Jakob Zinsstag

Monique Lechenne

Mirjam Laager

Rolande Mindekem

Service Naïssengar

Assandi Oussigéré

Kebkiba Bidjeh

Germain Rives

Julie Teissier

Seraphin Madjaninan

Mahamat Ouagal

Daugla D Moto

Idriss O Alfaroukh

Yvonne Muthiani

Abdallah Traoré

Jan Hattendorf

Anthony Lepelletier

Lauriane Kergoat

Hervé Bourhy

Laurent Dacheux

Tanja Stadler

Nakul Chitnis

Vaccination of dogs in an African city interrupts rabies transmission and reduces human exposure

à la diffusion de documents scientifiques de niveau recherche, publiés ou non, émanant des établissements d'enseignement et de recherche français ou étrangers, des laboratoires publics ou privés.

Introduction

Dog rabies has been eliminated in large parts of the industrialized countries in Europe and North America. In the last few decades, a concerted effort by South and Central American countries has reduced dog rabies transmission close to elimination [START_REF] Hampson | Synchronous cycles of domestic dog rabies in sub-Saharan Africa and the impact of control efforts[END_REF]. Despite the existence of effective vaccines for dogs, dog transmitted human rabies persists and has even re-emerged in Asia and Africa where still more than 59,000 people die annually from this preventable disease. The largest part of the burden is borne by India followed by Africa, China and South East Asian countries [START_REF] Hampson | Global Alliance for Rabies Control Partners for Rabies, Estimating the global burden of endemic canine rabies[END_REF]. Because of rabies' low propensity to transmit secondary infections beyond a bitten individual, it appears feasible to eliminate dog-mediated human rabies through the mass vaccination of dogs [START_REF] Cleaveland | Rabies control and elimination: a test case for One Health[END_REF][START_REF] Hampson | Transmission dynamics and prospects for the elimination of canine rabies[END_REF]. However, reaching this goal in partnership with the World Health Organization (WHO), the Food and Agriculture Organization of the United Nations (FAO), the World Organization for Animal Health (OIE) and the Global Alliance for Rabies Control (GARC, www.rabiesalliance.org) requires a rigorous scientific approach [START_REF] Zinsstag | Towards a science of rabies elimination[END_REF].

Reaching sufficient coverage to interrupt dog rabies virus transmission and prevent reintroduction requires an in-depth understanding of dog ecology, dog-human interactions, and the social and cultural determinants of vaccine acceptability, as well as the effective deployment of vaccines with a highly sensitive surveillance system [START_REF] Hampson | Transmission dynamics and prospects for the elimination of canine rabies[END_REF][START_REF] Kayali | Coverage of pilot parenteral vaccination campaign against canine rabies in N'Djamena, Chad[END_REF](7)[START_REF] Dürr | Owner valuation of rabies vaccination in dogs, Chad[END_REF][START_REF] Talbi | Phylodynamics and human-mediated dispersal of a zoonotic virus[END_REF]. It requires scientists to closely collaborate with authorities and communities as partners in a transdisciplinary way between human and animal health [START_REF] Hirsch Hadorn | Handbook of Transdisciplinary Research[END_REF][START_REF] Charron | Ecosystem approaches to health for a global sustainability agenda[END_REF]. Concomitant mathematical and economic frameworks can yield new insights into fundamental properties of pathogen transmission [START_REF] Townsend | Designing programs for eliminating canine rabies from islands: Bali, Indonesia as a case study[END_REF] and comparative cost-effectiveness [START_REF] Zinsstag | Transmission dynamics and economics of rabies control in dogs and humans in an African city[END_REF] but do not explain sufficiently how this effectiveness can be achieved [START_REF] Klepac | Towards the endgame and beyond: complexities and challenges for the elimination of infectious diseases[END_REF].

In 2003, a smallscale study showed the feasibility of dog rabies control in an African city [START_REF] Kayali | Coverage of pilot parenteral vaccination campaign against canine rabies in N'Djamena, Chad[END_REF] with low cost of US$ 2-3 per vaccinated dog [START_REF] Kayali | Cost-description of a pilot parenteral vaccination campaign against rabies in dogs in N'Djamena, Chad[END_REF]. However, in some African countries, dog owners cannot afford anti-dog rabies inoculations and depend on mass vaccination campaigns that are free of cost [START_REF] Dürr | Owner valuation of rabies vaccination in dogs, Chad[END_REF][START_REF] Jibat | Review on dog rabies vaccination coverage in Africa: a question of dog accessibility or cost recovery?[END_REF]. Analysis of pre-and post-vaccination rabies cases and economic data showed that a single simulated dog vaccination campaign was able to interrupt transmission and was less costly than human post-exposure prophylaxis [START_REF] Zinsstag | Transmission dynamics and economics of rabies control in dogs and humans in an African city[END_REF]. A proof of the feasibility of dog rabies elimination in an African city would have far reaching consequences for a regionally concerted effort to eliminate rabies in Africa.

A city-wide dog rabies mass vaccination campaign was set up in partnership with the Chadian authorities, the Institut de Recherches en Elevage pour le Developpement (IRED), the Centre de Support en Santé Internationale (CSSI) and the Swiss Tropical and Public Health Institute (Swiss TPH) [START_REF] Lechenne | Operational performance and analysis of two rabies vaccination campaigns in N'Djamena, Chad[END_REF]. The Chadian government paid for the costs of personnel and logistics and a philanthropic donor paid for the costs of dog vaccines and research. Passive dog rabies and human exposure surveillance started before the campaigns and is still ongoing. Here, we analyse the passive surveillance data of dogs brought to the diagnostic laboratory from this prior work using mathematical transmission models and phylodynamic analyses of dog-related rabies virus.

We investigate the impact of the vaccination campaigns for interrupting transmission and the potential for maintaining elimination.

Results

Mass vaccination and field data

The vaccination campaign operations are described in detail in a previous publication [START_REF] Lechenne | Operational performance and analysis of two rabies vaccination campaigns in N'Djamena, Chad[END_REF] and summarized in the materials and methods. Vaccination coverage surveys followed each sequence to assess the achieved coverage and the deficit to reach 70% target coverage [START_REF] Lechenne | Operational performance and analysis of two rabies vaccination campaigns in N'Djamena, Chad[END_REF]. In 2012, 72% of all dogs were vaccinated (95% confidence interval 69-76%) and in 2013 70% were vaccinated (95% confidence interval 69-75%).

Our results are based on data obtained about the weekly incidence of dogs newly infected with rabies virus(Fig. 1A) and the incidence of related human exposure (Fig. 1B). These data were collected through passive surveillance, i.e. by suspected dogs that were brought for testing to the rabies laboratory in N'Djaména and through collection of rabies virus isolates from rabid dogs throughout the vaccination campaign, described above. Recorded numbers of vaccinated dogs were used for the estimation of vaccination coverage [START_REF] Lechenne | Operational performance and analysis of two rabies vaccination campaigns in N'Djamena, Chad[END_REF]. These data were used to estimate the effective reproductive number R e (the number of new rabid dogs infected by one rabid dog at any time, accounting for immunity and interventions, estimated from the transmission model) and the threshold population density of susceptible dogs using mathematical models. The data suggested that mass dog vaccination campaigns in 2012 and 2013 reached sufficient coverage to interrupt rabies transmission from January 2014 to October 2014. Dog rabies incidence in the city of N'Djaména, estimated from passive surveillance, dropped from 0.33 rabid dogs / (10 000*week) prior to the mass vaccination campaign to 0.016 rabid dogs / (10 000 *week) in 2014 (Fig. 1A).

Similarly, the incidence of human exposure to rabid dogs, estimated from passive surveillance, dropped from one human exposed to rabies virus / (1 000 000*week) prior to the mass vaccination to less than 0.002 / (1 000 000*week) in 2014, which is less than one person per year (Fig. 1B).

Transmission model

We used a deterministic, population-based model of ordinary differential equations to model rabies virus transmission amongst dogs as well as between dogs and humans (Table S1). The transmission model showed that between the two campaigns in 2012 and 2013, effective recorded vaccination coverage decreased from a peak of 67% (December 2012) [START_REF] Lechenne | Operational performance and analysis of two rabies vaccination campaigns in N'Djamena, Chad[END_REF] to a trough of 33% (October 2013), assuming an exponential distribution for the persistence of immunity, which was estimated from 105 immunized dogs undergoing repeated serological measurements. This represents a 51% relative coverage loss (Fig. 2A). The model suggested that population replacement by the birth of susceptible dogs accounted for 29% of the relative coverage loss, whereas individual dog immunity loss accounted for 22% of this relative coverage loss.

The effectively vaccinated surface area in our campaign of 240 km 2 (2012) was much lower than the 770 km 2 assumed in an earlier simulation [START_REF] Zinsstag | Transmission dynamics and economics of rabies control in dogs and humans in an African city[END_REF]. The empirical data from this study provides a better estimate of parameter values, the threshold density of susceptible dogs and the basic reproductive number, i.e. the number of secondary infections resulting from a typical case in a completely susceptible population, as R 0 = 1.14, instead of R 0 = 1.01. This means that rabies is more infectious in N'Djaména, than previously reported [START_REF] Zinsstag | Transmission dynamics and economics of rabies control in dogs and humans in an African city[END_REF]. The effective reproductive number, R e , decreased from the equilibrium value of 1 from the start of the first vaccination campaign and remained below 1 through November 2014, implying that the conditions for rabies virus persistence were not maintained since the start of the vaccination campaigns. Simulations of a deterministic ordinary differential equation model (Fig. 1), fitted to rabies case data from N'Djaména, and a stochastic extension (Fig. 3) suggested that rabies transmission was interrupted from early 2013 onwards.

