Several recent published studies and preprints have suggested that the prevalence of COVID-19 31 disease varies by blood type, with type A being relatively susceptible and type O being less 32 susceptible [1] [2] [3] [4] [5] . Puzzlingly, however, there is no difference in the severity of disease, with the 33 case fatality ratio (CFR) and the probability of progressing to intensive care appearing independent 34 of blood type. This discrepancy between incidence and severity data has led some authors to 35 challenge the aforementioned findings [6] . Although not remarked on to date, in the majority of 36 these studies type AB appears even more susceptible than type A. Thus, the relative risk of infection 37 is AB > A > B > O, with type A and type B alleles functioning codominantly to increase risk. This 38 is immediately reminiscent of the rules governing blood transfusion compatibility. 39 Here, I investigate the behaviour of "ABO-interference": a model of epidemic spread in which 40 the transmission of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2, the causal 41 agent of COVID-19) is dependent on the ABO blood type compatibility between an infected 42 individual and the susceptible people they encounter. Mechanistically, this models a scenario in 43 which infectious virions acquire the glycosylation pattern and hence the ABO antigen status of their 44 current host. This in turn allows shed virions to be "rejected" by incompatible recipients, blocking 45 the initial infective step. This immediately explains the lack of correlation with disease severity, 46 since once an infection is established, virions produced within the new host are necessarily self-47 compatible and able to spread freely between cells. 48 The plausibility of this hypothesis has already been established by work on HIV [7] [8] , and was 49 also previously proposed for the 2003 epidemic of SARS [9-10], for measles [11] , and indeed for 50 enveloped viruses in general [12] [13] . SARS-CoV-2 has an outer lipid membrane containing spike, 51 membrane and envelope (S, M and E) proteins, all of which are exposed to immune recognition and 52 any or all of which may be glycosylated. Structural studies show that S is heavily glycosylated, 53 including fucosylated glycans that may potentially bear ABO determinants [14] [15] . The 54 glycosylation status of the M and E proteins has not yet been characterised, nor the glycosylation 55 . CC-BY-NC 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.
The copyright holder for this preprint this version posted July 14, 2020 . . https://doi.org/10.1101 Page 4 of 30 status of the membrane lipids. Experimental work using pseudotyped virus suggests that 56 transmission of the closely related SARS virus can be blocked by anti-A antibodies when virus 57 particles are grown in an A-expressing cell line [10] . This study also showed via modelling that 58 ABO-interference can reduce the progress of an epidemic dependent on the magnitude of the block 59 to transmission and the local population structure. However, despite the mechanistic plausibility of 60 this hypothesis and the preliminary data from the SARS epidemic, there has as yet been no detailed 61 modelling exploring the implications of ABO-interference for the relative susceptibility of 66 The simplest of all epidemic models assumes a homogeneously mixing population divided into 67 susceptible, infectious and recovered groups or "compartments". This yields three variables S, I and 68 R, which respectively represent the proportion of the population with each status. Such a model is 69 completely described by two parameters β and ν, representing the rate constants for infection and 70 recovery respectively. The duration of the infectious period d is given by 1 / ν. All simulations 71 presented here are based on d =7 days, and none of the results presented are sensitive to this 72 parameter. R0 is given by the product β.ν and represents the basic reproduction number, i.e. the 73 mean number of individuals infected by an infectious individual during their illness in a completely 74 susceptible population [16] . To this I add a further parameter ρ (0 ≤ ρ < 100%), representing the 75 relative probability of cross-type infection. Thus, each of the S, I and R compartments is split into 76 four sub-compartments SA, SB, SAB, SO and so forth, representing in this case the susceptible 77 individuals with each of the four blood types. Whereas in a standard SIR model, the rate of new B→A and AB→A by the factor ρ. Similar equations apply to other blood types according to the 81 . CC-BY-NC 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)
The copyright holder for this preprint this version posted July 14, 2020 . . https://doi.org/10.1101 rules of blood type compatibility. In this model R0 is not a well-defined quantity since even in a 82 fully susceptible population the current effective R value, denoted R(t), depends on ρ and on the 83 blood type distributions in both S and I. In this paper, I use Rmax to indicate the maximal possible 84 value of R(t). This will be observed when the population is fully susceptible and ρ = 100%, or when 85 all infected individuals are type O, and thus transmission is unimpeded. the A population, and also propagates to AB (since A→AB is a permissible vector of transmission).
