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

Open AccessPublished:November 20, 2020DOI:https://doi.org/10.1016/j.ijid.2020.11.171

      Highlights

      • The prevention of severe coronavirus disease 2019 (COVID-19) should be the main aim of public health efforts.
      • Low-dose or oral severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) may lead to asymptomatic or mild disease and immunize.
      • Some non-pharmaceutical interventions may mainly prevent low-dose or oral exposure.
      • Controlled SARS-CoV-2 human challenge studies could directly test this hypothesis.
      • Such studies could inform the design of targeted immunotherapeutics and vaccines.

      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.

      Keywords

      Where efficiently applied, a broad range of restrictive non-pharmaceutical interventions (NPI) has succeeded in preempting or mitigating explosive outbreaks of coronavirus disease 2019 (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 severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections does not result in severe morbidity, much less mortality. Although some individual- and population-level risk factors have been identified, it is not possible to predict individual outcomes.
      • 2
        Definitive evidence regarding the effectiveness of individual control measures is lacking.
      • 3
        There is a perception in some settings that the only way to gauge the effectiveness of NPI (such as face-masks) lies in their ability (or not) to prevent the transmission of SARS-CoV-2, rather than in their ability to prevent severe disease.
      To help address these, a carefully designed research program involving human challenge studies might help us refocus our medium-term public health goals and control measures, and guide the 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 COVID-19's ability to overwhelm hospital capacity and healthcare systems and the success of broadly targeted lockdown efforts in Wuhan, it was logical to initially focus on the elimination of SARS-CoV-2 transmission. While other countries in East Asia controlled transmission with narrowly targeted approaches, each built on historical experience with severe acute respiratory syndrome (SARS) and used extensive digital contact-tracing abilities that may not be acceptable in many settings (
      • Huang Y.
      • Sun M.
      • Sui Y.
      How Digital Contact Tracing Slowed Covid-19 in East Asia.
      ).
      We also learned that SARS-CoV-2 infection fatality rates were approximately 0.3–0.7% (
      • Rajgor D.D.
      • Lee M.H.
      • Archuleta S.
      • Bagdasarian N.
      • Quek S.C.
      The many estimates of the COVID-19 case fatality rate.
      ). While lower than SARS (10%) and Middle East respiratory syndrome (MERS) (35%), these are higher than influenza (∼0.05%;
      • Centers for Disease Control and Prevention
      Estimated influenza illnesses, medical visits, hospitalizations, and deaths in the United States — 2019–2020 influenza season.
      ). 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 to moderate respiratory symptoms, those with ≥3 co-morbidities and/or older than 80 years of age had a case-fatality rate of ≥17% (
      • Reilev M.
      • Kristensen K.B.
      • Pottegård A.
      • Lund L.C.
      • Hallas J.
      • Ernst M.T.
      • et al.
      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.
      ). 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 co-morbidity. This is consistent with a Centers for Disease Control and Prevention (CDC) report (
      • Garg S.
      • Kim L.
      • Whitaker M.
      • O’Halloran A.
      • Cummings C.
      • Holstein R.
      • et al.
      Hospitalization Rates and Characteristics of Patients Hospitalized with Laboratory-Confirmed Coronavirus Disease 2019 — COVID-NET, 14 States, March 1–30, (2020).
      ) indicating that 85–90% of patients hospitalized with COVID-19 possess one or more identifiable comorbidity, and also with population-based seroprevalence studies reporting that 88–98% of SARS-CoV-2 infections require no medical attention (
      • To K.K.W.
      • Cheng V.C.C.
      • Cai J.P.
      • Chan K.H.
      • Chen L.L.
      • Wong L.H.
      • et al.
      Seroprevalence of SARS-CoV-2 in Hong Kong and in residents evacuated from Hubei province, China: a multicohort study.
      ,
      • Stringhini S.
      • Wisniak A.
      • Piumatti G.
      • Azman A.S.
      • Lauer S.A.
      • Baysson H.
      • et al.
      Seroprevalence of anti-SARS-CoV-2 IgG antibodies in Geneva, Switzerland (SEROCoV-POP): a population-based study.
      ).
      These observations highlight the desirability of focusing on the prevention of severe COVID-19. The main reason is pragmatic: if host or environmental risk factors significantly differ for SARS-CoV-2 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. These are not infrequently translated into alarming newspaper headlines such as “SARS-CoV-2 could be spread in sea air” (
      • Robbins G.
      UC San Diego virus expert pleads with surfers to stay out of the ocean to avoid coronavirus.
      ) or by “the distant windborne spread of the virus wafting from untreated sewage” (
      • Fang F.C.
      • Benson C.A.
      • Del Rio C.
      • Edwards K.M.
      • Fowler Jr., V.G.
      • Fredricks D.N.
      • et al.
      COVID-19 - Lessons Learned and Questions Remaining.
      ), “virus is detectable on surfaces for hours” (
      • Van Doremalen N.
      • Bushmaker T.
      • Morris D.H.
      • Holbrook M.G.
      • Gamble A.
      • Williamson B.N.
      • et al.
      Aerosol and Surface Stability of SARS-CoV-2 as Compared with SARS-CoV-1.
      ), and “no evidence people can’t be re-infected” (). These are reminiscent of the 19th 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, and would be facilitated by answering some basic research questions as outlined below.

