key: cord-0299026-fdihbd22 authors: Faucher, B.; Assab, R.; Roux, J.; Levy-Bruhl, D.; Tran Kiem, C.; Cauchemez, S.; Zanetti, L.; Colizza, V.; Boëlle, P.-Y.; Poletto, C. title: Reactive vaccination of workplaces and schools against COVID-19 date: 2021-07-29 journal: nan DOI: 10.1101/2021.07.26.21261133 sha: 2cb102997e1e7895272befedb6217deabbcb9114 doc_id: 299026 cord_uid: fdihbd22 As vaccination against COVID-19 stalls in some countries, increased accessibility and more adaptive approaches may be useful to keep the epidemic under control. Here we study the impact of reactive vaccination targeting schools and workplaces where cases have been detected, with an agent-based model accounting for COVID-19 natural history, vaccine characteristics, individuals' demography and behaviour and social distancing. We study epidemic scenarios ranging from sustained spread to flare-up of cases, and we consider reactive vaccination alone and in combination with mass vaccination. With the same number of doses, reactive vaccination reduces cases more than non-reactive approaches, but may require concentrating a high number of doses over a short time in case of sustained spread. In case of flare-ups, quick implementation of reactive vaccination supported by enhanced test-trace-isolate practices would limit further spread. These results provide key information to promote an adaptive vaccination plan in the months to come. reactive vaccination alone and in combination with mass vaccination. With the same number 23 of doses, reactive vaccination reduces cases more than non-reactive approaches, but may 24 require concentrating a high number of doses over a short time in case of sustained spread. 25 In case of flare-ups, quick implementation of reactive vaccination supported by enhanced 26 test-trace-isolate practices would limit further spread. These results provide key information to 27 promote an adaptive vaccination plan in the months to come. 28 29 . CC-BY-ND 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 29, 2021. Achieving high vaccination coverage against COVID-19 is now the main strategy to reduce 31 disease burden and pressure on health care organisations and to lift non-pharmaceutical 32 interventions (NPI). To this end, mass vaccination campaigns started in Western countries 33 mainly prioritising health care workers and groups more at risk of severe infection 1-4 -i.e. the 34 elderly and those with comorbidities. However, now that vaccination has been opened to all 35 adults, vaccine uptake remains below needs -e.g. in France, the United States -due to 36 logistical issues, vaccine accessibility and/or hesitancy. With cases on the rise again due to 37 the emergence of new viral variants, vaccine delivery must become more adaptive in 38 response to the epidemic situation. For instance, it could preferentially target people at 39 higher risk of infection, e.g. because attending places where more cases are reported. As 40 people who are hesitant to vaccinate are more likely to accept vaccination when the 41 perceived risk of infection is higher 5 , this would help overcome barriers to vaccination 6 . 42 Hotspot vaccination, which involves redirecting vaccine supplies to geographic areas of 43 highest incidence, is already part of some European countries' plans to combat the 44 emergence of variant Delta 6 . But other reactive vaccination schemes are possible, such as 45 ring vaccination that targets contacts of confirmed cases or contacts of those contacts, or 46 vaccination in workplaces or schools where cases have been detected. This could potentially 47 improve vaccine impact by preventing transmission where it is active and even enable the 48 efficient management of flare-ups. For outbreaks of smallpox or Ebola fever, ring vaccination 49 has proved effective to rapidly curtail the spread of cases 7-10 . However, the experience of 50 these past epidemics cannot be transposed directly to COVID-19 due to the many differences 51 in the infection characteristics and epidemiological context. For example, COVID-19 cases 52 are infectious a few days before symptom onset 11 , but generally detected a few days later. 