If the index case is type B or AB, the epidemic never becomes established since there are too few 93 compatible susceptible individuals to sustain transmission. If the index case is type O, epidemics 94 occur within all four populations. In all cases the progress of the epidemic is profoundly suppressed 95 relative to an epidemic with no ABO-interference, however the epidemic stemming from a type O 96 index case is four times the size of that stemming from a type A index case. CC-BY-NC 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)
The copyright holder for this preprint this version posted July 14, 2020 . . https://doi.org/10.1101 show detail). All epidemics are based on a typical "Western" blood type distribution of 38% A / 106 14% B / 4% / AB / 44% O and initialised at t=0 with 1/1,000,000 of the population infected. . CC-BY-NC 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)
The copyright holder for this preprint this version posted July 14, 2020. . https://doi.org/10. 1101 Importantly, if ρ > 0 and there is any degree of spread between incompatible blood types, at least 121 some proportion of the O population will become infected. Thereafter the epidemic will behave 122 similarly to one seeded by type O index cases, as shown in Whenever infection is present among individuals with all four blood types (i.e. there is at least 134 one type O index case, or ρ > 0), the blood type distribution among infected people rapidly 135 converges upon a new equilibrium that is significantly skewed relative to the initial population 136 distribution. This equilibration process causes R(t) to also settle on an equilibrium value during the 137 early stages of the epidemic, hereafter called Rsteady. This is a rapid process, with R(t) reaching 138 Rsteady within a few serial intervals: in these simulations this equates to ~0.1% of the population 139 being infected. Therefore, in real-world epidemics subject to ABO-interference, estimates of R0 140 based on population statistics are likely to actually measure Rsteady and thus underestimate the true 141 value of Rmax. Figure 2 illustrates the nature of this steady state, which depends on ρ (compare rows CC-BY-NC 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.
The copyright holder for this preprint this version posted July 14, 2020. . https://doi.org/10. 1101 Page 8 of 30
. CC-BY-NC 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.
The copyright holder for this preprint this version posted July 14, 2020. . https://doi.org/10.1101/2020.07.13.20152637 doi: medRxiv preprint . CC-BY-NC 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.
The copyright holder for this preprint this version posted July 14, 2020. . https://doi.org/10.1101/2020.07.13.20152637 doi: medRxiv preprint CC-BY-NC 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.
The copyright holder for this preprint this version posted July 14, 2020. . https://doi.org/10.1101/2020.07.13.20152637 doi: medRxiv preprint
Page 11 of 30
The steady state at the start of the epidemic allows estimation of ρ for SARS-CoV-2 168 Since the worldwide SARS-CoV-2 pandemic appears to be still in its infancy, with low 169 seroprevalence in all countries studied, the pandemic appears to fall within the steady-state region 170 of the curve. Table 1 shows data compiled from all published studies that have reported ABO indicates the most likely value of ρ. Notably, for all data sets this lies between 25% and 40% despite 179 the different underlying blood type frequencies and relative risk ratios in each country. For the 180 Italian and Spanish study, data was also provided for area-matched control data from blood donors
[4]: using these instead of the internal control data does not affect the result.
Three caveats apply to this analysis. Firstly, while overall prevalence in each country remains 183 low, the local prevalence in "hotspots" is much higher [19] , and infected individuals will by 184 definition originate preferentially from these hotspots. In these areas, the epidemic may have 185 progressed beyond the steady state region of the epidemic curve, reducing the degree of blood type 186 skewing among the infected population and partially masking the effects of ABO-interference on 187 virus transmission. In this case, in order to generate the observed changes in blood type frequency, 188 then the degree of ABO-interference must be even more pronounced. i.e. the estimate of 40% is a 189 maximum bound, and the true frequency of cross-type transmission may be even lower. Secondly, 190 the SIR model assumes that population mixing and opportunities for transmission are independent 191 of blood type. This is unlikely to be the case since blood relatives living together are both more 192 likely to infect each other and more likely to share a blood type. This effect will also tend to mask 193 . CC-BY-NC 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.
