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1.  Fatal Pancreatitis in Simian Immunodeficiency Virus SIVmac251-Infected Macaques Treated with 2′,3′-Dideoxyinosine and Stavudine following Cytotoxic-T-Lymphocyte-Associated Antigen 4 and Indoleamine 2,3-Dioxygenase Blockade 
Journal of Virology  2012;86(1):108-113.
Human immunodeficiency virus (HIV) infection is associated with immune activation, CD4+-T-cell loss, and a progressive decline of immune functions. Antiretroviral therapy (ART) only partially reverses HIV-associated immune dysfunction, suggesting that approaches that target immune activation and improve virus-specific immune responses may be needed. We performed a preclinical study in rhesus macaques infected with the pathogenic simian immunodeficiency virus SIVmac251 and treated with ART. We tested whether vaccination administered together with cytotoxic-T-lymphocyte-associated antigen 4 (CTLA-4) blockade and treatment with the indoleamine 2,3-dioxygenase (IDO) inhibitor 1-methyl-d-tryptophan (d-1mT), decreased immune activation and improved vaccine efficacy. The treatment did not augment vaccine immunogenicity; rather, it dramatically increased ART-related toxicity, causing all treated animals to succumb to acute pancreatitis and hyperglycemic coma. The onset of fulminant diabetes was associated with severe lymphocyte infiltration of the pancreas and complete loss of the islets of Langerhans. Thus, caution should be used when considering approaches aimed at targeting immune activation during ART.
PMCID: PMC3255892  PMID: 22013040
2.  Highly Diverse Morbillivirus-Related Paramyxoviruses in Wild Fauna of the Southwestern Indian Ocean Islands: Evidence of Exchange between Introduced and Endemic Small Mammals 
Journal of Virology  2014;88(15):8268-8277.
The Paramyxoviridae form an increasingly diverse viral family, infecting a wide variety of different hosts. In recent years, they have been linked to disease emergence in many different animal populations and in humans. Bats and rodents have been identified as major animal populations capable of harboring paramyxoviruses, and host shifting between these animals is likely to be an important driving factor in the underlying evolutionary processes that eventually lead to disease emergence. Here, we have studied paramyxovirus circulation within populations of endemic and introduced wild small mammals of the southwestern Indian Ocean region and belonging to four taxonomic orders: Rodentia, Afrosoricida, Soricomorpha, and Chiroptera. We report elevated infection levels as well as widespread paramyxovirus dispersal and frequent host exchange of a newly emerging genus of the Paramyxoviridae, currently referred to as the unclassified morbillivirus-related viruses (UMRVs). In contrast to other genera of the Paramyxoviridae, where bats have been shown to be a key host species, we show that rodents (and, in particular, Rattus rattus) are significant spreaders of UMRVs. We predict that the ecological particularities of the southwestern Indian Ocean, where small mammal species often live in densely packed, multispecies communities, in combination with the increasing invasion of R. rattus and perturbations of endemic animal communities by active anthropological development, will have a major influence on the dynamics of UMRV infection.
IMPORTANCE Identification of the infectious agents that circulate within wild animal reservoirs is essential for several reasons: (i) infectious disease outbreaks often originate from wild fauna; (ii) anthropological expansion increases the risk of contact between human and animal populations and, as a result, the risk of disease emergence; (iii) evaluation of pathogen reservoirs helps in elaborating preventive measures to limit the risk of disease emergence. Many paramyxoviruses for which bats and rodents serve as major reservoirs have demonstrated their potential to cause disease in humans and animals. In the context of the biodiversity hot spot of southwestern Indian Ocean islands and their rich endemic fauna, we show that highly diverse UMRVs exchange between various endemic animal species, and their dissemination likely is facilitated by the introduced Rattus rattus. Hence, many members of the Paramyxoviridae appear well adapted for the study of the viral phylodynamics that may be associated with disease emergence.
PMCID: PMC4135957  PMID: 24829336
3.  First Full Genome Sequence of a Human Enterovirus A120, Isolated in Madagascar 
Genome Announcements  2014;2(3):e00568-14.
