Effect Measure

News reports that nonagenarians had robust antibodies against the 1918 flu strain were intriguing on several levels but I wasn’t sure how many doors were still open to these being antibodies that developed in the years after 1918. After all, the 1918 subtype was H1N1 which circulated freely until the 1950s when it was displaced by the next pandemic strain, H2N2. H2N2 in turn was pushed aside by H3N2 in 1968. Then H1N1 returned in 1977 (some say it escaped from a Russian laboratory) and since then H3N2 and H1N1 have been co-circulating. Some years are predominantly H1N1, some predominantly H3N2, with H3N2 years tending to be more severe flu seasons. How do we know the people studied in the new paper didn’t get their antibodies well after 1918? So I took a look at the paper, just published in Nature, and it answered my questions and then some. It is fascinating work on many levels. What’s it about?

The authors identified people still alive from the 1918 period and looked to see if they had antibodies in their blood to the flu variant of the 1918 pandemic:

We identified a panel of 32 subjects aged 91-101 years (that is, aged from 2 to 12 in 1918), many of whom recalled a sick family member in the household during the pandemic, which suggested direct exposure to the virus. Of the subjects tested, 100% had serum-neutralizing activity against the 1918 virus (mean titre 1:562), and 94% had serologic reactivity to the 1918 HA (as indicated by haemagglutination inhibition assay (HAI) titres of 1:40 or greater; mean titre 1:396), even though these samples were obtained nearly 90 years after the pandemic. In contrast, subjects born after the pandemic had markedly lower rates of positive serum-neutralizing tests against the 1918 virus (9 out of 10 subjects born 1926-35 had titres <1:100, 9 out of 10 subjects born 1936-45 had titres 1:40, 9 out of 10 subjects born 1946-55 had titres 1:40). (Yu et al., Nature)

Here’s what this means. The authors tested the blood of these aged survivors and found that they had antibodies in their blood that could prevent infection (neutralization) or reacted with a specific surface protein (hemagglutinin inhibition) of the 1918 virus. When they looked in the blood of people born and living at various times removed from 1918 they found lower and lower rates of anti-1918 activity (measured various ways). But they did more than that.

The antibodies in our blood are produced by a specific type of immune cell, called a B-cell. Each B-cell produces only one antibody. So we need a different B-cell for each thing we need an antibody against. The immune system is a marvelous device that educates B-cells to produce the right kind of antibodies when it is exposed to an antigen (an antigen is a protein that can call forth an antibody response). One the antigen is no longer present (the infection is over with, often with the help of the antibody), a few of the antibody specific B-cells hang around to act as long term memory so that if the antigen ever shows up again the body can react swiftly. It doesn’t have to learn to make the antibody again but merely gives the signal to make many copies of the memory cells. This is called clonal expansion and it’s like having the blueprint on the shelf so when a new order comes you can start the manufacturing process right away. No new design needed. No delay. That’s how vaccines work. They induce the body to make memory B-cells so the next time the tetanus or polio or anthrax antigen comes along you are good to go.

It’s not a certainty, though, that a particular memory B-cell will last your whole life (and since my memory is not so good these days, this is especially plausible to a geezer like me). But this paper seems to show that for some people, at least, the 1918 memory B-cells are still around after 90 years. But wait, there’s more. The research team isolated the B-cells from their subjects and found the ones that were making the antibodies against the virus. They then “immortalized” these B-cells by fusing them with blood cancer cells to produce clonal cultures of B-cells that only made one antibody. Since different spots on the virus visible to the immune system might elicit specific antibody responses (these features are called epitopes), there might be more than one distinct antibody against any particular virus. Indeed the researchers were successful in producing five distinct monoclonal antibodies against the 1918 virus. This is very pretty work and there are a lot of details I haven’t gone into with this brief description, but suffice to say the data convinced me that they really were looking at the immune response to the 1918 virus and not some subsequent virus which just cross-reacted with the 1918 virus. There are still a few alternative possibilities but I think this paper does a good job of making the case the antibodies are from 1918 memory cells.

We still don’t know how typical these people are. After all, they apparently didn’t get sick in 1918 despite being infected and they have a good enough immune system to last into their nineties. Maybe most of us aren’t so lucky and have waning immunity with the years. But this is some slick work and now that we have the actual antibodies in sufficient quantity to study we can begin to ask what features of the 1918 virus made it vulnerable. How much of this is transferable to bird flu, the current pandemic worry, is difficult to say. These antibodies didn’t protect against or react with H5 flu viruses so they aren’t a therapy for bird flu. But understanding the basic science of influenza virus is always a plus.

