Seroconversion and fever are dose-dependent in a nonhuman primate model of inhalational COVID-19

PLoS Pathog. 2021 Aug 23;17(8):e1009865. doi: 10.1371/journal.ppat.1009865. eCollection 2021 Aug.


While evidence exists supporting the potential for aerosol transmission of SARS-CoV-2, the infectious dose by inhalation remains unknown. In the present study, the probability of infection following inhalation of SARS-CoV-2 was dose-dependent in a nonhuman primate model of inhalational COVID-19. The median infectious dose, assessed by seroconversion, was 52 TCID50 (95% CI: 23-363 TCID50), and was significantly lower than the median dose for fever (256 TCID50, 95% CI: 102-603 TCID50), resulting in a group of animals that developed an immune response post-exposure but did not develop fever or other clinical signs of infection. In a subset of these animals, virus was detected in nasopharyngeal and/or oropharyngeal swabs, suggesting that infected animals without signs of disease are able to shed virus and may be infectious, which is consistent with reports of asymptomatic spread in human cases of COVID-19. These results suggest that differences in exposure dose may be a factor influencing disease presentation in humans, and reinforce the importance of public health measures that limit exposure dose, such as social distancing, masking, and increased ventilation. The dose-response data provided by this study are important to inform disease transmission and hazard modeling, and, ultimately, mitigation strategies. Additionally, these data will be useful to inform dose selection in future studies examining the efficacy of therapeutics and vaccines against inhalational COVID-19, and as a baseline in healthy, young adult animals for assessment of the importance of other factors, such as age, comorbidities, and viral variant, on the infectious dose and disease presentation.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • COVID-19 / transmission*
  • COVID-19 / virology*
  • Chlorocebus aethiops
  • Disease Models, Animal
  • Female
  • Fever / virology
  • Inhalation Exposure
  • Macaca fascicularis*
  • Male
  • Seroconversion*
  • Vero Cells
  • Viral Load

Grant support

Work performed by Battelle National Biodefense Institute (PAD, JB, KB, JAB, BG, GW, JY, JKB, BH, DM, ALR, DF, SM, TJ, SR, JM, DC, EM, AP, KR, TS, MW, LAA, HZ, ASH, VW, MH) and Censeo Insight (AH) was funded by the National Institute of Allergy and Infectious Disease (NIAID) under Interagency Agreement (IAA) #20056-001 between NIAID and the U.S. Department of Homeland Security Science and Technology Directorate (DHS S&T). Work was performed at the National Biodefense Analysis and Countermeasures Center (NBACC), a Federally Funded Research and Development Center. Funding from NIAID was provided through DHS S&T under Agreement No. HSHQDC-15-C-00064 awarded to Battelle National Biodefense Institute by DHS S&T for the management and operation of the NBACC. The views and conclusions contained in this document are those of the authors and should not be interpreted as necessarily representing the official policies, either expressed or implied, of DHS, the National Institutes of Health (NIH), or the U.S. Government. The DHS does not endorse any products or commercial services mentioned in this presentation. In no event shall the DHS, BNBI or NBACC have any responsibility or liability for any use, misuse, inability to use, or reliance upon the information contained herein. In addition, no warranty of fitness for a particular purpose, merchantability, accuracy or adequacy is provided regarding the contents of this document. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Work performed by Applied Research Associates, Inc. (JR and OP) and Gryphon Scientific LLC (JSS) was funded by the US Defense Threat Reduction Agency under contract number HDTRA1-19-C-0022.