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We thank the blood donors and RBTC staff who supported this work, importantly Drs Jocelyne Nirina ANDRIAMBELO (RBTC Toamasina), Léa Isabelle RAMANDIMBISOA (RBTC Toliara), Michael Marie Osé HARIOLY NIRINA (NRTC Antananarivo), Dr Danielle FITAHIANA (RBTC Fianarantsoa) and Pr Tahiry RABENANDRIANINA (RBTC Mahajanga).We thank the Immunology of Infectious Diseases unit staff for performing assays, as well as the 4 laboratories in Madagascar where RT-PCRs were run particularly the IPM virology unit.We express our gratitude to the National Institute of Statistics of Madagascar and its Director General Isaora Zefania ROMALAHY, for sharing with us the 2020 demographics of Madagascar; International audience; Background: The incidence of the 2020 COVID-19 epidemic in Africa seems to be different from that of the rest of the world, however its true extent is probably underestimated. Conducting population based sero-surveys during the epidemic has moreover been extremely challenging, driving our group and others to study blood donor samples.Methods: We collected regional epidemiological COVID-19 surveillance data, and simultaneously monitored anti-SARS-CoV-2 antibody seroprevalences monthly throughout the epidemic in 5 major Region-associated Blood Transfusion Centres of Madagascar over a period of 9 months.Findings: Soon after attaining the first epidemic peaks between May and August 2020, both crude and population-weighted test-performance-adjusted seroprevalences of anti-SARS-CoV-2 antibodies was in Malagasy blood donors rapidly increased up to over 40% positivity.Interpretation: These findings suggest a high cumulative incidence of infection and seroconversion, which may have contributed to the observed deceleration of infection rates, but was not sufficient to prevent the second epidemic wave that struck Madagascar in Spring 2021.

Background Plague is a highly fatal disease caused by Yersinia pestis. Late diagnosis hampers disease outcome and effectiveness of control measures, induces death and disease spread. Advance on its diagnosis was the use of lateral flow rapid diagnostic test (RDT). Methods We assessed the performance of the plague RDT based on Y. pestis F1 antigen detection more than 15 years after its deployment in Madagascar. We compared the RDT with bacteriological culture results, using data from plague notified cases collected during the periods for which both tests were performed independently and systematically. Results Used with bubonic plague (BP) patient samples, RDTs had a sensitivity of 100% (95% CI: 99.7–100%), a specificity of 67% (95% CI: 64–70%) with a good agreement between bacteriology and RDT results (86%; κ = 0.70, 95% CI 0.67–0.73). For pneumonic plague (PP), RDT had a sensitivity of 100% (95% CI: 91–100%) and a specificity of 59% (95% CI: 49–68%) and concordance between the bacteriological and plague RDT results was moderate (70%; κ = 0.43, 95% CI 0.32–0.55). Analysis focusing on the 2017–2018 plague season including the unprecedented epidemic of PP showed that RDT used on BP samples still had a sensitivity of 100% (95% CI: 85–100%) and a specificity of 82% (95% CI: 48–98%) with a very good agreement with bacteriology 94% (κ = 0.86, 95% CI 0.67–1); for PP samples, concordance between the bacteriological and plague RDT results was poor (61%; κ = − 0.03, 95% CI -0.17 – 0.10). Conclusions RDT performance appeared to be similar for the diagnosis of BP and PP except during the 2017 PP epidemic where RDT performance was low. This RDT, with its good sensitivity on both plague clinical forms during a normal plague season, remained a potential test for alert. Particularly for BP, it may be of great value in the decision process for the initiation of therapy. However, for PP, RDT may deliver false negative results due to inconsistent sample quality. Plague diagnosis could be improved through the development of next generation of RDTs.

International audience

Background: Madagascar accounts for 75% of global plague cases reported to WHO, with an annual incidence of 200–700 suspected cases (mainly bubonic plague). In 2017, a pneumonic plague epidemic of unusual size occurred. The extent of this epidemic provides a unique opportunity to better understand the epidemiology of pneumonic plagues, particularly in urban settings. Methods: Clinically suspected plague cases were notified to the Central Laboratory for Plague at Institut Pasteur de Madagascar (Antananarivo, Madagascar), where biological samples were tested. Based on cases recorded between Aug 1, and Nov 26, 2017, we assessed the epidemiological characteristics of this epidemic. Cases were classified as suspected, probable, or confirmed based on the results of three types of diagnostic tests (rapid diagnostic test, molecular methods, and culture) according to 2006 WHO recommendations. Findings: 2414 clinically suspected plague cases were reported, including 1878 (78%) pneumonic plague cases, 395 (16%) bubonic plague cases, one (

Background In the Armed Forces, knowledge about the causes of deaths is required in order to develop prevention strategies. This study presents the main characteristics of causes of deaths among male active-duty personnel in the French Armed Forces during the 2006–10 period and compares them with the general French male population. Methods The data are provided by military public health surveillance. Comparisons of the specific mortality rates (MR) were performed using a Poisson regression. Standardized mortality ratios (SMRs) were calculated to compare mortality with the general French male population. Results There were 1455 deaths among male active-duty personnel during the study period [MR: 100.9 per 100 000 person-years (PY); 95% confidence interval 95.7–106.1]. The 17–24 age group was characterized by violent deaths: transport accident (MR: 45.9 per 100 000 PY) and suicide (18.8 per 100 000 PY). Overall SMRs show significantly lower MR compared with the French national MR with the exception of SMR for transport accident and suicide in the 17–24 age group. Conclusions There is a significantly lower deficit of mortality compared with the French male general population, reflecting a strong healthy worker effect. However, health promotion programmes should continue to put emphasis on transport accident especially among the 17–24 age group.

