Heterogeneity in susceptibility among humans to common respiratory viral infections

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Abstract
Background: Human challenge trials provide a unique opportunity to quantify pathogen infectivity in terms of the probability of infection given an inoculated dose. However, between-pathogen comparisons are often distorted by individual heterogeneity in host susceptibility and by differences in background immunity across trial populations. We examined how dose–dependent infection risks differ across common respiratory viruses when such heterogeneity is explicitly incorporated. Methods: We conducted a systematic review of human challenge trials for four respiratory viruses: respiratory syncytial virus (RSV), influenza virus, rhinovirus, and adenovirus. Using the extracted data, we fitted dose–response models under different distributional assumptions, allowing both continuous susceptibility variation and discrete immune fractions. We compared alternative heterogeneity models and evaluated pathogen-specific dose–response patterns using original and scaled dose metrics. Results: All four viruses showed substantial heterogeneity in host susceptibility, and models assuming homogeneous susceptibility were unsupported. RSV and influenza were best described by models with a distinct immune or effectively non-susceptible subgroup, and the estimated immune proportions were approximately 40% and 25%, respectively. In contrast, rhinovirus and adenovirus were better explained by continuously distributed susceptibility, with little evidence of a fully immune subgroup. On a scaled dose axis, rhinovirus and adenovirus showed steeper increases in infection risk with dose than RSV and influenza. Conclusions: The structure of susceptibility heterogeneity differs across common respiratory viruses, which in turn shapes dose–dependent infection risks. Incorporating this heterogeneity is essential for valid cross-pathogen comparison and for interpreting human challenge data in epidemiologic and public health contexts. Summary: We systematically reviewed human challenge trials and analyzed the extracted data using dose–response models for four respiratory viruses. The analyses revealed between-pathogen differences in dose–dependent infection risks and highlighted substantial heterogeneity in host susceptibility, even under controlled exposure conditions.
Funding Information
  • Japan Science and Technology Agency (JST) PRESTO programme (JPMJPR23RA)

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