53 This means they may have had time to infect their direct contacts, potentially limiting the 54 efficacy of ring vaccination. Vaccinating an extended network of contacts, as could be done 55 with the vaccination of whole workplaces or schools, could have a larger impact, especially if 56 adopted in combination with strengthened protective measures to slow down transmission, 57 such as masks, physical distancing, and contact tracing. This could be feasible in many 58 countries, leveraging the established test-trace-isolate (TTI) system that enables prompt 59 detection of clusters of cases to inform where vaccines should be deployed. Properly 60 assessing the interest of reactive vaccination therefore requires to consider in detail the 61 interactions of vaccine characteristics, pace of vaccination, COVID-19 natural history, case 62 detection practices and overall changes in human contact behaviour. 63 . CC-BY-ND 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 29, 2021. To parametrise the epidemiological context, we assume 26% 20,21 of the population was fully 99 immune to the virus and the reproductive ratio is = 1.2, in the range of values estimated 100 during the ascending phase of winter 20-21/spring 2021 epidemic waves 22 . We model the 101 baseline TTI policy after the French situation, allowing 3.6 days on average from symptoms 102 . CC-BY-ND 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 29, 2021. ; https://doi.org/10.1101/2021.07.26.21261133 doi: medRxiv preprint 5 onset to detection and 2.8 average contacts detected and isolated per index case 23 (Figure 1 103 D). We assume that 50% of clinical cases and 10% of subclinical cases are detected. 104 Scenarios with enhanced TTI are described later in the text. 105 We then model vaccination of 18+ years old population assuming vaccination uptake is 106 bounded above by vaccine acceptance, set to 66% in the 18-65 years old and 90% in the 107 over 65 years old at baseline, based on surveys conducted on the French population 24 . 108 When the vaccine is proposed in the context of reactive vaccination, we also consider uptake 109 up to 100%. We model a reactive vaccination strategy, where the detection of a case thanks 110 to TTI triggers the vaccination of household members and those in the same workplace or 111 school ( Figure 1D ). In this scenario, a delay of 2 days on average is assumed between the 112 detection of the case and vaccination to account for logistical issues -i.e. ~5.6 days on 113 average from the index case's symptoms onset. We also model three non-reactive 114 vaccination strategies, i.e. i) where vaccination is deployed randomly throughout the mass 115 vaccination program (mass) or ii) in school sites (school location) or iii) 116 workplaces/universities (workplaces/universities) chosen at random, up to the maximum 117 number of doses available daily. In the school location vaccination, we assume vaccine sites 118 are created in relation with schools to vaccinate pupils and their household members who are 119 above 18 years old. The impact of these strategies is evaluated based on the comparison 120 with a reference scenario, where no vaccination campaign is conducted during the course of 121 the simulation and vaccination coverage remains at its initial level. 122 Comparison between reactive and non-reactive vaccination strategies 123 In Figure 2 we compare all strategies, assuming that vaccine uptake is the same in reactive 124 and non-reactive vaccination as reference, and initial vaccination coverage among adults is 125 small, i.e. 13% of the [18,60] group. During the course of the simulation we consider daily 126 first-dose vaccination rates for non-reactive strategies between 85 first doses per 100,000 127 inhabitants (corresponding to the initial vaccination capacity in France in January/February 128 2021) and 512 first doses per 100,000 inhabitants (close to highest vaccination capacity 129 values reached in May/June 2021 before it declined in June). Panels A-C show the results for 130 a high incidence scenario, here defined by initial incidence at ~160 clinical cases weekly per 131 100,000 inhabitants -close to values registered during the first half of May 2021 in France. 