RESUME La surveillance epidemiologique dans les armees francaises a du prendre en compte les changements observes ces dernieres decennies dans le domaine des maladies infectieuses. En effet, avec l’explosion de l’endemie VIH, l’extension de la resistance de Plasmodium falciparum dans tous les pays tropicaux et la survenue de maladies emergentes, les armees ont ete confrontees a de nouveaux risques. Ils sont infectieux avec les agents de la menace bio terroriste et environnementaux avec la rencontre de risques industriels et professionnels. C’est pour ces raisons que le service de sante des armees a instaure un nouveau concept reposant sur une surveillance epidemiologique active des maladies transmissibles, une veille renforcee portant sur la sante humaine, animale, vectorielle et environnementale. Elle complete ce dispositif par un systeme d’information geographique dont l’objectif est d’obtenir une surveillance temporelle et spatiale des maladies transmissibles et de detecter precocement d’eventuelles maladies emergentes. Avec ce systeme d’information epidemiologique, il est possible grâce a la modelisation de donnees d’enrichir le renseignement medical delivre aux etats majors avant le deploiement d’une force armee sur un theâtre inconnu.

Blackwater fever (BWF), one of the commonest causes of death of Europeans living in Africa at the beginning of the twentieth century, but rarely diagnosed since the 1950s, is related to Plasmodium falciparum malaria but there is considerable debate and controversy about its aetiology. From 1990 to 2000, the whole population of Dielmo, a village in Senegal, was involved in a prospective study of malaria. Three cases of BWF occurred in 3 children aged 4, 7 and 10 years, belonging to a subgroup of children who suffered malaria attacks every 4 to 6 weeks over many years, who had received repeated quinine treatment. The spread of chloroquine resistance, by increasing the use of more toxic alternative drugs, may expose endemic populations to a high incidence of severe side effects of antimalarials.

Plasmodium ovale is a common malaria parasite in Africa, but the epidemiology of P. ovale malaria is poorly known. Exposure to malaria, parasitemia, and morbidity were monitored for 6 years among the residents of a village in Senegal. The relationship between the level of P. ovale parasitemia and fever risk were analyzed, and diagnostic criteria for clinical P. ovale malaria were established. Then the relationships between the occurrence of P. ovale clinical malaria and a series of entomological, epidemiological, and genetic factors were investigated. There was no increased risk of fever when the P. ovale parasite count was

Summary Background A better understanding of the effect of malaria control interventions on vector and parasite populations, acquired immunity, and burden of the disease is needed to guide strategies to eliminate malaria from highly endemic areas. We monitored and analysed the changes in malaria epidemiology in a village community in Senegal, west Africa, over 22 years. Methods Between 1990 and 2012, we did a prospective longitudinal study of the inhabitants of Dielmo, Senegal, to identify all episodes of fever and investigate the relation between malaria host, vector, and parasite. Our study included daily medical surveillance with systematic parasite detection in individuals with fever. We measured parasite prevalence four times a year with cross-sectional surveys. We monitored malaria transmission monthly with night collection of mosquitoes. Malaria treatment changed over the years, from quinine (1990–94), to chloroquine (1995–2003), amodiaquine plus sulfadoxine-pyrimethamine (2003–06), and finally artesunate plus amodiaquine (2006–12). Insecticide-treated nets (ITNs) were introduced in 2008. Findings We monitored 776 villagers aged 0–101 years for 2 378 150 person-days of follow-up. Entomological inoculation rate ranged from 142·5 infected bites per person per year in 1990 to 482·6 in 2000, and 7·6 in 2012. Parasite prevalence in children declined from 87% in 1990 to 0·3 % in 2012. In adults, it declined from 58% to 0·3%. We recorded 23 546 fever episodes during the study, including 8243 clinical attacks caused by Plasmodium falciparum , 290 by Plasmodium malariae , and 219 by Plasmodium ovale . Three deaths were directly attributable to malaria, and two to severe adverse events of antimalarial drugs. The incidence of malaria attacks ranged from 1·50 attacks per person-year in 1990 to 2·63 in 2000, and to only 0·046 in 2012. The greatest changes were associated with the replacement of chloroquine and the introduction of ITNs. Interpretation Malaria control policies combining prompt treatment of clinical attacks and deployment of ITNs can nearly eliminate parasite carriage and greatly reduce the burden of malaria in populations exposed to intense perennial malaria transmission. The choice of drugs seems crucial. Rapid decline of clinical immunity allows rapid detection and treatment of novel infections and thus has a key role in sustaining effectiveness of combining artemisinin-based combination therapy and ITNs despite increasing pyrethroid resistance. Funding Pasteur Institutes of Dakar and Paris, Institut de Recherche pour le Developpement, and French Ministry of Cooperation.

