Effect Measure

Immunity and the 1918 and 2009 pandemics

Posted by revere on March 26, 2010
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We continue to learn a great deal about influenza infection as researchers harvest information from the recent swine flu pandemic. The pork producers don’t like to call it “swine flu” but it may well be that its long sojourn in that animal since 1918 (did we give Spanish flu to pigs or did pigs give it us?) may hold an important clue to why older people suffered less than younger ones. It seemed fairly likely that the difference was related to immunity, but since H1N1 came back in 1977 after being absent since 1957, it wasn’t clear why younger people born after 1977 would be as immune as older ones born before 1957. Now two papers published in Science and Science Translational Medicine shed some light on this.

I’ve read both papers and the full story would take a lengthy post. Ordinarily that’s just what I’d do, but I’m still writing the grant so I’ll have to give an abbreviated version. There are news stories in both Science and Nature that will fill in some of the details from a different point of view. Furthermore, we’ve covered a lot of the basic science of receptors and such here, here, here, here, here, here, here, here. So I’ll assume some background and that this brief description will be comprehensible. If not, try the links above.

The flu virus is studded with two proteins, hemagglutinin (HA) and neuraminidase (NA), whose various subtypes give the different flu viruses their macro naming system, e.g., H1N1 being the first kind of 16 different hemagglutinin proteins and the first kind of 9 different neuriminidase proteins. The HA is involved in getting the virus into the host cell, so it is highly exposed, and it is this exposed part that the immune system “sees” and mounts an attack against. The business end of HA is a globular structure at the end of a stalk, and the HAs of most flu viruses have a similar shape. Similar but not identical. In order to avoid immune attack, HA is continually changing its appearance to the immune system, which is the reason we need to make new seasonal flu vaccines every year or two. There are four different exposed areas on the HA head that are attacked by antibodies, and one of them, called Sa, is pretty much the same in the 1918 virus and its progeny, up to the 1940s or so, and different from the same small area in the seasonal flu viruses prevalent since 1977. This is not the only difference. The post 1977 seasonal H1N1 viruses, unlike the closer to 1918 H1N1 viruses prior to 1957, have host-derived sugars hanging around the same area that shield the underlying protein. That doesn’t mean that we can’t protect ourselves against them, but it does mean that we have to make a different antibody to do it, one that protects us against the post 1977 H1N1 but not the 1918-like HA more characteristic of H1N1s prior to 1957.

The interesting thing revealed by these two papers is that the 2009 swine-derived virus has an HA Sa region very similar to the 1918 virus and in addition has no shielding sugars. This explains lack of cross-reactivity with seasonal vaccines, explains why people who got the 1976 infamous swine-flu vaccine (44 million people) likely have some cross-protection against 2009 swine flu and why us older folks, born in the 1940s do, too. So that’s the story as it appears now. Again, more details in the links above. But there is one additional observation I’d like to make that doesn’t appear in those accounts.

At the outset of this pandemic the statement that the receptor binding domain of the 2009 swine flu virus was extremely close to the 1918 Spanish Flu virus would have sounded ominous. But infectivity, transmissibility and virulence are different things and require different properties. A virus can be just like the 1918 virus “on the outside” but still not a nasty actor “on the inside.” What’s the difference? We can’t say with any definiteness, yet. It’s still one of the big mysteries of influenza. But we’re getting there, and I have no doubt that we will learn yet more in the wake of this pandemic.

Pandemics are bad and they kill people. A lot of people. It would be better not to have to suffer them. But we can still learn a lot from them, if we invest the time, effort and resources.

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Comments

  1. #1 Hand Gel Man
    March 26, 2010

    An interesting post with much to interest but please will you forgive me if I focus on your last paragraph and question it:
    “Pandemics are bad and they kill people. A lot of people. It would be better not to have to suffer them.”
    Thomas Malthus and his theory on population would suggest otherwise.
    Leaving a hundred year old theory aside, it depends whether one looks at pandemics from a micro or macro view – yes, they’re obviously bad for the people affected; however, they might be good for humanity as a species.
    Delving further into history – thousands of years – the parable of the Taoist farmer highlights the difficulty of pronouncing anything good or bad :)

  2. #2 revere
    March 26, 2010

    Hand Gel Man: Malthus had a theory that predicted things, but based on incorrect assumptions: exponential growth of the population and not the food supply. So let’s leave him aside, indeed. If one uses the population viewpoint, things are complicated, as population dynamics responds to population density (it is non-linear), so invoking pandemics as the only or even as a desirable means of control is dangerous and certainly incorrect. Pandemics can play a part (although in human socieities usually not a large part in the modern era), but most population control is via other, more humane, means (e.g., lowering the birth rate).