As our model did not include importation of infections, we wondered whether dog rabies cases seen from the October 2014 onwards (Fig. 1A) were due to imported cases (with subsequent local transmission) rather than sustained ongoing transmission from the end of 2013 or the beginning of 2014. To test this hypothesis, we performed a maximum likelihood phylogeny of nucleoprotein sequences from rabies virus isolates collected in Chad (from N'Djaména and other regions) from August 2011 to January 2015. Indeed, the dog rabies cases from 2014 onwards were phylogenetically distinct from those previously circulating in N'Djaména (Fig. 4)). We therefore suspected that domestic dogs from surrounding peri-urban and rural areas were the more likely source of reinfection rather than ongoing transmission in dogs or wild animals.

Consistent with this, only dog-related rabies virus strains and no wildlife-related strains were found in a previous rabies virus phylogenetic analysis performed in N'Djaména [START_REF] Durr | Rabies diagnosis for developing countries[END_REF].

Sensitivity analysis

We performed sensitivity analysis to determine whether the simulation results were robust compared to our estimates of parameter values. Figure S1 shows simulation results of the density of infectious dogs over 6 years allowing for uncertainty in each of the parameter values (varied one at a time). In each simulation run, the dog transmission rate, , was refitted for that set of parameter values. The results were robust to uncertainty in the parameter values and except for low vaccine efficacy values, the simulations predicted that transmission would be interrupted after the first campaign. Fig. S2 shows a similar sensitivity analysis of the simulated number of infectious dogs but with a fixed value for the dog transmission rate, , estimated from the baseline set of parameter values (tableTS2). The ranges of the parameter values were greater than in Fig. S1 and the results showed the importance of that parameter on the expected number of rabid dogs over time. Most parameters had little effect, but similar to the sensitivity analysis for , high values for the carrying capacity of dogs and the probability of an exposed dog developing rabies and low values for the rabies induced death rate led to a high number of infectious dogs.

Fig. S3 shows the simulated densities of infectious dogs and exposed humans depending on the probability of detection of infectious dogs, , and of exposed humans, , used to fit and , respectively. Low values of these detection probabilities result in higher numbers of infectious dogs and exposed humans, leading to higher estimates for the dog to dog, , and dog to human, , transmission parameters. The results indicated that the simulation data were robust regarding these detection probabilities unless the probabilities were very low and that underreporting of rabies cases was unlikely to have a substantial effect on our results (Fig.

S 3).

This in turn suggested that underreporting of cases did not play a large role in the persistence of rabies transmission. Even accounting for heterogeneity in underreporting, it was unlikely that unreported transmission persisted for nine months and more likely that a re-introduction occurred, either from wildlife or from dogs with ongoing transmission outside the city of N'Djaména.

Phylodynamic analysis

29 nucleotide sequences encoding the N-protein from dog related rabies virus isolates collected between August 2011 and June 2013 were sequenced as previously described [START_REF] Talbi | Phylodynamics and human-mediated dispersal of a zoonotic virus[END_REF][START_REF] Talbi | Evolutionary history and dynamics of dog rabies virus in western and central Africa[END_REF]. Although the 95% highest posterior density intervals were wide because of the small number of sequences, the effective reproductive number estimated from the genetic data showed the same pattern as the R e estimated from the incidence data (Fig. 2B). We demonstrate thus by two different methods, transmission modelling and a phylodynamic analysis that dog rabies transmission can be interrupted by the mass vaccination of dogs in N'Djaména.

Discussion

The models and data presented here show that the period with no rabies transmission in N'Djaména was longer after mass vaccination campaigns than in the absence of such campaigns, suggesting that dog rabies virus transmission in this African city could be interrupted and consequently human rabies exposure reduced. However, the duration of interruption of transmission in our study was shorter than our model predictions presented here and in earlier work [START_REF] Zinsstag | Transmission dynamics and economics of rabies control in dogs and humans in an African city[END_REF], indicating that there was likely to be a re-introduction of infection from wildlife or latently infected dogs from the adjacent areas, similar to what was reported in a recent study on rabies transmission in Bangui [START_REF] Bourhy | Revealing the Micro-scale Signature of Endemic Zoonotic Disease Transmission in an African Urban Setting[END_REF].

Our study suggested that urban centres may not be hotspots of dog rabies transmission leading to spill over cases in rural areas, as previously thought. Dog rabies transmission is ongoing in periurban and rural African areas and is likely to be continuously transmitted into urban areas through human-mediated transport of dogs [START_REF] Talbi | Phylodynamics and human-mediated dispersal of a zoonotic virus[END_REF]. Sustainable elimination of dog rabies therefore will require action over a much larger geographical area. We have proposed a development impact bond financing scheme for dog rabies elimination in the entire country of Chad [START_REF] Anyiam | Cost-estimate and proposal for a development impact bond for canine rabies elimination by mass vaccination in Chad[END_REF].

There is still considerable uncertainty surrounding the role of density and spatial heterogeneity and external re-introduction in the transmission of dog rabies [START_REF] Morters | Evidence-based control of canine rabies: a critical review of population density reduction[END_REF]. A meta-population or contact network modeling approach may better represent the observed heterogeneity of the dog population in N'Djaména (Fig. S4). Further research is needed to assess how dog density and the spatial heterogeneity of dog populations influences the dynamics of dog rabies elimination [START_REF] Morters | Evidence-based control of canine rabies: a critical review of population density reduction[END_REF][START_REF] Begon | A clarification of transmission terms in host-microparasite models: numbers, densities and areas[END_REF].

Determining the optimal timing of vaccination campaigns in N'Djaména to maintain elimination would require better knowledge of the rabies importation rate into the city. Our results are in line with a recent study from Bangui, Central African Republic showing that rabies is continuously re-introduced in towns by human related transport of dogs from surrounding peri-urban and rural areas [START_REF] Bourhy | Revealing the Micro-scale Signature of Endemic Zoonotic Disease Transmission in an African Urban Setting[END_REF] and rapidly dispersed between cities [START_REF] Talbi | Phylodynamics and human-mediated dispersal of a zoonotic virus[END_REF]. Therefore, we suggest that dog rabies control in African cities should be planned for larger areas, including suburban and rural areas, and be coordinated regionally between neighboring countries for effective elimination of dog rabies in Africa [START_REF] Hampson | Synchronous cycles of domestic dog rabies in sub-Saharan Africa and the impact of control efforts[END_REF]. In particular, movement of dogs with or without their owners should be restricted to limit the rapid dispersal of dog associated rabies virus. Dog mass vaccination campaigns should also be complemented by affordable compulsory dog registration. Our study further supports the need for an improvement and a reinforcement of rabies surveillance in rural and more remote areas to achieve inclusive and comprehensive rabies reporting that can then be used to guide vaccination decisions. New rapid tests for rabies could be used in a decentralized manner and may enable collection of data about rabies epidemiology in remote locations [START_REF] Lechenne | Validation of a Rapid Rabies Diagnostic Tool for Field Surveillance in Developing Countries[END_REF].

In contrast to previous reports [START_REF] Durrheim | Mass vaccination of dogs, control of canine populations and post-exposure vaccination--necessary but not sufficient for achieving childhood rabies elimination[END_REF], our study suggests that mass vaccination of dogs, coupled with post-exposure prophylaxis, could be sufficient to eliminate rabies transmission in an Data files  RabiesData1.txt (incidence data)  RabiesData2.txt (genetic sequences of 33 dog rabies virus N-protein deposited in GenBank)

Materials and Methods

Study design

The objective of this study was to test the hypotheses a) that dog rabies virus transmission in an African city can be interrupted by the mass vaccination of dogs and b) that cities are hotspots of dog rabies virus transmission and that re-introduction would be slow. As we observed the reintroduction of dog rabies after the mass vaccination of dogs, we hypothesized that rabies virus was re-introduced from the outside of the city. The research subjects were the weekly number of routinely recorded rabies suspected dogs and the number of exposed humans per rabid dog.

The design of the present study is composed of four main components covering the city of N'Djaména, Chad i): An ongoing passive dog rabies surveillance system. Suspected rabid dogs (dead or alive) were brought to the rabies diagnostic laboratory. No active collection of suspected dogs was done. For every rabies suspected dog, information on exposed humans was collected on a routine basis. ii): A dog rabies mass vaccination campaign was done from October to December 2012 and 2013 [START_REF] Lechenne | Operational performance and analysis of two rabies vaccination campaigns in N'Djamena, Chad[END_REF] Blood was taken from 104 dogs in 2012, prior to the start of the mass vaccination campaign to assess the proportion of existing vaccination antibodies. The Fluorescent antibody virus neutralization test (FAVN) was used for this purpose [START_REF] Cliquet | Development of a fluorescent antibody virus neutralisation test (FAVN test) for the quantitation of rabies-neutralising antibody[END_REF] . Data on rabid dogs and exposed humans was collected up to the end of 2015 for this paper. iii) A mathematical transmission model of dog to dog and dog to human rabies transmission was parametrized from the weekly number of rabid dogs and exposed humans collected under i)

prior, during and after the mass vaccination campaign (ii). iv) A phylogenetic and phylo-dynamic analysis of the rabies virus strains collected under i) was used to assess their genetic closeness and to estimate the basic reproductive number of the rabies transmission in dogs independently from the mathematical transmission model (iii).