132 Panel A shows the relative reduction in the attack rate after two months as a function of the 133 number of first daily doses, while Figure 2B compares the incidence profiles under different 134 strategies at a similar number of vaccine doses. The mass, school location and 135 workplaces/universities strategies have a similar impact on the epidemic. They lead to a 136 reduction between 3.6% and 4.9% of the attack rate, when 85 first doses per 100,000 137 . CC-BY-ND 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 29, 2021. ; https://doi.org/10.1101/2021.07.26.21261133 doi: medRxiv preprint 6 inhabitants are administered each day, and between 20% and 22% with 511 per 100,000 138 inhabitants. Among the three, mass vaccination has the lowest impact. This is because the 139 workplaces/universities and school location strategies target a portion of the population with 140 more contacts -working population, or population living in large households -with a greater 141 potential to transmit the infection. Compared with each of the three strategies, reactive 142 vaccination produces a stronger reduction in cases at equal number of doses in the two-143 month period, i.e. a reduction of 24.5% with the number of first-dose vaccinations being 247 144 per 100,000 inhabitants each day on average. 145 In panel C we show the number of first doses in time and the number of places to vaccinate -146 as a proxy to the incurred costs of vaccine deployment. The number of daily inoculated doses 147 is initially high, with 1112 doses per 100,000 inhabitants used in a day at the peak of vaccine 148 demand, but declines rapidly afterwards down to 86 doses. More than 10 workplaces/schools 149 (0.3% of workplaces and eligible schools of the municipality considered) would need to be 150 vaccinated each day at the peak of vaccine demand. CC-BY-ND 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 29, 2021. ; https://doi.org/10.1101/2021.07.26.21261133 doi: medRxiv preprint 7 scenario with initial incidence of clinical cases 5 per 100,000 inhabitants. In panel E, the vaccination pace is 85 161 and 46 daily first-dose vaccinations per 100,000 inhabitants for the non-reactive and reactive strategies, 162 respectively. In all cases we assumed the following parameters: R=1. In Figure 2 D-F we consider a low incidence scenario, i.e. 5 clinical cases weekly per 100,000 168 inhabitants. In this scenario, reactive vaccination yields a relative reduction in the attack rate 169 that is twice the one produced by the workplaces/universities strategy with 85 daily doses per 170 100,000 inhabitants, but only using 46 daily doses per 100,000 on average in the two-months 171 period. The deployment of vaccines and the number of workplaces/schools to vaccinate is 172 initially low and increases gradually with incidence. 173 We have considered so far specific scenarios in terms of epidemiological and vaccine 174 parameters. In the Supplementary Information we explore alternative values of key 175 parameters, e.g. initial incidence, transmission, immunity level of the population, fraction of 176 adults initially vaccinated, reduction in contacts due to social distancing, vaccine efficacy and 177 time needed for the vaccine to become effective. In particular, we explore a reduction in 178 vaccine efficacy of 30% and a longer time needed for the vaccine protection to mount -179 parameterized according to 25 Figure 3B . A small cap on the number of doses 205 limits the impact of the reactive strategy. Figure 3C shows that the attack rate relative 206 reduction drops from 21% to 8.2% if only a maximum of 85 first doses per 100,000 207 inhabitants daily can be used in reactive vaccination. However, the inclusion of reactive 208 vaccination is beneficial (i.e. RR is above the mass strategy only with a similar number of 209 doses) as soon as the cap in the number of doses is higher than 85 per 100,000 inhabitants. 210 Doubling the time required to start reactive vaccination, from 2 days to 4 days, has a limited 211 effect on the reduction of the AR (relative reduction reduced from 29% to 27%, Figure 3D ). 212 Increasing the number of detected cases used to trigger vaccination to 2 (respectively 5) 213 reduces the relative reduction to 22% (respectively 15%) ( Figure 3E ). 214 We so far assumed that vaccine uptake is the same in mass and reactive vaccination. In 215 Figure 3F we consider a scenario where vaccine uptake with reactive vaccination climbs to 216 100%. Attack rate relative reduction increases in this case from 29% to 37%, with a demand 217 of 604 daily doses per 100,000 inhabitants on average. 