Posted by 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.
August 19, 2008
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