Variolation refers to a historical precursor of vaccination used for smallpox. Healthy subjects were inoculated with material from the scabs of smallpox patients, which usually gave them a mild version of the disease and protected them from contracting the full disease.

By analogy, is it possible that a low-dose exposure to the SARS-CoV-2 virus could result in a mild illness and immunity to subsequently contracting the disease?

Are Low Doses of COVID-19 Virus Safer?

One (imperfect) proxy for this question is whether lower viral titers of SARS-CoV-2 correspond to less severe disease. It seems intuitively plausible – smaller quantities of the virus in the body might be easier for the immune system to fight off and/or cause less extensive tissue damage.

Looking at viral RNA titers in COVID-19 patients doesn’t tell us whether they were initially exposed to large or small amounts of virus, though. If there’s a correlation between viral titer and disease severity, it could either be because the sicker patients got a higher initial “dose” of virus, or because the virus was more successful at multiplying in them. However, we can somewhat alleviate this ambiguity by looking at the trajectories of virus titer over time.

A retrospective study of 76 Chinese patients found that viral loads (as measured by nasal swab) were significantly higher in severe than mild cases of COVID-19, p < 0.005. All patients’ viral loads followed a similar trajectory over time – they started high and steadily declined. However, severe cases had detectable levels of virus for much longer – all severe cases still had viral RNA after 10 days from disease onset, while most mild cases were virus-free by 10 days.[1]

Viral load does not correlate perfectly with disease. Asymptomatic patients [2][3] can have similar viral loads to sick ones.

Another, smaller study with 23 COVID-19 patients found a significant association of peak viral load with age but no significant association of either initial or peak viral load with disease severity.[4] The correlation of viral load with age is explainable by immunosenescence (aging weakens the immune system) and tells us that higher viral load can be caused by a weaker immune system.

In the SARS epidemic, healthcare workers who were exposed to one of three index patients and tested positive for SARS were significantly more likely to be asymptomatic if they wore masks, which suggests that masks lower the amount of virus exposure and that lower virus exposure results in less severe disease.[5]

Another study of 16 individuals exposed to a single SARS index patient showed that the healthcare workers, who were wearing PPE, had significantly lower viral load than the non-healthcare workers, who had no masks. The non-healthcare workers were also more likely to have severe disease, but they were also older on average.[7]

Among people with exposure to a SARS index patient, they were significantly (p < 0.001) more likely to get SARS the longer the index patient stayed home after the onset of fever; when the patient stayed home for >6 days, as opposed to <=2 days, the risk of getting the disease jumps from 38% to 66%. You were more likely to get the disease if you shared a room and bed with the index patient, if you dined more frequently with the index patient, and if you had more frequent close contact with the index patient. This indicates that the volume of contact with the SARS virus influences the risk of contracting disease.[8]

Higher initial viral load is also associated with worse prognosis and shorter survival times in SARS.[6]

The evidence is relatively sparse but consistent with the hypothesis that lower volumes of exposure to SARS-CoV-2 and SARS-CoV result in lower viral titers and less severe disease.

Is COVID-19 Reinfection Possible?

Deliberately infecting a human with a low dose of virus, of course, has not been done enough for there to be a research literature about it.

But what happens when we do it with animals?

We have mixed results on reinfection in animals, some studies showing that prior exposure to a coronavirus protects against subsequent infection, while others showed that reinfection can indeed occur.

Rhesus monkeys that have been infected with SARS-CoV-2 do not get reinfected after a second challenge; they do not show viral replication or clinical symptoms.[15]

Mice who have previously been exposed to SARS-CoV are protected from disease for at least 28 days. Serum from mice that had previously been exposed to the virus, injected into SARS-naive mice, also had a protective effect, while serum from non-exposed mice did not.[12]

Ferrets infected with SARS-CoV who were reinfected 4 weeks later did not have as high viral titers upon reinfection and did not show lung histopathology.[14]

Alpacas and camels experimentally infected with MERS-CoV are protected against reinfection.[17] On the other hand, a longitudinal study of a camel herd showed that reinfection can occur in camels who have previously acquired antibodies to MERS-CoV.[18]

Reinfection is possible in cats previously exposed to feline coronavirus [19], and in cows with bovine coronavirus [20].

Exposure to an inactivated form of a virus is a standard type of vaccine, and it has been found effective in rodents for SARS-CoV.

Partially inactivated SARS-CoV virus samples (treated with formaldehyde) were no longer able to replicate in vitro. When mice were treated with this inactivated virus (by injection or intranasal administration) they produced detectable antibody responses.[9][10] SARS-CoV virus inactivated with UV radiation also produced an antibody response in mice.[11]

Whole killed SARS-CoV vaccine (inactivated with beta-propiolactone) protected mice against a challenge infection.[13]

Hamsters immunized with beta-propiolactone inactivated SARS-CoV virus had lower virus titers than non-immunized hamsters upon challenge with active SARS-CoV and had less severe lung lesions than non-immunized hamsters.[16]

There have been reports of reinfected COVID-19 patients in China and Japan[21] but some think that these are due to testing errors where the patients erroneously tested as having recovered when they were still infected.

The current state of evidence hasn’t ruled out that reinfection could occur for SARS-CoV-2, but tentatively it seems more likely that people who have been infected once are protected against further infections for some period of time. The duration of protection, and whether there are any individuals who don’t get immunological protection, is still unknown.


There’s reason to believe that exposure to a lower dose of the SARS-CoV-2 virus produces a milder disease than exposure to larger quantities of SARS-CoV-2.

And there’s reason to believe that people who have recovered from COVID-19 have some protection against the disease.

What we _don’t _know is whether a dose low enough not to cause severe symptoms is also high enough to cause immune protection against subsequent infections.

