Institut Pasteur International Network

REPORT 2010 32 Instituts Pasteur worldwide AFRICA AMERICAS ASIA-PACIFIC EUROPE MARC JOUAN RIIP SECRETARY-GENERAL OF THE INSTITUT PASTEUR INTERNATIONAL NETWORK

“In 2010, 32 Institutes signed the new Institut networks, in support of the International Health Regulations. Pasteur International Network partnership As national bodies for intervention, these institutes now agreement. This agreement confirms their commitment to constitute with their ability to mobilize expertise beyond borders international scientific cooperation, first and the fight against a single regional and international force of intervention, infectious diseases. Preoccupied with respect for ethical values ready to take action in areas where epidemics strike (Africa, and the commitment to the most vulnerable populations, the Asia, South America, etc.). Major efforts have been made network rallies in this fight different institutes very much involved recently to increase the network’s intervention abilities in public health research and monitoring and a new generation by creating high security BSL3 laboratories and new clinical contents of institutes boasting innovative research facilities. Grounded in research facilities, but also by strengthening new areas a close partnership with local health authorities, the network of expertise, particularly in entomology and epidemiology. relies integrated sustainable institutions, benefiting from statuses The network now constitutes a unique and original international scientific cooperation model that draws upon the development 01 RIIP adapted to their tasks: certain public institutions under the of local skills to guarantee the sustainability of its actions. supervision of Ministries of Health, such as the new Institut The ambitious international training program supported by all 02 EDITORIAL Pasteur in Laos, others benefiting from a private status under the institutes confirms this commitment. It is based on new local law like the Institut Pasteur in Dakar, which became a GLOBAL PRESENCE partnerships with universities and Ministries of health. It is one 04 private foundation under Senegalese law in 2010. Very keen to of the priority areas for the network’s development. This report meet the expectations of these countries and the international 06 SIGNIFICANT EVENTS describes some of the recent achievements of the International community in the prevention of infectious diseases, the network Network. It does not claim to be exhaustive but outlines faces new healthcare, demographic and environmental 10 PUBLIC HEALTH AND POPULATIONS the milestones and major achievements in the fields of public challenges in light of financial constraints and political health and research.” 16 RESEARCH ON INFECTIOUS DISEASES developments. In order to meet these challenges, the network has devised ambitious international programs in liaison with 38 INTERNATIONAL TEACHING AND TRAINING the different countries’ Ministries of health and the WHO: monitoring of bacterial meningitis in Africa, creation of a TECHNICAL PLATFORMS 44 network to monitor influenza in Africa and Asia, prevention of 50 THANKS AND PARTNERS respiratory and diarrhea-related infections, surveillance of resistance to anti-infectives, hepatitis, and neglected diseases such as Buruli ulcer, etc. The network’s WHO Collaborating Centers is currently key actor in the international monitoring

01 editorial

ALICE DAUTRY FRANÇOISE BARRÉ-SINOUSSI JÉRÔME SALOMON PRESIDENT OF INSTITUT PASTEUR HONORARY PRESIDENT OF THE INSTITUT PASTEUR HEAD OF THE INTERNATIONAL INTERNATIONAL NETWORK DIVISION

I hope that we will continue to move forward, together, The Institut Pasteur International For over 120 years the Institut Pasteur on the road to biomedical knowledge, communication and Network is unique in its global has accomplished its triple mission of collaboration, for the benefit of as many people as possible.” geographic presence but also in the public health, teaching and research, diversity of its activities, varying from defending its ethics and value of sharing and “This year we celebrate the 120th anniversary extraordinary wealth to the network and its partnerships. We fundamental research to diagnosis and drawing on a network of 32 institutions on the of the first Institut Pasteur overseas, located in Saigon. Many have formed close ties with major international partners, routine vaccination.” 5 continents.” other institutes followed in the same international spirit as demonstrated by the presence of senior representatives characterizing Institut Pasteur since it was founded in 1887. from the Wellcome Trust, NIH or the Riken at the network’s “More precisely, I have been pleased to “In the George Institute’s G-Finder study, the Institut Louis Pasteur’s desire was for progress in healthcare to be scientific meetings in Hong Kong in November 2010. note, over the years, a growing interest from RIIP members for Pasteur has pride of place, particularly in the prevention of Buruli ulcer. shared by all, as rapidly as possible, and to benefit those Aware that disease prevention requires mutual action, we thematic multicenter programs combining clinical research It is among the top 12 for malaria, leishmaniasis, trypanosomiases and affected by the disease, in the field. Driven by a sense have developed the network’s scientific meetings, facilitated and more fundamental research. This involvement in clinical dengue. Globally, Institut Pasteur is ranked 11th and even 5th among of ethics and the respect for pasteurian values, each of the regional meetings and decided to create a network research enhances the ties with national health structures, self-financed institutions. The work accomplished is impressive but we institutions belonging to the Institut Pasteur International association. The main objective of this Pasteur International particularly hospitals, which are essential to the creation of must face new challenges. The increasing number of exchanges and Network works in the name of disease research and Network Association, will be to facilitate the development efficient networks integrating research and care in a the circulation of infectious agents and resistance mechanisms require monitoring, particularly in infectious diseases, public health, of scientific projects involving several members of the translational spirit of multidisciplinarity. Through these close ties, partnerships to be strengthened on a global level. The endemics or prevention, the fight against epidemics and pandemics, and international network and other partners. It is expected to the RIIP member institutes are able to contribute fully to the epidemics in the southern hemisphere can affect countries in the the training of technicians, engineers and doctoral students increase the available means, broaden the network institutes’ training of researchers and health workers. Furthermore, the high northern hemisphere. The examples of the chikungunya virus or in countries where these institutions are located and are project opportunities, and provide them with even greater quality technological facilities present there can facilitate dengue are very much relevant today. A multidisciplinary synergic perceived as benefaction centers, heirs to Alexandre Yersin international visibility, for everyone’s benefit. Finally, I want to international partnerships with the public and private sectors. approach is now essential with a number of field partners. Current and Charles Nicolle. This said, the institutes’ work benefits the thank the staff of institutes from the international network who National data collected unearths scientific evidence meeting developments are putting the competitivity of our research system to entire world’s population. Diseases are unhindered by borders, have worked this year in local conditions may be extremely the expectations of health authorities and helping them to the test, and its ability to contribute to major international projects. hence it is essential that disease research and monitoring difficult and painful, as in Niger, Cote d’Ivoire and Tunisia.” make decisions adapted to national context. Very much rooted In order to develop innovative diagnostic tools and new therapeutic are too. In this respect, the Institut Pasteur International Network in the local reality, these RIIP institutes are a veritable means methods, the boundaries of research must be broken. We have to step is a unique collaboration tool that is particularly useful and of improvement in public health in the countries where they are up certain lines of research and enhance communication. Scientific effective for monitoring and raising the alert in the event present; their reason for existing.” priorities must take into account public health problems, niches of of an emerging disease as was the case with the potential expertise and the benefits of a multidisciplinary synergic network. influenza pandemic. I would like to salute the friendship New funding mechanisms are emerging, requiring monitoring and the binding the different institutes and their members, which adds use of experts in financing and specific administrators. The international network is a major contributor to infectious disease research. It is expanding, and shares its pasteurian values and ethics. It thrives on the wonderful breeding ground of ideas and skills of the Pasteur scientists in infectious disease research. It is unable and unwilling to work alone and is ready to welcome teams from Europe, the US or elsewhere while fostering pasteurian values and ethics. It thrives on the wonderful breeding ground of ideas and skills of Pasteur scientists the world over.”

02 INSTITUT PASTEUR INTERNATIONAL NETWORK ••• REPORT 2010 03 SAINT PETERSBURG

LILLE BRUSSELS LAVAL PARIS BUCHAREST ROME SOFIA

TEHRAN SEOUL ATHENS CASABLANCA ALGIERS TUNIS SHANGHAI

RIIP HANOI HONG KONG global presence VIENTIANE POINT-À-PITRE DAKAR NIAMEY NHA TRANG ABIDJAN PHNOM PENH HO CHI MINH CITY BANGUI CAYENNE The Institut Pasteur International Network (RIIP) is a partnership of 32 research and public health institutes on five conti- YAOUNDÉ nents. The Network was born from the will of Louis Pasteur to contribute, through high quality research activity, to the fight against infectious diseases directly in countries where they emerge. ANTANANARIVO NOUMEA RIO DE JANEIRO

MONTEVIDEO

1887 Institut Pasteur PARIS – FRANCE 1891 1893 1894 1894 1895 1898 1900 Institut Pasteur in Institut Pasteur in Tunis Institut Pasteur in Algeria Institut Pasteur in Lille Institut Pasteur Institut Pasteur Fondation Oswaldo Cruz Ho Chi Minh City TUNISIA ALGERIA FRANCE in Nha Trang in Madagascar FIOCRUZ – BRAZIL VIETNAM VIETNAM MADAGASCAR

1919 1920 1921 1921 1923 1923 1925 1929 Hellenic Institut Pasteur Institut Pasteur in Iran Scientific Institute Cantacuzino Institute Institut Pasteur Institut Pasteur in Dakar National Institute of Institut Pasteur in Morocco ATHENS – GREECE IRAN of Public Health ROMANIA in Saint Petersburg SENEGAL Hygiene and Epidemiology CASABLANCA, TANGER – MOROCCO BRUSSELS – BELGIUM RUSSIA HANOI – VIETNAM

1938 1940 1947 1948 1953 1955 1959 1961 Institut Armand Frappier Institut Pasteur Stephan Angeloff Institute Institut Pasteur Institut Pasteur Institut Pasteur Pasteur Centre Institut Pasteur in Bangui LAVAL – CANADA in French Guiana BULGARIA in Guadeloupe in Cambodia in New Caledonia in Cameroon CENTRAL GUIANA GUADELOUPE CAMBODIA NEW CALEDONIA CAMEROON AFRICAN REPUBLIC 2011 Institut Pasteur in Laos 1972 1976 1978 1999 2003 2004 2004 LAOS Institut Pasteur Institut Pasteur – Cenci CERMES Hong Kong University-Pasteur Institut Pasteur in Korea Institut Pasteur Institut Pasteur in Cote d’Ivoire Bolognetti Foundation NIAMEY – NIGER Research Centre KOREA of Shanghai – Chinese in Montevideo COTE D’IVOIRE ROME – ITALY HONG KONG Academy of Sciences URUGUAY CHINA

04 INSTITUT PASTEUR INTERNATIONAL NETWORK ••• REPORT 2010 05 2009 2010 significant events

Numerous events marked out these two years 2009-2010: international agreements, major building works, regional meetings....