We report the first complete genome sequence of an enterovirus isolate belonging to the human enterovirus A species of the Picornaviridae family and to type A120 (EV-A120). The EV-A120 isolate MAD-2741-11 was obtained from the stool of a healthy child living on Madagascar Island. The isolate genome was amplified by a reverse transcription-PCR method, and the consensus sequence was determined.
PMCID: PMC4064025  PMID: 24948760
4.  Outcome Risk Factors during Respiratory Infections in a Paediatric Ward in Antananarivo, Madagascar 2010–2012 
PLoS ONE  2013;8(9):e72839.
Acute respiratory infections are a leading cause of infectious disease-related morbidity, hospitalisation and mortality among children worldwide, and particularly in developing countries. In these low-income countries, most patients with acute respiratory infection (ARI), whether it is mild or severe, are still treated empirically.
The aim of the study was to evaluate the risk factors associated with the evolution and outcome of respiratory illnesses in patients aged under 5 years old.
Materials and Methods
We conducted a prospective study in a paediatric ward in Antananarivo from November 2010 to July 2012 including patients under 5 years old suffering from respiratory infections. We collected demographic, socio-economic, clinical and epidemiological data, and samples for laboratory analysis. Deaths, rapid progression to respiratory distress during hospitalisation, and hospitalisation for more than 10 days were considered as severe outcomes. We used multivariate analysis to study the effects of co-infections.
From November 2010 to July 2012, a total of 290 patients were enrolled. Co-infection was found in 192 patients (70%). Co-infections were more frequent in children under 36 months, with a significant difference for the 19–24 month-old group (OR: 8.0).
Sixty-nine percent (230/290) of the patients recovered fully and without any severe outcome during hospitalisation; the outcome was scored as severe for 60 children and nine patients (3%) died.
Risk factors significantly associated with worsening evolution during hospitalisation (severe outcome) were admission at age under 6 months (OR = 5.3), comorbidity (OR = 4.6) and low household income (OR = 4.1).
Co-mordidity, low-income and age under 6 months increase the risk of severe outcome for children infected by numerous respiratory pathogens. These results highlight the need for implementation of targeted public health policy to reduce the contribution of respiratory diseases to childhood morbidity and mortality in low income countries.
PMCID: PMC3771918  PMID: 24069161
5.  Dried-Blood Spots: A Cost-Effective Field Method for the Detection of Chikungunya Virus Circulation in Remote Areas 
In 2005, there were outbreaks of febrile polyarthritis due to Chikungunya virus (CHIKV) in the Comoros Islands. CHIKV then spread to other islands in the Indian Ocean: La Réunion, Mauritius, Seychelles and Madagascar. These outbreaks revealed the lack of surveillance and preparedness of Madagascar and other countries. Thus, it was decided in 2007 to establish a syndrome-based surveillance network to monitor dengue-like illness.
This study aims to evaluate the use of capillary blood samples blotted on filter papers for molecular diagnosis of CHIKV infection. Venous blood samples can be difficult to obtain and the shipment of serum in appropriate temperature conditions is too costly for most developing countries.
Methodology and principal findings
Venous blood and dried-blood blotted on filter paper (DBFP) were collected during the last CHIKV outbreak in Madagascar (2010) and as part of our routine surveillance of dengue-like illness. All samples were tested by real-time RT-PCR and results with serum and DBFP samples were compared for each patient. The sensitivity and specificity of tests performed with DBFP, relative to those with venous samples (defined as 100%) were 93.1% (95% CI:[84.7–97.7]) and 94.4% (95% CI:[88.3–97.7]), respectively. The Kappa coefficient 0.87 (95% CI:[0.80–0.94]) was excellent.
This study shows that DBFP specimens can be used as a cost-effective alternative sampling method for the surveillance and monitoring of CHIKV circulation and emergence in developing countries, and probably also for other arboviruses. The loss of sensitivity is insignificant and involved a very small number of patients, all with low viral loads. Whether viruses can be isolated from dried blood spots remains to be determined.
