key: cord-0754922-34cfq93y
authors: Hausdorff, William P.; Flores, Jorge
title: Low dose and oral exposure to SARS-CoV-2 may help us understand and prevent severe COVID-19
date: 2020-11-20
journal: Int J Infect Dis
DOI: 10.1016/j.ijid.2020.11.171
sha: 787a99afbe77a954f002f4067e767e90382b3a90
doc_id: 754922
cord_uid: 34cfq93y

Background The effectiveness and sustainability of current public health interventions designed to prevent SARS-2-CoV transmission remain of great concern in many settings, especially in the absence of a transmission-preventing vaccine. Hypothesis We hypothesize that a more targeted set of interventions focusing on preventing severe COVID-19, rather than SARS-2-CoV 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 and influence clinical outcome, immunological protection and likelihood of onward transmission. Proposal We suggest 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.

Where efficiently applied, a broad range of restrictive non-pharmaceutical interventions (NPI) has succeeded in preempting or mitigating explosive outbreaks of COVID-19 hospitalizations and deaths in many settings. Elsewhere, it has proven difficult to fully implement, maintain, or reimpose these interventions. Much of the public reluctance lies in their huge social and economic consequences, exacerbated by the failure of political leaders to convincingly advocate for these measures. We suggest that three other factors contribute:

1. The vast majority of SARS-CoV-2 infections does not result in severe morbidity, much less mortality, and although some individual and population level risk factors have been identified, it's not possible to predict individual outcomes.2. There is limited definitive evidence regarding the effectiveness of individual control measures.

3. There is a perception in some settings that the only way to gauge of effectiveness of NPI (such as face masks) lies in their ability (or not) to prevent transmission of SARS-CoV-2.

To help address these, a carefully designed research program involving human challenge studies might help us refocus our medium-term public health goal and control measures, and potentially guide design of novel immunotherapeutics and vaccines.

We learned early in the pandemic that SARS-CoV-2 transmissibility was much greater and with a longer infectious incubation period than for most other respiratory viral infections, and that all age groups could suffer severe disease. Given its ability to overwhelm hospital capacity and healthcare systems and the success of broadly targeted lockdown efforts in Wuhan, it was logical to focus on elimination of SARS-CoV-2 transmission. While other countries in East Asia controlled transmission with narrowly targeted approaches, each built on historical experience with SARS J o u r n a l P r e -p r o o f and used extensive digital contact tracing abilities that may not be acceptable in many settings (Huang et al 2020) .

We also learned that SARS-CoV-2 infection-fatality rates were approximately 0.3-0.7% (Rajgor et al 2020) . While lower than SARS (10%) and MERS (35%), these are higher than influenza (~0.05%;

Centers for Disease Control and Prevention, 2020a). Of course, average figures mask the wide range of COVID-19 case-fatality rates in different age and risk groups. In a recent Danish population-based survey of SARS-CoV-2 PCR-positive individuals presenting with mild-moderate respiratory symptoms, those with >3 co-morbidities and/or >80-years-old had a case-fatality rate of >17% (Reilev et al 2020) . Such high rates, coupled with the sheer explosiveness of COVID-19 hospitalized cases over a short period of time, merited extraordinary control measures. The same study reported no deaths among the large portion of the population <50-years-old with <1 comorbidity, consistent with a CDC report (Garg et al 2020) indicating that 85-90% of patients hospitalized with COVID-19 possess >1 identifiable comorbidity and population-based seroprevalence studies that 88-98% of SARS-CoV-2 infections require no medical attention Stringhini et al 2020) .

These highlight the desirability of focusing on prevention of severe COVID-19. The main reason is pragmatic: if host or environmental risk factors significantly differ for SARS-2-CoV infection versus severe disease, NPI might be tailored more specifically, efficiently, sustainably and less painfully for society as a whole.