      Can we identify biologically low-risk populations?

      Within the CDC study, 10–15% of putatively ‘low-risk’ individuals contracted severe disease (
      • Garg S.
      • Kim L.
      • Whitaker M.
      • O’Halloran A.
      • Cummings C.
      • Holstein R.
      • et al.
      Hospitalization Rates and Characteristics of Patients Hospitalized with Laboratory-Confirmed Coronavirus Disease 2019 — COVID-NET, 14 States, March 1–30, (2020).
      ), 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 (). 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.

      Is the infectious dose an important determinant of COVID-19 severity?

      Separate studies with mouse-adapted MERS coronavirus (
      • Li K.
      • Wohlford-Lenane C.L.
      • Channappanavar R.
      • Park J.-E.
      • Earnest J.T.
      • Bair T.B.
      • et al.
      Mouse-adapted MERS coronavirus causes lethal lung disease in human DPP4 knockin mice.
      ) and SARS coronavirus (
      • Roberts A.
      • Deming D.
      • Paddock C.D.
      • Cheng A.
      • Yount B.
      • Vogel L.
      • et al.
      A mouse-adapted SARS-coronavirus causes disease and mortality in BALB/c Mice.
      ) assessed disease severity across dose ranges spanning 103 and 106 the 50% tissue culture infectious dose (TCID50), respectively. While the highest dose levels proved uniformly lethal, the lowest 1 and 2–3 dose levels, respectively, were still infectious but did not result in mortality or significant weight loss.
      Similarly, recent studies with SARS-CoV-2 in the Syrian hamster model suggested that low infectious doses, despite eventually leading to replication to high titers in the respiratory tract, nonetheless resulted in reduced disease severity compared to higher doses (
      • Imai M.
      • Iwatsuki-Horimoto K.
      • Hatta M.
      • et al.
      Syrian hamsters as a small animal model for SARS-CoV-2 infection and countermeasure development.
      ,
      • Lee A.C.
      • Zhang A.J.
      • Chan J.F.
      • Li C.
      • Fan Z.
      • Liu F.
      • et al.
      Oral SARS-CoV-2 inoculation establishes subclinical respiratory infection with virus shedding in Golden Syrian Hamsters.
      ). 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 J.F.
      • Yuan S.
      • Zhang A.J.
      • Poon V.K.
      • Chan C.C.
      • Lee A.C.
      • et al.
      Surgical mask partition reduces the risk of non-contact transmission in a golden Syrian hamster model for Coronavirus Disease 2019 (COVID-19).
      ).
      In a controlled human infection model (CHIM) testing doses of H1N1 influenza virus (
      • Memoli M.J.
      • Czajkowski L.
      • Reed S.
      • Athota R.
      • Bristol T.
      • Proudfoot K.
      • et al.
      Validation of the wild-type influenza a human challenge model H1N1pdMIST: an A (H1N1)pdm09 Dose-Finding Investigational New Drug Study.
      ) over a 105-fold range of TCID50 titers, clinical symptoms in those that were infected were much more prevalent at the highest two doses. The severity of illness and median days of symptoms were positively associated with dose titer. Abnormal pulmonary computed tomography scans were apparent only at the highest two doses. Another CHIM examining doses of H3N2 influenza virus over a 104-fold range of TCID50 titers noted that only the highest two doses elicited mild to moderate influenza (
      • Han A.
      • Czajkowski L.M.
      • Donaldson A.
      • Baus H.A.
      • Reed S.M.
      • Athota R.S.
      • et al.
      A Dose-finding Study of a Wild-type Influenza A(H3N2) Virus in a Healthy Volunteer Human Challenge Model.
      ). In addition, intriguing observations correlating extensive mask wearing with lower COVID-19 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-19 in those who are infected by reducing the infectious dose (
      • Gandhi M.
      • Rutherford G.W.
      Facial Masking for Covid-19 - Potential for “Variolation” as We Await a Vaccine.
      ).