Surveillance of dog rabies and human exposure

Passive routine dog rabies surveillance started on 4 June 2012 and is currently ongoing in N'Djaména at the Institut de Recherches en Elevage pour le Développement by standard immunofluorescence as described in [START_REF] Zinsstag | Transmission dynamics and economics of rabies control in dogs and humans in an African city[END_REF][START_REF] Kayali | Incidence of canine rabies in N'Djamena, Chad[END_REF] . Prior to the mass vaccination campaign, the average weekly incidence of dog rabies was of 0.33 dogs per 10,000. For every laboratoryconfirmed rabid dog, on average 1.6 humans were reported to be exposed (from questioning the dog owner) leading to a weekly incidence of 0.11 per 100,000 people.

Dog rabies mass vaccination campaign 2012 and 2013

A citywide mass dog vaccination campaign including all 10 districts of N'Djaména took place in 2012 and was repeated in 2013. In both campaigns, the objective was to vaccinate 70% of the total dog population of N'Djaména with the dog rabies vaccine Rabisin TM (Merial Inc. Lyon, France). The vaccination campaigns began in the first week of October 2012 and 2013 and lasted for a total of 13 weeks until the first week of January of the next year. Vaccination took place only on Friday to Sunday due to availability of staff and participation of the public during these days (as evaluated in previous studies) [START_REF] Kayali | Coverage of pilot parenteral vaccination campaign against canine rabies in N'Djamena, Chad[END_REF]. Every Friday to Sunday, ten fixed post vaccination teams were set up in one of 12 (13 in 2013) areas of the city corresponding to administrative boundaries. Over the three day period, these teams vaccinated on average 1,433 (min. 24; max.

6,460) dogs in 2012 and 1,709 dogs (min. 67; max. 4,591) dogs in 2013, depending on the sociocultural and ecological context of the city district (Table 1). Details of the operational performance and the results of the vaccination campaigns are published elsewhere [START_REF] Lechenne | Operational performance and analysis of two rabies vaccination campaigns in N'Djamena, Chad[END_REF] .

Coverage assessment

A coverage assessment was carried out each week after vaccination in the previously vaccinated area Fig. S4. Vaccination zones and their analysis perimeter corresponded in most cases to a district. The coverage assessment was composed of a household survey in randomly selected geographical locations within the analysis perimeter to estimate the proportion of owned vaccinated dogs. In addition, random transects were carried out with a car in the same zone to estimate the dog density in the street and the proportion of ownerless dogs. Data from both studies were then combined in one Bayesian statistical model as reported elsewhere [START_REF] Lechenne | Operational performance and analysis of two rabies vaccination campaigns in N'Djamena, Chad[END_REF] .

Description of mathematical model of dog-dog and dog-human transmission

We use a deterministic population based model of ordinary differential equations extended from a previously published model for dog to dog rabies transmission [START_REF] Zinsstag | Transmission dynamics and economics of rabies control in dogs and humans in an African city[END_REF],

where the state variables and parameters are defined in Tables S1 andS2 respectively. The total dog population size is, and the density dependent death rate is, where is described in Table S2 and is required to be greater than . We note here that we assume density-dependent transmission and that in general, (1) is a non-autonomous model where varies with time, where is the (assumed) constant background vaccination rate, and are campaign-dependent vaccination values for the th week, and is a saturation parameter. Outside of the campaigns, . We further restrict the values of and to ensure that is continuous so that the system for rabies transmission (1) has a unique solution that exists for all time.

We similarly use an ordinary differential equation model for dog to human transmission based on [START_REF] Zinsstag | Transmission dynamics and economics of rabies control in dogs and humans in an African city[END_REF] , where the total human population size is, is the rate of progression from the exposed to the infectious state depending on the site of the bite, is the abortive rate of progression from the exposed back to the susceptible state, and the probabilities of biting different parts of the body ( through ), the probabilities of subsequent progression to rabies ( through ), and the average time to do so ( where is head, arm, trunk or leg), are described in more detail in the previous formulation of the model [START_REF] Zinsstag | Transmission dynamics and economics of rabies control in dogs and humans in an African city[END_REF]. Fig. S5 shows a schematic of the model system. We note that the dynamics for rabies transmission in humans is dependent on rabies transmission in dogs but the transmission in dogs is independent of transmission in humans.

Mathematical analysis

In the absence of vaccination campaigns ( ), the autonomous mathematical model for rabies transmission in dogs (1) has a trivial disease-free equilibrium point,

The control reproductive number for the dog rabies model is the number of dogs that one newly introduced rabid dog would infect, assuming no disease in the population (with only background vaccination),

We omit the mathematical details here but can show that with only background vaccination (no vaccination campaigns) when , the disease-free equilibrium point ( 9) is locally asymptotically stable and when , the disease-free equilibrium point is unstable and there exists a locally asymptotically stable endemic equilibrium point where rabies persists in the population. Additionally, if there is no background vaccination, the control reproductive number reduces to the basic reproductive number, At any time, , allowing for vaccination campaigns, the effective reproductive number, , represents the expected number of new infections caused by one infectious dog, [START_REF] Hirsch Hadorn | Handbook of Transdisciplinary Research[END_REF] If we assume that the total dog population is at carrying capacity (which is reasonable because the density of rabid dogs is low so has a minimal impact on the population density of dogs), the effective reproductive number simplifies to,

Dog vaccination rate

The baseline study found that 12% (n=105) of all owned dogs had antibodies (and so could be considered effectively vaccinated), implying that there was some ongoing background vaccination outside of the two campaigns conducted in 2012 and 2013. The coverage assessment estimated that for every 10 owned dogs, there was one unowned dog. Assuming that the background vaccination rate was constant and the proportion of vaccinated dogs was at equilibrium ( 9), with demographic and other vaccination parameters as in table S2, the per capita background vaccination rate was /week.

The number of dogs marked as vaccinated in each campaign is shown in Table 1. We estimated the vaccination rate parameters, and using a simple model of vaccination for each campaign, where is the density of all unmarked dogs, is the density of dogs marked in campaign week , and is the rate of marking dogs during campaign week . We define time, , as varying from at the start of each campaign week to at the end of each campaign week.

The coverage assessment could only determine whether dogs were marked as vaccinated or not and did not determine the immune status of dogs. We therefore ignore the efficacy of the vaccination and do not consider background vaccination because these dogs would not be marked as campaign-vaccinated dogs, so

For simplicity we ignore rabies virus transmission, assume the dog population is at carrying capacity, and ignore the death of marked dogs or the loss of marking collars during the campaign week. Since the coverage assessment was conducted within three days of the vaccination campaign, these assumptions are reasonable. We assume that the markings from the 2012 campaign do not last until 2013 so for both campaigns, the initial density of unmarked dogs is equal to the carrying capacity,

and from continuity,

The initial density of dogs marked during a campaign week is zero, We fix . To ensure that is continuous, we set

The final density of dogs marked in a campaign week, is set equal to the number of marked dogs estimated from the coverage assessment for that week (Table 1) divided by the campaign area for that year (240km 2 in 2012 and 285km 2 in 2013). Condition [START_REF] Durr | Rabies diagnosis for developing countries[END_REF] and the ordinary differential equations for the vaccination model ( 16) with its boundary conditions provide two sets of equations for each campaign week. For other parameter values as provided in table S2, we numerically simulate the vaccination model using an adaptive step-size Runge-Kutta method (ode45) and then use a root-finding algorithm (fzero) to calculate and (in MATLAB, version 8.5) for each campaign week. Fig. S6 shows the final estimated vaccination rates during the two campaigns.

Rate of loss of vaccine immunity

In 2012, before the vaccination campaigns were conducted, a total of 105 dogs in N'Djaména were tested for antibody titers, vaccinated and then followed up over a period of one year. Of these dogs, 58 had initial antibody titers that showed no previous vaccination and were successfully followed up over the entire year. After one year, 44 dogs had antibody titers above 0.5 IU, which, as a conservative estimate, we considered protective [START_REF] Moore | Rabies-specific antibodies: measuring surrogates of protection against a fatal disease[END_REF]. We calculated the rate of loss of vaccine decay, , assuming exponential decay and a relative value of 0.76 after 52

weeks.

Rabies transmission rates

The number of rabid dogs and exposed humans recorded per week since 4 June 2012 are shown in the additional file RabiesData1.txt. Recording of both human and dog cases is ongoing but the analysis only included cases until the end of October 2015. We divide the numbers of dogs and humans by the area estimated in the coverage assessment of the 2012 vaccination campaign (240 km 2 ) to provide the densities of rabid dogs and exposed humans.

We first fit the dog to dog transmission rate, , for the model with transmission only in dogs [START_REF] Hampson | Synchronous cycles of domestic dog rabies in sub-Saharan Africa and the impact of control efforts[END_REF] with the data for the number of rabid dogs with other parameter values as described in table S2 and the vaccination rate as described above. We then use this value for to estimate the dog to human transmission rate, , for the full model with transmission between dogs [START_REF] Hampson | Synchronous cycles of domestic dog rabies in sub-Saharan Africa and the impact of control efforts[END_REF] and to humans [START_REF] Zinsstag | Towards a science of rabies elimination[END_REF] with the data for number of exposed humans.

To fit , we numerically simulate (1) using an adaptive step-size Runge-Kutta method and minimise the Euclidean distance between the simulated incidence of infectious dogs (from the first term of the right hand side of (1c)), and the observed weekly incidence of infectious dogs in MATLAB. We assume that the probability of detecting a rabid dog, so that on average there were twice as many rabid dogs as those detected. There is little data on this parameter but our sensitivity analysis showed that unless is very low, the estimated values for did not change much (Fig. S3). We assume that the initial condition for the ordinary differential equations in June 2012 is at the unique endemic equilibrium (with ) and the dog density is at carrying capacity.