Author Summary
Chikungunya is a mosquito-transmitted viral disease. No treatment is currently available. The only way to prevent infection is to avoid mosquito bites. Surveillance of circulation by early diagnosis is useful to prevent or limit outbreak. CHIKV, like all RNA viruses, is heat-labile. Consequently, confirmatory diagnosis classically requires blood samples that are transported in appropriate conditions (i.e. at 4°C within 48 hours, in liquid nitrogen, or frozen at −80°C and transported on dry ice) to prevent false negative results. This is not always possible in field conditions in low income countries. Dried blood spots are already used to diagnose parasitic, bacterial and viral infection. We compared venous sample to dried blood sample to make diagnosis of Chikungunya infection. We demonstrate the usefulness of this sampling method for the molecular diagnosis of Chikungunya infection. In particular, dried blood spots were very nearly as suitable as frozen serum specimens for the diagnosis of recent infection by CHIKV.
PMCID: PMC3723542  PMID: 23936570
6.  Absence of Rift Valley Fever Virus in Wild Small Mammals, Madagascar 
Emerging Infectious Diseases  2013;19(6):1025-1027.
PMCID: PMC3713820  PMID: 23735220
Rift Valley fever; wild terrestrial mammals; Madagascar; viruses
7.  Reemergence of Recombinant Vaccine–derived Polioviruses in Healthy Children, Madagascar 
Emerging Infectious Diseases  2013;19(6):1008-1010.
PMCID: PMC3713839  PMID: 23735779
poliovirus; vaccine-derived polioviruses; recombinant; Madagascar; viruses; reemergence; vaccine coverage
8.  Vaccine Induced Antibodies to the First Variable Loop of Human Immunodeficiency Virus Type 1 gp120, Mediate Antibody-Dependent Virus Inhibition in Macaques 
Vaccine  2011;30(1):78-94.
The role of antibodies directed against the hyper variable envelope region V1 of human immunodeficiency virus type 1 (HIV-1), has not been thoroughly studied. We show that a vaccine able to elicit strain-specific non-neutralizing antibodies to this region of gp120 is associated with control of highly pathogenic chimeric SHIV89.6P replication in rhesus macaques. The vaccinated animal that had the highest titers of antibodies to the amino terminus portion of V1, prior to challenge, had secondary antibody responses that mediated cell killing by antibody-dependent cellular cytotoxicity (ADCC), as early as two weeks after infection and inhibited viral replication by antibody-dependent cell-mediated virus inhibition (ADCVI), by four weeks after infection. There was a significant inverse correlation between virus level and binding antibody titers to the envelope protein, (R = -0.83, p 0.015), and ADCVI (R = -0.84 p=0.044). Genotyping of plasma virus demonstrated in vivo selection of three SHIV89.6P variants with changes in potential N-linked glycosylation sites in V1. We found a significant inverse correlation between virus levels and titers of antibodies that mediated ADCVI against all the identified V1 virus variants. A significant inverse correlation was also found between neutralizing antibody titers to SHIV89.6 and virus levels (R = -0.72 p =0.0050). However, passive inoculation of purified immunoglobulin from animal M316, the macaque that best controlled virus, to a naïve macaque, resulted in a low serum neutralizing antibodies and low ADCVI activity that failed to protect from SHIV89.6P challenge. Collectively, while our data suggest that anti-envelope antibodies with neutralizing and non-neutralizing FcγR-dependent activities may be important in the control of SHIV replication, they also demonstrate that low levels of these antibodies alone are not sufficient to protect from infection.
PMCID: PMC3246802  PMID: 22037204
9.  The Spread of Influenza A(H1N1)pdm09 Virus in Madagascar Described by a Sentinel Surveillance Network 
PLoS ONE  2012;7(5):e37067.
The influenza A(H1N1)pdm09 virus has been a challenge for public health surveillance systems in all countries. In Antananarivo, the first imported case was reported on August 12, 2009. This work describes the spread of A(H1N1)pdm09 in Madagascar.
The diffusion of influenza A(H1N1)pdm09 in Madagascar was explored using notification data from a sentinel network. Clinical data were charted to identify peaks at each sentinel site and virological data was used to confirm viral circulation.