218 219 . CC-BY-ND 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. . CC-BY-ND 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 29, 2021. ; https://doi.org/10.1101/2021.07.26.21261133 doi: medRxiv preprint 2021. A mass vaccination campaign with 512 first doses per day per 100,000 inhabitants is 242 underway from the start and baseline TTI is in place prior to cases' introduction. To start a 243 simulation, three infectious individuals are introduced in the population where the virus variant 244 is not currently circulating. Upon detection of the first case, we assume that TTI is enhanced, 245 finding 100% of clinical cases, 50% of subclinical cases and three times more contacts 246 outside the household with 100% compliance to isolation (Table S4 of the Supplementary 247 Information) -the scenario without TTI enhancement is also explored for comparison. As 248 soon as the number of detected cases reaches a predefined threshold, reactive vaccination is 249 started on top of the mass vaccination campaign. We assume vaccine uptake increases to 250 100% for reactive vaccination but stays at its baseline value for other approaches. In Figure 251 4A, B, C we quantify the probability of extinction and the average attack rate. We compare 252 the combined scenario with mass vaccination alone at an equal number of doses, and we 253 investigate starting the reactive vaccination after 1, 5 or 10 detected cases. 254 With enhanced TTI and 100% uptake for reactive vaccination starting from the first detected 255 case, the probability of extinction would increase (from 0.41 to 0.45) and the attack rate 256 decrease (from 41 to 34 cases per 100 000 inhabitants), compared with the mass scenario. 257 The added value of reactive vaccination would decrease if more detected cases are required 258 to start the intervention. We consider a similar level of uptake for reactive vaccination and 259 mass vaccination, finding no advantage of reactive vaccination in this case. Assuming no 260 enhancement in TTI occurs after the detection of the first case, we find no effect of the 261 reactive vaccination in disease containment, irrespective of the level of vaccination uptake. CC-BY-ND 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 29, 2021. ; https://doi.org/10.1101/2021.07.26.21261133 doi: medRxiv preprint 11 reaches extinction (no active infections) within the first two months after the first detected case. Error bars are 271 computed assuming the probability of extinction follows a binomial distribution. For mass vaccination the number 272 of first-dose vaccinations during the period is the same as in the combined cl. size=1 of the same scenario. B Average attack rate two months after first detected case for the enhanced TTI scenario. C Average attack rate 274 two months after first detected case for the baseline TTI scenario. In panel B and C error bars are the standard 275 error from 8000 stochastic realisations. In all panels we assume the following parameters: R=1.2; Initial immunity 276 26%; 81% and 33% for 60+ and <60 already vaccinated at the beginning, respectively; no reduction in contacts 277 due to social distancing or teleworking. Corresponding incidence curves are reported in Figure proportion of the population. Vaccination must be made more accessible and able to adapt to 286 a rapidly evolving epidemic situation 6 . In this context, we have here analysed the reactive 287 vaccination of workplaces, universities and schools to assess its potential role in managing 288 the epidemic. 289 We presented an agent-based model that accounts for the key factors affecting the 290 effectiveness of reactive vaccination: disease natural history, vaccine characteristic, individual 291 contact behaviour, social distancing interventions in place and logistic constraints. Model 292 results suggest that: First, reactive vaccination would have a stronger impact on the COVID-293 19 epidemic than non-reactive vaccination strategies, when the comparison is done at equal 294 number of doses within the two months. Second, combining reactive and mass vaccination 295 would be more effective than mass vaccination alone in both mitigating the sustained spread 296 and containing a flare-up in a context of diffusion of an emerging variant of concern (VOC). 