Riding the influenza pandemic wave

1973927918_ce00011ef5_mOne notable characteristic of the four previous influenza pandemics is that they occurred in multiple waves. The 1918 pandemic began with outbreaks of low mortality in the spring and summer, followed by a more lethal wave in the winter. This pattern has fueled speculation that the current H1N1 pandemic strain will undergo mutation that leads to the emergence of a more lethal virus. What is the evidence that pandemic waves of increasing virulence are a consequence of viral mutation?

The only virus available from the 1918 pandemic was rescued from an Alaskan influenza victim who was buried in permafrost in November of that year, when higher mortality was already evident. This makes it impossible to correlate any genetic changes in the virus with increased virulence. Furthermore, as discussed on ProMedMail,

…there are many different ways of interpreting these differences other than more virulent virus. Some of these are differences in populations affected, more circulation of pneumococci and staphylococci during cold weather, more circulation of other viral pathogens, more virulence and larger inocula with the crowding and cold air inhaled.

The November 1918 influenza virus certainly has genetic and phenotypic properties expected of a virulent virus. These include the ability to multiply in the absence of trypsin*, lethality in mice and embryonated chicken eggs, and efficient replication in human bronchial epithelial cells. But we don’t know if these properties were absent from the virus that circulated in the spring of 1918.

Do the pandemics of 1957 and 1968, which also occurred in waves of increasing lethality, provide any information? Viruses are available from different stages of these pandemics, but to my knowledge the virulence studies have not been done.

This uncertainty makes it impossible to conclude that the 2009 H1N1 pandemic strain will become more virulent. Nevertheless, speculation is rampant, and accompanied the recent release of the Brazilian isolate. Another example is an amino acid change in the viral PB2 protein observed in some 2009 H1N1 isolates. According to Recombinomics,

Acquisition of E627K is a concern because it allows for optimal replication at 33 C, the temperature of a human nose in the winter, in contrast to E627, which is in the avian version of PB2 and allows for optimal replication at 41 C, the body temperature of birds. The appearance of E627K raises concerns that the level of swine flu with E627K will markedly increase in colder months. In 1918, the flu in the spring was mild, but the fall version of the virus, which had E627K, was much more virulent and targeted young, previously healthy adults…

If the amino acid at 627 is an important determinant of virulence, we would expect to find E627 in viruses isolated early in the 1918 pandemic – but such viruses are not available. Therefore the role of this amino acid change in virulence in humans cannot be tested. Further complicating the situation is that other amino acids in the viral PB2 protein can influence viral replication at low temperatures.

Fortunately, new H1N1 isolates are obtained every week, which provide a very accurate sampling of the entire pandemic. Should the new H1N1 strain become more virulent, it will be a relatively straightforward task to determine the genetic changes that accompany this property. Finally we will be able to determine if  pandemic waves of increasing virulence are a consequence of specific changes in the viral RNA.

*We’ll discuss the requirement of proteases for influenza virus replication next week.

Miller, M., Viboud, C., Balinska, M., & Simonsen, L. (2009). The Signature Features of Influenza Pandemics — Implications for Policy New England Journal of Medicine, 360 (25), 2595-2598 DOI: 10.1056/NEJMp0903906

Tumpey, T. (2005). Characterization of the Reconstructed 1918 Spanish Influenza Pandemic Virus Science, 310 (5745), 77-80 DOI: 10.1126/science.1119392.

20 thoughts on “Riding the influenza pandemic wave”

  1. Vincent, I have a question for you dealing with the immune response and Tamiflu. I understand that if you get the infection – it runs its course – and you recover, that you gain the antigen (learned) response that should help with similar influenza viruses in the future.

    Now what if you start to get sick and take Tamiflu – will this “stunt” your learned immune response and you will not produce enough antigens to help with future similar influenza infections (say, a similar fall wave of H1N1).