We similarly fit by numerically simulating (1) and ( 5) and minimising the Euclidean distance between the simulated density of exposed humans, , and the observed density of exposed humans on a weekly time step in MATLAB. Here we assume perfect detection of exposed humans ( ) and that the initial condition in June 2012 is at the unique endemic equilibrium with a population density of humans of 4833 humans/km 2 (from a total population size of 1.16 million in 2012 estimated from the 2011 population size of 1.079 million using a growth rate of 7.5% ) (35,[START_REF]Deuxième recensement général de la population ed de l'habitat[END_REF].

Phylogenetic importation analysis

To investigate the hypothesis of a reintroduction of dog rabies virus in N'Djamena from outside of the city after the vaccination campaigns, we performed a phylogenetic analysis using the previously described 29 complete nucleoprotein sequences of rabies virus isolates collected between August 2011 and January 2014, with the inclusion of one supplementary sequence of a isolate collected during this period (GenBank accession number KY124541), in addition to the sequences of the three first isolates collected in the city after this period (from February 2014 to January 2015, GenBank accession numbers MF538629-31) and to published available sequences from Chad (n=1) and from neighboring countries (n=14). Using jModelTest2 [START_REF] Darriba | jModelTest 2: more models, new heuristics and parallel computing[END_REF][START_REF] Guindon | A simple, fast, and accurate algorithm to estimate large phylogenies by maximum likelihood[END_REF], the best-fit model of nucleotide substitution according to the Bayesian Information Criterion was the general where is any state of the system at time and are the transmission rates deduced from the parameters in table S2, using the Gillespie algorithm with the tau-leaping simulation method [START_REF] Gillespie | Exact stochastic simulation of coupled chemical reactions[END_REF][START_REF] Cao | Efficient step size selection of the tau-leaping simulation method[END_REF] . Fig. S8 shows a sample stochastic simulation of the density of exposed and infectious dogs with the corresponding simulation of the deterministic model and the underlying data for the number of infectious dogs. Fig. 3B shows that the mean of 500 simulation runs of the stochastic model declines after the first vaccination campaign in a similar manner to the deterministic model.

Phylodynamic analysis

29 sequences of canine rabies viruses, collected between August 2011 and June 2013, were analysed with Beast v2 [START_REF] Bouckaert | BEAST 2: a software platform for Bayesian evolutionary analysis[END_REF]. We chose a Hasegawa-Kishino-Yano (HKY) model for substitutions with a relaxed log-normal clock [START_REF] Drummond | Relaxed phylogenetics and dating with confidence[END_REF]. We assumed an exponential prior for the mean rate, an exponential prior for the standard deviation, and a log-normal prior for kappa.

For the epidemiological model, we chose the birth-death skyline model [START_REF] Stadler | Birth-death skyline plot reveals temporal changes of epidemic spread in HIV and hepatitis C virus (HCV)[END_REF] . We used a log normal prior for the effective reproductive number, , and allowed to change in January 2013, August 2012, and April 2012, i.e. every 4.8 months prior to the last sample in June 2013. We assumed a uniform prior on the interval for the dog removal rate (corresponding to an expected infection time of exposed and active rabies between years, which is about months. The sampling probability of a rabid dog was assumed to be prior to the first sample, and uniform on between the first and last sample. The time of the initial case in that transmission chain was assumed to be a uniform prior on , prior to the most recent sample. We ran the Markov chain Monte Carlo (MCMC) simulations for steps. We neglected the first 10% of the states as a burn-in period. The effective sample size of all parameters was 350 or higher, implying that we obtained substantial mixing.

In order to investigate sensitivity towards our assumption of a constant sampling proportion, we performed a second analysis allowing the sampling proportion to change at the same time points as when the changes. As above, sampling was assumed to be 0 prior to the oldest sample.

Further sampling was assumed to be uniform on in each interval (compared to uniform on above. As shown in fig. S9 the results do not change qualitatively.

Limitations of the study

The study is limited by the low number of rabies viruses that were isolated during the rabies mass vaccination campaign. For this reason, the credibility intervals of the phylodynamic estimation of the basic reproductive number are wide. Another limitation is that we could not clearly identify the source of the rabies viruses that were re-introduced from outside the city. Further ongoing research will relate the rabies viruses collected in N'Djamena in this study with strains that will be collected countrywide.

Figures Fig. 1

 1 FiguresFig.1(A) Cumulative incidence of dog rabies cases and human exposure. Cumulative incidence

  Fig.1(A) Cumulative incidence of dog rabies cases and human exposure. Cumulative incidence

Fig. 2 (Fig. 3 (Fig. 4 :

 234 Fig. 2 (A) Density of vaccinated and unvaccinated dogs in relation to the effective reproductive

Table 1 .

 1 Number of dogs vaccinated in each week of the vaccination campaigns. The campaign 764

	762	Tables
	763
	765	in 2012 started on 8 October 2012 (week 19) and in 2013 started on 30 September 2013 (week
	766	70), as described in (23).
	767
		Vaccination Week Vaccinated dogs (2012) Vaccinated dogs (2013)
		1	834
		2	181
		3	376
		4	24
		5	793
		6	2901
		7	6460
		8	1393
		9	3074
		10	1698
		11	311
		12	385
		13	209
	768

Acknowledgements:

We thank all the community leaders and vaccinators in N'Djaména. We thank Thomas Smith for helpful comments and discussions, and anonymous reviewers for helpful comments and suggestions. There is no paid or unpaid consulting and there are no patents related to this work.

Funding:

Funding for this study was provided by the Chadian government, the UBS Optimus Foundation and the Swiss Federal Food Safety and Veterinary Office (FFSVO), the European Union Seventh Framework Programme PREDEMICS (grant #278433), the Wolfermann-Nägeli Foundation, the Emilia Guggenheim Schnurr Foundation and the Swiss National Science Foundation (grant#: 310030_160067 / 1).

Support was provided by the UBS Optimus

Foundation (M.Le, R.M.), the Swiss Federal Food Safety and Veterinary Office (FFSVO) (M.Le.), the Wolfermann-Nägeli Foundation (M.Le.), Swiss Nationals Science foundation grant number 310030-160067 (M. La.),. and the European Research Council under the Seventh Framework Programme of the European Commission (PhyPD: grant agreement number 335529)(T.S.). Requests for rabies virus strains require a Material Transfer Agreement and should be sent to Service Naissengar Institut de Recherches en Elevage pour le Développement, BP 433, N'Djaména, Chad email : naissengar@gmail.com

Data and materials availability:

The dog and human rabies incidence data and the genetic sequences of 29 dog rabies virus N-

African city, both in dogs and humans, as long as vaccination is extended to a larger area beyond the city itself. In the long term, eliminating the infectious rabies reservoir in dogs will be more cost-effective than perpetual post or pre exposure prophylaxis in humans [START_REF] Mindekem | Cost Description and Comparative Cost Efficiency of Post-Exposure Prophylaxis and Canine Mass Vaccination against Rabies in N'Djamena, Chad[END_REF]. Dog vaccination campaigns will require a regional approach similar to the well-coordinated dog rabies control efforts among Latin American countries [START_REF] Hampson | Synchronous cycles of domestic dog rabies in sub-Saharan Africa and the impact of control efforts[END_REF]. The recent creation of the Pan African Rabies Control Network (PARACON, paracon.rabiesalliance.org) is an important first step towards the goal of eliminating dog rabies from Africa by 2030.

Supplementary materials Supplementary Figures

Supplementary Figure 1 where all parameters are fixed at values described in Table 3 except for the parameter being varied (β_dd is fixed at 0.0292). The x-axis shows the time in weeks and y-axis shows the value of the parameter (in its corresponding units). The colour of each pixel represents the density of infectious dogs.

Supplementary Tables

Supplementary Table 1: State variables of dog rabies transmission (model) Supplementary Table 2. Parameters of the rabies transmission model with estimated values and sources. Most parameters have the same value as in the previous model ( 14), but some have been updated from more recent publications or from new data from the current study (as described in the section on parameter estimation). [START_REF] Charron | Ecosystem approaches to health for a global sustainability agenda[END_REF] The threshold density of susceptible dogs at which transmission occurs, is the density at which . From [START_REF] Charron | Ecosystem approaches to health for a global sustainability agenda[END_REF], outside of vaccination campaigns this is,

The threshold vaccination coverage reached in a campaign to eliminate transmission, , is given by, when background vaccination takes place outside the campaign. Equivalently this is, After the vaccination campaigns, the coverage of protected dogs decreases exponentially due to population loss of susceptible dogs (proportionally : 57% for parameter values in table S2) and due to loss of vaccine efficacy (proportionally : 43% for parameter values in table S2).

Parameter estimation

The values for most parameters are taken from the previous model ( 14) except where new published results or new data have allowed for revised values. The parameter values and their sources are summarised in table S2. The birth and death rates of dogs were calculated as in previous work but the carrying capacity of dogs was revised to reflect a total population of 25,103 dogs in an area of 240km 2 as estimated in the 2012 coverage assessment. The vaccination rate of dogs and the transmission rates from dogs to dogs and dogs to humans were estimated as described below.

time reversible model with proportion of invariable sites plus gamma-distributed rate heterogeneity (GTR+I+Γ4). A phylogenetic tree was then estimated using the maximum likelihood (ML) method available in PhyML 3.0 (39) utilizing SPR branch-swapping. The robustness of individual nodes on the phylogeny was estimated using 1,000 bootstrap replicates and using the approximate likelihood ratio test (aLRT) with SH-like supports [START_REF] Anisimova | Approximate likelihood-ratio test for branches: A fast, accurate, and powerful alternative[END_REF].

