Editors' ChoiceInfluenza

Original antigenic sin strikes again?

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Science Translational Medicine  03 Jun 2015:
Vol. 7, Issue 290, pp. 290ec94
DOI: 10.1126/scitranslmed.aac5092

Human immunity against influenza viruses is complicated, indeed. Although protective antibodies can be readily produced in response to vaccination or infection, it has long been observed that early exposure to a specific influenza strain can prevent optimal antibody responses against variants of that strain that are encountered later in life. This phenomenon, called “original antigenic sin,” is addressed in a recent paper by Huang and colleagues, who studied how early exposure to an H1 subtype influenza virus may decrease immunity against current H1 viruses in adults born before 1982.

The major target of protective antibodies against influenza viruses is the surface hemagglutinin (HA) protein. Flu viruses expressing H1 subtype HAs have been circulating in humans since 1977, with small antigenic changes in the H1 structure occurring each year until a major variant appeared that was similar to the original 1977 H1N1 virus, causing the 2009 flu pandemic. The 2009 pandemic virus continues to circulate as a seasonal influenza strain, but in recent years it has picked up a few amino acid changes in the HA molecule. These changes have not been detected, using standard methods, as causing significant structural change in the H1 protein, and therefore the 2009-like H1 protein remains a component of current seasonal flu vaccines. Concurrent with the amino acid changes, however, more severe disease caused by H1N1 viruses has been observed in middle-aged adults, suggesting a possible causative relationship.

Huang and colleagues explored the antibody specificities elicited by the 2009-like H1 vaccine component in an adult who was likely exposed to the 1977 H1N1 virus as a child. They found that antibodies elicited in their subject by the 2009-like HA protein could neutralize both the 1977 and the 2009 H1N1 viruses but could not neutralize recently circulating H1N1 strains. This observation revealed two interesting points. First, early exposure to the 1977 virus may skew the antibody response against the 2009 H1 protein to a specific region of the HA that has mutated in recent years, so that adults older than ~30 to 35 years old may be at higher risk for infection with current H1N1 viruses (individuals born after ~1982 do not seem to have the same defect in immunity). Second, the current method for detecting relevant antigenic changes in HA proteins may not be optimal since it is not sensitive enough to detect recent changes in H1 structure, which probably do warrant updating of the H1N1 vaccine strain.

The findings by Huang and colleagues suggest that original antigenic sin may have played a role in the increased H1N1 disease in adults in recent years and show that current methods for identifying significant structural changes in HA proteins may not be adequate.

K.-Y. A. Huang et al., Focused antibody response to influenza linked to antigenic drift. J. Clin. Invest.. 10.1172/JCI81104 (2015). [Full Text]

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