297 Third, for the reactive strategy to be effective, vaccines should be administered quickly -i.e. 298 right after the detection of the first case. In addition, when the goal is to contain a flare-up, 299 reactive vaccination should be combined with enhanced TTI. 300 Reactive vaccination has been studied for smallpox, cholera and measles, among others 7-301 9,31,32 . Hotspot vaccination was found to help in cholera outbreak response by both modelling 302 studies and outbreak investigation 32,33 . It may target geographic areas defined at spatial 303 resolution as diverse as districts within a country, or neighbourhoods within a city, according 304 to the situation. For Ebola and smallpox ring vaccination was successfully adopted to 305 accelerate epidemic containment 7-9 . For these infections, vaccine-induced immunity mounts 306 . CC-BY-ND 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 29, 2021. ; https://doi.org/10.1101/2021.07.26.21261133 doi: medRxiv preprint rapidly compared to the incubation period and contacts of an index case can be found before 307 they start transmitting since pre-symptomatic and asymptomatic transmission is almost 308 absent. Ring vaccination is also likely effective when the vaccine has post-exposure effects 10 309 -e.g. hepatitis A, B, measles, rabies and smallpox. Reactive vaccination of schools and 310 university campuses has been implemented in the past to contain outbreaks of meningitis 34 311 and measles 35, 36 . 312 For COVID-19, the use of reactive vaccination has been reported in Ontario, the UK, 313 Germany, France, among others 6,37-42 . In these places, vaccines were directed to 314 communities, neighbourhoods or building complexes with a large number of infections or 315 presenting epidemic clusters or surge of cases due to virus variants. The goal of these 316 campaigns was to minimise the spread of the virus, but it also addressed inequalities in 317 access and increased fairness, since a surge of cases may happen where people have 318 difficulty in isolating due to poverty and house crowding 43 However, the feasibility and advantage of the inclusion of reactive vaccination imply a trade-337 off between epidemic intensity and logistic constraints. At a high incidence level, combining 338 reactive and mass vaccination would substantially decrease the attack rate compared to 339 mass vaccination for the same number of doses, but the large initial demand in vaccines may 340 exceed the available stockpiles. Even with large enough stockpiles, issues like the timely 341 . CC-BY-ND 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 29, 2021. ; https://doi.org/10.1101/2021.07.26.21261133 doi: medRxiv preprint 13 deployment of additional personnel in mobile vaccine units and the need to quickly inform the 342 population by communication campaigns must be solved to guarantee the success of the 343 campaign. We explored with the model the key variables that would impact the strategy 344 effectiveness. Delaying the deployment of vaccines in workplaces/schools upon the detection 345 of a case (from 2 to 4 days on average) would not have a strong impact on its effectiveness -346 relative reduction going from 29% to 27% in Figure 3D . However, vaccines should be 347 deployed at the detection of the first case to avoid substantially limiting the impact of the 348 strategy -e.g. the relative reduction goes from 29% to 15% when workplaces/schools are 349 vaccinated at the detection of 5 cases ( Figure 3E ). At a low incidence level, the reactive 350 strategy would require a few extra doses in a few workplaces/schools, but the advantage with 351 respect to mass vaccination is overall reduced in this case. 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 29, 2021. ; https://doi.org/10.1101/2021.07.26.21261133 doi: medRxiv preprint the course of a measles outbreak 5 .Therefore reactive vaccination could be an important way 378 to improve access to vaccination -especially for the hard-to-reach population -and potentially 379 increase acceptability, e.g. due to risk perception. 380 The study is affected by several limitations. First, the synthetic population used in the study 381 accounts for the repartition of contacts across workplaces, schools, households, etc., Teleworking and social distancing 428 To model social distancing, we assume a proportion of nodes are absent from work, modelled 429 by erasing working contacts and transport contacts of these nodes. We also remove a 430 proportion of contacts from the community layer to account for reduction in social encounters 431 due to closure of restaurants and other leisure activities. We choose plausible reduction 432 values in the range reported by google mobility reports 58 during the first half of 2021 in 433 France. Specifically, we set the reduction of contacts in the community to 30% within the 434 range of the mobility reduction in places of retail and recreation (between ~50% to ~5%) 435 measured from January to June 2021, and the fraction of teleworkers to 20% within the 436 ballpark of reduction values registered for workplaces in the same period -in general between 437 ~35% to ~10%. Telework and social distancing is implemented at the beginning of the 438 simulation and remains constant for the duration of the simulation. Scenarios with no 439 reduction in contacts are also considered. 