MAJOR BUILDING WORKS STATUS Mediterranean, Southeast Asia, Latin The Institut Pasteur of A BSL-3 laboratory The status of the Institut America and the Indian Ocean. Shanghai signed two new The IRD and the Institut Pasteur hope was inaugurated at the Pasteur in Dakar has partnership agreements to fight to strengthen cooperation between Institut Pasteur in changed; it has become a private against infectious diseases their local teams in these countries in early foundation under Senegalese law. on June 23, 2010, with the Institute Madagascar and to pool their infrastructures and February 2009. for Glycomics at Griffith University, funding instruments. Sara Eyangoh’s Australia, to strengthen cooperation in Inauguration of the new laboratory at the Pasteur Centre in INTERNATIONAL AGREEMENTS the research and development building of the Institut Cameroon named as a “Young of new therapies The new MAY 2009 Team Associated with the IRD” for its Pasteur Korea. and to consolidate the institutes’ building of the Institut Pasteur Korea research on Buruli ulcer, becomes Signing of an agreement expertise in research into in Pangyo, south of Seoul, was the first joint Institut Pasteur–IRD between DNDi (the Drugs for anti-infective and antiviral agents. officially opened on May 8, 2009. research team. Neglected Diseases initiative) and cooperation in the fields of on August 13, 2010, with the the Institut Pasteur Korea Construction work on the biomedical and biotechnological APRIL 2010 Children’s Hospital of Institut Pasteur in Laos during the official inauguration research. This cooperation, which Adoption of a new RIIP Fudan University, for clinical will be finalized in September 2011. of the Institut Pasteur Korea’s new will also involve the RIIP institutes, will cooperation agreement research into hand, foot building. The agreement concerns take the form of exchanges of Construction work is under that confirms the institutes’ and mouth disease, the therapeutic development in the experience and personnel, joint way on phase II of the Institut membership to the International JUNE 2010 second most deadly disease in area of neglected diseases. research programs, the organization Pasteur of Shanghai. Network. China in 2010. of bilateral seminars and the setting Renewal of the Institut The Institut Pasteur and the up of joint teaching and training Pasteur–Total Foundation Centers for Disease programs. corporate funding Control and Prevention agreement, demonstrating the (CDC) sign a declaration APRIL 2010 determination of both parties to of intention in the public health Signing of a partnership strengthen the partnership begun domain. in 2005. The new funding will be agreement between the used to create a Françoise Institut de Recherche pour OCTOBER 2009 Barré-Sinoussi Chair for HIV/AIDS le Développement training and research, for the Fiocruz–Pasteur (Development Research development of research Agreement Institute – IRD) and the programs to combat infectious Signing of a new bilateral Institut Pasteur to develop joint diseases and for public health DECEMBER 2010 cooperation agreement between research projects in France’s initiatives, notably against Partnership between the the Oswaldo Cruz Foundation overseas regions and collectivities emerging and re-emerging Principality of Monaco (Fiocruz) and the Institut Pasteur for and in countries in Africa, the diseases. and the Institut Pasteur.

06 INSTITUT PASTEUR INTERNATIONAL NETWORK ••• REPORT 2010 07 2009 2010 significant events

MEETINGS / EVENTS conference on ‘The challenges The RIIP annual meeting was ON MAY 11, 2010 HONORS facing biomedical science at the organized by the HKU–Pasteur 2009 Roselyne Bachelot, IN SEPTEMBER 2010 beginning of the 21st century’, Research Centre at the campus French Minister for Health and Celebration of the 50th organized by Fiocruz and the of the University of Hong Kong’s Dr Imen Rabhi, from the Sports, visited the Institut anniversary of the Pasteur Institut Pasteur, was held Faculty of Medicine. This annual Immunopathology, Vaccinology and Pasteur of Shanghai. Centre in Cameroon. on October 20-22, 2009, meeting, a major scientific event for Molecular Genetics Laboratory at in Rio de Janeiro. On October the RIIP, was opened with a lecture by the Institut Pasteur in Tunis, Regional Meetings – North 19-20, 2009, to coincide with Françoise Barré-Sinoussi. It was ON JULY 6, 2010 was awarded the L’Oréal– attended by international scientists Africa and Iran in Tunis in this conference, the Council of the DECEMBER 7-10, 2010 Valérie Pécresse, French UNESCO Fellowship ‘For including representatives from the NIH, January and the Americas in Directors of the RIIP was held. Minister for Higher Education and Women in Science’ for her RIKEN and the Wellcome Trust, who Madagascar. The Institut Guadeloupe in September. work on the biological validation of reflected on four themes (Vaccine Research, visited the Institut MAY 18-20, 2010 Pasteur in Madagascar the effect of Leishmania parasitic Preventable Diseases, Neglected hosted the closing meeting Pasteur of Shanghai on OCTOBER 20-22, 2009 infection on macrophage metabolic To mark the Year of France in Russia Diseases, Networking to Improve of the project aimed at “Support, July 7. She expressed her wish to see pathways. Franco-Brazilian scientific and the Year of Russia in Health, and The Nature of Altruism). Training and Capacity Building the institute contributing to the France in 2010, the The Council of the Directors of the RIIP for Infectious Disease Surveillance development of new diagnostic conference, Rio de Janeiro, in COMMUNICATIONS connection with the Year of France international conference was held on November 24-25. Networks”, led jointly by the tools, new medicines and new in Brazil, a Franco-Brazilian scientific on ‘Scientific research Institut Pasteur, the Institut Pasteur vaccines in the humanist spirit of New website and monitoring of DECEMBER 4, 2010 International Network and the Louis Pasteur. www.pasteur-international.org United States Department of infectious diseases’, French Guiana. To mark its Health and Human Services (HHS), was organized by the Institut 70th anniversary, the Institut with representatives from the Pasteur in Saint Petersburg Pasteur in French Guiana Centers for Disease Control with the support of the Ministry of opened its doors to the public on and Prevention (CDC) in Kenya Public Health and the Russian Saturday December 4. Research and the United States Department HAL-RIIP Academy of Medical Sciences. This stands – Lectures for the general of Defense. important event was attended by public – Meetings with researchers The scientific publications of the RIIP are listed on the – Laboratory tours. 300 scientists, doctors and leading VISITS online open bibliographc archive HAL-RIIP: public health figures, as well http://hal-riip.archives-ouvertes.fr/, operational as health monitoring organizations APRIL 2010 since July 2009. The platform HAL-RIIP allows the from Russia and other countries. Yves Jégo, French State Secretary for Overseas Affairs, held on-line submission of scientific publications from the RIIP NOVEMBER 22-25, 2010 a meeting for the Directors and and their consultation by institute, author, year or thematic. Hong Kong – Scientific representatives of research bodies All works mentioned in this report can be found by Meeting and Council of at the Institut Pasteur in consulting the online open bibliographic archive HAL-RIIP. the Directors of the RIIP. French Guiana.

08 INSTITUT PASTEUR INTERNATIONAL NETWORK ••• REPORT 2010 09 One of the primary vocations of the Institut Pasteur International Network (RIIP) is to protect the health of populations in the countries where it works. RIIP member institutes perform a wide range of public health and service activities including vaccination, voluntary counseling and testing for HIV and other infections, and also Public health including support for national health programs. RIIP institutes are linked into an international network that can be mobilized to respond to outbreaks and contain epidemics using the latest techniques and in partnership and populations with worldwide bodies such as the World Health Organization (WHO).