Recalibration of the goal could also help put in context hypothetical or ambiguous statements from scientific studies often translated into alarming newspaper headlines such as "SARS-CoV-2 J o u r n a l P r e -p r o o f could be spread in sea air" (Robbins G 2020) or by "the distant windborne spread of the virus wafting from untreated sewage" (Fang et al 2020) , "virus is detectable on surfaces for hours,"

(Van Doremalen et al 2020) and "no evidence people can't be re-infected." (World Health Organization 2020). These are reminiscent of the 19 th century theory attributing communicable diseases to insidious, virtually inescapable miasma. The reframed, potentially more reassuring question would become, "What is the evidence that any of these are likely to lead to severe disease?"

The goal of better targeting interventions is aspirational, based on answering some basic research questions including:

Within the CDC study 10-15% of putatively "low-risk" individuals contracted severe disease 4 , raising questions as to whether any group is intrinsically at low-risk. Most striking were deaths of young Chinese medical personnel in the Wuhan outbreak, yet at least some were apparently associated with deep inhalation of high doses of SARS-CoV-2 while performing intubations (Penn et al 2020). High attack rates of severe COVID-19 in prisons and retirement homes may also be attributable to higher viral dose exposures. Research on behavioral or environmental risk factors of severe disease cases in otherwise low-risk populations could strengthen the case that the vast majority of individuals within some populations is indeed biologically low-risk.

Separate studies with mouse-adapted MERS-CoV (Li et al 2017) and SARS-CoV (Roberts 2007) assessed disease severity across dose ranges spanning 3 and 6 logs (respectively) of viral titers.

While the highest dose levels proved uniformly lethal, the lowest 1 and 2-3 dose levels, respectively, were still infectious but didn't result in mortality or significant weight loss.

Similarly, recent studies with SARS-CoV-2 in the Syrian hamster model suggested that low infectious doses eventually leading to replication to high titers in the respiratory tract nonetheless resulted in reduced disease severity compared to higher doses (Imai et al 2020; Lee et al 2020) . Intriguingly, the use of facial masking material between hamster cages resulted not only in less frequent transmission, but those that were infected had much more mild disease (Chan et al 2020) .

In a controlled human infection model (CHIM) testing doses of H1N1 influenza (Memoli et al 2015) over five log TCID50 titers, clinical symptoms were much more prevalent at the highest two doses. Severity of illness and median days of symptoms were positively associated with dose titer. Abnormal pulmonary CT scans were apparent only at the highest 2 doses. Another CHIM examining doses of H3N2 influenza over four log TCID50 titers noted that only the highest 2 doses elicited mild-moderate influenza (Han et al 2019) . In addition, intriguing observations correlating extensive mask wearing with lower COVID case-fatality rates in different populations support the hypothesis that besides reducing the risk of transmission of SARS-CoV-2, mask wearing may also decrease the severity of COVID in those who are infected by reducing the infectious dose (Gandhi et al 2020) .

Adenoviruses 4 and 7 cause pneumonia when infection occurs via the airways, but not when acquired through the gastrointestinal tract despite replicating efficiently. This behavior is the J o u r n a l P r e -p r o o f 8 basis for licensed wild type-based adenovirus vaccines, of proven high level of safety and efficacy when orally administered (Couch et al 1963) . Diarrhea and SARS-CoV-2 shedding are frequently reported to precede other COVID-19 symptoms, and though the virus can be detected in stools by PCR in half of patients, the incidence of GI symptoms is limited (Mao et al 2020) . Might these findings and the common detection of SARS-CoV-2 in stool in the absence of symptoms reflect oral ingestion? Could oral ingestion, and/or low exposure doses, account at least partly for the wide prevalence of asymptomatic infections?

In the Syrian hamster model, oral inoculation with what would be a high intranasal dose of SARS-CoV-2 could establish a subclinical respiratory infection in only a subset of animals. These animals showed no weight loss and exhibited decreased lung histopathology scores and viral loads compared to animals who had been intranasally infected with a dose 1000 -fold lower (Lee et al 2020).

Understanding the relationship between infectious dose, the resultant viral titer, and clinical outcome could allow quantitative differences in PCR diagnostic results to be meaningfully interpreted (Mandavilli A 2020) . The shedding parameters are presumably major determinants of the probability of further transmission, and perhaps of its clinical consequences.