440 Transmission model is an extension of the model in 12 (see Figure 1D ). This accounts for 442 heterogeneous susceptibility and severity across age groups 59,60 , the presence of an 443 exposed and a pre-symptomatic stage 11 , and two different levels of infection outcome -444 . CC-BY-ND 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 29, 2021. contact with infectious ones, may get infected and enter the exposed compartment ( ). After 447 an average latency period 5& they become infectious, developing a subclinical infection ( 89 ) 448 with age-dependent probability 89 ; and a clinical infection ( 9 ) otherwise. From , before 449 entering either 89 or 9 , individuals enter first a prodromal phase (either <,89 or <,9 ), that lasts 450 on average < 5& days. Compared to <,9 and 9 individuals, individuals in the <,89 and 89 451 compartments have reduced transmissibility rescaled by a factor ? . With rate infected 452 individuals become recovered. Age-dependent susceptibility and age-dependant probability 453 of clinical symptoms are parametrised from 59 . In addition, transmission depends on setting as 454 in 12 . Parameters are summarised in Table S1 Under the assumption that no serological/virological/antigenic test is done before vaccine 475 administration, the vaccine is administered to all individuals, except for clinical cases who 476 show clear signs of the disease or individuals that were detected as infected by the TTI in 477 place. In our model a vaccine administered to infected or recovered individuals has no effect. 478 . CC-BY-ND 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 29, 2021. In the scenario of virus re-introduction, we consider enhanced TTI, corresponding to a 496 situation of case investigation, screening campaign and sensibilisation (prompting higher 497 compliance to isolation). We assume a higher detection of clinical and subclinical cases 498 (100% and 50% respectively), perfect compliance to isolation by the index case and 499 household members and a three-fold increase in contacts identified outside the household. 500 Step-by-step description of contact tracing is provided in the Supplementary Information. 501 Parameters for baseline TTI are provided in Table S3 , while parameters for enhanced TTI are 502 provided in Table S4 . 503 A vaccine opinion (willingness or not to vaccinate) is stochastically assigned to each 505 individual at the beginning of the simulation depending on age (below/above 65). Opinion 506 does not change during the simulation. In some scenarios we assume that all individuals are 507 willing to accept the vaccine in case of reactive vaccination, while maintaining the opinion 508 originally assigned to them when the vaccine is proposed in the context of non-reactive 509 vaccination. Only individuals above a threshold age, MP,A = 18 years old, are vaccinated. We 510 . CC-BY-ND 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 29, 2021. Reactive: When a case is detected, vaccination is done in her/his household with rate A . 527 When a cluster -i.e. at least 9U cases detected within a time window of length 9U -is 528 detected in a workplace/school, vaccination is done in that place with rate A . In the baseline 529 scenario, we assume vaccination in workplace/school to be triggered by one single infected 530 individual ( 9U = 1). In both household and workplace/school, all individuals belonging to the 531 place above the threshold age and willing to be vaccinated are vaccinated. Individuals that 532 were already detected and isolated at home are not vaccinated. No more than RSTUV Code availability 540 We provide all C/C++ code files of the model on github 63 . 541 . CC-BY-ND 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 29, 2021. . CC-BY-ND 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 29, 2021. aquitaine.ars.sante.fr/communique-de-presse-covid-19-la-necessite-de-se-faire-vacciner-649 rapidement-pour-eviter-la. (Table S1) , and the effect of vaccination (Table S2 ). For a detailed explanation of the 719 transmission model without vaccination we refer to 1 . 