Independent action hypothesis (IAH), dose response, and ID50 thread 🧵
IAH = idea that each single virion has chance to infect
Dose response curves. Related to the ID50, or infectious dose to make 50% of organisms sick. Measuring how much of a pathogen is needed to cause %age of infection.
A thread about stuff the talking heads don't want you to know.*
(*In fairness they probably don't understand it.)
Keywords: #DoseResponseCurve #ID50 #ID10 #QMRA #QuantitativeMicrobiobialRiskAnalysis
Dose response curve for SARS-CoV-1
In order to develop a dose‐response model for SARS coronavirus (SARS‐CoV), the pooled data sets for infection of transgenic mice susceptible to SARS‐CoV and infection of mice with murine hepatitis virus strain 1, which may be a ...
A single droplet about 50uM large has a 37% chance of containing a single virus.
https://www.pnas.org/doi/10.1073/pnas.2006874117
So, you'd need say 500 droplets to hit mucus membranes and deliver 200 viruses (to cause infection 50% of time).
Kiss of death for droplet.
We are done here.
(Napkin math obviously.)
Of course, numbers rough, ID50 not settled, viral load (that calculates how many in each droplet emitted) may vary, sizes of droplets may vary, but theory here seems solid.
More information about virus particles in droplets, if anyone comes across, would be greatly appreciated.
The assumption has always been one large droplet would contain all the virus particles needed to infect - but I've never seen this elaborated, calculated, discussed anywhere except by the aerosol people who calculate how many in the tiny aerosols
Fine particles may have MORE than coarse. This in fact may make sense. Anyway, some numbers in this paper. No time to review right now.
2020 Fennelly
https://www.thelancet.com/journals/lanres/article/PIIS2213-2600(20)30323-4/fulltext
--- SARS-CoV-2:
Haas. "Action Levels for SARS‐CoV‐2 in Air: Preliminary Approach"
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8251121/
Estimated dose response approach to SARS-CoV-2. From April 2021 so it's well out of date. Also, not experimental, just laying out a framework.*
*(I give you the best commentary - do the talking heads do this? Of course not.)
Quantitative microbial risk assessment has been used to develop criteria for exposure to many microorganisms. In this article, the dose–response curve for Coronavirus 229E is used to develop preliminary risk‐based exposure criteria for ...
--- SARS-CoV-2:
Here is another article that is estimating dose response for SARS-CoV-2:
Parhizkar, Wymelenberg, Haas, Corsi. 2021-10. "A Quantitative Risk Estimation Platform for Indoor Aerosol Transmission of COVID‐19"
Aerosol transmission has played a significant role in the transmission of COVID‐19 disease worldwide. We developed a COVID‐19 aerosol transmission risk estimation model to better understand how key parameters associated with indoor spaces ...
--- Tuberculosis:
Dose response for TB on a plane?
"Enough is enough! I have had it with this mf TB on this mf plane"
[ed. stop fooling]
- Low rates but superspreaders
- Use of mask (by source and/or susceptibles) can reduce infection incidence by 10x
Jones et al. ‘Characterizing the Risk of Infection from Mycobacterium Tuberculosis in Commercial Passenger Aircraft Using Quantitative Microbial Risk Assessment’. Risk Analysis 29, no. 3 (2009): 355–65. https://doi.org/10.1111/j.1539-6924.2008.01161.x.
--- TB dose estimated to be 1.6 Colony Forming Unit (CFU)
That might be about 1 to 2 bacteria, dear peoples of the world.
"Infection by a single bacterium was hypothesized by Dannenberg and the results of our study support his hypothesis (5)."
Saini et al ‘Ultra-Low Dose of Mycobacterium Tuberculosis Aerosol Creates Partial Infection in Mice’. Tuberculosis (Edinburgh, Scotland) 92, no. 2 (March 2012): 160–65. https://doi.org/10.1016/j.tube.2011.11.007.
--- SARS-CoV-2:
"on the order of 10 aerosolized virions"
Bazant, Martin Z., and John W. M. Bush. ‘A Guideline to Limit Indoor Airborne Transmission of COVID-19’. Proceedings of the National Academy of Sciences 118, no. 17 (27 April 2021).
--- Article with minimum infective dose for a bunch of different viruses:
TINY AMOUNTS MAKE YOU SICK
Doses of <1 TCID50 of flu, rhinovirus, and adenovirus ... infected 50% of people ...