The copyright holder for this preprint this version posted July 14, 2020. . https://doi.org/10.1101/2020.07.13.20152637 doi: medRxiv preprint the effect of ABO-interference. Thirdly: when there is nosocomial spread within a hospital, an 194 increase in frequency of one blood type among infected patients will lead to a decrease in frequency 195 of that blood type in the remaining uninfected hospital patients. This will exaggerate the effects of 196 ABO-interference if uninfected hospitalised patients are used as controls.
Overall, the third of these appears not to be an important factor since for both the Italian and 
. CC-BY-NC 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.
The copyright holder for this preprint this version posted July 14, 2020. . https://doi.org/10. 1101 Page 13 of 30
In principle, an optimal vaccination strategy will cause the distribution among susceptible 220 individuals to move "down" the gradient, i.e. towards more effective suppression of the epidemic.
Conversely, the vaccination strategy must also be careful not to disrupt the intrinsic protection 222 afforded by ABO-interference. To illustrate this, consider a population with 50% type A and 50% CC-BY-NC 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.
The copyright holder for this preprint this version posted July 14, 2020. . CC-BY-NC 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.
The copyright holder for this preprint this version posted July 14, 2020. CC-BY-NC 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.
The copyright holder for this preprint this version posted July 14, 2020. The model presented here shows that if ABO-interference is the cause of the widely observed 272 bias in SARS-CoV-2 infection rates among different blood types, then ABO incompatibility 273 reduces SARS-CoV-2 transmission by at least 60% and potentially more. This implies that the 274 apparent R0 for most of the largest epidemics around the world has already been suppressed by at 275 least ~25%, and that Rmax is likely to be substantially higher than the actually-measured Rsteady.
However, it is key to appreciate that no blood type is necessarily high-or low-risk: rather the nature surface glycans (e.g. Lewis and P antigens) behave similarly, this will further magnify the 292 differences between "super-spreaders" and "super-recipients".
Paradoxically, however, although in this model both disease vulnerability and infectiousness 294 vary substantially between different blood types, it is important not to simplistically target 295 vaccination on this basis. Rather, once a vaccine is available, care should be taken not to 296 . CC-BY-NC 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.
The copyright holder for this preprint this version posted July 14, 2020. . https://doi.org/10.1101/2020.07.13.20152637 doi: medRxiv preprint
Page 17 of 30 inadvertently destroy the existing blood type frequency structure that provides population-wise 297 disease resistance, by ensuring good vaccine uptake among all communities. There is a danger that 298 the growing public perception that "type O = low risk" will lead type O individuals to neglect or 299 even refuse vaccination. If this tendency is not monitored and compensated for, it may 300 disproportionately reduce the efficacy of public vaccination programs. Other types of blood-type-301 aware non-pharmaceutical interventions are not modelled here. If protective equipment is in limited 302 supply, it may for example be appropriate for hospitals and care facilities to emphasise source 303 control measures for type O "super-spreaders", and recipient protection measures for type A and 304 AB "super-recipients". More sophisticated agent-based approaches will be needed to model this In testing this model, the key experiment will be to directly determine whether A or B antigens 321 are present on the virus envelope, and whether A-or B-specific antisera can neutralise virus from 322 . CC-BY-NC 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.
The copyright holder for this preprint this version posted July 14, 2020 . . https://doi.org/10.1101 patients with the appropriate blood types. However, there are at least five other testable predictions 323 from this model that may be addressable using existing epidemiological data: 324 (i) in countries with high type B frequency such as India, type B individuals should be at higher 325 risk than type A individuals.
(ii) in studies of super-spreading events, the index cases should be disproportionately type O.
(iii) Direct contact-tracing data should in general follow the blood transfusion rules. For in-328 family tracing, transmission between blood relatives -being more likely to share a blood type -may 329 be more common than transmission between spouses, though this will be substantially confounded 330 by age and behavioural effects.
(iv) In hotspot areas, once the overall case frequency exceeds approximately 20%, the relative 332 risks will begin to decline, as the epidemic proceeds through the type O population in a delayed 333 manner.
(v) In communities with high type O frequency, Rsteady will be higher, the doubling time shorter CC-BY-NC 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.
The copyright holder for this preprint this version posted July 14, 2020. 
. CC-BY-NC 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.
The copyright holder for this preprint this version posted July 14, 2020. 
. CC-BY-NC 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.
The copyright holder for this preprint this version posted July 14, 2020. . CC-BY-NC 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.