Pregnancy is associated with increased susceptibility to malaria. It is generally agreed that this increased risk ends with delivery, but the possible persistence of increased susceptibility during the puerperium had not been investigated.From June 1, 1990, to December 31, 1998, we monitored exposure to malaria, parasitemia, and morbidity among the residents of a village in Senegal in which the rate of transmission of malaria was high. In this population we analyzed 71 pregnancies in 38 women from the year before conception and through one year after delivery.Among the 38 women, there were 58 episodes of clinical Plasmodium falciparum malaria during 61,081 person-days of observation. The incidence of malaria was 20.2 episodes per 1000 person-months during the year preceding conception and 12.0 episodes per 1000 person-months during the period from 91 to 365 days after delivery. The incidence of episodes of malaria increased significantly during the second and third trimesters of pregnancy and reached a maximum of 75.1 episodes per 1000 person-months during the first 60 days after delivery. The adjusted relative risk of an episode of malaria was 4.1 (95 percent confidence interval, 1.8 to 9.5) during the first 60 days post partum, as compared with the year preceding pregnancy. The duration of fever during the episodes of malaria was longer and the prevalence and density of asymptomatic malarial parasitemia were significantly higher during pregnancy and the early postpartum period than during the other periods.Among women who live in areas with high rates of transmission of malaria, the susceptibility to malaria is highest during the second and third trimesters of pregnancy and the early postpartum period.

In endemic areas, asymptomatic infection by the malaria parasite Plasmodium falciparum was found associated with elevated percentages of human host's mononuclear cell spontaneous in-vitro apoptosis. In Dielmo, a village where malaria is holoendemic, apoptosis was age-and parasite-dependent. In-vitro exposure of peripheral blood mononuclear cells (PBMC) to the parasite extract induced a marked increase in the mononuclear cell membrane expression of functional CD95 antigen: a 3-h exposure of the mononuclear cells to anti-CD95 antibodies led to a detectable increase in the mean percentage of apoptotic nuclei found in the cultures carried out in the presence of P. falciparum extracts compared to control cultures. IL-2, IL-4, IL-6 and IL-10 promoted the viability of PBMC in cultures while IL-1alpha or IFN-gamma had no obvious impact and TNFalpha gave conflicting results. IL-2 was the most efficient cytokine at rescuing PBMC from cell death and this effect was associated with a strong increase in T cell activation. In contrast, IL-4 and IL-10 had no such effect on T cell activation, hence they acted as survival factors and not through their mitogenic activity. Taken together, these different observations suggested that the levels of in-vitro apoptosis observed were not only associated with parasite infection, but also potentially modulated by the human host through different pathways.

Prolonged carriage of #Plasmodium falciparum$ in humans during the dry season is critical for parasite survival, as the infected subjects constitute a major reservoir in the absence of transmission. Yet, very little is known about the host/parasite interactions contributing to parasite persistence. In order to study the characteristics of #P. falciparum$ infections during the dry season, we have genotyped parasites collected from untreated, asymptomatic individuals during 3 cross-sectional surveys conducted during the dry season in Ndiop, a Senegalese village with seasonal, mesoendemic malaria. Monthly entomological surveillance did not detect any transmission during that period. Parasite prevalence decreased markedly in the children aged less than 7 years after 7 months of undetected transmission, but was stable in older children and adults throughout the dry season. In all chronically infected individuals, infection complexity remained stable, but there were substantial fluctuations of individual genotype(s), reflecting complex dynamics of multiple-clone infections during chronic asymptomatic parasite carriage. This fluctuation resulted in changes in the msp1 and msp2 allelic distribution within the cohort after 7 months of undetected transmission, contrasting with the stability observed during the preceding rainy season in that village. (Résumé d'auteur)

The C-terminal 19 000 MW fragment of merozoite surface protein-1 (MSP119) is one of the most promising candidate antigens for a malaria vaccine. Baculovirus recombinant Plasmodium falciparum MSP119 has been used to define conditions for the in vitro production of specific antibodies by purified human blood B cells in a culture system where T-cell signals were provided by the engagement of CD40 molecules and exogenous cytokines. MSP119 preferentially induced surface immunoglobulin G (IgG) -positive (sgamma+) B lymphocytes from P. falciparum-immune donors to differentiate and produce antigen-specific IgG. In contrast, naïve B cells or cells from non-immune donors could not be induced to secrete parasite-specific IgG in vitro. Although IgG secretion was obtained in the absence of exogenous cytokines, it was dependent on B-cell-derived interleukin-10 (IL-10) and/or B-cell factor(s) under the control of IL-10, since IgG levels were significantly decreased in the presence of neutralizing anti-IL-10 antibodies. These results demonstrate at the cellular level that a single malaria vaccine candidate polypeptide can direct parasite-specific antibody production mediated by the secretion of potentiating factors.