J o u r n a l P r e -p r o o f Mild and severe COVID are accompanied by sometimes marked differences in various aspects of the innate and adaptive immune responses, and it has been postulated that the dose of the initial viral inoculum can partly explain these differences (Van Damme et al 2020). However, we are not aware of any direct evidence that this is the case.

One study conducted 30 years ago examined whether mild and asymptomatic infections with common cold coronaviruses affected the clinical severity of a subsequent infection with the same virus. This study utilized a CHIM model with coronavirus 229E and concluded that reinfection with the same virus resulted in milder disease (Callow et al 1990) .

SARS-CoV-2 infection can protect non-human primates against disease, though not reinfection, upon rechallenge. However, rhesus monkeys only exhibit mild disease even upon exposure to extremely high titer challenges (Chandrashekar et al 2020) , and thus represent an imperfect model to study disease attenuation. At present, the nature and extent of protection provided by previous infection in humans is currently unknown and it is unlikely that a longitudinal observational study, given uncertainties about the dose and nature of the original and subsequent infectious exposures, can determine whether exposure to single or multiple low doses, or by oral ingestion, protects against symptomatic disease. It is promising, however, that an observational study (Sagar et al 2020) suggested an association between recent cold coronavirus infection and less severe COVID-19.

We propose CHIM studies that would involve young adult volunteers selected for the absence of identifiable co-morbidities and pre-screened for genetic markers associated with severe disease J o u r n a l P r e -p r o o f such as those involving the type 1 interferon pathway . These volunteers would be exposed to low doses of SARS-CoV-2 through nasal instillation or oral ingestion in a closely monitored environment with surveillance duration taking into consideration that COVID-19 can result in prolonged illness even among persons with milder outpatient illness (Tenforde et al 2020) . In the initial phase, only subjects previously naturally infected would be challenged. The clinical endpoint of such studies would be induction of asymptomatic or mild disease. Detailed discussion and quantitation of those risks, and how they compare to risks in other CHIM studies or other societal risks, have been extensively detailed by a WHO Advisory Group (Levine et al., 2020) and others (Eyal et al., 2020; Deming et al., 2020; Plotkin et al 2020) with no need to recapitulate them here.

In contrast, the potential public health benefit from these studies proposed here differ as they would not be predicated on shortening vaccine development timelines. Instead, the proposed studies could provide a stronger evidence base to allow de-emphasis of NPI not likely to decrease severe disease, and conversely allow more streamlined public health messaging around those that are. If low doses or alternate ROI protection protect against severe disease without providing sterilizing immunity, identification of immune correlates could guide the development of vaccines or immunotherapeutics specifically aimed at preventing severe disease.

J o u r n a l P r e -p r o o f Importantly, direct benefit to patient volunteers may accrue if low dose and/or oral administration provides immunity against more severe disease. We note that some of the analyses described here might actually be incorporated into the development stages of a CHIM whose primary goal is to expedite vaccine development, as sequential dose-ranging studies will be necessary to establish a consistently infectious dose (Levine et al., 2020) .

A major limitation is the generalizability of conclusions observed in lower-risk younger subjects to higher-risk populations. Ideally, CHIM participants would progressively include somewhat "riskier" cohorts as confidence grows in the safety of the low dose and/or oral administration regime, and as adequate therapies are identified. In addition, the numbers of subjects needed to provide definitive conclusions may require innovative study designs to be feasible. It may be questioned whether CHIM studies, which induce mild disease, are sufficiently predictive of what would happen with severe cases, a general criticism of all challenge models.

We suggest that acceptance of a refined public health goal focused on clinically severe disease, informed by results from carefully designed observational and CHIM studies addressing the roles of dose and ROI, could allow the elaboration of more targeted and sustainable, or at least more scientific justifiable, disease control measures (Table) .

