title: Does Glycosylation as a modifier of Original Antigenic Sin explain the case age distribution and unusual toxicity in pandemic novel H1N1 influenza?
abstract: BACKGROUND
  A pandemic novel H1N1 swine-origin influenza virus has emerged. Most recently the World Health Organization has announced that in a country-dependent fashion, up to 15% of cases may require hospitalization, often including respiratory support. It is now clear that healthy children and young adults are disproportionately affected, most unusually among those with severe respiratory disease without underlying conditions. One possible explanation for this case age distribution is the doctrine of Original Antigenic Sin, i.e., novel H1N1 may be antigenically similar to H1N1 viruses that circulated at an earlier time. Persons whose first exposure to influenza viruses was to such similar viruses would be relatively immune. However, this principle is not sufficient to explain the graded susceptibility between ages 20 and 60, the reduced susceptibility in children below age 10, and the unusual toxicity observed.
  
  
  METHODS
  We collected case data from 11 countries, about 60% of all cases reported through mid-July 2009. We compared sequence data for the hemagglutinin of novel H1N1 with sequences of H1N1 viruses from 1918 to the present. We searched for sequence differences that imply loss of antigenicity either directly through amino acid substitution or by the appearance of sites for potential glycosylation proximal to sites known to be antigenic in humans. We also considered T-cell epitopes.
  
  
  RESULTS
  In our composite, over 75% of confirmed cases of novel H1N1 occurred in persons < or = 30 years old, with peak incidence in the age range 10-19 years. Less than 3% of cases occurred in persons over 65, with a gradation in incidence between ages 20 and 60 years.The sequence data indicates that novel H1N1 is most similar to H1N1 viruses that circulated before 1943. Novel H1N1 lacks glycosylation sites on the globular head of hemagglutinin (HA1) near antigenic regions, a pattern shared with the 1918 pandemic strain and H1N1 viruses that circulated until the early 1940s. Later H1N1 viruses progressively added new glycosylation sites likely to shield antigenic epitopes, while T-cell epitopes were relatively unchanged.
  
  
  CONCLUSIONS
  In this evolutionary context, Original Antigenic Sin exposure should produce an immune response increasingly mismatched to novel H1N1 in progressively younger persons. We suggest that it is this mismatch that produces both the gradation in susceptibility and the unusual toxicity. Several murine studies suggest specific cell types as a likely basis of the unusual toxicity. These studies also point to widely available pharmaceutical agents as plausible candidates for mitigating the toxic effects. The principle of Original Antigenic Sin modified by glycosylation appears to explain both the case age distribution and the unusual toxicity pattern of the novel H1N1 pandemic. In addition, it suggests pharmaceutical agents for immediate investigation for mitigation potential, and provides strategic guidance for the distribution of pandemic mitigation resources of all types.
authors.affiliation: Entropy Research Institute, 345 S, Great Road, Lincoln, Massachusetts 01773, USA. treichert@entropylimited.com
authors.forename: Tom
authors.initials: T
authors.lastname: Reichert
authors.forename: Gerardo
authors.initials: G
authors.lastname: Chowell
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Nishiura
authors.forename: Ronald A
authors.initials: RA
authors.lastname: Christensen
authors.forename: Jonathan A
authors.initials: JA
authors.lastname: McCullers
mesh_terms: D000293:Adolescent; D000328:Adult; D017677:Age Distribution; D000956:Antigens, Viral / Q000235:genetics* / Q000276:immunology; D002648:Child; D004196:Disease Outbreaks; D019143:Evolution, Molecular; D006031:Glycosylation; D019267:Hemagglutinin Glycoproteins, Influenza Virus / Q000235:genetics* / Q000276:immunology; D006801:Humans; D053118:Influenza A Virus, H1N1 Subtype / Q000235:genetics* / Q000276:immunology; D007251:Influenza, Human / Q000453:epidemiology*; D008875:Middle Aged; D012367:RNA, Viral / Q000235:genetics; D017423:Sequence Analysis, RNA; D055815:Young Adult
chemical_list: D000956:Antigens, Viral; D019267:Hemagglutinin Glycoproteins, Influenza Virus; D012367:RNA, Viral