From August 1, 2009 to February 28, 2010, 7,427 patients with influenza-like illness were reported. Most patients were aged 7 to 14 years. Laboratory tests confirmed infection with A(H1N1)pdm09 in 237 (33.2%) of 750 specimens. The incidence of patients differed between regions. By determining the epidemic peaks we traced the diffusion of the epidemic through locations and time in Madagascar. The first peak was detected during the epidemiological week 47-2009 in Antananarivo and the last one occurred in week 07-2010 in Tsiroanomandidy.
Sentinel surveillance data can be used for describing epidemic trends, facilitating the development of interventions at the local level to mitigate disease spread and impact.
PMCID: PMC3353907  PMID: 22615893
10.  Smallpox Vaccine Safety Is Dependent on T Cells and Not B Cells 
The Journal of Infectious Diseases  2011;203(8):1043-1053.
(See the editorial commentary by Bray, on pages 1037–9.)
The licensed smallpox vaccine, ACAM2000, is a cell culture derivative of Dryvax. Both ACAM2000 and Dryvax are administered by skin scarification and can cause progressive vaccinia, with skin lesions that disseminate to distal sites. We have investigated the immunologic basis of the containment of vaccinia in the skin with the goal to identify safer vaccines for smallpox. Macaques were depleted systemically of T or B cells and vaccinated with either Dryvax or an attenuated vaccinia vaccine, LC16m8. B cell depletion did not affect the size of skin lesions induced by either vaccine. However, while depletion of both CD4+ and CD8+ T cells had no adverse effects on LC16m8-vaccinated animals, it caused progressive vaccinia in macaques immunized with Dryvax. As both Dryvax and LC16m8 vaccines protect healthy macaques from a lethal monkeypox intravenous challenge, our data identify LC16m8 as a safer and effective alternative to ACAM2000 and Dryvax vaccines for immunocompromised individuals.
PMCID: PMC3068024  PMID: 21450994
11.  An Unexpected Recurrent Transmission of Rift Valley Fever Virus in Cattle in a Temperate and Mountainous Area of Madagascar 
Rift Valley fever is an acute, zoonotic viral disease of domestic ruminants, caused by a phlebovirus (Bunyaviridae family). A large outbreak occurred in Madagascar in 2008–2009. The goal of the present study was to evaluate the point prevalence of antibodies against Rift Valley Fever Virus (RVFV) in cattle in the Anjozorobe district, located in the wet and temperate highland region of Madagascar and yet heavily affected by the disease, and analyse environmental and trade factors potentially linked to RVFV transmission. A serological study was performed in 2009 in 894 bovines. For each bovine, the following variables were recorded: age, location of the night pen, minimum distance from the pen to the nearest water point and the forest, nearest water point type, and herd replacement practices. The serological data were analyzed using a generalized linear mixed model. The overall anti-RVFV IgG seroprevalence rate was 28% [CI95% 25–31]. Age was statistically linked to prevalence (p = 10−4), being consistent with a recurrent RVFV circulation. Distance from the night pen to the nearest water point was a protective factor (p = 5.10−3), which would be compatible with a substantial part of the virus transmission being carried out by nocturnal mosquito vectors. However, water point type did not influence the risk of infection: several mosquito species are probably involved. Cattle belonging to owners who purchase animals to renew the herd were significantly more likely to have seroconverted than others (p = 0.04): cattle trade may contribute to the introduction of the virus in this area. The minimum distance of the night pen to the forest was not linked to the prevalence. This is the first evidence of a recurrent transmission of RVFV in such an ecosystem that associates a wet, temperate climate, high altitude, paddy fields, and vicinity to a dense rain forest. Persistence mechanisms need to be further investigated.
Author Summary
Rift Valley fever (RVF) is a viral disease of domestic ruminants, which may affect humans. The RVF virus (RVFV) may be transmitted either by mosquitoes or through direct contact with vireamic body fluids or products. Until now, this disease had been described in arid, hot and irrigated or tropical areas. Performed in the year following the 2008–2009 RVFV outbreak in Madagascar, this study demonstrates for the first time a regular and intense transmission of this disease in a temperate and mountainous region.The area chosen as a pilot project shows that cattle are regularly and heavily affected in the highlands of Madagascar. Statistical analyses suggest that (i) a substantial part of the transmission is due to mosquito vectors; (ii) many mosquito species such as Culex and Anopheles, are probably involved in the transmission; (iii) cattle trade, by a regular introduction of the virus via herds coming from infected areas of the island, may explain the recurrence of the disease in this region. Further investigations are needed to understand the mechanisms of transmission of the disease, and design and implement appropriate surveillance and control measures in this area.