  3. #3 elephantman
    March 26, 2010

    The detailed data on age specific incidence of death from the 2009 Pandemic H1N1 displays an interesting phenomenon: rates and incidence of death in the US and most other countries are actually highest among persons in the 50-60 year age range, among persons who were in fact exposed to pre-1957 H1N1 viruses in their youth (see data in CDC powerpoint at link below).

    The “residual immunity” inflection point in the mortality data actually occurs between the ages of 60 to 65 years, which suggests that observed residual immunity effect comes from exposure to pre-1947 H1N1 viruses, and not H1N1 viruses from the period between 1948-1957.

    It worth remembering in this context that genetic studies determined that the 1977 H1N1 virus was virtually identical to H1N1 viruses collected in Scandinavia during 1950-1951, which accounts for the lack of immunity in persons exposed to more recent H1N1 seasonal influenza viruses which were derived from a post-1947 ancestral strains.

    REF:

    see Slide 11 in CDC powerpoint posted at:

    http://www.ianphi.org/uploads/file/US%20Situation%20Update%20and%20CDC%20International%20Response.ppt.

  4. #4 revere
    March 26, 2010

    elephantman: A comment and a question. Comment first. Rates for lab confirmed cases may not reflect actual mortality rates, but the new findings suggest that sugars were added to the H1N1 continually from 1918 on, so these data aren’t inconsistent with what was found, although I phrased it in pre-1957 rather than 1940s which may be more accurate. Regarding the Scandinavian virus, do you have a cite? I understood there were no isolates from the 1951 flu season (which was very severe and which we wrote about here. From what I remember, the 1977 was said to be identical to an isolate in a Russian lab freezer from 1950.

  5. #5 Jody Lanard M.D.
    March 27, 2010

    ElephantMan wrote:

    The “residual immunity” inflection point in the mortality data actually occurs between the ages of 60 to 65 years, which suggests that observed residual immunity effect comes from exposure to pre-1947 H1N1 viruses, and not H1N1 viruses from the period between 1948-1957.

    Very interesting, in the context of the 1946-7 influenza epidemic.

    In 1946-1947, there was a major change in the circulating A/H1N1 flu virus, as described in The total influenza vaccine failure of 1947 revisited: Major intrasubtypic antigenic change can explain failure of vaccine in a post-World War II epidemic

    This 1953 article, The influenza virus: its morphology, immunology, and kinetics of multiplication, is said by Walter Dowdle to contain one of the first discussions of the concept of antigenic shift, in which its author states: “…in certain periods major shifts in antigenic constitution seem to have occurred. Such a happening apparently took place in 1946-7 with the appearance of virus strains of the FM1 (1947) type (the so-called A-prime group), which had not been encountered before.”

    Edwin D. Kilbourne discusses the drastic change in the 1946-7 A/H1N1 subtype – and emphasizes the limits of our knowledge — in Perspectives on Pandemics: A Research Agenda, a wonderful after-dinner speech in 1995.

  6. #6 Swift Loris
    March 27, 2010

    Very dumb, very elementary question: What does “exposed to” mean in this context? Just being alive when the virus was around? Or actually having contracted the flu?

  7. #7 revere
    March 27, 2010

    Swift Lois: Not a dumb question but it has a dumb answer: it depends. “Just being alive” is a surrogate for being infected (which is what exposed means here), but in reality it is only potentially infected. However during flu outbreaks your chance of being infected can be anywhere from 20% to 40%, still not 100% but over the years starts to get up there. However if you weren’t alive then, you don’t even have the possibiliy (which is fairly high over a decade or two) of being infected.