Sex Differences in Influenza: The Challenge Study Experience

J Infect Dis. 2022 Feb 15;225(4):715-722. doi: 10.1093/infdis/jiab422.


Background: Preclinical animal studies and retrospective human studies suggest that adult females have worse outcomes from influenza than males. Prospective studies in humans are missing.

Methods: Data from 164 healthy volunteers who underwent influenza A/California/04/2009/H1N1 challenge were compiled to compare differences between sexes. Baseline characteristics, including hormone levels, hemagglutination inhibition (HAI) titers, neuraminidase inhibition (NAI) titers, and outcomes after challenge were compared. Linear and logistic regression models were built to determine significant predictor variables with respect to outcomes of interest.

Results: HAI titers were similar between the sexes, but NAI titers were higher in males than females at 4 weeks and 8 weeks postchallenge. Females were more likely to have symptoms (mean, 0.96 vs 0.80; P = .003) and to have a higher number of symptoms (median, 3 vs 4; P = .011) than males. Linear and logistic regression models showed that prechallenge NAI titers, but not HAI titers or sex hormone levels, were predictive of all shedding and symptom outcomes of interest.

Conclusions: Females in our cohorts were more likely to be symptomatic and to have a higher number of symptoms than males. NAI titers predicted all outcomes of interest and may explain differential outcomes between the sexes.

Keywords: estrogen; hemagglutinin; influenza; neuraminidase; sex differences; testosterone.

Publication types

  • Research Support, N.I.H., Intramural

MeSH terms

  • Animals
  • Antibodies, Viral
  • Female
  • Hemagglutination Inhibition Tests
  • Humans
  • Influenza A Virus, H1N1 Subtype*
  • Influenza Vaccines*
  • Influenza, Human* / epidemiology
  • Male
  • Neuraminidase
  • Prospective Studies
  • Retrospective Studies
  • Sex Characteristics


  • Antibodies, Viral
  • Influenza Vaccines
  • Neuraminidase