J o u r n a l P r e -p r o o f 

SARS-CoV-2-reactive T cells in healthy donors and patients with COVID-19

The time course of the immune response to experimental coronavirus infection of man

Centers for Disease Control and Prevention. Estimated Influenza Illnesses, Medical visits, Hospitalizations, and Deaths in the United States -2019-2020 Influenza Season

Centers for Disease Control and Prevention. Coronavirus Disease (COVID-19): Cleaning and Disinfecting your Facility

Surgical mask partition reduces the risk of non-contact transmission in a golden Syrian hamster model for Coronavirus Disease 2019 (COVID-19)

SARS-CoV-2 infection protects against rechallenge in rhesus macaques

Immunization with types 4 and 7 adenovirus by selective infection of the intestinal tract

Accelerating development of SARS-CoV-2 vaccines-the role for controlled human infection models

COVID-19 -Lessons Learned and Questions Remaining

COVID-19 -ANSES's recommendations on food

Facial Masking for Covid-19 -Potential for "Variolation" as We Await a Vaccine

Hospitalization Rates and Characteristics of Patients Hospitalized with Laboratory-Confirmed Coronavirus Disease 2019 -COVID-NET, 14 States

A Dose-finding Study of a Wild-type Influenza A(H3N2) Virus in a Healthy Volunteer Human Challenge Model

How Digital Contact Tracing Slowed Covid-19 in East Asia

Syrian hamsters as a small animal model for SARS-CoV-2 infection and countermeasure development

Subclinical Respiratory Infection with Virus Shedding in Golden Syrian Hamsters

Viewpoint of a WHO Advisory Group Tasked to Consider Establishing a Closely-Monitored Challenge Model of COVID-19 in Healthy Volunteers

Mouse-adapted MERS coronavirus causes lethal lung disease in human DPP4 knockin mice

Your coronavirus test is positive. Maybe it shouldn't be. NY Times

Manifestations and prognosis of gastrointestinal and liver involvement in patients with COVID-19: a systematic review and meta-analysis

Validation of the Wildtype Influenza A Human Challenge Model H1N1pdMIST: An A(H1N1)pdm09 Dose-Finding Investigational New Drug Study

Measuring the Risk Among Clinicians Who Intubate Patients with COVID-19

Extraordinary diseases require extraordinary solutions

The many estimates of the COVID-19

Characteristics and predictors of hospitalization and death in the first 11 122 cases with a positive RT-PCR test for

SARS-CoV-2 in Denmark: a nationwide cohort

A Mouse-Adapted SARS-Coronavirus Causes Disease and Mortality in BALB/c Mice

UC San Diego virus expert pleads with surfers to stay out of the ocean to avoid coronavirus

Recent endemic coronavirus infection is associated with less severe COVID-19

SEROCoV-POP): a population-based study

Symptom Duration and Risk Factors for Delayed Return to Usual Health Among Outpatients with COVID-19 in a Multistate Health Care Systems Network -United States

Seroprevalence of SARS-CoV-2 in

Hong Kong and in residents evacuated from Hubei province, China: a multicohort study

COVID-19: Does the infectious inoculum dose-response relationship contribute to understanding heterogeneity in disease severity and transmission dynamics?

Aerosol and Surface Stability of SARS-CoV-2 as Compared with SARS-CoV-1

World Health Organization

Inborn errors of type I IFN immunity in patients with life-threatening COVID-19

We thank Dr. Montse Soriano-Gabarro for helpful critical comments on an earlier version of the manuscript.

The authors declare no competing interests.

Both authors contributed equally to this work. The views expressed in this article are those of the authors, and do not necessarily reflect those of PATH or Université de Bruxelles Funding Source:No funding supported this work.Ethical Approval:No ethical approval was sought or required for this perspective article.

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

We thank Dr. Montse Soriano-Gabarro for helpful critical comments on an earlier version of the manuscript.

The authors declare no competing interests.

William Hausdorff and Jorge Flores have equally contributed to all aspects of manuscript design, development, and writing. The views expressed in this article are those of the authors, and do not necessarily reflect those of PATH or Université de Bruxelles Funding Source:There was no funding source specifically for this study and article development.Ethical Approval:Approval was not required for this perspective article as no original study was conducted.