Testing SARS-CoV-2 vaccine efficacy through deliberate natural viral exposure

Clin Microbiol Infect. 2021 Mar;27(3):372-377. doi: 10.1016/j.cmi.2020.12.032. Epub 2021 Jan 6.


Background: A vaccine trial with a conventional challenge design can be very fast once it starts, but it requires a long prior process, in part to grow and standardize challenge virus in the laboratory. This detracts somewhat from its overall promise for accelerated efficacy testing of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccine candidates, and from the ability of developing countries and small companies to conduct it.

Aims: We set out to identify a challenge design that avoids this part of the long prior process.

Sources: Literature in trial design (including a proof of concept flu challenge trial by B. Killingley et al.), vaccinology, medical ethics, and various aspects of COVID response.

Content: A challenge design with deliberate natural viral exposure avoids the need to grow culture. This new design is described and compared both to a conventional challenge design and to a conventional phase III field trial. In comparison, the proposed design has ethical, scientific, and feasibility strengths.

Implications: The proposed new design should be considered for future vaccine trials.

Keywords: Coronavirus; Ethics; Human challenge studies; Randomized controlled trials; Research design; Vaccines.

Publication types

  • Review

MeSH terms

  • COVID-19 / immunology
  • COVID-19 / prevention & control*
  • COVID-19 / transmission
  • COVID-19 Vaccines / administration & dosage*
  • COVID-19 Vaccines / adverse effects
  • COVID-19 Vaccines / immunology
  • Clinical Trials as Topic* / ethics
  • Humans
  • Research Design
  • SARS-CoV-2 / immunology*
  • SARS-CoV-2 / isolation & purification
  • Safety
  • Time Factors


  • COVID-19 Vaccines