Deliberate Exposure as a Policy

A trial of deliberate exposure of young, healthy volunteers to COVID-19 has been proposed by Robin Hanson.

The case for deliberate exposure is to produce a population of immune people who don’t have to be quarantined – for instance, so that they can continue to work as healthcare workers, janitors, and other essential employees in a mostly housebound economy.

The downside, of course, is that deliberately infecting people with a disease harms them.

Deliberate exposure looks better relative to other options under certain conditions:

  • if deliberate exposure causes little harm to the exposed (either because the dose is low or because young people rarely get severe disease)
  • if reinfection after safe doses of virus is rare or impossible
  • if exposure to the active virus is much easier and/or more effective than alternative, safer types of immune protection (like convalescent serum or inactivated virus)
  • if containing the virus is expected to be impossible (i.e. most people will get the disease, the question is when) or so costly that countries decide it’s not worth continuing the lockdowns.
  • if developing an effective vaccine or treatment is expected to be slow

I am doubtful about the first three conditions. We don’t know much about what a “safe” dose of SARS-CoV-2 is, and we haven’t fully ruled out reinfection.

And young people, while less vulnerable than older people, are not immune from severe COVID-19 – in New York, 9% of patients age 18-44 had to be hospitalized. For any given young person, it might be safer to try to stay home and avoid getting the disease until a vaccine or treatment can be developed than to risk deliberate exposure.

An animal study prior to a human one can identify what the infectious dose of the virus is, as well as what the minimum active dose to produce an immune response and protection against reinfection is.

Moreover, it seems that it would be safer, and not obviously less effective, to treat healthy subjects with convalescent serum or inactivated virus rather than live virus.


[1]Liu, Yang, et al. “Viral dynamics in mild and severe cases of COVID-19.” The Lancet Infectious Diseases (2020).

[2]Zou, Lirong, et al. “SARS-CoV-2 viral load in upper respiratory specimens of infected patients.” New England Journal of Medicine 382.12 (2020): 1177-1179.

[3]Kam, Kai-qian, et al. “A Well Infant with Coronavirus Disease 2019 with High Viral Load.” Clinical Infectious Diseases (2020).

[4]To, Kelvin Kai-Wang, et al. “Temporal profiles of viral load in posterior oropharyngeal saliva samples and serum antibody responses during infection by SARS-CoV-2: an observational cohort study.” The Lancet Infectious Diseases (2020).

[5]Wilder-Smith, Annelies, et al. “Asymptomatic SARS coronavirus infection among healthcare workers, Singapore.” Emerging infectious diseases 11.7 (2005): 1142.

[6]Chu, Chung-Ming, et al. “Initial viral load and the outcomes of SARS.” Cmaj 171.11 (2004): 1349-1352.

[7]Lu, Yen-Ta, et al. “Viral load and outcome in SARS infection: the role of personal protective equipment in the emergency department.” The Journal of emergency medicine 30.1 (2006): 7-15.

[8]Lau, Joseph TF, et al. “Probable secondary infections in households of SARS patients in Hong Kong.” Emerging infectious diseases 10.2 (2004): 236.

[9]Yang, Zhi-yong, et al. “A DNA vaccine induces SARS coronavirus neutralization and protective immunity in mice.” Nature 428.6982 (2004): 561-564.

[10]Xiong, Sheng, et al. “Immunogenicity of SARS inactivated vaccine in BALB/c mice.” Immunology letters 95.2 (2004): 139-143.

[11]Takasuka, Naomi, et al. “A subcutaneously injected UV-inactivated SARS coronavirus vaccine elicits systemic humoral immunity in mice.” International immunology 16.10 (2004): 1423-1430.

[12]Subbarao, Kanta, et al. “Prior infection and passive transfer of neutralizing antibody prevent replication of severe acute respiratory syndrome coronavirus in the respiratory tract of mice.” Journal of virology 78.7 (2004): 3572-3577.

[13]See, Raymond H., et al. “Comparative evaluation of two severe acute respiratory syndrome (SARS) vaccine candidates in mice challenged with SARS coronavirus.” Journal of general virology 87.3 (2006): 641-650.

[14]Cameron, Mark J., et al. “Lack of innate interferon responses during SARS coronavirus infection in a vaccination and reinfection ferret model.” PLoS one 7.9 (2012).

[15]Bao, Linlin, et al. “Reinfection could not occur in SARS-CoV-2 infected rhesus macaques.” bioRxiv (2020).

[16]Roberts, Anjeanette, et al. “Immunogenicity and protective efficacy in mice and hamsters of a β-propiolactone inactivated whole virus SARS-CoV vaccine.” Viral immunology 23.5 (2010): 509-519.

[17]Wernery, Ulrich, Susanna KP Lau, and Patrick CY Woo. “Middle East respiratory syndrome (MERS) coronavirus and dromedaries.” The Veterinary Journal 220 (2017): 75-79.

[18]Hemida, Maged Gomaa, et al. “Longitudinal study of Middle East respiratory syndrome coronavirus infection in dromedary camel herds in Saudi Arabia, 2014–2015.” Emerging microbes & infections 6.1 (2017): 1-7.

[19]Addie, D. D., and O. Jarrett. “Use of a reverse-transcriptase polymerase chain reaction for monitoring the shedding of feline coronavirus by healthy cats.” Veterinary Record 148.21 (2001): 649-653.

[20]Heckert, R. A., et al. “Epidemiologic factors and isotype-specific antibody responses in serum and mucosal secretions of dairy calves with bovine coronavirus respiratory tract and enteric tract infections.” American journal of veterinary research 52.6 (1991): 845-851.

[21]Omer, Saad B., Preeti Malani, and Carlos del Rio. “The COVID-19 Pandemic in the US: A Clinical Update.” JAMA.