Low-dose and oral exposure to SARS-CoV-2 may help us understand and prevent severe COVID-19

Abstract

Background: The effectiveness and sustainability of current public health interventions designed to prevent severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) transmission remain of great concern in many settings, especially in the absence of a transmission-preventing vaccine. Hypothesis: It was hypothesized that a more targeted set of interventions focusing on preventing severe coronavirus disease 2019 (COVID-19), rather than SARS-CoV-2 transmission, would be less disruptive to society. To identify these, it would be helpful to better understand how the infecting dose of SARS-CoV-2 and its route of infection influence the clinical outcome, immunological protection, and likelihood of onward transmission. Proposal: It is suggested that carefully controlled human infection model (CHIM) studies involving intranasal and oral administration of progressively increasing doses of SARS-CoV-2, starting with low levels, to healthy young adult volunteers may be the most expeditious and definitive way to answer these questions. Such studies would differ in objective from CHIM proposals designed to expedite vaccine development, although the latter might be adapted to address some of the questions raised here. Implications: Results from the studies proposed here could help elucidate the relationship of infection to COVID-19 and thereby provide a scientific basis for more targeted and sustainable application of public health control measures, and inform the design of improved immunotherapeutics and more targeted vaccine development.

Repeated Exposure to Subinfectious Doses of SARS-CoV-2 May Promote T Cell Immunity and Protection against Severe COVID-19

“…Nevertheless, some studies have explored low dose challenge with SARS-CoV-2, using nebulized virus, or co-housing of infected and uninfected animals [ 27 , 28 , 29 , 30 ]. Interestingly, human challenge models of SARS-CoV-2 infection have also been proposed [ 31 , 32 , 33 ]. A fieldwork in humans supporting the statement that low SARS-CoV-2 doses induce less severe disease manifestations as compared to high doses is provided by studies performed on front-line healthcare workers.…”

“…In this case the uptake of small virus amounts may occur in the gut, where epithelial cells express ACE2 and can be efficiently infected by SARS-CoV-2 [ 48 ]. SARS-CoV-2 exposure in the gastrointestinal tract has been previously shown to be less pathogenic as compared to the respiratory tract [ 49 ] and has been proposed to contribute to COVID-19 asymptomatic infections [ 32 ]. A factor that may crucially influence the generation of protective immunity upon low antigenic stimulation may be represented by the repeated contacts of the immune system with the pathogen, according to the principle of recall widely exploited in vaccination schedules.…”

Hausdorff and Flores Author Reply to Letter to the Editor by Prof G. Bauer (THEIJID-D-21-00652)

“…While we found this letter to be interesting and share the belief that widespread vaccination is ultimately the best way to stop the present pandemic, we are a bit puzzled as to the relevance of these findings to our article ( Hausdorff and Flores, 2021 ). We had highlighted the importance of having as the primary public health goal the prevention of serious COVID disease, as opposed to prevention of every SARS-CoV-2 infection.…”

Prioritizing second-generation SARS-CoV-2 vaccines through low-dosage challenge studies

“…Others have recently explored different potential scientific applications of low-dosage challenge studies to COVID-19, for a host of non-vaccine-related uses (Hausdorff and Flores, 2021). We explore the advantages and potential disadvantages of low-dosage challenge over conventional challenge designs in the particular role of developing second-generation vaccines: as an initial efficient test of experimental vaccine efficacy that determines which candidates proceed to standard phase 3 testing (herein, 'field trials') (Jamrozik and Selgelid, 2020;Douglas and Hill, 2020;Levine et al, 2020).…”

“…This limitation may seem to be accentuated in low-dosage challenge studies, which go to even greater lengths to prevent severe disease in the cohort. However, this limitation does not affect the usage of challenge studies to assess impact on infection rather than severe disease (as discussed above) and some other uses (Hausdorff and Flores, 2021).…”