PMCID: PMC3243698  PMID: 22206026
12.  Laboratory Surveillance of Rabies in Humans, Domestic Animals, and Bats in Madagascar from 2005 to 2010 
Background. Rabies virus (RABV) has circulated in Madagascar at least since the 19th century. Objectives. To assess the circulation of lyssavirus in the island from 2005 to 2010. Materials and Methods. Animal (including bats) and human samples were tested for RABV and other lyssavirus using antigen, ribonucleic acid (RNA), and antibodies detection and virus isolation. Results. Half of the 437 domestic or tame wild terrestrial mammal brains tested were found RABV antigen positive, including 54% of the 341 dogs tested. This percentage ranged from 26% to 75% across the period. Nine of the 10 suspected human cases tested were laboratory confirmed. RABV circulation was confirmed in 34 of the 38 districts sampled. No lyssavirus RNA was detected in 1983 bats specimens. Nevertheless, antibodies against Lagos bat virus were detected in the sera of 12 among 50 Eidolon dupreanum specimens sampled. Conclusion. More than a century after the introduction of the vaccine, rabies still remains endemic in Madagascar.
PMCID: PMC3170745  PMID: 21991442
13.  Risk Factors for Severe Outcomes following 2009 Influenza A (H1N1) Infection: A Global Pooled Analysis 
PLoS Medicine  2011;8(7):e1001053.
This study analyzes data from 19 countries (from April 2009 to Jan 2010), comprising some 70,000 hospitalized patients with severe H1N1 infection, to reveal risk factors for severe pandemic influenza, which include chronic illness, cardiac disease, chronic respiratory disease, and diabetes.
Since the start of the 2009 influenza A pandemic (H1N1pdm), the World Health Organization and its member states have gathered information to characterize the clinical severity of H1N1pdm infection and to assist policy makers to determine risk groups for targeted control measures.
Methods and Findings
Data were collected on approximately 70,000 laboratory-confirmed hospitalized H1N1pdm patients, 9,700 patients admitted to intensive care units (ICUs), and 2,500 deaths reported between 1 April 2009 and 1 January 2010 from 19 countries or administrative regions—Argentina, Australia, Canada, Chile, China, France, Germany, Hong Kong SAR, Japan, Madagascar, Mexico, the Netherlands, New Zealand, Singapore, South Africa, Spain, Thailand, the United States, and the United Kingdom—to characterize and compare the distribution of risk factors among H1N1pdm patients at three levels of severity: hospitalizations, ICU admissions, and deaths. The median age of patients increased with severity of disease. The highest per capita risk of hospitalization was among patients <5 y and 5–14 y (relative risk [RR] = 3.3 and 3.2, respectively, compared to the general population), whereas the highest risk of death per capita was in the age groups 50–64 y and ≥65 y (RR = 1.5 and 1.6, respectively, compared to the general population). Similarly, the ratio of H1N1pdm deaths to hospitalizations increased with age and was the highest in the ≥65-y-old age group, indicating that while infection rates have been observed to be very low in the oldest age group, risk of death in those over the age of 64 y who became infected was higher than in younger groups. The proportion of H1N1pdm patients with one or more reported chronic conditions increased with severity (median = 31.1%, 52.3%, and 61.8% of hospitalized, ICU-admitted, and fatal H1N1pdm cases, respectively). With the exception of the risk factors asthma, pregnancy, and obesity, the proportion of patients with each risk factor increased with severity level. For all levels of severity, pregnant women in their third trimester consistently accounted for the majority of the total of pregnant women. Our findings suggest that morbid obesity might be a risk factor for ICU admission and fatal outcome (RR = 36.3).
Our results demonstrate that risk factors for severe H1N1pdm infection are similar to those for seasonal influenza, with some notable differences, such as younger age groups and obesity, and reinforce the need to identify and protect groups at highest risk of severe outcomes.