"Similarly, low doses of the enteric viruses, norovirus, rotavirus, echovirus, poliovirus, and hepatitis A virus, caused infection in at least some of the volunteers tested."
Yezli et al ‘Minimum Infective Dose of the Major Human Respiratory and Enteric Viruses ...’.
https://doi.org/10.1007/s12560-011-9056-7.
I don't have time to post more but it probably just takes one virus to productively infect you. You inhale x virions and the one gets through.
Infection is likely pretty stochastic.
For more, read about the "independent action hypothesis" (that one pathogen can cause infection)
Also interesting are articles studying how many virus genomes they find in the infected; it is very few.
@ProfCharlesHaas talks about it all here. Highly recommended.
https://chaasblog.wordpress.com/2020/05/18/its-the-dose-response-stupid/
--- Influenza:
Ten particles for flu infects half the time (one ID50). From 1954.
Was looking for something else completely
This is why of course all the fomite studies they have to absolutely cover surfaces with virus to get anything infected.
Oh wait that _disproves_ fomites, silly me.
Carry on, ridiculous hand wash. /S
https://www.microbiologyresearch.org/content/journal/micro/10.1099/00221287-10-3-457
SUMMARY: Particle counts of influenza virus preparations were made by two independent techniques; there was good agreement in the counts found by the two methods. Counts made on four strains of influenza virus and one strain of ‘incomplete’ virus showed that at the agglutination end-point there was about one virus particle per red cell. Parallel infectivity measurements of these strains made under optimal conditions showed that about ten virus particles corresponded to one ID 50.
---SARS-CoV-2:
Prentiss:
"We [] estimate these values based on the literature. We find N0 values for the 5 cases ranging between 322 and 2,012 virions, with avg of Nˆ0∼600. Our range of N0 values is also consistent with recent work of Gale [15] who uses a very different method (thermodynamic response model) to estimate an ID50 for SARS-CoV-2 of ∼500 virions (N0 of 500/ln(2) ∼ 700 virions). We also note the similarity of this dose to the ∼300–9,000 copy inhaled infectious dose for flu A [16-18]"
We probed the transmission of COVID-19 by applying an airborne transmission model to five well-documented case studies—a Washington state church choir, a Korean call center, a Korean exercise class, and two different Chinese bus trips. For all events the likely index patients were pre-symptomatic or mildly symptomatic, which is when infective patients are most likely to interact with large groups of people. Applying the model to those events yields results that suggest the following: (1) transmission was airborne; (2) superspreading events do not require an index patient with an unusually high viral load; (3) the viral loads for all of the index patients were of the same order of magnitude and consistent with experimentally measured values for patients at the onset of symptoms, even though viral loads across the population vary by a factor of >108. In particular we used a Wells-Riley exposure model to calculate q, the total average number of infectious quanta inhaled by a person at the event. Given the q value for each event, the simple airborne transmission model was used to determined Sq, the rate at which the index patient exhaled infectious quanta and N0, the characteristic number of COVID-19 virions needed to induce infection. Despite the uncertainties in the values of some parameters of the superspreading events, all five events yielded (N0∼300–2,000 virions), which is similar to published values for influenza. Finally, this work describes the conditions under which similar methods can provide actionable information on the transmission of other viruses.
--- Influenza:
"The approximate 50% human infectious dose (HID50-50% human infectious dose) of virus per volunteer was from 1 to 126 TCID50 (the tissue culture 50% infectious dose). The dose for half of the volunteers was 5 TCID50. The other half of the men, who had very low or nondetectable preinoculation antibody titers, were infected with 0.6 to 3 TCID50. ..."
"...The study reliably shows that the human infectious dose of the influenza A virus, when administered by aerosol to subjects free of serum neutralizing antibodies, is approximately 3 TCID50."
--- TB / IAH
1 to 3 TB bacteria to infect
"It is estimated that the number of bacilli ... in a droplet nucleus 5 urn in diameter is of the order of l-10. Moreover, based on the examination of X-ray films of a large number of humans,16 the number of calcified primary lesions observed is usually one and never more than 3. Accordingly, these observations suggest that the infectious dose in tuberculosis is very low.”