Sensitivity analysis

We conducted local and global sensitivity analysis of the control reproductive number, , [START_REF] Zinsstag | From "one medicine" to "one health" and systemic approaches to health and well-being[END_REF] to the model parameters (Fig. S7). We used the normalized forward sensitivity index for the local analysis [START_REF] Chitnis | Determining important parameters in the spread of malaria through the sensitivity analysis of a mathematical model[END_REF][START_REF] Arriola | Mathematical and statistical estimation approaches in epidemiology[END_REF] at the parameter values defined in table S2 and the partial rank correlation coefficients for the global analysis [START_REF] Wu | Sensitivity analysis of infectious disease models: methods, advances and their application[END_REF], assuming all parameters were uniformly distributed in the intervals: ,

. Both the local and global analysis showed that the probability of developing rabies, , the transmission rate, , the carrying capacity, and the rabies virus induced mortality rate, , had a strong impact on the threshold for sustained transmission, , while the other parameters had minimal impact.

Stochastic model simulations

We


Narjes Benameur

Ramzi Mahmoudi

Asma Ammari

Younes Arous

Rachida Saouli

Mohamed Hédi Bedoui

Mohamed Hedi Bedoui

Data Analysis to investigate the correlation between myocardial injury and SARS-CoV-2 mortality rate

Keywords: SARS-CoV-2, Cardiovascular disease, mortality rate, myocardial injury

Introduction

The first outbreak of Coronavirus SARS-CoV-2 was reported in Wuhan, China, in December 2019. It was responsible for more than 54 million confirmed infection cases, including 1,318, 286 deaths spread over more than 217 countries on five continents until November 2020 [START_REF]Coronavirus disease (COVID19) outbreak[END_REF]. The most common symptoms of SARS-CoV-2 are fever, respiratory problems, fatigue and a dry cough. Some patients present with pain, nasal congestion, runny nose, sore throat or diarrhea. These symptoms are generally mild and appear gradually. In addition, some other infected people do not manifest any symptoms [START_REF]Coronavirus disease (COVID19) outbreak[END_REF].

The transmission of covid-19 from one person to another is effortless and fast by respiratory droplets expelled from the nose or mouth when a person coughs or sneezes. These droplets can be found on objects or surfaces around the person. It is possible to contract SARS-CoV-2 if you touch these objects or surfaces and then touch your eyes, nose or mouth. SARS-CoV-2 can also be transmitted by inhaling droplets from a sick person who has just coughed or sneezed [START_REF] Mackenzie | COVID-19: a novel zoonotic disease caused by a coronavirus from China: what we know and don't[END_REF]. Since this virus appearance, all the laboratories of the world have been busy looking for a treatment or a vaccine against SARS-CoV-2. Nothing can prove that there is an effective vaccine usable against this infection [START_REF] Sahin | COVID-19 vaccine BNT162b1 elicits human antibody and TH1 T cell responses[END_REF]. On March 24, 2020, the World Health Organization (WHO) declared that people with cardiovascular diseases might be the most vulnerable to infection with SARS-CoV-2. This can be explained by the fact that SARS-CoV-2 enters cells via protein receptors called angiotensin-converting enzyme 2 (ACE2), expressed in the lungs and in the myocardium which is the site of cardiac contraction [START_REF] Verdecchia | The pivotal link between ACE2 deficiency and SARS-CoV-2 infection[END_REF]. Moreover, the presence of SARS-CoV-2 in the lung results in inadequate oxygen supply to the myocardium, which contributes to a cardiac injury. Therefore, this virus appears to have a particular impact on the cardiovascular system and, more specifically, on the myocardium's contractile capacity [START_REF] Guo | Cardiovascular Implications of Fatal Outcomes of Patients with Coronavirus Disease 2019 (COVID-19)[END_REF].

This paper aims to study the relationship between myocardial injury and mortality rate from SARS-CoV-2.

The paper is organized as follows: Section 2 describes the material and method. Section 3 deals with the statistical analysis used to evaluate the correlation between mortality rate and myocardial injury. Section 4 presents the outcomes of this study that will be discussed in section 5. Section 6 concludes this work.

Materials and Methods

Fifty patients with confirmed SARS-CoV-2 who had previously undergone CT study were retrospectively included in the study (30 patients had a history of CVD and 20 patients did not). Twenty-nine patients Table1: baseline characteristic of patients with SARS-CoV-2 with CVD history suffered from myocardial injury while one patient presented with atrial fibrillation.

The mean age was 45±17 years and 43.7% of the studied patients were women, while 56.3% were men. All clinical, radiological characteristics and outcome data during the hospital admission were collected. In this study, elevated cardiac troponin and NTerminal-proBNP (NT-proBNP) levels were used as biomarkers for cardiac injury [START_REF] Yancy | ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines[END_REF]. All clinical characteristic of studied patients with SARS-CoV-2 are summarized in table 1

Statistical analysis

The quantitative variables were expressed as mean ± standard deviation (SD) or as median and interquartile range. Linear regression and bland-Altman analysis were used to evaluate the association between myocardial injury biomarkers and mortality rate. The entire statistical analysis was performed using IBM-SPSS Statistics (Windows, version 21.0).

Results

In total, 55 patients with SARS-CoV-2 were included in this study. Among them, 46 patients (83.63%) fully recovered and were discharged while 9 patients (16.36%) died. Mortality rate was 12 % (3 of 25) for patients without a CVD history, and 20 % (6 of 30) for those with a CVD history (see fig. 1).

Additionally, Patients with CVD were more likely to show elevated troponin levels (73.3% (21/30) Vs. 44% (11/25)) compared to those without CVD. Similarly, plasma NT-proBNP levels were higher for patients with CVD.

Table2: Cardiac troponin and NT-proBNP levels for SARS-CoV-2 patients with and without CVD. This outcome was confirmed by Bland-Altman analysis (see fig. 2) that revealed troponin levels were higher in patients with CVD history than those without cardiac complications. (Mean difference = + 19.24 ng/l). injury biomarkers and the outcomes of SARS-CoV-2 patients, two experts participated as independent readers in this study. First, the outcome of each patient was collected at the end of hospital admission. The studied population was classified into two categories: patients without myocardial injury and patients with myocardial injury.

After that, the SARS-CoV-2 severity for each patientcategory was quantified by two radiologists based on the CT images findings and the outcome data. A five-point scale was used to score the severity as 1: without complications, 2: mild complications, 3: moderate complications, 4: severe complications, and 5: death. During this study analysis, 9 patients died, 42 completely recovered, while 4 patients were still hospitalized.

A total of 14 out of the surviving patients with myocardial injury (n=24) developed a severe complication during hospitalization while nine had a moderate complication. A mild severity was observed only for one patient. Additionally, the analysis showed that 22 patients without CVD history recovered. The majority of cases showed mild (n= 11) and moderate complications (n=8), while three patients developed severe complications. Another interesting finding was that among the patients without CVD history, two patients died after developing acute myocardial injury while one died from respiratory failure.

Discussion

Fig. 3 Bland-Altman (BA) diagrams show the agreement between the plasma NT-proBNP levels in patients with and without myocardial injury.

Similarly, the results showed a discrepancy of plasma NT-proBNP values between the two categories of patients .NT-proBNP levels are higher in patients with myocardial injury (see fig. 3).

Correlation between myocardial injury biomarkers and the outcomes of diseased patients

In order to quantify the relationship between myocardial 3

In this study, we demonstrate that there is an association between myocardial injury and mortality rate for patients with SARS-CoV-2. This association can be explained by the fact that ACE2 is extensively expressive in the myocardial muscle. Previous studies have demonstrated that cardiac diseases are associated with a high risk of death in patients with SARS-CoV-2 [START_REF] Chen | Clinical characteristics of 113 deceased patients with coronavirus disease 2019: a retrospective study[END_REF][START_REF] Zou | Cardiac Injury and COVID-19: A Systematic Review and Meta-analysis[END_REF]. Gao et al. [START_REF] Gao | Prognostic value of NT-proBNP in patients with severe COVID-19[END_REF] showed a relationship between cardiac complications and the risk of mortality in COVID-19 patients. Their study used the plasma NT-proBNP level of 54 infected patients as a biomarker of myocardial dysfunction. A recent study demonstrated that cardiac troponin levels increased in patients with SARS-CoV-2 [START_REF] Tersalvi | Elevated Troponin in Patients With Coronavirus Disease 2019: Possible Mechanisms[END_REF]. Other studies investigated the relationship between different forms of cardiac complication and SARS-CoV-2. However, the majority included a heterogeneous population of patients with SARS-CoV-2, including several cardiac complications [START_REF] Chen | Comparison of predictive values of high-sensitivity cardiac troponin T and Nterminal prohormone brain natriuretic peptide to assess mortality in elderly inpatients[END_REF]. Additionally, most advanced studies used a single biomarker as a predictor of myocardial injury. For this reason, more biomarkers of myocardial injury are needed to confirm the results [START_REF] Wu | Relationship between high-sensitivity cardiac troponin T and the prognosis of elderly inpatients with non-acute coronary syndromes[END_REF].

In the present analysis, we used elevated levels of cardiac troponin and NT-proBNP as biomarkers for cardiac injury. Our research outcomes showed that the levels of NTerminal-proBNP and cardiac troponin increased considerably in SARS-CoV-2 patients with myocardial injury. This suggests that the measurement of these two biomarkers is necessary for patients with SARS-CoV-2 during hospital admission.

