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Mice: seasonal flu vaccine and vulnerability to pandemic strain

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Earlier this year, Dutch scientists showed that vaccinating mice against seasonal strains of flu rendered the animals unnecessarily vulnerable to dying if they later encountered a pandemic flu strain. Okay, their mice didn’t really “encounter” pandemic flu: The scientists injected them with a lethal dose of the germs. But mice that had gotten seasonal flu — not avoided it with a vaccination — survived later infection with a pandemic avian-flu virus.

The authors of this rodent study now ask whether there are lessons in their data for parents. Such as whether to ignore recommendations that youngsters get seasonal-flu shots during years when pandemic flu is raging.

In a commentary accompanying this paper in Lancet Infectious Diseases (published online Oct. 30), researchers in Finland conclude the Dutch hypothesis, though interesting, is essentially bunk (although they do use a more academically respectful phrase).

Both sides make a host of interesting — and potentially contradictory — observations. Which would seem to boil down to the simple truth that mice aren’t people, and as such may not always predict effects in people.

At issue is what the researchers refer to as heterosubtypic immunity. The idea: By falling prey to one strain of flu, the body’s immune system can create antibodies and a host of other immune sentinels (such as CD4 T cells, CD8 T cells and B cells) that will be primed to quash a return of that virus — or one that resembles it. When those not-quite-the-same viruses do show up, the immune system may not launch a full-scale assault, but it puts up a good fight. Bottom line: Even if you get sick, you’ll likely recover.

In the Dutch study, mice that got a seasonal flu strain and then later encountered a lethal dose of avian flu virus developed heterosubtypic immunity. They got sick, but only one out of 11 got so sick that the researchers felt a need to put it out of its misery.

Mice vaccinated against the seasonal flu, however, acquired no heterosubtypic protection. When injected with bird flu virus, they lost far more weight than the unvaccinated animals had and more quickly. They also became especially lethargic. Any mouse sick enough to have lost more than a fifth of its body weight was euthenized. Nine of 10 infected animals who had been vaccinated for seasonal flu had to be put down, virologist Guus F. Rimmelzwaan and his colleagues at Erasmus Medical Center in Rotterdam reported in the May PLoS One.

Rimmelzwaan and two of the nine other authors of that paper briefly summarized their animal data in the new Lancet publication and then ruminated on its potential implication: that seasonal flu shots “might be a disadvantage to immunologically naïve people — e.g. infants.”

The Dutch researchers acknowledge that under ordinary circumstances, flu shots are a good thing for babies and youngsters. A very good thing. They save lives.

However, they point out that the idea there might be any immunological drawbacks to seasonal flu shots “has been given little thought.” In fact, they argue that recommending annual flu shots for the very young “should perhaps be re-evaluated” in the context of flu pandemics.

Rimmelzwaan’s team notes that the problem they describe should exist only where vaccinations involved an inactivated virus. Those vaccines that use live-attenuated viruses — which are types not typically administered in the United States and Europe — should provoke heterosubtypic protection. And several other types of new flu vaccines appear to rev up much of the immunological attentiveness normally encountered with an actual flu infection. So they too might pose no risk of pandemic-flu sensitivity.

Terho Heikkinen and Ville Peltola of Turku University Hospital in Finland considered the Dutch team’s arguments and concluded that concern over seasonal flu shots “does not seem warranted.”

For starters, if the Dutch hypothesis held, then pandemic viruses should preferentially hammer the immune systems of babies. But they point out that the 2009 swine-flu pandemic has so far primarily affected adolescents and young adults. Heikkinen and Peltola also cite a Mexican study in press at the British Medical Journal that finds people who had received a seasonal flu shot and later became inflected with the H1N1 virus actually developed a milder case of swine flu.

I probed the issues a little further with Peltola, a pediatric infectious-diseases specialist, when he got home from work today. Although he praised the animal studies by Rimmelzwaan’s group, he sees no evidence for a human corollary. “We don’t see any protection in those children who are not vaccinated against seasonal influenza. They are not protected from pandemic H1N1 swine influenza.”

I fully anticipate the anti-vaccine crowd will jump all over the new Dutch report — even though its authors acknowledge they have no human data to support their concerns. And even though Peltola’s group argues that the opposite may actually be true based on their personal observations of flu-sickened kids and a combing of the biomedical literature.


Bodewes, R., J.H.C.M. Kreijtz, and G.F. Rimmelzwaan. 2009. Yearly Influenza Vaccinations: A Double-Edged Sword? Lancet Infectious Diseases (Oct. 30). DOI: 10.1016/S1473-3099(09)70263-4

Heikkinen, T. and V. Peltola. 2009. Influenza Vaccination of Children. Lancet Infectious Diseases (Oct. 30). DOI: 10.1016/S1473-3099(09)70266-X

Bodewes, R., . . . and G.F. Rimmelzwaan. 2009. Vaccination against Human Influenza A/H3N2 Virus
Prevents the Induction of Heterosubtypic Immunity against Lethal Infection with Avian Influenza A/H5N1 Virus. PLoS One 4(May):e5538. DOI:10.1371/journal.pone.0005538
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