Balasubramanian et al ‘Pathogenesis of Tuberculosis: https://doi.org/10.1016/0962-8479(94)90002-7
--- smallpox, one virion to infect
Conclusions
On balance, we believe there is adequate in vitro and in vivo evidence that infection can be produced by a single particle of variola virus. Across different experimental systems the number of poxvirus per infectious unit has been found to vary, but it appears that favorable conditions enable all virus particles to infect (Overman & Tamm, 1956; Parker, Bronson, & Green, 1941; Sprunt & McDearman, 1940). ...
Further, we see no biologically plausible reason that the one-hit model would not apply to inhaled virus. Conditions in the upper or lower respiratory tract may increase or decrease the probability that a given virus particle initiates a focus of infection, but infection is possible in either region.” (Nicas et al., 2004, p. 124)
Nicas et al ‘The Infectious Dose of Variola (Smallpox) Virus’. Applied Biosafety 9, no. 3 (September 2004): 118–27. https://doi.org/10.1177/153567600400900302.
--- influenza
"Viral infections can be initiated by a small number of infectious particles or even a single virion. In these cases, successful replication of the virus relies on reactions that comprise very few molecules (for example, a single copy of the viral genome and a handful of proteins). Such reactions are, however, subject to stochastic fluctuations inherent to all molecular processes, which can cause large cell-to-cell heterogeneity.”
"Interestingly, our simulations of single-hit infections yield a large number of non-productive cells. This prediction is in good agreement with experiments at low MOI in which nearly 90% of the cells are incapable of producing infectious virus progeny24”
Heldt et al ‘Single-Cell Analysis and Stochastic Modelling Unveil Large Cell-to-Cell Variability in Influenza A Virus Infection’. Nature Communications 6, no. 1 (20 November 2015): 8938. https://doi.org/10.1038/ncomms9938.
--- plant virus, testing IAH - yes
"The ‘independent action hypothesis’ (IAH) states that each pathogen individual has a non-zero probability of causing host death and that pathogen individuals act independently. IAH has not been rigorously tested. In this paper, we (i) develop a probabilistic framework for testing IAH and (ii) demonstrate that, in two out of the six virus–insect pathosystems tested, IAH is supported by the data.” (Zwart et al., 2009, p. 2233)
---plant
"The independent action hypothesis (IAH) states that each virion has a probability of infection, and that virions act independent of one another during the infection process. A corollary of IAH is that Ne must be dose dependent. A test of IAH for a plant virus has not been reported yet. Here we perform a test of an IAH infection model using a plant RNA virus, Tobacco etch virus (TEV) variants carrying GFP or mCherry fluorescent markers, in Nicotiana tabacum and Capsicum annuum plants.
"...
The number of primary infection foci increased linearly with dose, and was similar to a Poisson distribution.”
Zwart, Mark P., José-Antonio Daròs, and Santiago F. Elena. ‘One Is Enough: In Vivo Effective Population Size Is Dose-Dependent for a Plant RNA Virus’. Edited by Peter D. Nagy. PLoS Pathogens 7, no. 7 (7 July 2011): e1002122. https://doi.org/10.1371/journal.ppat.1002122.
Author Summary Plant viruses have been used to test quantitative models of infection for over 80 years. Recent advances in molecular biology have made it possible to make empirical estimates of the effective population size, the number of virions (i.e., virus particles) that are actually infecting a plant. The relationship between effective population size and virion dose has not been elucidated, and there are discrepancies between estimates of effective population size made for different plant viruses. We therefore formulated a simple model of infection based on the independent action hypothesis, the idea that each virion can infect the plant independently of the presence of other virions. Next, we exposed plants to different doses of two viral genotypes carrying fluorescent markers, which allow for tracking infection. We found that our infection model could describe the overall rate of infection, the number of starting infections, and the number of virus genotypes infecting the entire plant. These tests show that effective population size is dependent on dose and proportional to the number of virions the plant has been exposed to. The minimum effective population size is 1, suggesting that genetic drift can play a dominant role in the evolution of plant viruses.
Remember the Diamond Princess modelling everyone went bananas over?
They assumed single hit model.
"Dose–Response Model. To estimate the infection probability of SARS-CoV-2 viruses deposited to different body sites of susceptible individuals, we used a negative exponential dose–response model, which implies that a single particle can start an infection and all single particles are independent of each other. ...