720 . CC-BY-ND 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 29, 2021. Test-trace-isolate 725 We model case detection and isolation, combined with tracing and isolation of contacts 726 according to the following rules: 727 • As an individual shows clinical symptoms, s/he is detected with probability R,9 . If 728 detected, case confirmation and isolation occur with rate R upon symptoms onset. 729 • Subclinical individuals are also detected with probability R,89 , and rate R . 730 • The index case's household contacts are isolated, with probability , , the same time 731 the index case is detected and isolated. We assume that these contacts are tested at the 732 time of isolation and among those all subclinical, clinical, pre-subclinical, and pre-clinical 733 cases are detected (testing sensitivity 100%). 734 • Once the index case is detected, contacts of the index case occurring outside the 735 household are traced and isolated with an average delay 9M 5& . We define an acquaintance 736 as a contact occurring frequently, i.e. with a frequency of activation higher than S . We 737 assume that an acquaintance is detected and isolated with a probability 9M,; , while other 738 contacts (i.e. sporadic contacts) are detected and isolated with probability 9M,8< , with 739 9M,; > 9M,8< . We assume that traced contacts are tested at the time of isolation and 740 among those all subclinical, clinical, pre-subclinical, and pre-clinical cases are detected 741 (testing sensitivity 100%). 742 . CC-BY-ND 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 29, 2021. . CC-BY-ND 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 29, 2021. Vaccination strategies 758 We provide here in the following the parameters values for the vaccination strategies detailed 759 in the Methods section of the main paper. 760 . CC-BY-ND 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 29, 2021. . CC-BY-ND 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 29, 2021. ; https://doi.org/10.1101/2021.07.26.21261133 doi: medRxiv preprint Figure S5 shows the relative reductions in the number of hospitalisations, deaths, ICU 878 entries, life-year lost, quality-adjusted life-year lost and ICU bed occupancy at the peak, 879 comparing each vaccination scenario with the reference scenario -i.e. vaccination only at the 880 start. We consider here the high incidence scenario and vaccination strategies are compared 881 at the same vaccine uptake, analogously to Figure incidence scenario. In all cases we assumed the following parameters: R=1.2; Initial immunity 26%; vaccinated at 894 the beginning are 81% and 13% of 60+ and <60, respectively; teleworking 20% and reduction in contacts in the 895 community 30%; initial incidence 160 per 100,000 inhabitants. Figure 3A . We assumed the following parameters: initial 906 incidence of clinical cases 160 per 100 000 inhabitants; R=1.2; Initial immunity 26%; vaccinated at the beginning 907 are 81% and 13% of 60+ and <60, respectively; teleworking 20% and reduction in contacts in the community 30%. In Figure S7 we show the incidence curve corresponding to the scenarios analysed in Figure 913 4 of the main paper. Mass and combined vaccination with the different vaccination scenarios 914 considered are compared. 915 916 . CC-BY-ND 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. Effectiveness of COVID-19 vaccines against variants of concern 56. Investigation of SARS-CoV-2 variants of concern: technical briefings. GOV.UK The French Connection: The First Large Population-Based Contact 688 Survey in France Relevant for the Spread of Infectious Diseases COVID-19 Community Mobility Report Age-dependent effects in the transmission and control of COVID-693 19 epidemics Modelling 695 safe protocols for reopening schools during the COVID-19 pandemic in France Epidemiological characteristics of COVID-19 cases and estimates 698 of the reproductive numbers 1 month into the epidemic, Italy Adherence to the test, trace and isolate system: results from a time 701 series of 21 nationally representative surveys in the UK (the COVID-19 Rapid Survey Adherence to Interventions and Responses [CORSAIR] study). medRxiv Anatomy of digital contact tracing: role of age, transmission setting, 925 adoption and case detection Early Transmission Dynamics in Wuhan, China, of Novel Coronavirus-Infected 928 Temporal dynamics in viral shedding and transmissibility of COVID-19 Evolution of outcomes for patients hospitalised during the first 9 960 months of the SARS-CoV-2 pandemic in France: A retrospective national surveillance 961 data analysis. The Lancet Regional Health Age-dependent effects in the transmission and control of COVID-963 19 epidemics Tables de mortalité par sexe, âge et niveau de vie − Tables de mortalité par niveau 967 de vie | Insee Valuing EQ-5D using time trade-off in France 707 We acknowledge financial support from Haute Autorité de Santé; the ANR and Fondation de 708 . CC-BY-ND 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 29, 2021. ; https://doi.org/10.1101/2021.07.26.21261133 doi: medRxiv preprint 25 France through the project NoCOV (00105995); the Municipality of Paris 709 (https://www.paris.fr/) through the programme Emergence(s); EU H2020 grants MOOD 710 (H2020-874850), and RECOVER (H2020-101003589); Institut des Sciences du Calcul et de 711 la Donnée (ISCD). 