Please see later in the article for the Editors' Summary
Editors' Summary
In April 2009, a new strain of influenza A H1N1 was first identified in Mexico and the United States and subsequently spread around the world. In June 2009, the World Health Organization (WHO) declared a pandemic alert phase 6, which continued until August 2010. Throughout the pandemic, WHO and member states gathered information to characterize the patterns of risk associated with the new influenza A H1N1 virus infection and to assess the clinical picture. Although risk factors for severe disease following seasonal influenza infection have been well documented in many countries (for example, pregnancy; chronic medical conditions such as pulmonary, cardiovascular, renal, hepatic, neuromuscular, hematologic, and metabolic disorders; some cognitive conditions; and immunodeficiency), risk factors for severe disease following infection early in the 2009 H1N1 pandemic were largely unknown.
Why Was This Study Done?
Many countries have recently reported data on the association between severe H1N1 influenza and a variety of underlying risk factors, but because these data are presented in different formats, making direct comparisons across countries is difficult, with no clear consensus for some conditions. Therefore, to assess the frequency and distribution of known and new potential risk factors for severe H1N1 infection, this study was conducted to collect data (from 1 April 2009 to 1 January 2010) from surveillance programs of the Ministries of Health or National Public Health Institutes in 19 countries―Argentina, Australia, Canada, Chile, China, France, Germany, Hong Kong (special administrative region), Japan, Madagascar, Mexico, the Netherlands, New Zealand, Singapore, South Africa, Spain, Thailand, the United States, and the United Kingdom.
What Did the Researchers Do and Find?
As part of routine surveillance, countries were asked to provide risk factor data on laboratory-confirmed H1N1 in patients who were admitted to hospital, admitted to the intensive care unit (ICU), or had died because of their infection, using a standardized format. The researchers grouped potential risk conditions into four categories: age, chronic medical illnesses, pregnancy (by trimester), and other conditions that were not previously considered as risk conditions for severe influenza outcomes, such as obesity. For each risk factor (except pregnancy), the researchers calculated the percentage of each group of patients using the total number of cases reported in each severity category (hospitalization, admission to ICU, and death). To evaluate the risk associated with pregnancy, the researchers used the ratio of pregnant women to all women of childbearing age (age 15–49 years) at each level of severity to describe the differences between levels.
The researchers were able to collect data on approximately 70,000 patients requiring hospitalization, 9,700 patients admitted to the ICU, and 2,500 patients who died from H1N1 infection. The proportion of patients with H1N1 with one or more reported chronic conditions increased with severity—the median was 31.1% of hospitalized patients, 52.3% of patients admitted to the ICU, and 61.8% of patients who died. For all levels of severity, pregnant women in their third trimester consistently accounted for the majority of the total of pregnant women. The proportion of patients with obesity increased with increasing disease severity—median of 6% of hospitalized patients, 11.3% of patients admitted to the ICU, and 12.0% of all deaths from H1N1.
What Do These Findings Mean?
These findings show that risk factors for severe H1N1 infection are similar to those for seasonal influenza, with some notable differences: a substantial proportion of people with severe and fatal cases of H1N1 had pre-existing chronic illness, which indicates that the presence of chronic illness increases the likelihood of death. Cardiac disease, chronic respiratory disease, and diabetes are important risk factors for severe disease that will be especially relevant for countries with high rates of these illnesses. Approximately 2/3 of hospitalized people and 40% of people who died from H1N1 infection did not have any identified pre-existing chronic illness, but this study was not able to comprehensively assess how many of these cases had other risk factors, such as pregnancy, obesity, smoking, and alcohol misuse. Because of large differences between countries, the role of risk factors such as obesity and pregnancy need further study—although there is sufficient evidence to support vaccination and early intervention for pregnant women. Overall, the findings of this study reinforce the need to identify and target high-risk groups for interventions such as immunization, early medical advice, and use of antiviral medications.
Additional Information
Please access these Web sites via the online version of this summary at
WHO provides a Global Alert and Response (GAR) with updates on a number of influenza-related topics
The US Centers for Disease Control and Prevention provides information on risk factors and H1N1
PMCID: PMC3130021  PMID: 21750667
14.  Viral Etiology of Influenza-Like Illnesses in Antananarivo, Madagascar, July 2008 to June 2009 
PLoS ONE  2011;6(3):e17579.