This is fascinating science. And for a scientist, that’s a Big Deal.

Comments

  1. #1 RobT
    August 19, 2008

    Very interesting work and it was discussed on Fluwiki several years ago that this would be a good thing to do i.e.find 1918 survivors and see if their immune response to H1N1 was still viable and what else could be learned.

    I was interested in this because my Dad, who died last year at 92, was a survivor. He was three at the time and gravely ill with the flu, was given the last rights while in Sick Kids hospital in Toronto, but survived. He had lifelong hearing loss from ear infection at the same time, but otherwise was a lucky one. I hope I got those genes!

    I tried to get ANYONE interested here in Australia to investigate his immune factors, but was told repeatedly by medical researchers that there was “probably not much to learn”, which I found curious at the time, given the outbreaks of H5N1 that were occurring. There was a definite lack of scientific curiosity, that’s for sure. So I’m pleased to see that this line of investigation has been taken up.

    The more we learn, the better, and these 1918 survivors are melting away faster than the Arctic sea ice. So they better hurry up.

  2. #2 Tom DVM
    August 19, 2008

    So it looks like the old immune system is a little more capable then it is given credit for…

    …and maybe the reason that the old and the young don’t respond to influenza vaccines is because they don’t work…rather than because the immune system isn’t developed and isn’t efficient.

    Whenever the target group for a vaccine isn’t protected…at all…you have to wonder.

  3. #3 Perezoso
    August 19, 2008

    Being the contrarian that I am, I beg to difer.

    Since when did we not know that persons exposed to flu virus X produced antisera to flu virus X? Tell me that it’s not predictable that people alive in 1918 and in the subsequent years when H1N1 ruled the world would produce H1N1 antisera? Okay, maybe the length of time passed since 1918 is possibly newsworthy; but his it earth-shattering news? I don’t think so.

    The whole 1918 business is a dangerous distraction from more important contemporary issues. And the fact that Nature published it is further confirmation, to me at least, of what the Sunshine Project was saying about this valueless 1918 distraction years ago: it attracts people because mediocre science gets rewarded with high profile publications, since the date “1918″ appears prominently.

  4. #4 revere
    August 19, 2008

    Perezoso: I’m not against contrarians, but I’m not sure what you are getting at. This isn’t about H5N1 (news reports notwithstanding), it’s about immunology and influenza. And it wasn’t just H1 antisera. It was antibody to 1918 epitopes not present on later viruses. I suggest you read the paper if you want to see what was done and what was learned. The issue of longevity of memory cells is also of interest. There is nothing mediocre about the science reported here as far as I can see. Perhaps you have a specific criticism of it?

    We have noted here often that things can get published in excellent journals because they are hot topics, but to make that judgment you have to read the paper to see if it is an example. Fishing out B memory cells from nonagenarians was extremely interesting and a clever thing to do. It could easily have failed and this was not “quickie” project. It’s been underway for 4 years.

    The idea that publication in Nature makes a paper of lesser value is not contrarian. It is bizarre. Nature does publish articles of lesser value, as do all journals, but its average quality is far, far above most journals. When you read the paper you will see that this is not a cross reactivity issue and there was nothing obvious about it. Contrary to your contrarianism, it was definitely high risk as far as an investment of effort is concerned.

  5. #5 Perezoso
    August 19, 2008

    Revere: Contrary to your contra-contrararianism, that’s not what I meant. I probably didn’t express myself well.

    What I meant was (trying again):

    1) If the article was about antibodies to the prevalent flu strain circulating in, say, 1915 or 1955, I suspect we would have been reading about it in the Outer Mongolian Journal of Meat Cutting Technology and Garage Tinkering, rather than Nature.

    2) 1918 subject matter, whether interesting, novel, and truly useful science or not, tends to get rewarded by Nature and Science – at least PNAS – when it seems like a lot of these articles describe science that would not be otherwise prominently published. This attracts people to work on 1918 whether it’s a pressing public health need or not. (And a disease that disappeared decades ago is not a public health need.)