To investigate the impact of transmission on the development of immunity to malaria and on parasite diversity, longitudinal surveys have been conducted for several years in Dielmo and Ndiop, 2 neighbouring Senegalese villages with holo- and mesoendemic transmission conditions, respectively. We analysed Plasmodium falciparum msp1 block 2 and msp2 genotypes of isolates collected from 58% of the Dielmo villagers during the same week as those studied recently from Ndiop. Allele frequencies differed in both villages, indicating considerable microgeographical heterogeneity of parasite populations. The complexity of the infections, estimated using individual or combined msp1 and msp2 genotyping, in Dielmo was more than double that in Ndiop and it was age-dependent in Dielmo but not in Ndiop. Thus, this study confirmed the influence of age on the complexity of asymptomatic malaria infections in a holoendemic area. The age distribution of complexity in Dielmo substantiates the interpretation that the number of parasite types per isolate reflects acquired antiparasite immunity. This cross-sectional survey also confirms that the sickle cell trait has no impact on complexity but influences the distribution of P. falciparum genotypes.

This virulent clone has already spread to other continents., We report 2 outbreaks of Panton-Valentine leukocidin–positive, doxycycline-resistant, methicillin-susceptible Staphylococcus aureus infections in French soldiers operating in Côte d’Ivoire. In a transssectional survey, nasal carriage of this strain was found in 2.9% of 273 soldiers about to be sent to Côte d’Ivoire and was associated with prior malaria prophylaxis with doxycycline.

In French Guiana, from 1984 to 2011, 14 animal rabies cases and 1 human rabies case (2008) were diagnosed. In January 2011, vampire-bat attacks occurred in 2 isolated villages. In mid-January, a medical team from the Cayenne Centre for Anti-Rabies Treatment visited the sites to manage individuals potentially exposed to rabies and, in April, an anti-rabies vaccination campaign for dogs was conducted. Twenty individuals were bitten by bats in 1 month, most frequently on the feet. The median time to start management was 15 days. The complete Zagreb vaccination protocol (2 doses on day 0 and 1 dose on days 7 and 21) was administered to 16 patients, 12 also received specific immunoglobulins. The antibody titration was obtained for 12 patients (different from those who received immunoglobulins). The antibody titers were ≥0.5 EU/mL for all of them. The serology has not been implemented for the 12 patients who received immunoglobulins. Accidental destruction of a vampire-bat colony could be responsible for the attacks. The isolation and absence of sensitization of the populations were the main explanations for the management difficulties encountered. Sensitization programs should be conducted regularly., Author Summary Rabies is a disease almost invariably fatal in humans once the first clinical signs appear. In French Guiana bats represent the virus reservoir, especially vampire bats. From 1984 to 2011, 14 animal rabies cases and 1 human rabies case (2008) were diagnosed. In case of bat bite, anti-rabies immunoglobulins (RIG) and rabies vaccine must be rapidly administrated. The specific rabies management is exclusively performed by Centre for Anti-Rabies Treatment (CART), located at the Institut Pasteur in Cayenne, the prefecture of French Guiana, and 6 Anti-Rabies Treatment Outposts distributed along the coastal edge and along the two main rivers. Only a CART physician can administer RIG. In January 2011, vampire-bat attacks occurred in 2 isolated villages. In mid-January, a medical team from the CART visited the sites to manage individuals potentially exposed to rabies and, in April, an anti-rabies vaccination campaign for dogs was conducted. The most relevant contribution of this study is to underline difficulties to provide rabies post-exposure prophylaxis to remote populations exposed to bat rabies in the Amazonian region and to show the lack of awareness of these rural populations concerning rabies and the risk associated to vampire bats.

Presented in part as an oral communication at the 10th Journées Nationales d’Infectiologie, Marseille, France, June 10-12, 2009.; International audience; On May 27, 2008, a patient died from rabies at the Cayenne Hospital in French Guiana. Postexposure prophylaxis vaccination was implemented for all health care workers exposed to this patient. Examining the management of such a rare risk reveals important factors in the education of personnel who may have contact with a patient with rabies, to permit appropriate risk assessment and reduce unnecessary postexposure prophylaxis, taking into account the risks and costs of adverse events.