18 16 WHO collaborating vaccination centers (WHOCCs) centers

10 INSTITUT PASTEUR INTERNATIONAL NETWORK ••• REPORT 2010 11 Public health and populations

SURVEILLANCE presence of mosquito vectors, including Aedes africanus and Aedes aegypti. Vaccination cam- Surveillance and HUMAN AND AVIAN INFLUENZA IN AFRICA paigns have been organized in response. The sentinel network for human influenza in outbreak intervention Africa operates via a multi-center study grou- ENTEROVIRUS AND POLIOVIRUS ping together the six RIIP member institutes in The Instituts Pasteur in Tunis, Saint Petersburg sub-Saharan Africa: Central African Republic, and Bangui are strongly involved in monitoring With its global presence and the top-level expertise of its scientists, the RIIP is Cote d’Ivoire, Madagascar, Niger, Senegal and some diseases that are targets for vaccination. well-positioned to perform infectious disease surveillance and participate in Cameroon. Since the emergence of influenza Enterovirus surveillance activities carried out the global response to major epidemics. The Network hosts several A(H1N1), its detection is a priority for this in the framework of the global program for the network with the opening of sentinel sites.. This eradication of poliomyelitis have enabled Reference Centers and WHO Collaborating Centers, which carry out network demonstrated the circulation of the researchers to establish a profile of the circula- constant surveillance for diseases with epidemic potential such as influenza, influenza virus in Niger and Central African tion of these viruses in North Africa and in cholera, dengue, yellow fever and emerging infectious diseases. As such, Republic (CAR) for the first time. The first cases Europe. Investigations are often conducted to of influenza associated with the A(H1N1) virus provide more detailed characterization of RIIP member institutes provide technical advice at the national and were detected in Niger by the CERMES in the viral strains in circulation and to assess the international level. The RIIP interacts with local and international public health February 2010 and in CAR at the Institut Pas- impact of poliomyelitis vaccination on the authorities and works closely with health ministries, the WHO’s Global teur in Bangui in September 2010. population. Outbreak Alert and Response Network (GOARN) and the Institut Pasteur’s The RIIP’s initiative is all the more important LEISHMANIASIS Laboratory for Urgent Response to Biological Threats (CIBU). given that very few African countries monitor In Tunisia, data relating to morbidity due to influenza viruses, which makes any efforts leishmaniasis at a national level over the past made to counter this disease on the African twenty years have been gathered from local continent particularly complicated. surveys at health services in the endemic area. Vaccination Center, Institut Pasteur in Bangui. Environmental information and clinical para- DENGUE meters are being analyzed at the Institut Pas- The Institut Pasteur in Cambodia is working teur in Tunis, which is also developing a spatio- with the National Anti-Dengue Program in temporal model to predict the emergence of demic of dengue-3, a highly virulent strain that Guadeloupe and the Institut Pasteur in French Cambodia and carries out laboratory sur- epidemics. is rare in Africa, has emerged for the first time Guiana, were actively involved in the response veillance of the clinical syndromes of severe in West Africa, in Senegal and in Cape Verde in to the cholera epidemic in Haiti. dengue in patients in public hospitals on five particular. The initial investigation was followed This CNR also intervened during the cholera sentinel sites. Various techniques (serological, RESPONSE TO EPIDEMICS up with support from laboratories, diagnosis epidemic in Vietnam, working together with the molecular and viral isolation) are used to efforts and entomological and epidemiological National Institute of Hygiene and Epidemiology search for infection by the dengue virus or by YELLOW FEVER AND DENGUE OUTBREAKS studies. The response also involves vector (NIHE) in Hanoi. other medically important arboviruses in IN COTE D’IVOIRE control and recording and analyzing trends. Southeast Asia (the Japanese encephalitis, In 2010, Cote d’Ivoire suffered a joint epidemic Maintaining vector control efforts in the long LEPTOSPIROSIS Langat, Sindbis and Chikungunya viruses). of yellow fever and dengue. The Ministry of term will help contain the emergence of other Health and Public Hygiene set up a technical The RIIP is mobilizing its efforts to fight against In 2009, even though surveillance of endemic arbovirus infections such as chikungunya. committee, including the Institut Pasteur in leptospirosis, an emerging disease recognized dengue in Cambodia demonstrated normal Cote d’Ivoire, to assess the epidemics. The The Instituts Pasteur in French Guiana and by WHO, in particular in the Asia–Pacific region. circulation of the four serotypes, a system to various cases of yellow fever and dengue were New Caledonia also intervened during dengue The Institut Pasteur in New Caledonia was res- monitor the emergence of new viral genotypes confirmed by the Institut Pasteur in Cote epidemics in their respective regions. ponsible for the biological diagnosis of leptos- was set up. d’Ivoire and the Institut Pasteur in Dakar. The pirosis in Futuna during the recent outbreaks of A prospective and descriptive study on the pre- Ministry of Health and Public Hygiene in Cote PLAGUE IN PERU: MISSION CARRIED OUT BY cases. valence of dengue during febrile episodes is d’Ivoire implemented a number of initiatives to THE INSTITUT PASTEUR IN MADAGASCAR IN being carried out by the Institut Pasteur in Cote curb this epidemic. A vaccine strategy was also AUGUST 2010 d’Ivoire. applied in Grand-Bassam and Bouaké and In a coastal region of Peru, intense circulation around the city of Abidjan; this strategy consis- of Yersinia pestis led to the death of three YELLOW FEVER ted of a targeted vaccination campaign around people out of a total of 27 recorded cases. The In connection with the surveillance activities for the confirmed cases. A mosquito eradication first confirmations of cases were made using yellow fever being carried out in Central African program (elimination of larvae breeding antigen detection tests supplied by the Institut Republic, the Institut Pasteur in Bangui has grounds) was also carried out with the support Pasteur in Madagascar. The only way that pla- diagnosed several fatal cases of this arbovirus of the local authorities. gue can be brought under control is by impro- infection, confirmed by the WHO Regional Cen- ving understanding of the region’s natural ter for Arbovirus Research at the Institut Pas- THE INSTITUT PASTEUR IN DAKAR cycle, agricultural practices and poverty. teur in Dakar. A total of 29 cases, including DIAGNOSES THE FIRST DENGUE EPIDEMIC 9 deaths, were recorded in 2009. Entomological IN CAPE VERDE CHOLERA IN HAITI research conducted jointly by the Institut Pas- Scientists from the Institut Pasteur in Dakar, in The National Reference Center (CNR) for teur in Bangui, the Ministry of Health and WHO cooperation with WHO and the Cape Verdean Vibrios and Cholera at the Institut Pasteur in into these positive cases has shown a strong Ministry of Health, have confirmed that an epi- Paris, in cooperation with the Institut Pasteur in