In Madagascar, despite an influenza surveillance established since 1978, little is known about the etiology and prevalence of viruses other than influenza causing influenza-like illnesses (ILIs).
Methodology/Principal Findings
From July 2008 to June 2009, we collected respiratory specimens from patients who presented ILIs symptoms in public and private clinics in Antananarivo (the capital city of Madagascar). ILIs were defined as body temperature ≥38°C and cough and at least two of the following symptoms: sore throat, rhinorrhea, headache and muscular pain, for a maximum duration of 3 days. We screened these specimens using five multiplex real time Reverse Transcription and/or Polymerase Chain Reaction assays for detection of 14 respiratory viruses. We detected respiratory viruses in 235/313 (75.1%) samples. Overall influenza virus A (27.3%) was the most common virus followed by rhinovirus (24.8%), RSV (21.2%), adenovirus (6.1%), coronavirus OC43 (6.1%), influenza virus B (3.9%), parainfluenza virus-3 (2.9%), and parainfluenza virus-1 (2.3%). Co-infections occurred in 29.4% (69/235) of infected patients and rhinovirus was the most detected virus (27.5%). Children under 5 years were more likely to have one or more detectable virus associated with their ILI. In this age group, compared to those ≥5 years, the risk of detecting more than one virus was higher (OR = 1.9), as was the risk of detecting of RSV (OR = 10.1) and adenovirus (OR = 4.7). While rhinovirus and adenovirus infections occurred year round, RSV, influenza virus A and coronavirus OC43 had defined period of circulation.
In our study, we found that respiratory viruses play an important role in ILIs in the Malagasy community, particularly in children under 5 years old. These data provide a better understanding of the viral etiology of outpatients with ILI and describe for the first time importance of these viruses in different age group and their period of circulation.
PMCID: PMC3048401  PMID: 21390235
15.  Preexisting Infection with Human T-Cell Lymphotropic Virus Type 2 neither Exacerbates nor Attenuates Simian Immunodeficiency Virus SIVmac251 Infection in Macaques ▿  
Journal of Virology  2010;84(6):3043-3058.
Coinfection with human T-cell lymphotropic virus type 2 (HTLV-2) and human immunodeficiency virus type 1 (HIV-1) has been reported to have either a slowed disease course or to have no effect on progression to AIDS. In this study, we generated a coinfection animal model and investigated whether HTLV-2 could persistently infect macaques, induce a T-cell response, and impact simian immunodeficiency virus SIVmac251-induced disease. We found that inoculation of irradiated HTLV-2-infected T cells into Indian rhesus macaques elicited humoral and T-cell responses to HTLV-2 antigens at both systemic and mucosal sites. Low levels of HTLV-2 provirus DNA were detected in the blood, lymphoid tissues, and gastrointestinal tracts of infected animals. Exposure of HTLV-2-infected or naïve macaques to SIVmac251 demonstrated comparable levels of SIVmac251 viral replication, similar rates of mucosal and peripheral CD4+ T-cell loss, and increased T-cell proliferation. Additionally, neither the magnitude nor the functional capacity of the SIV-specific T-cell-mediated immune response was different in HTLV-2/SIVmac251 coinfected animals versus SIVmac251 singly infected controls. Thus, HTLV-2 targets mucosal sites, persists, and importantly does not exacerbate SIVmac251 infection. These data provide the impetus for the development of an attenuated HTLV-2-based vectored vaccine for HIV-1; this approach could elicit persistent mucosal immunity that may prevent HIV-1/SIVmac251 infection.
PMCID: PMC2826058  PMID: 20071587
16.  Sentinel surveillance system for early outbreak detection in Madagascar 
BMC Public Health  2010;10:31.
Following the outbreak of chikungunya in the Indian Ocean, the Ministry of Health directed the necessary development of an early outbreak detection system. A disease surveillance team including the Institut Pasteur in Madagascar (IPM) was organized to establish a sentinel syndromic-based surveillance system. The system, which was set up in March 2007, transmits patient data on a daily basis from the various voluntary general practitioners throughout the six provinces of the country to the IPM. We describe the challenges and steps involved in developing a sentinel surveillance system and the well-timed information it provides for improving public health decision-making.