712 713 . CC-BY-ND 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 29, 2021. ; https://doi.org/10.1101/2021.07.26.21261133 doi: medRxiv preprint Details on the epidemic simulations 763 A schematic representation of the main program and of the simulation code and of the 764 algorithm used for a single stochastic realisation are shown in Figure S1 and S2, respectively. 765Simulations are discrete-time and stochastic. At each time step, corresponding to one day, 766 three processes occur ( Figure S2) and transition through the different stages of the infection (e.g. from exposed to pre-773 symptomatic, from pre-symptomatic to symptomatic) 774A single-run simulation is executed with no modelled intervention, until the desired immunity 775 level is reached. This guarantees that immune individuals are realistically clustered on the 776 network. We added some noise, by reshuffling the immune/susceptible status of 30% of the 777 nodes to account for travelling, infection reintroduction from other locations and large 778 gathering with consequent super-spreading not accounted for by the model. In Figure 2 . CC-BY-ND 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 29, 2021. Comparison between reactive and non-reactive vaccination strategies: 798 sensitivity analysis 799 We compare here reactive vaccination with non-reactive vaccination strategies under a 800 variety of epidemic scenarios. 801 . CC-BY-ND 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 29, 2021. ; https://doi.org/10.1101/2021.07.26.21261133 doi: medRxiv preprint The impact of reactive vaccination and its demand in terms of vaccine doses varies 802 depending on the incidence level. Figure S3 compares reactive and workplaces/universities 803 vaccination in scenarios with variable initial incidence. As initial incidence increases the 804 reduction in the attack rate due to workplaces/universities vaccination diminishes, while the 805 one due to reactive vaccination slightly increases. Therefore, the advantage of the reactive 806 vaccination compared with the other strategy increases. This is explained by the dynamic 807 adaptation of reactive vaccination to the epidemic situation: the higher the incidence is, the 808 more vaccines are deployed. Figure S4 shows how the relative reduction of the attack rate after two months changes with 815 transmission, immunity level of the population, fraction of adults initially vaccinated, reduction 816 in contacts due to social distancing, vaccine efficacy and time needed for the vaccine to 817 become effective. Here we consider the high incidence scenario (Figure 2A -C of the main 818 paper) and we compare mass and reactive strategies assuming the same vaccine uptake. 819Increasing the transmissibility (panel A) has no significant effect on the efficacy of vaccination 820 for all strategies considered. Panel B and C show that decreasing the initial proportion of 821 susceptible, due to increasing either natural immunity or initial vaccination coverage, reduces 822 the impact of all vaccination strategies. In particular, reactive vaccination has a limited effect 823 when the initial vaccination coverage is high, as the number of people remaining to vaccine is 824 limited. In panel D we explore the impact of teleworking and reduction in community contact 825 by comparing the baseline scenario with a scenario with no restrictions. Impact of non-826 . CC-BY-ND 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. 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 29, 2021. . CC-BY-ND 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 29, 2021. ; https://doi.org/10.1101/2021.07.26.21261133 doi: medRxiv preprint 970 971 972 . CC-BY-ND 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 29, 2021. ; https://doi.org/10.1101/2021.07.26.21261133 doi: medRxiv preprint