12 INSTITUT PASTEUR INTERNATIONAL NETWORK ••• REPORT 2010 13 Public health and populations

VACCINATION AND OTHER • diagnostic tests for dengue, salmonella, National and international HEALTHCARE SERVICES bacterial meningitis, etc. • food and environmental safety tests Vaccines are the most effective weapon to fight infectious diseases in individuals and • microbiological and physicochemical ana- technical expertise populations. Given their prerogative to protect lyses of water, food and agricultural pro- public health, many RIIP institutes provide ducts, as well as toxicological assessments The RIIP includes a large number of national and international reference centers for infectious diseases and vaccination services or otherwise support • support for national and international health resistance to antimicrobial agents. National Reference Centers act as microbiological observatories for in-country vaccination campaigns. programs focused on several diseases (HIV+/ communicable diseases in the countries where they are located. WHO Collaborating Centers perform a AIDS, tuberculosis, dengue, malaria, etc.) INTERNATIONAL VACCINATION CENTERS through epidemiological surveys, monitoring similar function for the WHO network. National and regional reference laboratories are recognized by national The Instituts Pasteur in Algeria, Bangui, of vaccination programs, genotyping, clinical health ministries as competent to diagnose certain diseases. Cambodia, Dakar, Guadeloupe, Ho Chi Minh trials, etc.) City, Iran, Lille, New Caledonia, Madagascar, • occupational and school health Morocco and Saint Petersburg and the Pasteur Centre in Cameroon have a vaccination center • vector control IN THE RIIP that provides several essential vaccines. • health education The rabies vaccination is available at the INSTITUTE WHO COLLABORATING NATIONAL REFERENCE CENTERS REGIONAL REFERENCE LABORATORIES Pasteur Centre in Cameroon and at the Insti- SOME ACTIVITIES CARRIED OUT CENTERS RECOGNIZED BY WHO tuts Pasteur in Algeria, Bangui, Cambodia, BY THE PASTEUR CENTRE IN Pasteur Centre in Cameroon Influenza. Yellow fever. Poliomyelitis. Bacteriology (WHO). Avian influenza Dakar, French Guiana, Ho Chi Minh City, Iran, Measles (WHO) – Food-borne infections (WHO). Madagascar, Morocco and Tunis. A total of CAMEROON, YAOUNDÉ (2009) Poliomyelitis (WHO) 200,000 rabies vaccinations are performed • Activities conducted by medical analysis duces vaccines for rabies and typhoid, and is Institut Pasteur in Bangui Arboviruses, Measles. Rubella Poliomyelitis (WHO) each year. As we celebrate the 125th anniver- laboratories: 320,000 tests 450 people responsible for importing and distributing hemorrhagic fevers. sary of the first rabies vaccination, this disease each day (average over 200 working days), Influenza. Rabies. HIV/ continues to cause devastation in many areas several vaccines to the Algerian population. 90,000 people and 107,939 samples AIDS across the world. The Cantacuzino Institute supervises the pro- • Anatomical Pathology and Cytology Service: Institut Pasteur in Cote d’Ivoire Avian influenza (WHO) duction of vaccines for measles, influenza and In Paris, the Institut Pasteur carries out routine 2,080 histological analyses (66% biopsies and Institut Pasteur in Dakar Arboviruses, Influenza and respiratory viruses. Avian influenza (WHO) infant vaccination and performs the vaccina- tuberculosis and the DTP. The Institut Pasteur 34% operative specimens), 5,240 cytopatho- hemorrhagic fevers Poliomyelitis. Measles. Rotaviruses tions required for international travel, including in Tunis produces vaccines and serums to meet logical analyses Institut Pasteur in Madagascar Plague Influenza. Avian influenza. Poliomyelitis. Avian influenza (WHO) the needs of the country (intradermal BCG vac- the rabies vaccine. • The International Vaccination Center: Measles cine, therapeutic serums). 29,700 vaccinations performed, including Institut Pasteur in Cambodia Influenza. Avian influenza Rapid diagnostic test for malaria (WHO) PRODUCTION OR SUPERVISION 8,300 yellow fever vaccinations Evaluation of the diagnostic test for OF THE PRODUCTION OF SERUMS The RIIP institutes are also responsible for pro- • The Anti-Rabies Center: 1,380 post-bite dengue (WHO) AND VACCINES IN SOME INSTITUTES viding several healthcare services for local consultations and 760 rabies vaccinations NIHE (Vietnam) Health in the workplace Influenza. Poliomyelitis IN THE NETWORK populations, including: Institut Pasteur in Guadeloupe Supranational Reference Laboratory for Some of the RIIP member institutes are also • counseling and testing for HIV and hepatitis C • Intradermal reactions to tuberculin: Tuberculosis involved in the production of vaccines. The Ins- 2,130 performed • a variety of medical tests carried out by medi- Institut Pasteur in French Guiana Arboviruses and Influenzae viruses*. titut Pasteur in Dakar runs the only yellow fever cal biology centers and laboratories (anato- Malaria chemoresistance* vaccine production unit in Africa. The Institut mical pathology and cytology, hematology, Cantacuzino Institute (Romania)** Influenza Influenza. Poliomyelitis. Measles/ Influenza (WHO) Pasteur in Ho Chi Minh City and the Institut rubella Pasteur in Iran produce the BCG and the rabies biochemistry, immunoserology, mycobacte- vaccine. The Institut Pasteur in Algeria pro- riology, microbiology, parasitology, virology) Hellenic Institut Pasteur Influenza. Poliomyelitis. Measles/ Leishmaniasis. rubella. Avian influenza Neisseria gonorrhoeae Institut Pasteur in Saint Petersburg Poliomyelitis Avian influenza. SARS. Poliovirus. Rabies. Papillomavirus. Viral hepatitis. CNRS AND WHOCCS UNDER THE RESPONSIBILITY OF THE INSTITUT PASTEUR (PARIS) Measles. Rubella Scientific Institute of Public Health Influenza. Measles. Rubella. Rabies. FIELD OF INTERVENTION • Toxicogenomic Corynebacteria (CNR) • Meningococcus (CNR–WHOCC) (Belgium) Viral hepatitis • Arboviruses and Viral Hemorrhagic Fevers • Enteroviruses (viral vaccines – poliovirus) • Mycology and Antifungals (CNR) (CNR–WHOCC) (WHOCC) • Human Papillomavirus (CNR) Institut Pasteur in Algeria Influenza. Poliomyelitis. Rabies prevention. Measles. Tuberculosis • Arboviruses and Influenzae Viruses (Antilles– • Escherichia coli and Shigella (CNR) • Plague and other Yersinia Infections French Guiana region) (CNR) • Viral Hemorrhagic Fevers (Lyon) (CNR) (CNR–WHOCC) Institut Pasteur in Iran Rabies Arboviruses and hemorrhagic fevers. • Anaerobic Bacteria and Botulism (CNR) • Influenza –Influenzae Viruses (France-North) • Rabies (CNR–WHOCC) Rabies • Borrelia (CNR) (CNR) • Resistance to antibiotics (CNR) Institut Pasteur in Tunis Leishmaniasis Poliovirus. Salmonellosis. Shigella. Poliovirus (WHO). Measles (WHO). • Anthrax (CNR) • Viral Hepatitis B, C and Delta (laboratory • Salmonella (CNR–WHOCC) Vibrios–Cholera • Malaria Chemoresistance (Antilles–French associated with CNRs) • Streptococcus (laboratory associated * In the Antilles–French Guiana region. Guiana region) (CNR) • Leptospirosis (CNR–WHOCC–FAO) with CNRs) ** Accredited as a competent body for surveillance, response to epidemics and scientific expertise by the ECDC (European Centre for Disease Prevention and Control). • Pertussis and other Bordetella (CNR) • Listeria (CNR–WHOCC) • Vibrios and Cholera (CNR)

14 INSTITUT PASTEUR INTERNATIONAL NETWORK ••• REPORT 2010 15 Research Infectious diseases are the leading cause of mortality in countries with limited resources, particularly in Africa. Beyond the few health consequences, their economic and social impact is a considerable brake for deve- on infectious lopment, leader to greater poverty and inequality. diseases

15% 68% of global mortality of the mortality of children under 5 years

16 INSTITUT PASTEUR INTERNATIONAL NETWORK ••• REPORT 2010 17 Research on infectious diseases

INTRODUCING early initiation of ARVs, 15 days after beginning HIV/AIDS IMMUNOVIROLOGICAL treatment with antituberculosis drugs, reduced MONITORING TOOLS the risk of death in patients at an advanced stage of HIV infection by 34%. This paves the Human immunodeficiency virus (HIV) is a retrovirus which causes FOR PATIENTS UNDERGOING way for optimal management of the most chronic immune deficiency leading to the development of acquired TREATMENT widespread and deadly co-infection in deve- (5) immunodeficiency syndrome (AIDS). Thanks to research efforts, there Since 2001, the international political commit- loping countries . are currently six classes of effective antiretroviral drugs (ARVs), reducing ment to universal access to prevention, care and Other more fundamental research projects treatment(2) has led to considerable progress in treated patient mortality by over 85%. Today, 5.4 million patients from low- (CAPRI-NK and CAPRI-T) are associated with the global response to the HIV/AIDS epidemic. this trial; these focus on the immunopathoge- income countries have access to ARVs, compared with under 500,000 Eight countries with limited resources, including nesis of immune reconstitution inflammatory in 2002(1). However, this progress is still not enough. In resource-limited Cambodia, have now achieved the aim of provi- syndromes (IRIS). These IRIS phenomena, countries, only 36% of patients are treated, and AIDS still kills 1.8 million ding treatment to 80% of patients in need. “In sometimes associated with a worsening of 2003, a few hundred patients in Cambodia were tuberculosis (paradoxical reaction), occur in people in the world each year. treated by NGOs. By the end of 2010, patients recei- 20 to 30% of co-infected patients treated with ving treatment numbered 40,000, most of whom antituberculosis drugs and ARVs. “We have were being treated through the national program. demonstrated that the level of NK cell activation This rapid development must be accompanied by before the initiation of ARVs was a predictive mar- the introduction of financially accessible immuno- ker for the occurrence of a paradoxical reaction: virological tools that allow treated patients to be the higher the level, the higher the risk of occur- monitored. These include CD4+ T-lymphocyte and rence of a paradoxical syndrome,” explained Dr viral load counts and ARV resistance tests. In Cam- Pean Polidy, immunologist in charge of pro- bodia, the analysis of these virological markers is jects at the Institut Pasteur in Cambodia. currently only available at the Institut Pasteur,” explains Dr Eric Nerrienet, Virologist at This approach combining operational and fun- Institut Pasteur in Cambodia. the Institut Pasteur in Cambodia. Thanks to damental research for HIV is also implemented these tools, the effectiveness of ARVs used as at the Pasteur Centre in Cameroon through the first-line treatment was confirmed in the ANRS 12140-PEDIACAM project. The aim of this project is to assess, in a Cameroonian medium and long term in follow-up patients gram on Immunization (EPI), which follows and Bibliography context, the feasibility, tolerance and efficacy of treated by NGOs(3). “Second-line treatments are extends the study previously conducted as part early antiretroviral multitherapy in infants (1) Toward Universal Access – Progress Report 2010, also very effective, offering a 93% virological suc- of an RIIP project in the framework of the infected with HIV. “This study will enable us to WHO UNAIDS UNICEF. cess rate after a 4-year monitoring period. We are Inter-Pasteurian Concerted Actions. This stu- support the national program in implementing (2) Declaration of Commitment on HIV/AIDS – General currently looking to move to third-line therapy by dy, conducted from 2004 to 2006 in cooperation Assembly of the United Nations, Special Session on the WHO recommendations for early ARV treat- examining the profile of patients that develop with the Instituts Pasteur in Bangui and Paris, HIV/AIDS (June 25-27, 2001). ment of HIV-infected infants,” explained Mathu- (3) Pujades-Rodríguez M et al., Immunovirological resistance to these treatments,” continued Dr showed that children infected by HIV had a rin Tejiokem, a researcher at the Pasteur outcomes and resistance patterns at 4 years of Nerrienet. However, given that this research is lower persistence of antibodies induced in res- antiretroviral therapy use in HIV-infected patients in Centre in Cameroon. “Since the study began in usually carried out on cohorts of patients moni- ponse to EPI vaccines than non-infected chil- Cambodia – Trop Med Int Health. November 2007, we have demonstrated that the tored in optimal conditions, it is essential to dren born to seropositive mothers. 2011 Feb;16(2):205-13. application of the WHO recommendations for pre- (4) ANRS 12186. confirm these results in patients treated through Furthermore, non-infected children born to venting mother-to-child transmission of HIV in (5) Results pending publication. national structures. seropositive mothers responded less than (6) Tejiokem MC et al., The impact of different the operational context of a country with limited children born to HIV-seronegative mothers, antiretroviral regimens on prevention of HIV mother to (6) resources is feasible and effective . The prelimi- suggesting that in utero exposure to HIV has an child transmission in routine practice in Cameroon (ANRS 12140-PEDIACAM) – XVIII International AIDS FROM CLINICAL nary results for ARV initiation in infected infants influence on immune response. The ANRS were presented in Casablanca, at the Franco- Conference (AIDS 2010), Vienna, July 2010. TO FUNDAMENTAL… 12207-PRIVAR study, associated with PEDIA- (7) Tejiokem MC et al., Faisabilité des multithérapies phone Conference on HIV/AIDS(7).” The support HIV virus transfer between AND VICE VERSA CAM, focuses specifically on the response to anti-rétrovirales précoces systématiques chez les provided by the Total Foundation for the PEDIA- the measles vaccine in HIV-infected children. nourrissons âgés de moins de 7 mois infectés par le T cells. VIH dans un pays à ressources limitées: ANRS 12140 As well as serving public health, these assess- CAM project has led to an improvement in The goal is to determine whether HIV-infected conditions for the medical and psychosocial – PEDIACAM – 5th Francophone Conference on ment and surveillance tools can also support newborns are capable of developing and main- HIV/AIDS, Casablanca, March 2010. the development of operational research pro- management of HIV-infected children at the taining a specific CD4 and CD8 cellular res- jects, such as the Camelia study. This clinical sites where the study is being conducted. ponse to measles, and which NK cell popula- trial, supported by the Agence Nationale de tions are activated in these children when Recherche sur le Sida et les Hépatites Virales vaccinated. This project will help to identify (French National Agency for Research on AIDS ASSESSING THE RESPONSE potential indicators of vaccine failure in these and Viral Hepatitis – ANRS) and the National TO VACCINATION children and to suggest an adaptation of the Institutes of Health (NIH) in association with IN HIV-INFECTED INFANTS vaccination schedule if necessary. the Instituts Pasteur in Cambodia and Paris(4), was performed on patients co-infected with HIV A further aim of the PEDIACAM project is to and tuberculosis presenting a very low CD4+ assess the immune response in HIV-infected lymphocyte count. It was demonstrated that infants to vaccines from the Expanded Pro-