The analysis of the relationship between myocardial injury biomarkers and the outcomes of SARS-CoV-2 patients shows that patients with myocardial injury are more likely to develop severe and moderate complications compared to those without CVD history, namely acute respiratory distress syndrome and arrhythmias.

Another consistent finding was that SARS-CoV-2 is likely to promote the appearance of severe cardiac complications, including myocardial injury and arrhythmias.

Conclusion

The outcomes of this study demonstrated that there was a strong association between myocardial injury and the worst outcomes of patients with SARS-CoV-2. From this scientific analysis, we can conclude that mortality rate is associated with higher levels of NTerminal-proBNP and cardiac troponin. This study revealed that SARS-CoV-2 could also contribute to the development of myocardial injury. However, further studies on a larger population should be conducted to confirm these findings.

  NT-proBNP (per 85 [20-197] 403[201-903] 100 pg/ml) troponin levels 14.78 [11-69] 46.91 [10-98] (ng/l) *Values are expressed as median and interquartile range.

Fig. 1

 1 Fig.1 Mortality rate for SARS-CoV-2 patients with /without myocardial injury.

Fig. 2

 2 Fig.2 Bland-Altman (BA) diagrams of troponin values showing the mean difference (solid line) and the upper and lower limits of agreement between troponin levels in patients with and without myocardial injury.

  :

	Characteristics	Total (n=55)
	Male/ femme	31/24
	Mean age (years)	47±17
	Temperature (°C)	37.7 []
	Pulse (/min)	81[]
	History of CVD	30 (54.54 %)
	Hypertension	8 (14.54)
	Diabetes	5 (9%)
	Smoking history	11 (20 %)
	Autoimmune diseases	2 (3.6%)
	NT-proBNP, per 100 pg/ml	243[37.9-837]
	troponin level (ng/l)	68 [6-98]


Nihed Yousfi

Ramzi Mahmoudi

Mohamed Hedi Bedoui

Potential correlation

Keywords: BCG, COVID-19, Correlation, Tunisia, Switzerland

published or not. The documents may come

Introduction

On 11 February 2020, the World Health Organization announced the official name of the disease causing the 2019 epidemic, first identified in Wuhan, China. The new name of the disease is Coronavirus 2019, abbreviated to COVID-19.The disease was responsible for 53,588,016 confirmed infection cases, including 1,306,803 deaths that spread in more than 180 countries on 5 continents until October 25, 2020 [START_REF] Coutinho | Adequate, reliable and timely information in times of the COVID-19 pandemic[END_REF]. The virus that causes COVID-19 is most often spread between people who are in close contact with each other (within a radius of about 1.80 m, or 2 arm lengths).

In general, individuals at increased risk include: Seniors and people of any age with certain underlying diseases [START_REF] Sharjeel Sofi | Coronavirus COVID-19: A critical review of its history, pathogenesis, transmission, diagnosis and treatment[END_REF][START_REF] Robert | Estimates of the severity of coronavirus disease 2019:a model-based analysis[END_REF] and a weakened immune system may be vulnerable to covid-19 infection. In this context, the World Health Organization is studying the prevention of tuberculosis and other major infectious diseases in order to fight COVID -19 more effectively and more quickly.

Since the appearance all laboratories worldwide have been trying to find a treatment or a vaccine against covid-19, but until now nothing has proved there is an effective vaccine usable against this disease [START_REF] Ong | COVID-19 coronavirus vaccine design using reverse vaccinology and machine learning[END_REF]. Until a specific vaccine is available, there is evidence that other existing vaccines can be reused. Indeed, Bacillus Calmette-Guérin (BCG), a more than 80-year-old vaccine, is today one of the most used vaccines as it has a proven protective effect against tuberculous meningitis and tuberculosis in children [START_REF] Simona | History of BCG Vaccine[END_REF][START_REF] De Bree | Bacillus Calmette-Guérin-Induced Trained Immunity Is Not Protective for Experimental Influenza[END_REF]. At the outbreak of the pandemic, it was predicted that developing countries would face the highest number of deaths due to poor health infrastructure. Surprisingly, fewer cases were reported in Africa compared to Europe and USA, with the majority of cases recovering with mild illnesses.

The document is organized as follows: section 2 describes the spread of COVID-19 in Tunisia. Section 3 deals with the effects of the BCG vaccine and its policy in Tunisia while section 4 is a comparison between Tunisia and Switzerland. The last section is a conclusion.

COVID-19 in Tunisia

When the first the Corona virus infection was confirmed on March 6, 2020, the Tunisian Ministerial Council reacted quickly to the virus by taking several measures, such as the suspension of future cruises to Tunisia from northern Italy, the implementation of quarantine in the 24 governorates, and other measures, unlike other countries. This led to control the total number of confirmed cases, since the total number reached 980 distributed in all regions on April, where the governorate of Tunis witnessed the highest percentage of confirmed cases, 211 cases, while Jendouba governorate recorded the lowest percentage of confirmed cases (one case) as shown in

BCG vaccination proves protective against viral infections and vaccine in Tunisia

BCG vaccination proves protective against viral infections

Bacille Calmette-Guérin (BCG) is a live attenuated bacterial vaccine derived from M.bovis used since 1921 in humans known by induction of a specific classical immune response leading to protection against tuberculosis [START_REF] Kleinnijenhuis | Bacille Calmette-Guérin induces NOD2dependent nonspecific protection from reinfection via epigenetic reprogramming of monocytes[END_REF] which generally affects the lungs and other organs.t is the "extra pulmonary tuberculosis" (especially to children). Some epidemiological evidence shows that BCG vaccination can have effects on other pathogens like lepers, Buruli ulcer and nontuberculous mycobacterial infections like lymphadenia. It is also used in the treatment of bladder cancer [START_REF] Simona | History of BCG Vaccine[END_REF] and has reduced the death rate from pneumonia up to 50% in children under one year of age. The World Health Organization (WHO) recommends this vaccine at birth or as soon as possible after birth. In addition to its specific effects on target diseases, several studies have shown that there are other non-specific effects BCG vaccines.

In fact, evidence shows in the first place that BCG vaccination can induce adaptive trained immunity, non-specific protection against infections and also an immune response during reinfection explained by a (functional) reprogramming of innate immune cells. [START_REF] Kleinnijenhuis | Bacille Calmette-Guérin induces NOD2dependent nonspecific protection from reinfection via epigenetic reprogramming of monocytes[END_REF] Thus a non-specific response at the level of heterologous Th1 / Th17 responses one year after vaccination produces heterologous immunity which has beneficial effects observed on perinatal immunity [START_REF] Kleinnijenhuis | Long-Lasting Effects of BCG Vaccination on Both Heterologous Th1/Th17 Responses and Innate Trained Immunity[END_REF]. However, this vaccine is not rec-ommended for people infected with HIV (human immunodeficiency virus) or pregnant women because of the damage it can cause [START_REF] Simona | History of BCG Vaccine[END_REF].

BCG vaccine in Tunisia

After independence on February 4, 1959, the Secretary of State for public health and affairs took a decision concerning vaccination with BCG. Indeed this vaccination became one of the compulsory vaccines in Tunisia with three doses, a first dose of BCG for all newborns, a BCG booster at 6 years of age, a second booster at 12 and a third booster at 18. In 1996, the Tunisian vaccination schedule was reviewed and the booster shots at 12 and 18 were removed from the calendar and a single booster dose at 6 was maintained. Another revision of the Tunisian vaccination calendar took place in 2006 when the Tunisian ministry of health kept only the dose taken at birth and it suppressed BCG booster shot at 6 years old. Now, the BCG vaccination is carried out in Tunisia only once, at birth [START_REF] Bennasrallah | BCG vaccination and tuberculosis prevention: A forty years cohort study[END_REF].

Discussion

In a country of nearly 8.6 million inhabitants, Switzerland health care system is considered one of the most efficient in the world, according to indicators of life expectancy and patient satisfaction1. Nevertheless, it is also one of the most expensive, with the highest per capita expenditure of the Organization for Economic Cooperation and Development (OECD) countries and one of the highest patient copayments [START_REF] Pietro | [END_REF].

According to world statistics on corona viruses [13], it is noted that there are differences between countries at the level of mortality and the number of confirmed COVID 19 cases from one country to another for several reasons. This difference can be explained on the one hand by the BCG vaccination policy in each country, and in this context, we conducted a comparative study between Tunisia and Switzerland which recorded cases infected with covid-19 but did not have the same BCG vaccination policy.

In Switzerland, it's the first death was recorded on March 6, 2020, but quickly the total number of deaths rose to 2133 due to COVID 19 while the confirmed cases rate was 103653 on October 25, 2020 [START_REF]Coronavirus statistiques nombre de cas coronavirus suisseevolution du nombre de contaminations jour par jour[END_REF], as shown in Fig 3 . BCG vaccination is no longer recommended for permanent residents of Switzerland [14]. Since its entry in 1960, BCG is only authorized for people over 12 years without tuberculosis, newborns and infants only fed to high-risk groups, such as those with tuberculosis in the family. Then, in 1970, there was a revaccination of BCG in children with tuberculosis at 10-12 years old. People who are at most 50 years old were not vaccinated with BCG except those with tuberculosis while the majority of the infected population was of foreign origin. Vaccination was discontinued in 1987 and potentially any person aged 25 to 33 not vaccinated with BCG. From 1996 to 2018, it was recommended to vaccinate BCG only for very specific groups such as newborns and infants under 12 years of age, months at risk of infection and whose parents feed them in areas where the incidence and return of tuberculosis are high and children born prematurely (VLBW), children less than 33 weeks or less than 1500 kg if people under 24 years have not been vaccinated with BCG, except for the groups indicated. [14, 15, 16]. Finally, according to the 2019 vaccination plan in Switzerland [START_REF]Plan de vaccination suisse[END_REF], BCG vaccination for premature babies has been canceled. This policy is explained by the recommendation to vaccinate BCG in Switzerland by a decrease in tuberculosis cases in this country [14].