Surveillance was based on data collected from sentinel general practitioners (SGP). The SGPs report the sex, age, visit date and time, and symptoms of each new patient weekly, using forms addressed to the management team. However, the system is original in that SGPs also report data at least once a day, from Monday to Friday (number of fever cases, rapid test confirmed malaria, influenza, arboviral syndromes or diarrhoeal disease), by cellular telephone (encrypted message SMS). Information can also be validated by the management team, by mobile phone. This data transmission costs 120 ariary per day, less than US$1 per month.
In 2008, the sentinel surveillance system included 13 health centers, and identified 5 outbreaks. Of the 218,849 visits to SGPs, 12.2% were related to fever syndromes. Of these 26,669 fever cases, 12.3% were related to Dengue-like fever, 11.1% to Influenza-like illness and 9.7% to malaria cases confirmed by a specific rapid diagnostic test.
The sentinel surveillance system represents the first nationwide real-time-like surveillance system ever established in Madagascar. Our findings should encourage other African countries to develop their own syndromic surveillance systems.
Prompt detection of an outbreak of infectious disease may lead to control measures that limit its impact and help prevent future outbreaks.
PMCID: PMC2823701  PMID: 20092624
17.  Immune Activation Driven by CTLA-4 Blockade Augments Viral Replication at Mucosal Sites in Simian Immunodeficiency Virus Infection1 
The importance of chronic immune activation in progression to AIDS has been inferred by correlative studies in HIV-infected individuals and in nonhuman primate models of SIV infection. Using the SIVmac251 macaque model, we directly address the impact of immune activation by inhibiting CTLA-4, an immunoregulatory molecule expressed on activated T cells and a subset of regulatory T cells. We found that CTLA-4 blockade significantly increased T cell activation and viral replication in primary SIVmac251 infection, particularly at mucosal sites, and increased IDO expression and activity. Accordingly, protracted treatment with anti-CTLA-4 Ab of macaques chronically infected with SIVmac251 decreased responsiveness to antiretroviral therapy and abrogated the ability of therapeutic T cell vaccines to decrease viral set point. These data provide the first direct evidence that immune activation drives viral replication, and suggest caution in the use of therapeutic approaches for HIV infection in vivo that increase CD4+ T cell proliferation.
PMCID: PMC2768121  PMID: 18390726
18.  Differential Antigen Requirements for Protection against Systemic and Intranasal Vaccinia Virus Challenges in Mice ▿  
Journal of Virology  2008;82(14):6829-6837.
The development of a subunit vaccine for smallpox represents a potential strategy to avoid the safety concerns associated with replication-competent vaccinia virus. Preclinical studies to date with subunit smallpox vaccine candidates, however, have been limited by incomplete information regarding protective antigens and the requirement for multiple boost immunizations to afford protective immunity. Here we explore the protective efficacy of replication-incompetent, recombinant adenovirus serotype 35 (rAd35) vectors expressing the vaccinia virus intracellular mature virion (IMV) antigens A27L and L1R and extracellular enveloped virion (EEV) antigens A33R and B5R in a murine vaccinia virus challenge model. A single immunization with the rAd35-L1R vector effectively protected mice against a lethal systemic vaccinia virus challenge. The rAd35-L1R vector also proved more efficacious than the combination of four rAd35 vectors expressing A27L, L1R, A33R, and B5R. Moreover, serum containing L1R-specific neutralizing antibodies afforded postexposure prophylaxis after systemic vaccinia virus infection. In contrast, the combination of rAd35-L1R and rAd35-B5R vectors was required to protect mice against a lethal intranasal vaccinia virus challenge, suggesting that both IMV- and EEV-specific immune responses are important following intranasal infection. Taken together, these data demonstrate that different protective antigens are required based on the route of vaccinia virus challenge. These studies also suggest that rAd vectors warrant further assessment as candidate subunit smallpox vaccines.
PMCID: PMC2446990  PMID: 18448519

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