18 INSTITUT PASTEUR INTERNATIONAL NETWORK ••• REPORT 2010 19 Research on infectious diseases

SURVEILLANCE AND PUBLIC HEALTH TUBERCULOSIS The International The Instituts Pasteur in Bangui, Cote d’Ivoire, Network hosts Tuberculosis (TB) is an infectious disease caused by the Mycobacterium Madagascar, Guadeloupe, New Caledonia, two WHO tuberculosis bacterium, also known as “Koch’s bacillus”, transmitted through Cambodia, Ho Chi Minh City, Saint Petersburg, Algeria, Morocco and Tunisia, as well as the supranational the air. There are close to 10 million cases in the world each year, and Pasteur Centre in Cameroon and the Scientific reference between 1.6 and 2.3 million patients die from the disease. A large number Institute of Public Health in Brussels, are laboratories (SRLs) of these are not diagnosed or are not sufficiently monitored. 25% of deaths involved in surveillance and diagnosis activities, in Algeria in HIV-seropositive patients are due to tuberculosis. The concomitant and most of them are involved in national pro- and Guadeloupe grams to fight tuberculosis. The institutes in circulation of strains exhibiting multiple resistance to treatment is particularly Cote d’Ivoire and Madagascar host regional The aims of the SRLs are worrying. The epidemiological predictions are also a cause for concern: the reference laboratories. to assess the level of WHO estimates that by 2020 almost a billion more people will be infected pharmacoresistance in the and 35 million patients will die. EPIDEMIOLOGY world, to anticipate trends, to supply data useful for policy The Stephan Angeloff Institute, the Institut Pas- decision-making, to evaluate teur in Saint Petersburg and the Institut Pasteur progress made in in Lille are working on the diversity and global distribution of strains of M. tuberculosis(1-3). The anti-tuberculosis programs, and Institut Pasteur in Guadeloupe is recording the finally to strengthen laboratory results of molecular typing studies in a database networks. Since 2009, the Institut accessible on the Internet (genetic map construc- Pasteur in Guadeloupe has Bibliography ted with 75,000 isolates from 160 countries). For hosted the 6th SRL in the To differentiate M. tuberculosis from other many years now, this expertise has led to involve- members of the mycobacterium family, the Ins- Americas region (North and (1) Valcheva V et al., FEMS Immunol Med Microbiol. ment in epidemiological and molecular phyloge- titut Pasteur in Guadeloupe has developed a 2010. 59:90-9. netic studies, on all continents and particularly in South). simple method based on the detection of an (2) Mokrousov I et al., Infect Genet Evol. 2009. 9:1400-5. the Caribbean and South America(4) (more than enzyme (nitrate reductase) directly from patho- (3) Doherty M et al., Curr Opin Pulm Med, 2009, 14 publications in 2009-2010). logical samples. At the Institut Pasteur in Lille, 15:181-187. (4) Rosales S et al., BMC Microbiol. 2010, 10(1):208. improve understanding of the sequential mole- the heparin-binding protein has proved to be a (5) Namouchi A et al., J Infect Dis. 2010, 201:390-398. cular events that caused the emergence of precious tool in helping diagnose latent infec- (6) Minime-Lingoupou F et al., Int J Tuberc Lung Dis GENETIC AND MOLECULAR 2010, 14(6):782–785. these resistant strains. The Institut Pasteur in tion. This method could also be used to dia- STUDIES gnose active tuberculosis, particularly extra- (7) Brodin P et al., PLoS Pathogens. Madagascar has studied the diversity of clinical 2010, 6 (9):e1001100. strains of M. tuberculosis and their impact on pulmonary tuberculosis, in less than 24 hours. The Institut Pasteur in Saint Petersburg has (7) (6) Teams at the Institut Pasteur Korea have demonstrated that the virulence of some infection . Research carried out at the Institut developed a new technique for large-scale strains is acquired because of the high circula- Pasteur in Guadeloupe has helped identify the automated screening to select highly virulent tion of the bacteria in certain regions such as existence in Trinidad of an emerging M. tuber- mutants and analyze their biochemical deter- Russia. By unraveling the evolutionary path of culosis clone. These approaches have also minants. strains with multidrug-resistance (MDR), enabled a rare Beijing strain that was res- As part of their efforts to improve treatments, researchers from the Institut Pasteur in Tunis(5) ponsible for a deadly tuberculosis outbreak in scientists at the Institut Pasteur in Lille have have been able to identify the pre-epidemic Colombia to be genotyped for the first time. validated the “ETH-boost” concept. This susceptible parent strain. This research could These genetic and molecular approaches are involves developing molecules which, when being pursued and developed in several insti- associated with ethionamide (an antibiotic), Tuberculosis Laboratory, Institut Pasteur in Bangui. tutes, particularly comparative genetics studies would increase its efficacy. based on MDR strains in Cambodia, Central African Republic and Cote d’Ivoire. REGPOT 2 Project OTHER MYCOBACTERIA A European Union–funded project Discovery of new genes involved in the parasitism IMPROVING THE DIAGNOSIS Diagnosis of leprosy caused by Mycobacterium involving the Instituts Pasteur in of cells by the tubercle bacillus AND TREATMENT leprae is carried out in connection with the Algeria, Paris, Guadeloupe surveillance and monitoring of this disease at A European–Asian group of scientists, particularly involving the CNRS, the Institut Pasteur in Paris, the Institut Pasteur and Tunis and the Stephan Although a suitable antibiotic treatment should the Instituts Pasteur in Guadeloupe and New Korea and the University of Toulouse in the framework of the European Union–funded TB-VIR Project, has recently be introduced as quickly as possible, confirmed Caledonia. Angeloff Institute in Sofia. The aim identified ten virulence genes of the tubercle bacillus. The inactivation of these genes reduces the pathogenic effect diagnosis of M. tuberculosis infection can take is to build a sustainable of the bacillus. This discovery, published in the journal PLoS Pathogens, will be particularly useful in proposing new up to two months. Research into methods for Euro–Mediterranean network to therapeutic strategies and testing new tuberculosis vaccine candidates. the rapid diagnosis of tuberculosis is therefore combat tuberculosis. vitally important if the management of patients is to be improved.