According to data recorded by the Federal Office of Public Health Affairs (FOPH) in 2017, it appears that 77% of tuberculosis cases of foreign origin, only around 20% of all cases of Swiss origin and 3% of unknown origin [14], it may therefore be concluded that the majority of the population has not been vaccinated with BCG.

Although this is not the case in Tunisia, where he recorded his first death on March 06, 2020, reaching 40 deaths and 103653 cases confirmed by COVID-19 on October 25, 2020 (Fig) [7]. These results are explained by the BCG vaccination pillar in Tunisia. Indeed, it integrates the BCG vaccination policy from 1959 to the present day with some adjustments to the vaccine doses. Until now, BCG vaccination was part of the vaccination calendar in Tunisia applied at birth for all inhabitants [7].

So through this comparison between the two countries based on the number of deaths and the number of confirmed cases confirmed (Fig 4 and

Conclusion

From this scientific analysis represented by a comparison between Tunisia and Switzerland according to the number of registered deaths, the number of confirmed cases and the BCG vaccination policy in the two countries, we note that the mortality rate and the rate of confirmed cases in Tunisia are very low compared to the rates recorded in Switzerland according to statistics from 25 October 2020. Through this result, we can say that there is a possibility of existence of a link between BCG vaccination and the number of deaths due to COVID-19. But this vaccination is not the only factor that can influence this increase in mortality, there are in fact several other factors that can influence the death rate and the spread of the virus in both countries and in the world in general as the age, food and climate.

Fig 1 ,Fig. 1 .

 11 Fig.1. Evolution of confirmed cases in Tunisia by governorate.

Fig. 2 .

 2 Fig.2. Evolution of confirmed cases and deaths in Tunisia.

Fig. 3 .

 3 Fig.3. Evolution of confirmed cases and deaths in Switzerland.

Fig 5 )Fig. 4 .

 54 Fig. 4. Evolution of deaths in Tunisia and Switzerland.

Fig. 5 .

 5 Fig. 5. Evolution of confirmed cases in Tunisia and Switzerland.


L Hofer

D Lasi

M Tulej

P Wurz

M Cabane

D Cosica

M Gerasimov

A Sapgir

Prototype of the gas chromatographmass spectrometer to investigate volatile species in the lunar soil for the Luna-Resurs mission

In preparation for the Russian Luna-Glob and Luna-Resurs missions we combined our compact timeof-flight mass spectrometer (TOF-MS) with a chemical pre-separation of the species by gas chromatography (GC). Combined measurements with both instruments were successfully performed with the laboratory prototype of the mass spectrometer and a flight-like gas chromatograph. The system was tested both with a mix of hydrocarbons and a mixture of noble gases. Due to its capability to record mass spectra over the full mass range at once with high sensitivity and a dynamic range of up to 10 6 within 1s, the TOF-MS system is a valuable extension of the GC analysis. The combined GC-MS complex is able to detect concentrations of volatile species in the soil sample of about 2•10 -9 by mass.

Introduction

To investigate the lunar poles, the Russian Space Agency, Roskosmos, will launch the two spacecraft Luna-Glob and Luna-Resurs landing on these poles in 2015 and 2019, respectively. Since all lunar soil samples available on Earth originate from a restricted area at the lunar near side, close to the equator, the investigation of the lunar poles is of interest for extending understanding of the Moon's composition and history.

The detection and analysis of the volatile species in the lunar soil sample will be performed by a gaschromatography mass spectrometer complex, the GC-MS analytic complex. As a part of this experiment our Neutral Gas Mass Spectrometer (NGMS) was selected to detect and analyse the volatile species in the lunar soil. The NGMS is a time-of-flight type mass spectrometer (TOF-MS) with a grid-less ion mirror (reflectron) integrated in the ion path to enhance mass spectrometric performance [START_REF] Scherer | A novel principle for an ion mirror design in time-of-flight mass spectrometry[END_REF]. The ions are generated out of the neutral gas by electron impact ionisation. The ion optical design of NGMS is based on the P-BACE instrument [START_REF] Abplanalp | A neutral gas mass spectrometer to measure the chemical composition of the stratosphere[END_REF]. A detailed description of the instrument currently under development for the lunar missions can be found in [START_REF] Wurz | A Neutral Gas Mass Spectrometer for the Investigation of Lunar Volatiles[END_REF]. With NGMS, as a TOF-MS, complete mass spectra are recorded at once without the necessity of scanning over the desired mass range. The high cadence of recorded mass spectra allows the accumulation of mass spectra with a large dynamic range of up to 10 6 within 1s integration time. These qualities together with the high sensitivity are needed for the analysis of the gas at the output of a gas chromatographic column (GC), which provides temporal pre-separation of the sample.

An additional feature of NGMS is that it can be operated as a standalone instrument for sampling the tenuous lunar exosphere.

Experimental

GC-MS Setup

The prototype of NGMS is the refurbished mass spectrometer of the P-BACE mission. On the one hand this mass spectrometer was modified to allow an interface with a gas chromatographic column and on the other hand same elements of the ion optics were replaced with prototype parts of the flight design for NGMS. To get significant measurements with the GC-MS prototype, spare units of the gas chromatographic instrument from the Phobos-Grunt mission were used. Available are two GC modules of identical build, one assembled with an MXT-5 chromatographic column for separation of hydrocarbons and one populated with a Carbobond column for noble gas separation. Both modules are equipped with a Thermal Conductivity Detector (TCD).

For sampling reasons a sample loop with a defined volume is filled with the calibration gas mixture. The sample volume in the loop is then injected by the use of a standard sample valve (cf. Figure 1). The injected sample is carried by helium as carrier gas through the gas chromatographic column. In this 30 m of capillary column the gas mix in the sample is separated based on the different retention times of the different species. At columns output the gas is guided through a short piece of standard 1/32" stainless steel capillary to the gas inlet interfacing the GC with the NGMS. Since only a fraction of the GC gas can be introduced into the mass spectrometer due to pressure reasons, this gas inlet consists of a flow splitter with an approximately 30 μm hole in diameter. Safe operation of NGMS is guaranteed by the pressure reduction of the flow splitter while using as much as possible of the GC gas to be as sensitive as possible. The rest of the GC gas leaves the GC-MS instrument through the exhaust, which is simulated in the prototype by a roughing vacuum pump. The delicate hole in the gas inlet is protected against dust by two frit-filters, each one at entrance and exit capillary.

There is a certain pressure needed in the capillary to provide good flow conditions for sample transportation until the sample reaches the gas inlet of NGMS. Since the output capillary is connected to vacuum a pressure gauge is installed in the capillary line for monitoring and characterising this pressure in the prototype setup (see Figure 1).

Measurements

GC-MS analysis of hydrocarbons

The very first measurements with the lunar GC-MS prototype were performed with the MXT-5 chromatographic module using a relatively large sample with a 250 µl sample loop. The first calibration sample was a gas mixture of mostly He with a variety of hydrocarbons at 1000 ppm concentration each: CO 2 , n-butane, n-pentane, n-hexane, benzene and toluene. After sample injection into the GC column NGMS recorded one mass spectrum after the other, each with 1s integration time at 10 kHz extraction frequency. This means each spectrum is a histogram of 10 4 single measurements. The top panel of Figure 2 shows TCD data over the full retention time span, where the hydrocarbons are well separated. Start of the chromatogram is at XXXX, where the large peak occurs, a feature of the TCD ??? A water peak is also indicated in this chromatogram, but its identification was only possible with the help of the mass spectrometer, as explained below. CO 2 ???

The lower panel shows mass spectrometric analysis of the GC peaks with NGMS. Since these organic compounds are partially destroyed during analysis due to electron impact ionization, several peaks of one compound are available in each mass spectrum. By selecting the most favourable fragments of each compound the signal-to-noise ratio can be maximised as it is done in Figure 2. Using the same composite signal gives the signal-to-noise values in Table 1 for each GC peak visible on TCD (cf. top panel in Figure 2). Beside the possibility to increase signal-to-noise the fragments can be used to identify the measured species, since the fragmentation pattern is characteristic to the molecular structure. According to the retention times determined from these measurements, Table 1 shows clearly that with a helium flow of 2.3 ml/min and a column temperature of only 40°C a good separation of all the hydrocarbon compounds can be achieved and that one single GC-MS analysis with the available organic compounds needs approximately 5 min. The measurements also show the value of having NGMS at the columns output, since the achievable signal-to-noise ratio of a GC peak measured with NGMS is a few decades better than with TCD alone. The best example for this is Toluene. Due to the longest retention time Toluene spends the longest time in the column and gets therefore a broader peak shape with smaller amplitude. This leads to a very low signal-to-noise ratio on TCD while the signal-to-noise value of NGMS is still very good.

The big advantage of GC-MS coupling is that also species can be detected on a mass line where relatively large background is present. An evidence for this is the water peak in Figure 2. Initially it was unknown to which compound the corresponding peak in TCD data was belonging, but the analysis of the mass spectra recorded with NGMS showed clear features on the mass lines belonging to water. With the help of NGMS it was possible to identify the chemical nature of the unknown GC peak, although there is large background on these mass lines, since the water group and especially the water peak itself are very prominent in residual gas mass spectra of this prototype instrument. The origin of this water GC peak has to be searched in the sampling system. While no measurements are performed the output of the sample loop is at air pressure and therefore also exposed to the water in the air. Even if the sample loop is purged before injecting the volume of the sample loop to the column it is very likely that the calibration gas mixture is contaminated by a small portion of water.