      Is the route of infection an important determinant of COVID-19 severity?

      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 basis for licensed wild-type-based adenovirus vaccines, of proven high level of safety and efficacy when administered orally (
      • Couch R.B.
      • Chanock R.M.
      • Cate T.R.
      • Lang D.J.
      • Knight V.
      • Huebener R.J.
      Immunization with types 4 and 7 adenovirus by selective infection of the intestinal tract.
      ). Diarrhea and SARS-CoV-2 shedding are frequently reported to precede other COVID-19 symptoms, and although the virus can be detected in stools by PCR in half of patients, the incidence of gastrointestinal symptoms is limited (
      • Mao R.
      • Qiu Y.
      • He J.-S.
      • Tan J.-Y.
      • Li X.-H.
      • Liang J.
      • et al.
      Manifestations and prognosis of gastrointestinal and liver involvement in patients with COVID-19: a systematic review and meta-analysis [published correction appears in Lancet Gastroenterol Hepatol. Jul;5, e6 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 that had been intranasally infected with a dose 103-fold lower (
      • Lee A.C.
      • Zhang A.J.
      • Chan J.F.
      • Li C.
      • Fan Z.
      • Liu F.
      • et al.
      Oral SARS-CoV-2 inoculation establishes subclinical respiratory infection with virus shedding in Golden Syrian Hamsters.
      ).

      Do low doses or the route of administration affect the viral titer achieved, as well as the amount, route, and duration of viral shedding?

      Understanding the relationship between the infectious dose, resultant viral titer, and clinical outcome could allow quantitative differences in PCR diagnostic results to be meaningfully interpreted (
      • Mandavilli A.
      Your coronavirus test is positive. Maybe it shouldn’t be.
      ). The shedding parameters are presumably major determinants of the probability of further transmission, and perhaps of its clinical consequences.

      Do low doses or the route of administration elicit qualitatively different immune responses than those seen with higher doses?

      Mild and severe COVID-19 may be accompanied by 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 W.
      • Dahake R.
      • van de Pas R.
      • Vanham G.
      • Assefa Y.
      COVID-19: Does the infectious inoculum dose-response relationship contribute to understanding heterogeneity in disease severity and transmission dynamics?.
      ). However, we are not aware of any direct evidence that this is the case.

      Do low doses or an alternate route of administration protect against COVID-19?