20 INSTITUT PASTEUR INTERNATIONAL NETWORK ••• REPORT 2010 21 Research on infectious diseases

Given the major problem of the emergence of ASSESSING NEW MALARIA MALARIA strains of Plasmodium showing resistance to DIAGNOSTIC TOOLS antimalarial therapy, the RIIP’s work is focused on diagnostic capability with the assessment of In Cambodia, Senegal, Madagascar, Niger and Malaria is an infectious disease caused by parasites belonging to new diagnostic tools, on resistance to treatment, French Guiana, an assessment of rapid diagnos- the genus Plasmodium, transmitted to humans by a mosquito of the genus and on immunovaccinology. tic tests showed that detection capabilities were limited when the tests were used in field condi- Anopheles. There are almost 300 million cases of this infectious disease tions. In Cambodia, a DNA microarray (Flexi- each year, leading to one million deaths, mainly in children under five. RESISTANCE Chip) with high-throughput analysis capability It threatens some 3.3 billion people in over 100 countries, but 90% of cases TO ANTIMALARIAL THERAPY comparable to sequencing methods was are concentrated in the 19 most populous countries in sub-Saharan Africa. assessed. New innovative and effective detection The analysis of markers of treatment resistance techniques such as pyrosequencing have been has been the subject of several publications by developed in Cambodia and Madagascar; these the Instituts Pasteur in Cambodia and Madagas- enable the detection of rare parasite variants. car, the CERMES in Niger and the Institut Pas- teur in French Guiana. The aim of this research is to quantify and contain the risk of dissemina- IMMUNOVACCINOLOGY tion of treatment-resistant strains. OF MALARIA

Several studies reviewing the current situation Research in the field of immunovaccinology has or looking at new progress concerning the been developed in Dakar, based on the longitu- dinal monitoring survey being carried out in the emergence and dissemination mechanisms of villages of Dielmo and Ndiop and the recruit- resistance to antimalarial drugs were published ment of patients suffering from urban and hos- in 2009-2010. The emergence of resistance to pital-based malaria (see inset). Immune res- artemisinin in Cambodia and Thailand was ana- ponses to a vaccine candidate have been lyzed and reported in the New England Journal of confirmed, enabling the identification of a pro- Medicine, and other publications have assessed tective epitope. In Ndiop, an effective prospective the development of resistance in Cambodia and approach is being used to assess the impact of Search for mosquito larvae, French Guiana. Madagascar. Comparative in vivo and in vitro stu- different intervention methods aiming to reduce dies in Madagascar have improved understan- exposure and infection at an early stage based ding of the dynamics and distribution of chloro- on reduced cohorts. quine-resistant mutants. In Cote d’Ivoire, a study has confirmed the effectiveness of a new combi- A new functional test to assess the degree nation therapy using artemisinin and naphtho- quine as a treatment for malaria. of protection against P. falciparum Researchers at the Institut Pasteur in Dakar, the IRD and the Institut Pasteur Understanding the molecular basis of resis- in Paris have developed a new test for the in vitro analysis of the efficacy tance, particularly resistance to artemisinin, as of antibodies induced naturally or after vaccination against merozoite surface Gut of Anopheles gambiae well as its associated genotypes and pheno- parasitized by Plasmodium types, is a field of research that is being actively antigens, important vaccine targets. This functional assay correlates with falciparum. explored. prospective immunity. Joos C et al. 2010. Clinical protection from falciparum malaria correlates with neutrophil respiratory bursts induced by merozoites opsonized with human serum antibodies. PLoS ONE, 5, e9871.

Severe urban malaria: low transmission and high parasite polymorphism The parasite P. vivax infects resistant human populations Severe malaria in Dakar mainly affects adults. It is associated with A multidisciplinary study conducted by the Institut Pasteur in Madagascar, in cooperation with the Malagasy Ministry infection by a pool of P. falciparum isolates with a high degree of of Health and the Institut Pasteur in Paris, focused locally on the comparison of Duffy blood group-positive variability, unlike benign cases of malaria. The treatments used favor the populations of Indonesian or Asian origin with Duffy-negative populations of African origin. The researchers showed selection of a group of parasites; this raises the problem of inappropriate that some individuals develop malaria despite their Duffy-negative blood group, believed to protect them self-medication leading to longer delays in treating patients and a from infection by P. vivax. These results signal the possibility of a spread of P. vivax to regions of the world where it is worsening of the outcome of the disease. currently absent. Bob NS et al. 2010. Parasite polymorphism and severe malaria in Dakar (Senegal): Menard D et al. 2010. Plasmodium vivax clinical malaria is commonly observed in Duffy-negative Malagasy people. PNAS, 107, 13. a west african urban area. PLoS ONE, 5, e9817.

22 INSTITUT PASTEUR INTERNATIONAL NETWORK ••• REPORT 2010 23 Research on infectious diseases

A LARGE-SCALE PROBLEM tions conducted during epidemics. It is funded by the US Department of Health and Human INFLUENZA Influenza is recognized as a health problem Services (HHS)/ASPR and involves the Instituts faced by both developed and developing Pasteur in Cambodia, Ho Chi Minh City, Nha Influenza is an acute viral infection caused by three types of influenza countries. Each year it causes hospital admis- Trang, Laos, Bangui, Cote d’Ivoire, Dakar and virus (A, B and C) that circulate in all regions of the world(1). These viruses sions and a high number of deaths among Madagascar, the NIHE in Hanoi and the Pas- populations at risk (children, the elderly and teur Centre in Cameroon. are capable of infecting birds and some mammals, including pigs and the chronically ill). According to the latest esti- humans. Influenza generally occurs in seasonal epidemics, but influenza mates published by the World Health Organiza- • The Reinforcement of a Surveillance Network pandemics can occur several times per century when new viral strains tion (WHO), influenza viruses are responsible for Flu in Africa Program (2006-2012) involves the detection and characterization of influenza emerge. This was the case with “Spanish” influenza, the most deadly for about 3 to 5 million severe cases leading to almost 500,000 deaths each year(1). viruses and the strengthening of corresponding outbreak known to date, which hit in 1918 and 1919, and more recently the laboratories. This is achieved by harmonizing influenza epidemic caused by the A(H1N1)pdm virus, which emerged in The year 2009 was marked by the A(H1N1)pdm and standardizing existing systems to improve influenza pandemic, caused by a virus presen- the integration and processing of data collected Mexico during spring 2009. ting a genetic recombination that had never through networks, and also by consolidating the previously been described. Several RIIP mem- research dimension through improved diagnosis ber institutes designated as WHO National of influenza and other respiratory viruses. It is Reference Laboratories for influenza were funded by the French Ministry of Health (EPRUS) directly involved in diagnosing this new virus. and involves the Instituts Pasteur in Bangui, The various programs set up for the sentinel Cote d’Ivoire, Dakar and Madagascar, as well as surveillance of respiratory viruses represented the Pasteur Centre in Cameroon and the the Instituts Pasteur in Cambodia, Dakar, Modelling (Warsaw, Poland) and the Wuhan a precious tool for the epidemiological monito- CERMES in Niger. This program complements Madagascar and Paris, and the Pasteur Centre Institute of Virology (China). ring of this pandemic. the project funded by the US Department of in Cameroon. Health and Human Services (HHS)/ASPR. The • The RESPARI (Research-driven rESPonse to project is also subsidizing the setting up of a • The RIVERS (Resistance of Influenza Viruses in Acute Respiratory Infection) site contains infor- MAJOR INTERNATIONAL cross-disciplinary study (SURGIRA) for typing Environmental Reservoirs and Systems) Project(3) mation on all the RIIP’s activities in the area of (4) PROJECTS LED BY THE RIIP and sequencing influenza strains circulating in (2006-2010) aims to study the role played by the respiratory infections . FOR INFLUENZA VIRUSES sub-Saharan Africa with the aim of improving environment in the survival of the highly patho- understanding of transmission pathways and Research on influenza covers various aspects of genic A(H5N1) avian influenza virus and in the Bibliography the emergence of resistance on this continent. infection by influenza viruses and is carried out re-emergence of the disease. It is co-funded by the European Commission and involves Insti- (1) Source: WHO. within the framework of innovative multidiscipli- • A multi-center case-control study (2010- (2) SISEA Project, www.pasteur-international.org/ip/ nary projects that establish links between biolo- 2012) will enable the characterization of factors tuts Pasteur in Europe and Asia (Cambodia, easysite/pasteur-international/activites- gists, clinicians, epidemiologists and fundamen- associated with severe forms of influenza in Shanghai, Lille and Paris), along with the Can- scientifiques/projets/tous-les-projets/sisea tacuzino Institute in Romania, the Stephan (3) RIVERS Project, www.manuguerra.eu/rivers/ tal research scientists from the RIIP. developing countries, where there is a heavy (4) RESPARI Program, www.hkupasteur.hku.hk/ burden of viral, bacterial and parasitic co-infec- Angeloff Institute in Bulgaria, the Centre de respari/ • The SISEA (Surveillance and Investigation of Epi- tions. Co-funded by the Institute of Microbiology Coopération Internationale en Recherche Agro- (5) Garcia et al., Optimization and evaluation of an demic Situations in Southeast Asia) Project(2) and Infectious Diseases (IMMI) and the Institut nomique pour le Développement (International influenza A (H5) pseudotyped lentiviral particle-based (2006-2011) aims to develop surveillance and serological assay. J Clin Virol. 2010 Jan;47(1):29-33. Pasteur, it is conducted in Asia and Africa on Cooperation Center of Agricultural Research response capabilities to tackle the emergence of patients infected by influenza virus. It is the for Development – CIRAD), the Interdisciplinary new pathogenic agents with epidemic potential result of interdisciplinary cooperation between Centre for Mathematical and Computational in Southeast Asia, focusing particularly on respi- ratory infections and acute encephalitis(3). It is funded by the Agence Française de Développe- ment (French Development Agency – AFD) and involves the Instituts Pasteur in Cambodia, Shan- ghai, Ho Chi Minh City and Nha Trang, as well as Progress on influenza diagnosis the National Institute of Hygiene and Epidemio- 2009 pandemic The A(H5N1) avian influenza virus is a highly virulent pathogen than can be transmitted to humans by aerosols logy (NIHE) in Hanoi and the National Center for flu A(H1N1) virus. (~ 60% mortality rate). This means that it has to be manipulated in a Biosafety Level 3 laboratory (BSL-3 on a scale Laboratory and Epidemiology (NCLE) in Laos. – of 1 to 4), subject to very strict procedures. The Hong Kong University–Pasteur Research Centre has developed • The Support, Training and Capacity Building a new diagnostic test. It is as sensitive as the current reference test known as “microneutralization” and offers the Program (2006-2011) aims to strengthen the significant advantage of not using the A(H5N1) virus. It therefore allows avian influenza to be diagnosed in a surveillance networks for influenza viruses in Biosafety Level 2 laboratory(5). Africa and Southeast Asia, particularly for avian influenza, and to perform epidemiological stu- During the A(H1N1)pdm pandemic in 2009, the RIIP helped in the distribution of diagnostic tools for the rapid dies on these diseases. To achieve these objec- identification of this new virus that were developed at the Institut Pasteur in Paris (Molecular Genetics of RNA Viruses tives, the program is setting up surveillance Laboratory / Influenza CNR (France-North). networks and providing suitable training so that effective support can be offered for investiga-