Background Until 2008, human rabies had never been reported in French Guiana. On 28 May 2008, the French National Reference Center for Rabies (Institut Pasteur, Paris) confirmed the rabies diagnosis, based on hemi-nested polymerase chain reaction on skin biopsy and saliva specimens from a Guianan, who had never travelled overseas and died in Cayenne after presenting clinically typical meningoencephalitis. Methodology/Principal Findings Molecular typing of the virus identified a Lyssavirus (Rabies virus species), closely related to those circulating in hematophagous bats (mainly Desmodus rotundus) in Latin America. A multidisciplinary Crisis Unit was activated. Its objectives were to implement an epidemiological investigation and a veterinary survey, to provide control measures and establish a communications program. The origin of the contamination was not formally established, but was probably linked to a bat bite based on the virus type isolated. After confirming exposure of 90 persons, they were vaccinated against rabies: 42 from the case's entourage and 48 healthcare workers. To handle that emergence and the local population's increased demand to be vaccinated, a specific communications program was established using several media: television, newspaper, radio. Conclusion/Significance This episode, occurring in the context of a Department far from continental France, strongly affected the local population, healthcare workers and authorities, and the management team faced intense pressure. This observation confirms that the risk of contracting rabies in French Guiana is real, with consequences for population educational program, control measures, medical diagnosis and post-exposure prophylaxis., Author Summary Until 2008, rabies had never been described within the French Guianan human population. Emergence of the first case in May 2008 in this French Overseas Department represented a public health event that markedly affected the local population, healthcare workers and public health authorities. The antirabies clinic of French Guiana, located at Institut Pasteur de la Guyane, had to reorganize its functioning to handle the dramatically increased demand for vaccination. A rigorous epidemiological investigation and a veterinary study were conducted to identify the contamination source, probably linked to a bat bite, and the exposed population. Communication was a key factor to controlling this episode and changing the local perception of this formerly neglected disease. Because similar clinical cases had previously been described, without having been diagnosed, medical practices must be adapted and the rabies virus should be sought more systematically in similarly presenting cases. Sharing this experience could be useful for other countries that might someday have to manage such an emergence.

Background African populations are considered to be particularly vulnerable to fever illnesses, including malaria, and acute respiratory disease, owing to limited resources and overcrowding. However, the overall burden of influenza in this context is poorly defined and incidence data for African countries are scarce. We therefore studied the fever syndrome incidence and more specifically influenza incidence in a cohort of inhabitants of Dielmo and Ndiop in Sokone district, Senegal. Methods Daily febrile-illness data were prospectively obtained from January 2012 to December 2013 from the cohort of the villages of Dielmo and Ndiop, initially dedicated to the study of malaria. Nasopharyngeal swabs were collected from, and malaria diagnosis tests (thick blood smears) carried out on, every febrile individual during clinical visits; reverse transcriptase-polymerase chain reaction was used to identify influenza viruses in the samples. Binomial negative regression analysis was used to study the relationship between the monthly incidence rate and various covariates. Results In Dielmo and Ndiop, the incidence of malaria has decreased, but fever syndromes remain frequent. Among the 1036 inhabitants included in the cohort, a total of 1,129 episodes of fever were reported. Influenza was present all year round with peaks in October-December 2012 and August 2013. The fever, ILI and influenza incidence density rates differed significantly between age groups. At both sites, the adjusted incidence relative risks for fever syndromes and ILI were significantly higher in the [6–24 months) than other age groups: 7.3 (95%CI: [5.7–9.3]) and 16.1 (95%CI: [11.1–23.3]) respectively. The adjusted incidence relative risk for influenza was significantly higher for the [0–6 months) than other age groups: 9.9 (95%CI: [2.9–33.6]). At both sites, incidence density rates were lowest among adults > = 50 years. Conclusions In this rural setting in Senegal, influenza was most frequent among the youngest children. Preventive strategies targeting this population should be implemented.

French Guiana is a French Province located on the northern coast of South America that had 221,500 inhabitants in 2008 (1). Malaria is endemo-epidemic to the Amazon basin. Since 2000, the annual number of Plasmodium falciparum and P. vivax malaria cases in French Guiana has ranged from 3,500 to 4,500 (2). Approximately 3,000 French military personnel are deployed annually in French Guiana, and malaria occasionally affects their operational capabilities. Only military personnel on duty in the Amazon basin are required to take malaria chemoprophylaxis; personnel deployed in coast regions are not. Until February 2001, the chemoprophylaxis regimen consisted of chloroquine (100 mg/d) and proguanil (200 mg/d). During March 2001–October 2003, mefloquine (250 mg/wk) was used. Since November, 2003 malaria chemoprophylaxis has been doxycycline (100 mg/d), which is initiated on arrival in the Amazon basin. All chemoprophylaxis is continued until 4 weeks after departure. Because of the absence of marketing authorization as chemoprophylaxis by the French Medicines Agency, primaquine was not used until recently. Other individual and collective protective measures did not change during 1998–2008. Despite the availability of chemoprophylaxis, since 2003, several malaria outbreaks have been identified after operations against illegal mining in the Amazon basin (3,4). The purpose of those studies was to describe outbreaks and determine factors related to malaria cases. We report French military health surveillance epidemiologic data on malaria among military personnel deployed to French Guiana during 1998–2008.

In 2006, a French Army unit reported 39 malaria cases among service persons returning from Ivory Coast. Thirty, including three serious forms, occurred after the return to France. The risk of post-return malaria was higher than the risk in Ivory Coast. Half of the imported cases had stopped post-return chemoprophylaxis early.

To perform epidemiological surveillance during deployments, the French military health service has developed a real-time surveillance approach. The objective was to identify the benefits and problems of this approach. A prototype of real-time surveillance has been set up in French Guiana since 2004. Its permanent evaluation has allowed identifying strengths and weaknesses. The experience has permitted expansion of the concept to French forces in Djibouti and also development of a global approach for the whole French armed forces. Real-time surveillance has shown its usefulness for early warning during different real and simulated situations. Functional and architectural choices have permitted interoperability with allied nations. However, the information produced was only the first step of the diagnostic epidemiological situation followed by other investigations. This first step of development has highlighted the required complementarity with traditional epidemiological surveillance.