The copyright holder for this preprint this version posted July 14, 2020. (internal controls) B 6.84% 9.16% 6.84% 6.80% 6.75% 6.70% 6.64% 6.58% 6.51% 6.44% 6.36% 6.27% 6.17% 6.06% 5.93% 5.78% 5.61% 5. 
A standard SIR model of infection divides the population into three compartments, Susceptible, Infectious, Recovered, representing the proportion of individuals in the population with each status, and thus S + I + R = 1. These compartments are linked by three differential equations:
The parameters β and ν represent the rate constants for infection and recovery, and their reciprocals 1 / β and 1 / ν represent the average time required for one infectious individual to transmit to one susceptible individual, and the average duration of the infectious period. The product β ⋅ ν represents the basic reproductive number R0. The parameter ω represents the rate constant for loss of immunity, and thus transfer from the R compartment back to S. Its reciprocal 1 / ω represents the average duration of immunity following recovery.
Here, I extend this model by splitting each of S, I and R into four subcompartments representing the four ABO blood group phenotypes. These are then linked by a set of twelve equations: These equations were implemented as a Microsoft Excel spreadsheet (available from URL TO ADD). In this model R0 is not a well-defined quantity since even in a fully susceptible population the current effective R value, denoted R(t), depends on ρ and on the blood type distributions in both S and I. In this paper, I use Rmax to indicate the product β ⋅ ν, i.e. the R0 that would be observed in the absence of any ABO-interference. This is thus the maximal possible value of R(t), and would be observed if ρ = 100%, or if all infected individuals are type O. For the work presented here, all epidemics were initiated by transferring 1/1,000,000 of the population from S to I at time t=0. This for example represents an initial importation of ~9 infected index cases into a city the size of London. Varying these boundary conditions from 1/10,000 to 1/100,000,000 has no effect other than accelerating or retarding the initial progress of the epidemic (not shown). Except where otherwise specified in the main text, all index cases 4 were assumed to be of blood group O. For the main text, immunity was assumed to be permanent and thus ω = 0. The case where ω = 0 and immunity wanes over time is considered below.
The effect of waning immunity for a virus subject to ABO-interference When immunity is allowed to wane over time, and the duration of immunity (1 / ω) is substantially longer than the duration of infection (1 / ν), then population spread of the virus can resume once the population level of immunity falls below the herd immunity threshold. Over time this leads to damped oscillatory behaviour, with recurrent pulses of infection converging on a final steady state. In this final steady state, by definition R(t) = 1, i.e. there is steady sustained transmission with levels neither growing nor shrinking. (Figure S1 ). The relative risk to non-O blood groups is less pronounced during this final steady state compared to the initial quasisteady state during the early phase of pandemic spread, but remains non-zero. In the final steady state, with waning immunity and recurrent infection, the relative risk is best interpreted as a difference in the frequency of infection: e.g. if type A has a relative risk of 1.1 compared to type O, it means type A individuals are 10% more likely to suffer an infection within any given time period. The final population disease burden, i.e. the final value of I depends on the duration of immunity, with a shorter immune duration leading to a higher final prevalence.
Intriguingly, while the initial quasi-steady state is independent of Rmax (see main text for details), the final steady state does depend on Rmax. When Rmax is high, the final relative risk for all blood groups is close to unity. When Rmax is low, then the final relative risk for all blood groups is similar to that seen in the initial steady state. Intuitively, this follows from the fact that for a highly contagious disease with a high Rmax, everyone will become infected as soon as their 5 immunity wears off, irrespective of blood type. For a less contagious disease with a low Rmax, then there is more scope for differential susceptibility to play a part in how frequently individuals become infected.
For seasonal coronaviruses, if these are subject to ABO-interference, this means similar results should be observed for these as for SARS-CoV-2. It would therefore be interesting to determine whether non-O blood groups are indeed more likely to suffer more frequent repeat coronavirus infections. More speculatively, given the emerging evidence that COVID-19 is a multisystemic infection with particular impact on clotting pathways [1], could it be possible that the endemic coronaviruses may also have some effect on the likelihood of thrombosis? This could potentially explain the widely-observed phenomenon that type O individuals are on average slightly less likely to suffer from thrombosis and clotting-related myocardial infarction.
This has been hitherto ascribed to an effect of ABO blood group on von Willebrand factor levels, but the causal link between the two remains obscure [2].