The probability of infection for one susceptible individual (Pinfection) in the cruise ship was calculated using Eq. 1:”
Azimi, Parham, Zahra Keshavarz, Jose Guillermo Cedeno Laurent, Brent Stephens, and Joseph G. Allen. ‘Mechanistic Transmission Modeling of COVID-19 on the Diamond Princess Cruise Ship Demonstrates the Importance of Aerosol Transmission’. Proceedings of the National Academy of Sciences 118, no. 8 (23 February 2021): e2015482118. https://doi.org/10.1073/pnas.2015482118.
--- If you just want to read about the model, this is a good article.
Lunn, Tamika J., Olivier Restif, Alison J. Peel, Vincent J. Munster, Emmie De Wit, Sanna Sokolow, Neeltje Van Doremalen, Peter Hudson, and Hamish McCallum. ‘Dose–Response and Transmission: The Nexus between Reservoir Hosts, Environment and Recipient Hosts’. Philosophical Transactions of the Royal Society B: Biological Sciences 374, no. 1782 (30 September 2019): 20190016. https://doi.org/10.1098/rstb.2019.0016.
--- This article didn't quite land on single hit, but their results were not inconsistent with it. They were testing a virus in shrimp
Ngo, Thuy T. N., Alistair M. Senior, Antica Culina, Eduardo S. A. Santos, Just M. Vlak, and Mark P. Zwart. ‘Quantitative Analysis of the Dose–Response of White Spot Syndrome Virus in Shrimp’. Journal of Fish Diseases 41, no. 11 (November 2018): 1733–44. https://doi.org/10.1111/jfd.12877.
--- number of particles to productively infect, SARS-CoV-2
Two articles about how many particles it takes to infect someone. From 2020/2021 so out of date.
Popa et al. ‘Genomic Epidemiology of Superspreading Events in Austria Reveals Mutational Dynamics and Transmission Properties of SARS-CoV-2’. Science Translational Medicine 12, no. 573 (9 December 2020): eabe2555. https://doi.org/10.1126/scitranslmed.abe2555.
Comment to authors saying it might be much fewer than they thought.
Martin, Michael A., and Katia Koelle. ‘Comment on “Genomic Epidemiology of Superspreading Events in Austria Reveals Mutational Dynamics and Transmission Properties of SARS-CoV-2”’. Science Translational Medicine 13, no. 617 (27 October 2021): eabh1803. https://doi.org/10.1126/scitranslmed.abh1803.
The fomite thing still has me stumped re: Covid. Are they a danger or not?
Thanks. So hands to mouth or eyes is okay without danger of infection?
I do not like the phrase "without danger of infection" as that implies it can never transmit that way.
However, I would say that the efforts ought to be put into protecting against other modes.
So basically, a very low probability? Of course, I'm with you on all other mitigations- a must!
So low that if you go looking for proof of it, the articles trying to support it generally use wording expressing doubt it is a real mode.
It can't mathematically support outbreaks. You need to coat finger with virus to get some to transmit. No explanation for how gets to mouth other than "we touch face a lot". Etc. It's nonsense.
Big picture: things tend to die when outside our bodies for any length of time.
Did you know we secrete RNAse on skin that eats viruses? 😄
Thank you! That's really helpful!
Sorry for Twitter link but
1.
https://twitter.com/jmcrookston/status/1334851435444531200
https://nitter.net/jmcrookston/status/1334851435444531200
2.
https://twitter.com/jmcrookston/status/1415746706533195785
https://nitter.net/jmcrookston/status/1415746706533195785
I will eventually get all this moved over here and deleted there.
I definitely will check it out. Thanks!
Oh, and thank you for the info and all your hard work. Much appreciated.
I always tell people if it makes someone feel good to wash, or whatever, then do it, but in a modern sanitary society, I doubt we are catching any substantial number of infections from door handles (etc) versus over millions of years the viruses adapting to our (animals') weak spot: lungs.
By the way the washroom should be a bloodbath of infection no? Because basically nobody washes their hands and _the fomites_ 😮 😉 .
But it's not. Although I bet the air ain't good in there.
Thanks, Lightning. That's the first time I've found the phrasing acceptable. Nice choice of words! I finally get it!
Yeah, I figure it's better to be safe than sorry. I'm all for overkill on mitigations.
@jmcrookston And yes, we have published dose response curves for influenza.
https://onlinelibrary.wiley.com/doi/full/10.1111/j.1539-6924.2011.01680.x
Jonathan
PlantingTrees😷🇨🇦🌻👠
Lightning Bjornsson* 
Professor Charles Haas