BackgroundThe time necessary for malaria parasite to re-appear in the blood following treatment (re-infection time) is an indirect method for evaluating the immune defences operating against pre-erythrocytic and early erythrocytic malaria stages. Few longitudinal data are available in populations in whom malaria transmission level had also been measured.MethodsOne hundred and ten individuals from the village of Ndiop (Senegal), aged between one and 72 years, were cured of malaria by quinine (25 mg/day oral Quinimax™ in three equal daily doses, for seven days). Thereafter, thick blood films were examined to detect the reappearance ofPlasmodium falciparumevery week, for 11 weeks after treatment. Malaria transmission was simultaneously measured weekly by night collection of biting mosquitoes.ResultsMalaria transmission was on average 15.3 infective bites per person during the 77 days follow up. The median reappearance time for the whole study population was 46.8 days, whereas individuals would have received an average one infective bite every 5 days. At the end of the follow-up, after 77 days, 103 of the 110 individuals (93.6%; CI 95% [89.0–98.2]) had been re-infected withP. falciparum. The median reappearance time ('re-positivation') was longer in subjects with patent parasitaemia at enrolment than in parasitologically-negative individuals (58 days vs. 45.9; p = 0.03) and in adults > 30 years than in younger subjects (58.6 days vs. 42.7; p = 0.0002). In a multivariate Cox PH model controlling for the sickle cell trait, G6PD deficiency and the type of habitat, the presence of parasitaemia at enrolment and age ≥ 30 years were independently predictive of a reduced risk of re-infection (PH = 0.5 [95% CI: 0.3–0.9] and 0.4; [95% CI: 0.2–0.6] respectively).ConclusionResults indicate the existence of a substantial resistance to sporozoites inoculations, but which was ultimately overcome in almost every individual after 2 1/2 months of natural challenges. Such a study design and the results obtained suggest that, despite a small sample size, this approach can contribute to assess the impact of intervention methods, such as the efficacy vector-control measures or of malaria pre-erythrocytic stages vaccines.

The distribution and range of 50% inhibitory concentrations (IC 50 s) of doxycycline were determined for 747 isolates obtained between 1997 and 2006 from patients living in Senegal, Republic of the Congo, and Gabon and patients hospitalized in France for imported malaria. The statistical analysis was designed to answer the specific question of whether Plasmodium falciparum has different phenotypes of susceptibility to doxycycline. A triple normal distribution was fitted to the data using a Bayesian mixture modeling approach. The IC 50 geometric mean ranged from 6.2 μM to 11.1 μM according to the geographical origin, with a mean of 9.3 μM for all 747 parasites. The values for all 747 isolates were classified into three components: component A, with an IC 50 mean of 4.9 μM (±2.1 μM [standard deviation]); component B, with an IC 50 mean of 7.7 μM (±1.2 μM); and component C, with an IC 50 mean of 17.9 μM (±1.4 μM). According to the origin of the P. falciparum isolates, the triple normal distribution was found in each subgroup. However, the proportion of isolates predicted to belong to component B was most important in isolates from Gabon and Congo and in isolates imported from Africa (from 46 to 56%). In Senegal, 55% of the P. falciparum isolates were predicted to be classified as component C. The cutoff of reduced susceptibility to doxycycline in vitro was estimated to be 35 μM.

International audience; Background. Inadequate treatment practices with antimalarials are considered major contributors to Plasmodium falciparum resistance to chloroquine, pyrimethamine and sulfadoxine. The longitudinal survey conducted in Dielmo, a rural Senegalese community, offers a unique frame to explore the impact of strictly controlled and quantified antimalarial use for diagnosed malaria on drug resistance. Methodology/Principal Findings. We conducted on a yearly basis a retrospective survey over a ten-year period that included two successive treatment policies, namely quinine during 1990-1994, and chloroquine (CQ) and sulfadoxine/pyrimethamine (SP) as first and second line treatments, respectively, during 1995-1999. Molecular beaconbased genotyping, gene sequencing and microsatellite analysis showed a low prevalence of Pfcrt and Pfdhfr-ts resistance alleles of Southeast Asian origin by the end of 1994 and their effective dissemination within one year of CQ and SP implementation. The Pfcrt resistant allele rose from 9% to 46% prevalence during the first year of CQ reintroduction, i.e., after a mean of 1.66 CQ treatment courses/person/year. The Pfdhfr-ts triple mutant rose from 0% to 20% by end 1996, after a mean of 0.35 SP treatment courses/person in a 16-month period. Both resistance alleles were observed at a younger age than all other alleles. Their spreading was associated with enhanced in vitro resistance and rapidly translated in an increased incidence of clinical malaria episodes during the early post-treatment period. Conclusion/Significance. In such a highly endemic setting, selection of drug-resistant parasites took a single year after drug implementation, resulting in a rapid progression of the incidence of clinical malaria during the early post-treatment period. Controlled antimalarial use at the community level did not prevent dissemination of resistance haplotypes. This data pleads against reintroduction of CQ in places where resistant allele frequency has dropped to a very low level after CQ use has been discontinued, unless drastic measures are put in place to prevent selection and spreading of mutants during the post-treatment period.