24 INSTITUT PASTEUR INTERNATIONAL NETWORK ••• REPORT 2010 25 Research on infectious diseases

THE INSTITUT PASTEUR DENGUE INTERNATIONAL NETWORK: A UNIQUE INSTRUMENT Dengue is a viral disease transmitted by the bite of mosquitoes, mainly FOR DENGUE SURVEILLANCE Aedes aegypti, infected by one of the four dengue viruses (DENV-1 to ON SEVERAL CONTINENTS DENV-4) of the Flavivirus genus. The tiger mosquito, Aedes albopictus, an The global expansion of dengue observed in aggressive species undergoing rapid expansion across the world, and even recent decades is a major cause for concern. While in 1970 only 9 countries had experienced in non-tropical areas, can also transmit the dengue virus. In most cases, hemorrhagic dengue outbreaks, by 1995 this the disease’s symptoms are similar to those of influenza. At the global level, figure had more than quadrupled(1), mainly 50 million people are infected each year, and 500,000 of them, mostly affecting Southeast Asia and the South Ameri- children, suffer from the hemorrhagic form of the disease. At least 2.5% of can continent. Dengue is now endemic in more than a hundred countries, and it is belie- (1) these severe cases lead to death . There are currently no commercially ved that two fifths of the world’s population is available vaccines or specific antiviral treatments for dengue. exposed to it. This inexorable propagation of dengue is thought to be caused by an exten- sion of the geographical distribution area of the four virus types and of their vector mos- quito, together with the growing urbanization of tropical areas favorable to the proliferation of these insects. In the light of this increasingly urgent health threat, the Institut Pasteur International Network is playing an active role in health Treated bed net. and epidemiological surveillance. In late 2009, the health authorities in Cape Verde reported more than 17,000 cases although the country had never previously suffered an “WORKING TOGETHER TO TRY TO samples from people infected asymptomati- patients and also epidemiological studies car- epidemic outbreak of dengue. The team from UNDERSTAND WHAT DETERMINES THE cally. They hope to compare immunological and ried out on the circulation of dengue. the Institut Pasteur in Dakar, in its capacity SEVERITY OF THE DISEASE” genetic criteria of the host, and also to analyze as a regional reference center, analyzed ini- The Institut Pasteur International Network is a the mutations of the virus observed in each tial samples and confirmed the presence of unique instrument for dengue observation and person with the aim of identifying which inte- dengue serotype 3, identified for the first time research on all continents and has the potential ractions are involved in the progression to a Bibliography in West Africa (Cote d’Ivoire) one year earlier. to make a major contribution to progress in severe or non-severe form of the disease. “No (1) Source: WHO. A joint mission with the WHO Regional Office treatment and prevention of the disease. This one has done this before,” continues Anavaj (2) WHO, WER No. 45, 2009, 84, 469–476. also enabled rapid assistance to be provided idea was the basis for the creation of the GLO- Sakuntabhai. “Researching asymptomatic (3) Meynard JB et al., Eur J Public Health. 2009 in terms of diagnosis, entomology, epidemio- DEN network (Global Network for Dengue patients and also those exposed to the virus but Apr;19(2):183-8. logy and the implementation of vector control Research), which should coordinate 12 not infected can throw up valuable information on (4) European project DENFRAME (2005-2009) (2) www.denframe.org – results currently pending activities . research teams working on dengue from seven the protection mechanisms that an effective vac- publication. of the Network’s institutes. Anavaj Sakuntab- cine should induce.” (5) Wang PG et al., Efficient assembly and secretion of In 2009, a team from the Institut Pasteur in hai, from the Viral Pathogenesis Unit at the recombinant subviral particles of the four dengue French Guiana published an article on a den- Alongside these efforts, it is vital to improve Institut Pasteur in Paris, explains that “the fre- serotypes using native prM and E proteins., PloS One gue epidemic that had occurred three years diagnostic techniques for the infection. A team 2009 Dec 15;4(12). quency of severe cases of dengue is higher in earlier in Maripasoula, an inland town in from the Hong Kong University–Pasteur Southeast Asia. Is this due to factors relating to French Guiana along the Maroni River(3). Research Centre was the first to develop a the host, the virus, the vector or the environment? According to Philippe Dussart, Head of the stable production system for non-infectious By working together, we will be able to compare Aedes aegypti. CNR for Arboviruses and Influenza Viruses for viral particles known as VLPs (virus-like par- these parameters between continents to try to the Antilles-French Guiana region, “This study ticles) for the four dengue serotypes(5). On the Dengue virus type 1 understand what determines the severity of the explores uncharted territory because dengue basis of these VLPs, a research project invol- (center) infecting murine disease.” neuronal cells. outbreaks are usually observed on the coast and ving teams from the RIIP institutes in Hong result from people traveling to and from the The European project DENFRAME(4), involving Kong, New Caledonia and Paris is under way Antilles. An epidemiological study has now the Instituts Pasteur in French Guiana, Cambo- with the aim of developing a diagnostic test for demonstrated the presence of indigenous cases dia, Ho Chi Minh City and Paris, enabled dengue specific to each serotype and assessing on the Maroni for the very first time. By analyzing research to be carried out on asymptomatic the potential of VLPs in the development of the viral strains circulating in Maripasoula, we patients. By taking blood samples from the seroneutralization tests for the dengue viruses. were subsequently able to clearly demonstrate members of a single household in which there These applications – more rapid, less restric- that this dengue was introduced from neighbo- is a confirmed case of dengue(4), researchers tive and less costly than current techniques – ring Surinam.” have for the first time been able to obtain will help to improve the serodiagnosis of

26 INSTITUT PASTEUR INTERNATIONAL NETWORK ••• REPORT 2010 27 Research on infectious diseases

THE INCIDENCE OF RABIES DISTRIBUTION OF RABIES RISK WORLDWIDE RABIES IS LARGELY UNDER-ESTIMATED Whereas effective control strategies have Rabies is a fatal viral infection of the nervous system. Accountable for 99% succeeded in almost eradicating the native of fatal cases in humans, dogs are the primary vector of the disease, which animal reservoir of rabies in industrialized countries such as France(2), in low-income is also carried by wildlife (e.g. bats, wolves, foxes, etc.). Although an effective countries, this infection is still very wides- preventive vaccine was discovered by Louis Pasteur more than 125 years pread and ranks among the “neglected” ago, every year around the world 55,000 people, who did not receive diseases. Due to the Institut Pasteur’s histo- any post-exposure treatment, die from rabies. 95% of them are of Asian rical involvement and the presence of insti- tutes in countries with a high endemic status, or African descent. Moreover, each year 14 million people receive post- the Institut Pasteur International Network exposure treatment following contact with an animal that may have been continues to play a major global role in the carrying the virus(1). monitoring and control of rabies. Each year within the Network, over 200,000 post-bite vaccinations are performed on patients who are at risk(3). Additionally, ­several teams are n involved in development work and in imple- High risk n Moderate risk menting control programs specifically targe- n Low risk ted at canine rabies. n No risk

