination. Since influenza viruses are subject to continual antigenic changes (‘antigenic drift’), vaccine updates are recommended by the WHO each February for the Northern Hemisphere and each September for the Southern Hemisphere [which has winter when we have summer]. This guide relies on global viral surveillance data from the previous 5 to 8 months and occurs 6 to 9 months before vaccine deployment. In addition, there are always several closely related strains circulating; therefore, experts must combine antigenic and genetic characterization and modeling to predict which strains are likely to predominate in the coming season.”

An antigen is a substance (molecule) that is capable of inducing an immunologic response from the host organism. Viral antigens induce your body to produce antibodies, but they are too late to prevent symptoms of illness. Influenza vaccines are designed to protect against the three or four viruses that worldwide research suggests will be most common.

When antigenic drift occurs, changes occur in the genes of the viruses that code for antibody-binding sites in humans, usually because of an accumulation of mutations. Antigens “drift” or shift enough that the antibodies you develop pursuant to vaccination don’t adequately thwart them.

“Vaccine mismatches,” write the four infectious disease specialists who authored the NEJM article, “have occurred in years in which circulating influenza strains change after the decision is made about vaccine composition, resulting in reduced vaccine effectiveness.”

Such a mismatch occurred during the 2014-2015 flu season in the United States when more than 80 percent of the circulating influenza A(H3N2) viruses that were characterized differed from the vaccine virus, and the vaccine effectiveness was only 13 percent against influenza A(H3N2).

For the 2017-2018 flu season, the trivalent vaccine contains:

*an A/Michigan/45/2015 (H1N1)pdm09-like virus

*an A/Hong Kong/4801/2014 (H3N2)-like virus

*a B/Brisbane/60/2008-like (B/Victoria lineage) virus

The quadrivalent vaccine contains these three viruses, plus a B/Phuket/3073/2013-like (B/Yamagata lineage) virus.

The WHO’s nomenclature for human influenza viruses reflects the following components, in order:

1)      The antigenic type (A, B, or C)

2)      Geographical origin

3)      Strain number

4)      Year of isolation

5)      For influenza A viruses, the hemagglutinin and neuraminidase antigen description in parentheses; and for B, the lineage

(For more about nomenclature, see https://www.cdc.gov/flu/about/viruses/types.htm.)

In 2009, the WHO issued an alert for a new pandemic influenza A(H1N1) virus, which it named pdm09. This flu strain caused more fatalities than the then-circulating A(H1N1) virus and affected mostly younger people. An estimated one-third of all people over age 60 had antibodies for it because of previous exposure to other A(H1N1) strains. (See below for more on pandemics.)

By October 2017, the Southern Hemisphere’s influenza season experience was known: Influenza A (H3N2) viruses predominated, and the vaccines were only 10 percent effective.

Inasmuch as the vaccines used this season in the United States are identical in composition to the ones given in the Southern Hemisphere, this news did not bode well for us Yanks.

But even in years when influenza vaccines “are well matched to circulating viruses,” the NEJM authors point out, “estimates of vaccine effectiveness range [only] from 40 to 60 percent, which is lower than that for most licensed noninfluenza vaccines.”

Immunizing against influenza is a challenge, to say the least.

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‘MULTIFACTORIAL’ CAUSE

The NEJM authors, who include the eminent Dr. Anthony Fauci, director of the National Institute of Allergy and Infectious Diseases at the NIH, and scientists with the WHO center for influenza research in Melbourne, Australia, describe the cause of suboptimal vaccine effectiveness as “probably multifactorial.”

I’ve already noted that one factor is a change in the influenza virus strain. In the 1918-1920 (“Spanish”) influenza pandemic—pandemic meaning worldwide—an especially virulent new strain of influenza appeared and quickly spread. Like the new influenza A(H1N1)pdm09, the Spanish flu primarily affected younger people.

Pandemic influenza usually originates with an animal influenza virus. It has been suggested that the Spanish flu of 1918 came from a swine influenza virus, which itself may have descended from an avian virus. The 1918 pandemic was the first of two pandemics caused by the A(H1N1) virus, also known as swine flu. The other occurred in 2009. (See  https://www.cdc.gov/flu/pandemic-resources/basics/past-pandemics.html.)

Such factors as a person’s prior influenza exposure and vaccination history also can influence his or her subsequent responses to seasonal influenza vaccines, as can his or her age and any coexisting medical conditions that affect the immune system.

Another key causation factor is the substrate used to produce the vaccines. Most influenza-vaccine viruses are grown in chicken eggs, although a small proportion of them are produced either in cell culture or through recombinant DNA technologies.

“During the egg-based production process,” Dr. Fauci et al write, “the vaccine virus acquires amino acid changes that facilitate replication in eggs, notably changes in the hemagglutinin (HA) protein that mediates receptor binding. Since the influenza HA is the primary target of neutralizing antibodies, small modifications in this protein can cause antigenic changes in the virus and decrease vaccine effectiveness.”

Such changes during production are referred to as egg adaptation. It is believed, for example, that circulating influenza A(H3N2) viruses in the 2016-2017 season possessed an HA glycosylation site that was lost in the vaccine strain during egg adaptation. The human antibodies elicited by this vaccine strain, thus, performed poorly.

Investigators point to a better performance by vaccines produced through cell-culture and recombinant DNA processes. It may be that, in time, these methods will replace the egg manufacturing system.

Dr. Fauci and his colleagues support striving for a universal influenza vaccine that would protect against seasonal influenza drift variants, as well as potential pandemic strains, “with better durability than current annual vaccines.” They don’t believe such a vaccine would be subject to egg-based vaccine technology, but they have no data yet to support this opinion.

For an overview of influenza and vaccines, see the U.S. Centers for Disease Control and Prevention’s FAQ at https://www.cdc.gov/flu/about/season/flu-season-2017-2018.htm.

Stay well!

Ann, 1/6/18

*Vomiting and diarrhea may occur with influenza, but, typically, only in children, not adults. There is no such thing as stomach flu. You can credit gastrointestinal viruses, not influenza viruses, with the misery that many people incorrectly call stomach flu.