Antimalarial drugs, when used as monotherapies, are rapidly losing their effectiveness. One promising new drug is the antimalarial 8-aminoquinoline tafenoquine (SB-252263 [formerly WR-238605]), a new synthetic primaquine analogue codeveloped by the U.S. Army and GlaxoSmithKline, which has been shown effective not only against the liver stages, gametocytes, and sporozoites of Plasmodium falciparum (4), but also against the blood stages of the parasite (13). Tafenoquine demonstrated significant protection against P. falciparum infection in Gabon, Ghana, and Kenya (6, 7, 12). Tafenoquine has been reported to be well tolerated, with only mild gastrointestinal effects (8). Isolates were collected in 1999 from malaria patients from Libreville (Gabon, Central Africa), Dielmo and Ndiop (Senegal, West Africa), and Djibouti (East Africa). The isotopic, microdrug susceptibility test used was described previously (10). The 50% inhibitory concentration (IC50) values for tafenoquine were in the range 0.9 to 9.7 μM in Djibouti, 0.6 to 33.1 μM in Gabon, and 0.5 to 20.7 μM in Senegal. The geometric mean IC50 was 2.68 μM in Djibouti, versus 4.62 μM in Gabon and 5.06 μM in Senegal (Table ​(Table1).1). Tafenoquine was found to possess marked blood schizonticidal activity in P. falciparum in areas with high percentages of multidrug-resistant parasite populations. There was no difference in the tafenoquine mean IC50 values between Dielmo-Ndiop and Libreville, even though the levels of reduced susceptibility for chloroquine, mefloquine, cycloguanil, and pyrimethamine were different. Conversely, tafenoquine was significantly more active in Djibouti than in Gabon or Senegal (P = 0.016). The results of these in vitro tests were comparable with those reported by other authors in culture-adaptated P. falciparum clones and strains (2, 11). TABLE 1. In vitro susceptibilities and prevalence of resistance or reduced susceptibility of wild isolates of Plasmodium falciparum from Djibouti, Gabon, and Senegal to the drugs shown Published in vitro data for the blood schizonticidal activity of primaquine in P. falciparum show a range of IC50 values between 0.3 μM and 14 μM (1, 2, 13). In this study, there was no difference in the tafenoquine mean IC50 values between the three areas (P = 0.111). Tafenoquine is more active in vitro than primaquine, wherever the area. Tafenoquine exerts a blood schizonticidal activity 4 to 100 times higher than that of primaquine in the Plasmodium berghei and Plasmodium yoelii mouse model (9). Tafenoquine had a half-life that is more than 50 times longer than that of primaquine (3, 5). The difference in kinetics results in more prolonged, high concentrations of tafenoquine in the blood. These properties permit weekly dosing for prophylaxis and short-term or single-dose therapy for radical cure. Only 3.5% of the variation of response to tafenoquine is explained by response variation to primaquine. The coefficients of determination, r2, ranging from 0.001 to 0.113, are too weak to consider that cross-resistance may exist between tafenoquine and standard antimalarial drugs. Since correlation analysis provides an insight into the mode of action and cross-susceptibilities between different drugs, these data may be seen as an indication of the relative independence of tafenoquine from the susceptibility of P. falciparum to standard antimalarial drugs. In conclusion, these data permit definition of the baseline of in vitro susceptibility to tafenoquine before its use and will allow the monitoring of its resistance or its reduced susceptibility when tafenoquine will be commonly used. Given its greater schizonticidal activity, tafenoquine is a promising candidate as a short treatment for P. falciparum and Plasmodium vivax malaria. However, the potential side effects of tafenoquine, such as the production of methemoglobin and the risk of hemolysis in glucose-6-phosphate dehydrogenase-deficient patients, have to be taken into consideration (14).

In 1998, circulation of the Rift Valley Fever (RVF) virus was revealed in Diawara by detection of IgM antibodies in sheep and isolation of the virus from mosquitoes caught outside a village. A seroprevalence study was carried out. Finger-prick blood samples, individual and collective details were obtained. One thousand five hundred twenty people (6 months - 83 years) were included. Overall prevalence in this group was approximately 5.2%. The prevalence in infants (6 months - 2 years) was 8.5%. Age, gender, contact with a pond, presence of sheep, and abortion among sheep, and individual or collective travel history were not statistically associated with prevalence. Prevalence increased significantly when the distance to a small ravine, located in the middle of the village, decreased. The results suggest a low, recent, not endemic circulation of the virus. Culex quinquefasciatus was captured near the ravine. This mosquito, similar to Culex pipiens, can play a similar role in human-to-human transmission of the RVF virus.