      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 K.A.
      • Parry H.F.
      • Sergeant M.
      • Tyrrell D.A.J.
      The time course of the immune response to experimental coronavirus infection of man.
      ).
      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 C.A.
      • Liu J.
      • Martinot A.J.
      • McMahan K.
      • Mercado N.B.
      • Peter L.
      • et al.
      SARS-CoV-2 infection protects against rechallenge in rhesus macaques.
      ), 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 unknown. It is unlikely that a longitudinal observational study, given uncertainties about the dose and nature of the original and subsequent infectious exposures, could 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 M.
      • Sagar M.
      • Reifler K.
      • Ross M.
      • Miller N.S.
      • Sinha P.
      • et al.
      Recent endemic coronavirus infection is associated with less severe COVID-19.
      ) 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, such as those involving the type 1 interferon pathway (
      • Zhang Q.
      • Bastard P.
      • Liu Z.
      • Le Pen J.
      • Moncada-Velez M.
      • Chen J.
      • et al.
      Inborn errors of type I IFN immunity in patients with life-threatening COVID-19.
      ). These volunteers would be exposed to low doses of SARS-CoV-2 through nasal instillation or oral ingestion in a closely monitored environment. The surveillance duration would necessarily take into consideration that COVID-19 can result in a prolonged illness, even among persons with milder outpatient illness (
      • Tenforde M.W.
      • Kim S.S.
      • Lindsell C.J.
      • Billig Rose E.
      • Shapiro N.I.
      • Files D.C.
      • et al.
      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, March–June 2020.
      ). In the initial phase, only subjects previously naturally infected would be challenged. The clinical endpoint of such studies would be the induction of asymptomatic or mild disease.
      Various investigators have recently proposed CHIM studies in order to expedite clinical testing of COVID-19 vaccines (
      • Eyal N.
      • Lipsitch M.
      • Smith P.G.
      Human challenge studies to accelerate coronavirus vaccine licensure.
      ;
      • Plotkin S.A.
      • Caplan A.
      Extraordinary diseases require extraordinary solutions.
      ). The ethical validity of such studies depends in large part on whether the anticipated public health benefit (and/or individual benefit to study participants) outweighs the risk of contracting severe COVID-19, as such studies must induce sufficiently severe disease to be relevant for the evaluation of vaccine efficacy. Detailed discussion and quantitation of those risks, and how they compare to risks in other CHIM studies or other societal risks, have been detailed extensively by a World Health Organization Advisory Group (
      • Levine M.M.
      • Abdullah S.
      • Arabi Y.M.
      • Darko D.M.
      • Durbin A.P.
      • Estrada V.
      • et al.
      Viewpoint of a WHO Advisory Group Tasked to Consider Establishing a Closely-Monitored Challenge Model of COVID-19 in Healthy Volunteers.
      ) and others (
      • Deming M.E.
      • Michael N.L.
      • Robb M.
      • Cohen M.S.
      • Neuzil K.M.
      Accelerating development of SARS-CoV-2 vaccines— the role for controlled human infection models.
      ,
      • Eyal N.
      • Lipsitch M.
      • Smith P.G.
      Human challenge studies to accelerate coronavirus vaccine licensure.
      ,
      • Plotkin S.A.
      • Caplan A.
      Extraordinary diseases require extraordinary solutions.
      ) with no need to recapitulate them here.
      In contrast, the potential public health benefits from the 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 an alternate route of administration protect against severe disease, even without providing sterilizing immunity, the identification of immune correlates could guide the development of vaccines or immunotherapeutics specifically aimed at preventing severe disease.
      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 be efficiently 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 M.M.
      • Abdullah S.
      • Arabi Y.M.
      • Darko D.M.
      • Durbin A.P.
      • Estrada V.
      • et al.
      Viewpoint of a WHO Advisory Group Tasked to Consider Establishing a Closely-Monitored Challenge Model of COVID-19 in Healthy Volunteers.
      ).
      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 the 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 route of administration, could allow the elaboration of more targeted and sustainable, or at least more scientific justifiable, disease control measures (Table 1).
      Table 1How study observations could affect public health control measures and messaging
      Potential observationPossible practical implications
      1Low-dose infection results in asymptomatic or mild disease and low-titer, short-term viral shedding
      • Strengthened and streamlined messaging on the value of masks as a way to minimize the infectious dose received.
      2Previous natural infection provides some protection against symptomatic disease
      • Possibility of relaxing certain public health measures in lower-risk groups, while efforts to protect high-risk populations from any infection remain in place. For example:
        • Mask-less outdoor recreation activities for the ‘low-risk’ population and the previously infected explicitly allowed as long as social distancing is maintained. Social/work interactions allowed if likely to result in only low-dose exposure (due to distancing and/or masks) for lower-risk populations.
      3Oral ingestion of SARS-CoV-2 in CHIM leads to little or no symptomatic disease or shedding
      4An immune parameter induced by previous coronavirus infection, such as SARS-CoV-2 reactive T-cells (
      • Braun J.
      • Loyal L.
      • Frentsch M.
      • Wendisch D.
      • Georg P.
      • Kurth F.
      • et al.
      SARS-CoV-2-reactive T cells in healthy donors and patients with COVID-19.
      ), is closely associated with the prevention of symptomatic disease upon challenge in CHIM
      • Targeted vaccine or immunotherapeutic development to elicit, mimic, or enhance this parameter.
      • Incorporation of this parameter into screening programs to estimate population immunity.
      5Low-dose infection and/or ingestion of SARS-CoV-2 in CHIM provide some protection against disease
      • More focused public health messaging around avoiding situations with higher dose exposure.
      • Prioritization of SARS-CoV-2 vaccine candidates that prevent disease but not reinfection, like rotavirus, especially if they allow natural infections to boost short-lived immunity.
      • Development pursued of enterically administered live vaccines.
      CHIM, controlled human infection model; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2.

      Author contributions

      William Hausdorff and Jorge Flores contributed equally 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

      No funding supported this work.

      Ethical approval

      No ethical approval was sought or required for this perspective article.

      Conflict of interest

      The authors declare no competing interests.

      Acknowledgement

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

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