    3) The net effect, especially when popular press linking nearly century-old H1N1 and contemporary H5N1 gets thrown in, is public confusion and the mistaken perception – encouraged by Tony Fauci and Julie Gerberding – that this messing around with 1918 is getting us somewhere with H5N1. I don’t think it is.

    Maybe the study is interesting in its own right for flu-ologist; but it ain’t fixing the conemporary pandemic problem.

  6. #6 Perezoso
    August 19, 2008

    Let me take one thing back:

    I mindlessly mimed the anti-popular press tune. In fact, some of the authors of this study are playing up the H5N1 angle. So it’s not journalists fault that people confuse 1918 and H5N1. 1918 scientists – who are busily proliferating a truly pandemic virus, God forbid an accident – are more than happy to create that confusion themselves.

  7. #7 revere
    August 19, 2008

    Perezoso: OK. We don’t disagree that much. But as a journal editor, one makes decisions about papers based on a variety of concerns, and one of them is scientific interest, and this paper has that. They wouldn’t have gone to all this trouble over 4 years for a virus no one cared about. The 1918 connection is integral to the science here, as it allows them to benchmark the initiation of the memory cells and then demonstrate that they are still around, something that surprised a lot of immunologists. They did a lot of work to close off the possibilities that this was cross reactivity with more recent viruses, something I suspected initially, and they are also able to find vulnerable areas in the antibody binding site that could well be useful for current H1 viruses. They did test it against H3 and H5 and the antibody doesn’t bind and they state this clearly. This is also useful information because it fills in some info on prepandemic vaccines and cross reactivity.

    So while I share your skepticism in general and certainly your opinion about Gerberding (and to a lesser extent) Fauci, I think this paper is pretty interesting science. I approached it with skepticism and was surprised by what I read.

  8. #8 anon
    August 19, 2008

    the virus from 1926-1935 had become different from the 1918-virus,
    so it’s no surprise that those born later didn’t have so good anti-1918-bodies.
    (did they have good anti-1934-bodies ?)

  9. #9 pft
    August 19, 2008

    There were 2 waves to the 1918 pandemic. The flu hit in the spring first, but it was a mild version and not very deadly, and those who got sick then had partial or full immunity to the much deadlier fall version.

    As pointed out earlier in previous posts here, many of the deaths attributed to the 1918 influenza were in fact secondary complications from bacterial pneumonia that could be prevented in the next pandemic by prophylactic use of antibiotics for those who come down with flu like symptoms.

  10. #10 anon
    August 20, 2008

    protection by immunity gained from the first wave
    was not so good. I guesstimate you had a ~30% better
    chance to be spared from the 2nd wave, when you
    were infected in the 1st wave.
    And protection from wave2 to wave3 was even smaller,
    as was protection from wave1 to wave3.
    And then there was a wave4 in 1920 in USA.
    In practice the antibodies didn’t seem to work so well.

  11. #11 phytosleuth
    August 20, 2008

    Prevention against a bacterial pneumonia associated with the next pandemic? And if it is MRSA what antibiotics are left?

  12. #12 RobT
    August 20, 2008

    And what if the next pandemic is H5N1? Are H5N1 victims dying of secondary bacterial lung infections? Not from what I have read. I have read that the post mortems show viremia, heart/kidney/brain damage, as well as massive lung damage. So why all the chatter about the benefit of antibiotics?

    What am I missing here?

  13. #13 biologist
    August 21, 2008

    Great paper!

    To comment on a side thread: Tamiflu (or other NA inhibitors) should also be considered for prophylactic use for preventing secondary bacterial pneumonia. Part of what makes a secondary bacterial infection settle in the lung so cozily is that the flu virus strips sialic acids off everything in the environment; Tamiflu can reduce this. There’s a considerable literature suggesting that Tamiflu could be of benefit for reducing death from bacterial pneumonia secondary to influenza infection. So, not just antibiotics could be of benefit.

  14. #14 The Doctor
    August 23, 2008

    One of the interesting features of the people studied in this paper was the fact that as far as they knew, they never contracted the virus. Obviously they did but the infection was relatively trivial or even asymptomatic. As I recall, 80% of the U.S. population had high antibody titers to N2H2 in 1958 despite the fact the CAR was judged to be only 30%. The same may well have been the case in 1918 given that 100% of those found alive from that time had neutralizing antibody titers.

  15. #15 anon
    August 30, 2009

    can we have the 5 epitopes, please ?
    So we can see which other strains the 1918
    infection protects against