In 2001, an outbreak of typhoid fever occurred among the members of the French Armed Forces. All had received a typhoid vaccination as per the immunization schedule practiced in the Armed Forces (every 5 years). A retrospective cohort study was conducted in 94 personnel. The objectives were to confirm the diagnosis, determine the source of contamination and identify the factors associated with defective vaccinal efficacy. Twenty-four cases were clinically identified. A cucumber salad was identified as the contaminating dish (Risk Ratio = 3.6; 95%CI 1.5-8.9). Only one factor was related to defective vaccinal efficacy; the risk of typhoid fever was two-fold higher in people vaccinated more than 3 years previously (Risk Ratio = 2.2; 95%CI, 1.1-4.2). Compliance with food hygiene rules could have prevented 24 cases of typhoid fever. Nevertheless, repeat vaccination against typhoid fever is now conducted every 3 years in the French Forces, in compliance with the manufacturers' recommendations.

Many genes have been implicated in the risk of severe malaria, generally based on candidate gene studies in case/control populations. Among these genes, there has been conflicting reports for the implication of a variant of the intercellular adhesion molecule 1 (ICAM1), ICAM1 K i l i f i , in the risk of severe malaria, while in vitro studies provided independent support for a functional role of this variant. In order to explore the possible implication of ICAM1 in the susceptibility/resistance to malaria and to try to understand its clinical relevance in the disease process, we have conducted linkage and association studies of ICAM1 in two Senegalese villages located in regions of endemic malaria. We explored the full genetic variability of ICAM1, and tested it on several clinical malarial traits which are under genetic control, focusing principally on variables related to the parasite density and the number of malarial attacks. Our study provides no evidence for a role of ICAM1 variability on the malarial phenotypes studied.

Epidemiological surveillance within the French Armed Forces has had to take into account various changes in infectious diseases in recent years. The French Armed Forces are encountering new hazards, such as the spread of HIV infection, Plasmodium falciparum chemoresistance, and outbreaks of emerging diseases. Bioterrorism, industrial and occupational hazards are added concerns. For these reasons, the French Military Medical Service has introduced a new concept based on permanent epidemiological surveillance of communicable diseases. This is completed by a real-time spatial surveillance designed to detect very rapidly potential communicable diseases or new emerging diseases. This epidemiological system, based on data modeling, enhances the medical information available to staff commands before deployment to new areas.

This study examined the evolution of immunoglobulin (Ig) G1 and IgG3 antibodies against the asexual stage Plasmodium falciparum protein, MSP1(19), before and after a heavy malaria transmission period in clinically immune Senegalese subjects living under different epidemiological conditions. Plasma was tested for antibodies to a yeast-produced, recombinant PfMSP1(19) antigen (the Q-KNG allelic variant) that has previously been demonstrated to react with IgG1, IgG3, or both in the majority of these people. Anti-P. falciparum antibodies of the IgG1 and IgG3 subclasses, previously reported to be associated with protection, were shown to evolve independently one from another after the transmission period in both settings. These results suggest differential regulation of MSP1(19)-specific IgG1 and IgG3. The precise role of these antibody isotypes in maintaining malaria immunity remains to be determined.

Cytophilic antibodies (Abs) play a critical role in protection againstPlasmodium falciparumblood stages, yet little is known about the parameters regulating production of these Abs. We used an in vitro culture system to study the subclass distribution of antigen (Ag)-specific immunoglobulin G (IgG) produced by peripheral blood mononuclear cells (PBMCs) from individuals exposed toP. falciparumor unexposed individuals. PBMCs, cultivated with or without cytokines and exogenous CD40/CD40L signals, were stimulated with a crude parasite extract, recombinant vaccine candidates derived from conserved Ags (19-kDa C terminus of merozoite surface protein 1 [MSP119], R23, and PfEB200), or recombinant Ags derived from the polymorphic Ags MSP1 block 2 and MSP2. NoP. falciparum-specific Ab production was detected in PBMCs from unexposed individuals. PBMCs from donors exposed frequently toP. falciparuminfections produced multiple IgG subclasses when they were stimulated with the parasite extract but usually only one IgG subclass when they were stimulated with a recombinant Ag. Optimal Ab production required addition of interleukin-2 (IL-2) and IL-10 for all antigenic preparations. The IgG subclass distribution was both donor and Ag dependent and was only minimally influenced by the exogenous cytokine environment. In vitro IgG production and subclass distribution correlated with plasma Abs to some Ags (MSP119, R23, and MSP2) but not others (PfEB200 and the three MSP1 block 2-derived Ags). Data presented here suggest that intrinsic properties of the protein Ag itself play a major role in determining the subclass of the Ab response, which has important implications for rational design of vaccine delivery.

The spread of antimalarial drug resistance has major consequences for malaria control in tropical Africa. Here, the impact of chloroquine resistance on the burden of malaria is analyzed and its implications for the Roll Back Malaria initiative are examined. Malaria mortality has increased at least twofold during the past two decades. Combination therapy should be available for home treatment of young children. The potential toxicity of most antimalarials will require special surveillance programs. The main contribution to malaria control using methods to reduce the entomological inoculation rate is expected in areas with low or unstable transmission. Classic vector-control methods could potentially eliminate malaria in most urban areas and such programs deserve high priority.