    Many thanks,


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  3. So if I've got this right, the result of severe, virulent influenza (no matter what strain) may involve one or more of these four pathologies:

    Cytokine storm: where the immune system ravages one's own tissues in the lungs or other organs; an over-response or dysregulation of the immune system

    Secondary bacterial infection: usually Strep or Staph or Hemophilus (but there are many more) that takes advantage of the primary influenza viral infection which also infects the respiratory tissues; MRSA being among the most dangerous bacterial infections

    Viral pneumonia: influenza virus infects the cells of the lower respiratory tract; a possibly similar mechanism in human cases of H5N1 bird flu

    Ventilator-associated pneumonia: hospital-acquired, bacterial infection of the lung caused by ventilator treatment (most often Pseudomonas)

    These conditions may occur whether or not the strain is considered virulent? Yes?
    My point being, just because someone develops ventilator-associated pneumonia or the other three conditions, it doesn't mean the flu strain is virulent. Yes?

  4. If you take Tamiflu when you feel ill, the virus has already
    multiplied extensively – therefore you will produce an immune response
    against the virus, and immunologic memory will occur. Therefore
    Tamiflu will not 'stunt' the immune response against influenza.

  5. Correct, the complications of influenza may occur even with less
    virulent strains, such as the 2009 H1N1. A more virulent strain would
    likely be an increase in the number of infections leading to

  6. Hello,
    It would be good to hear your thoughts on A/Shanghai/71T/2009 that has just appeared with both the PB2 E627K and D701N mutations. It took 43 days to adapt! D701N is thought to allow E627 viruses to become infectious to humans and perhaps has led to the E627K arising. Both are quite scary individually and together I think they look very worrying – transmissibility should be increased due to more efficient replication in the cooler temperatures of the respiratory tract.

    (I posted this elsewhere on your site – sorry for the duplication but I just read this section on this exact matter).

  7. We do have several samples from 1918,Alaska,New York,South Carolina.
    They are almost identical.
    It was globally more virulent in the 2nd wave. This isn't explained by the alternatives.
    We can also track how the more virulent strain spreads e.g. on the ships,
    and it's not just the same virus as in wave 1, because it would have started
    everywhere simultaneously then.

  8. I suggest you read the recent JAMA article by Taubenberger:
    “Understand Influenza Backward”
    (http://jama.ama-assn.org/cgi/content/full/302/6…). Here is an

    “Spring circulation of the novel virus in the Northern Hemisphere at
    the end of the 2008-2009 influenza season inevitably has led to
    comparisons with events in 1918-1919, which in some settings were
    preceded and followed by outbreaks of respiratory illnesses. Some also
    believe that the 1918 pandemic began with a premonitory “herald wave,”
    a term related to an old hypothesis, which influenza and dengue fever
    appeared to have supported, that as new viruses begin to circulate in
    human populations they inevitably acquire mutations that increase
    transmissibility and virulence.

    Evidence for unusual influenza activity in the years before 1918 is
    inconclusive. Occasional outbreaks of severe and fatal bacterial
    pneumonia possibly related to influenza or other respiratory viruses,
    detected in the European war theater in 1916-1918, are difficult to
    interpret in the absence of pathological or other diagnostic material.

    In spring 1918 there were widespread but distinct outbreaks and
    epidemics of probable influenza in many different parts of Europe,
    most featuring low to negligible mortality and a scattershot pattern
    that differed from the undoubted epidemic waves seen later in the
    year. Outbreaks of mostly nonfatal acute respiratory diseases were
    also described in the United States in late 1917 and early 1918,
    especially in military camps but also in cities. Whether the same or
    different viruses caused any of these outbreaks is speculative. The
    first documented wave of 1918 often confusingly referred to as the
    spring wave, was actually a summer surge of influenza fatalities
    concentrated in some but not all northern European countries between
    late June and August 1918. Despite enormous wartime traffic, it is
    curious that many English cities had a summer wave but France did

    In the absence of genetic differences among virus isolates, the cause
    of increased virulence is unknown.

  9. The original sequence had both mutations. The current (revised) sequence has neither. It is 627E and 701D. The errors were attributed to passage effects.

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  11. 3 months on and what's changed? Oh, yeah… and the Southern Hemisphere has survived.. in tact!!

    With about 11 % of the 25 million populace infected and around 200 deaths the countries of Australia and New Zealand reveal an infection fatality rate of around 1:25,000,… given that there have been about 4,500 deaths recorded globally so far that equates to about 105 million infections… The CDC has said 5-10 percent of communities in the USA where the virus has been were infected… that equates to about 15-30 Million USA citizens… This is not the monster we were lead to believe…

    A good article that has withstood the test of time.

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