The values for the peak width in time (full width at half maximum) presented in Table 1 show that the short transfer line between the GC output and the gas inlet to NGMS do not affect the peak shape much for most of the peaks, except for water, where the peak shape is much broader in the mass spectrometer than measured with TCD. Generally it seems the peaks are slightly broader measured with NGMS, but this might be also because mass spectra were accumulated for 1 second each: More data points per GC peak would help to detect the peak shape better. As it will be shown in the next chapter, this can be done easily with NGMS.

Different measurements with this column showed that even with a smaller sample loop of only 25 µl (instead of 250 µl) and a decade less concentrated calibration gas mixture (only 100 ppm of the same components as described above) NGMS is able to detect clear features of all the species without any problem.

To derive a detection limit for the prototype of the GC-MS system, it can be assumed that NGMS is able to detect gas concentrations that are again one decade lower based on our measurements presented in Table/Figure ….. Further assuming a mean molar mass of 2.2 g for moon's regolith [START_REF] Wurz | The Lunar Exosphere: The Sputtering Contribution[END_REF]] and a typical oven volume of 52 mm 3 [Alex Sagpir fragen], a detection limit of about 2•10 -9 by mass can be calculated for the GC-MS prototype setup. For comparison, for the SAM instrument on the Curiosity rover a sensitivity for organic compounds of 1 -10 ppb by mass has been quoted [START_REF] Mahaffy | The Sample Analysis at Mars Investigation and Instrument Suite[END_REF].

GC-MS analysis of noble gases

The first measurements with the Carbobond GC module were again done with a 250 µl sample loop and a noble gas mix containing each 1000 ppm of neon, krypton and xenon in pure helium. Typically NGMS recorded continuous mass spectra of the GC gas with 1 s integration time and 10 kHz extraction frequency (Figure 3). Table 2 shows the resulting values of these measurements. With the same operation parameters as used for the MXT-5 column (40°C column temperature, 2.3 ml/min helium flow) a separation of all components out of the gas mix is achievable. Again NGMS is able to detect the species with a much better signal-to-noise ratio than the TCD does. Conspicuous is the very long retention time of xenon, which leads to a smeared GC peak with small amplitude (c.f. Figure 3), similar to toluene in the hydrocarbon analysis (Table 1). Due to this behaviour the signalto-noise ratio is smaller and the peak is nearly at the TCD detection limit, despite the relatively large sample.

This non-optimal GC operation shows also that NGMS is able to detect species without any problems at conditions where a TCD fails. Since the calculated signal-to-noise ratios for the noble gases are in the same range as for the hydrocarbons and the same setup was used it can be estimated that the detection limit is also in the same range of about 2•10 -9 by mass for our GC-MS prototype.

By increasing the column temperature from 40°C to 80°C the situation for xenon can be improved:

The retention time of xenon is nearly 5 min shorter and the signal-to-noise ratio can be improved due to a narrower and therefore larger GC peak. While xenon needs with the higher column temperature nearly 5 min less time to pass the chromatographic column, the retention times of the remaining noble gases are shortened only by a few seconds. Depending on the width of a GC peak the typical continuous acquisition of mass spectra with 1s integration time might not lead to an optimal sampling of the peak shape. This problem can be avoided by changing the integration time of a single mass spectrum. With NGMS the integration time per spectrum can be chosen in GC mode between 100ms and up to 1s. Figure 4 shows a comparison between two different sampling rates. In both cases the sample was injected under identical conditions with the only difference of the sampling rate of NGMS. The left panel shows the neon peak sampled with 1s mass spectra while the right panel shows the same peak sampled with 200ms mass spectra. These integration times correspond with an extraction frequency of 10kHz to a histogram of 10000 respectively 2000 extractions per data point. Naturally the signal-to-noise value decreases with shorter integration times why the highest possible sampling rate is not necessarily the best choice.

Conclusion

Coupled measurements with chemical pre-separation of the gaseous sample by gas chromatography and subsequent analysis by our time-of-flight type neutral gas mass spectrometer NGMS were performed successfully. Both a mix of hydrocarbons and a noble gas mixture were tested successfully. While a GC-MS measurement is running, NGMS is able to record continuously mass spectra over the full mass rage of the GC output to record the maximum possible chemical information from the sample. In GC-MS mode the integration time per mass spectrum and therewith the sampling frequency of the GC output by NGMS can be chosen between 100ms and 1s. Due to the high sensitivity and the large dynamic range of up to 10 6 , we can detect about 2ppb by mass with the prototype setup of the GC-MS instrument. For comparison, a sensitivity of 1 -10ppb for organic compounds has been quoted for the SAM instrument on the Curiosity rover [Mahaffy2012]. Due to the successful measurements with the NGMS prototype the development of the flight design for NGMS was accomplished and currently the manufacturing of flight hardware is in progress to be ready for flying to the moon.

  source: https://doi.org/10.7892/boris.81672 | downloaded: 17.1.2021

Figure 1 :

 1 Figure 1: Scheme of the laboratory GC-MS setup with sample gas (sample), He carrier gas (He), sample valve (SV), gas chromatographic column (GC), frit-filters, pressure gauge (PG), and NGMS inlet.

Figure 2 :

 2 Figure 2: TCD data of a hydrocarbon mix (top) and mass spectrometric analysis of the peaks at GC output by NGMS (bottom).

Figure 3 :

 3 Figure 3: Mass spectrometric analysis of the peaks at GC output by NGMS for the noble gas mix.

Figure 4 :

 4 Figure 4: Comparison between sampling of a GC peak with 1 s (left panel) and 200 ms (right panel) integration time per mass spectrum.

Table 1 : Retention times and signal-to-noise ratios for each GC peak during the first GC-MS measurement using the MXT-5 GC module for hydrocarbon separation at a column temperature of 40°C and 2.3ml/min helium flow in combination with a 250 µl sample loop.

 1

	Event	c [ppm]	t_ret [s]	S/N	S/N (TCD)	FWHM	FWHM
				(NGMS)		(NGMS) [s]	(TCD) [s]
	CO 2	1000	92.0	358	317	1.4	1.4
	H 2 O	?	95.4	32	36	7.0	1.6
	Butane	1000	98.1	863	51	1.5	1.5
	Pentane	1000	108.3	1037	45	1.5	1.5
	Hexane	1000	134.0	2494	34	1.1	1.7
	Benzene	1000	170.1	818	20	2.0	1.9
	Toluene	1000	293.2	518	9	2.8	2.8


Hybrid simulation of the Solar wind interaction with the Martian ionosphere and magnetic field S. L. G. Hess (1), R. Modolo (1), E. Richer (2), M. Mancini (1,6), F. Leblanc (1)

Abstract

In the frame of the HELIOSARES project (PI F.Leblanc) dedicated to the modeling of Mars environment (neutral and charged species) from the lower atmosphere to the solar wind, a modeling effort has been conducted to parallelize a multi-species hybrid simulation code. This code now provides a kinetic description of the ions with a rather improved spatial resolution (smaller than the ion inertial length). The latest progresses are reported and simulations results with a uniform spatial resolution of 80 km are presented. This fully parallelized code describes both the dynamics and physical and chemical processes involved in the interaction. Photoproduction, charge exchange and electron impact ionization are computed dynamically through the simulation domain. The Martian ionosphere can be described either by external profile -e.g. by coupling with the result of ionosphere-exosphere simulations -or internally computed profiles obtained by assuming an equilibrium between several chemical processes (in which case transport is neglected). Moreover, the Martian crustal field can be integrated in our model to study its influence on the interaction dynamic and the ionosphere escape rate. We hereby show the results of these simulations and discussed their impact on the understanding of the Martian environment.

Introduction

Due to the absence of strong intrinsic magnetic field, the Martian atmosphere/exosphere is directly in contact with the Solar Wind (SW), exchanging part of its momentum and energy. This coupling occurs via ionization processes and contributes to the erosion of the neutral environment of the planet.

Hybrid code

In this scope, and in the frame of the HELIOSARES project granted by the French National Research Agency, we have parallelized our previous hybrid model [1]. In the hybrid frame, only kinetic effects related to ions are taken into account. Ions are considered as macro-particles and electrons are treated as an inertia-less fluid ensuring the neutrality of the plasma and contribute to the total current and electronic pressure. The model solves the Maxwell equations to provide the temporal evolution of the electromagnetic field.

The numerical code we developed simulates several physical and chemical processes. This capability can be used to compute ionosphere profiles for each species from specified chemical processes. Alternatively, simulation results from different codes [5,6] can be used to specify the ionosphere and exosphere profiles.

Simulations

This study presents simulation results with a 80km spatial resolution from a 3-dimensional parallel ) hybrid model of the Martian interaction with the SW. Physical and chemical processes (photoproduction, electron impact ionization and charge exchange) modifying the concentration of these species are dynamically computed by the model. Their effect on the Martian interaction are identified and discussed.

Our code also permits us to model the effect of the crustal field on the interaction between Mars and the solar wind. As the Mars crustal field presents fine structures and varies a lot depending on the Sun sublongitude (SSL), we perform several runs with different SSLs. The results are discussed and compared with previous studies [1,2,3,4].

Acknowledgements

The authors wish to thanks the ANR-HELIOSARES, the PNST and the CSA for their support.