The reason that rabies is not considered a Source: WHO. public health priority in many countries Bibliography stems from the fact that its incidence is lar- (1) Source: WHO. gely under-estimated, due to an absence of (2) InVS - BEH (September 14, 2010). reliable epidemiological data. The teams of (3) Bourhy H et al., Rabies, still neglected after 125 years nated and maintained in a given environment. dominant factor in the propagation of rabies Philippe Buchy in Cambodia and Hervé Bou- of vaccination, PloS Negl Trop Dis 4(11). A study carried out in North Africa with the in North Africa that must be considered when (4) Sowath L et al., Rabies situation in Cambodia, PloS rhy in Paris have implemented a mathemati- Institut Pasteur in Morocco and Algeria, as developing policies to fight rabies. Negl Trop Dis 3(9). cal model that uses a collection of epidemio- (5) Dacheux L et al., A reliable diagnosis of Human logical data in a given region to calculate the part of the European project RABMED- Rabies seems to be a disease that is often rabies based on analysis of skin biopsy specimens, incidence at a national level. This model has CONTROL (see inset), has managed to overlooked, but the associated human and CID 2008; 47. highlight the low transmission rate of the (6) Dacheux L et al., Application of Broad-Spectrum shown an incidence in Cambodia of 5.8 cases financial cost is far from insignificant. The Resequencing Microarray for Genotyping for every 100,000 inhabitants (15 times higher rabies virus across administrative borders increased number of fatal cases of rabies in Rhabdoviruses, J Virol 2010 Sep; 84(18). than the official figures), positioning rabies between countries, but on the other hand its certain African and Asian countries, pro- (7) Talbi C et al., Phylodynamics and human-mediated ahead of dengue fever and malaria in terms high national spread along the main blems with access and the cost of post-expo- dispersal of a zoonotic virus, PloS Pathog 6(10). (4) (7) (8) Touihri L et al., Evaluation of Mass Vaccination of mortality . highways . Human intervention, through the sure treatment all call for the programs in Campaign Coverage Against Rabies in Dogs in Tunisia. transportation of infected dogs, is thus a pre- the fight against rabies to be stepped up. Zoonoses Public Health 2009 Dec 23. IMPROVING DIAGNOSTIC AND CONTROL TECHNIQUES Epidemiological monitoring can also be Chokri Bahloul, coordinator of the RABMEDCONTROL improved by using reliable, field-specific dia- gnostic tools. A research project that brings project, Laboratory of Immunopathology, Vaccinology and together the Institut Pasteur in Cambodia, Molecular Genetics, Institut Pasteur in Tunis Madagascar and Paris has enabled the deve- “The aim of this European project that came to a close in 2009 was to identify in Algeria, Egypt, Morocco and Tunisia, lopment and validation at various sites of a all countries where the rabies virus is highly endemic, the key ecological and epidemiological factors that influence highly sensitive diagnostic technique using a the dynamics of the disease. We adopted a multi-disciplinary approach that simultaneously involved descriptive biopsy from the skin at the base of the neck or samples of saliva(5). In addition, a detection epidemiological studies of rabies within the Mediterranean perimeter, analysis of the circulation of the virus among bats, Rabies virus. technique that is heavily based on DNA molecular study of strains in circulation and also the impact of humans on the propagation of the virus and the fight microarrays has been developed with the Ins- against the disease. In Tunisia, our work succeeded in highlighting differences between the North of the country, where titut Pasteur in Dakar(6). This technique not the vaccine is widely administered, and the South. At the time of our study, only 31% of dogs in this region had been only facilitates diagnosis of rabies, but also vaccinated, thus leaving a sufficient reservoir to maintain the virus(8). Since the publication of our work, the authorities the identification of new viruses belonging to the same family of rhabdoviruses. have increased efforts to reduce the number of rabies cases. We are currently analyzing epidemiological data collected during the project in order to be able to recommend ways to raise the population’s awareness of the Intervention strategies to fight canine rabies transmission factors and of dog vaccination.” cannot succeed without an exact understan- ding of the ways in which the virus is dissemi-

28 INSTITUT PASTEUR INTERNATIONAL NETWORK ••• REPORT 2010 29 Research on infectious diseases

LOCATING HIGH-RISK in Cameroon and the Institut Pasteur in Ban- VIRAL HEPATITIS PATIENTS AND IMPROVING gui and in Paris. Its aim is to characterize the THEIR CARE biomarkers of hepatic cancers in African patients. “We want to detect straight from the Hepatitis viruses that cause acute and/or chronic infections and In the light of this major threat to public blood of patients, not a protein, but raw DNA or inflammations of the liver are one of the greatest global public health health, several Network teams are working microRNA released by the tumor. By analyzing concerns, particularly the hepatitis B and C viruses. WHO estimates that together to specifically research the markers these markers, we should be able to highlight of liver cancer (hepatocellular carcinoma) in mutations that are characteristic of liver can- about two billion people have been infected with the hepatitis B virus – over patients infected with a hepatitis virus. In cers, but also chromosome defects. We thus 350 million with the chronic form – and that 130 to 170 million people are China, which has the world’s highest popula- hope to be able to detect the occurrence of liver chronic carriers of hepatitis C. These two viruses, both very different in nature, tion of people infected with the hepatitis B cancer very early on in patients that are chroni- cally infected with a hepatitis virus and monitor are responsible for 57% of cirrhosis and 78% of primary liver cancer cases, virus, the Institut Pasteur of Shanghai is wor- king with the Institut Pasteur in Paris to iden- them more closely” says Richard Njouom, and kill a million people every year. According to experts, the already high tify these markers in patients who are infected medical virologist at the Pasteur Centre in global mortality burden due to acute hepatitis B and C, as well as to cancer with the hepatitis B virus and have developed Cameroon. To date, alpha-fetoprotein is the and cirrhosis (around 2.7% of all deaths) is set to rise over the next two liver cancer. The project that began in 2009 only known tumor marker of liver cancer. Although this protein is highly specific, it has (1) and is funded by the Total Foundation also decades . focuses on comparing viral quasispecies low sensitivity since it is not secreted by all found in tumor or healthy cells of these tumors. There is therefore a need to discover patients. “The presence of a signature of viral new markers that will allow for intervention at quasispecies in cancerous cells has never really the earliest possible stage. This should be been looked for. Yet, it seems to be increasingly possible through the molecular techniques evident that, despite their viral etiology, the used in these research projects. development of liver cancers is highly influenced by numerous viral as well as host factors. By linking all these data to patient virological moni- RESEARCH ON THE toring parameters, we can hope to locate those MECHANISMS OF INFECTION who are at high risk and improve their care”, BY THE HEPATITIS C VIRUS explains Ke Lan, a virologist at the Institut Pasteur of Shanghai. Researchers at the Institut Pasteur in Saint Petersburg and Iran have been working with the Hepacivirus Unit of the Institut Pasteur in CHARACTERIZING Paris in efforts to understand the entry and NEW PREDICTIVE MARKERS transport mechanisms of the hepatitis C virus OF EVOLUTION TOWARDS in hepatocytes. This work has shown that an enzyme, lipoprotein lipase, was involved in CANCER IN PATIENTS binding the virus to target cells and was (4) Bibliography Similarly, a project is underway to assess the capable of inhibiting infection . It also far never been detected in cases of human infection. In addition, researchers have shown role of hepatitis viruses in the development of highlighted the significance of microtubules in (1) 63rd World Health Assembly – Secretariat Report that synonymous mutations found in these hepatocellular carcinoma in Eastern Europe, initiating the infection and transporting the on viral hepatitis - WHO (March 25, 2010). patients at RNA level lead to changes in the involving the Cantacuzino Institute and the Ins- virus inside the cell, notably through an origi- (2) Ezzikouri S et al., MDM2 SNP309T>G polymorphism nal mechanism of interaction with the capsid structure of the viral genome that could pro- and risk of hepatocellular carcinoma: a case-control titut Pasteur in Saint Petersburg and in Paris. analysis in a Moroccan population, Cancer Detect (5) mote production of the alternative protein. The aim is to correlate viral variability with the proteins . Prev. 2009;32(5-6):380-5. The study of pathologies in this type of patient specific genetics of tumors in an attempt to (3) Ezzikouri S et al., Single nucleotide polymorphism Work resulting from a Transversal Research would provide fresh information regarding the explain the clinical differences observed at in DNMT3B promoter and its association with Program funded by the Institut Pasteur and respective roles of the capsid protein and the hepatocellular carcinoma in a Moroccan population, population level. For the first time in Europe, involving the Hellenic Institut Pasteur, the protein encoded by an alternate reading Infect Genet Evol. 2009 Sep;9(5):877-81. this project has succeeded in highlighting a (4) Andreo U et al., Lipoprotein lipase mediates Institut Pasteur in Cambodia, Dakar, Saint frame and new elements for diagnosing the specific mutation of the tumor suppressor pro- hepatitis C virus (HCV) cell entry and inhibits HCV Petersburg and in Paris has shown that spe- infection. tein p53, which had thus far only been obser- infection, Cell Microbiol. 2007 Oct; 9(10):2445-56. cific mutations in the gene encoding the cap- (5) Roohvand F, Initiation of hepatitis C virus infection ved in Africa and Asia. In North Africa, a trans- sid protein of the hepatitis C virus produced requires the dynamic microtubule network: Hepatitis B virus. versal research program between the Institut an unusual serological profile in infected role of the viral nucleocapsid protein, J Biol Chem. 2009 May 15;284(20):13778-91. Pasteur in Algeria, Morocco, Tunisia and Paris patients(6). The article published in PloS ONE is concerned with the molecular epidemiology (6) Budkowska A et al., Synonymous mutations in the shows, in three Cambodian patients, the core gene are linked to unusual serological profile of hepatocellular carcinoma. The results of absence of anti-capsid antibodies commonly in hepatitis C virus infection, PLoS One. 2011 Jan this collaboration have highlighted risk factors seen in individuals infected with the hepatitis 6;6(1):e15871. linked to gender, specific mutations of certain C virus. In comparison, these patients have a (2, 3) genes or to heredity . high level of antibodies directed against the Finally, in Equatorial Africa, there are plans to protein encoded by a frameshift mutation in set up a program involving the Pasteur Centre the capsid gene. This specific protein had so

30 INSTITUT PASTEUR INTERNATIONAL NETWORK ••• REPORT 2010 31 Research on infectious diseases

IMPROVING THE FIGHT BACTERIAL AGAINST MENINGITIS IN SUB-SAHARAN AFRICA MENINGITIS A program was started in 2007 to improve the diagnostic capability of meningitis given the findings observed in the laboratories of the Aside from outbreaks of the disease, an average 1.2 million cases of African belt countries in the last decade. Fun- bacterial meningitis are reported worldwide each year, 135,000 of which ded by the French Ministry of Foreign and prove to be fatal(1). Although bacterial meningitis is diagnosed in all European Affairs as part of the Priority Solida- rity Fund (FSP), this program is coordinated by continents, it poses a particular threat in the region known as “the African the Institut Pasteur on a partnership between meningitis belt”, which extends from Ethiopia to Gambia. In these countries, the following countries: Niger, Mali, Burkina the disease is endemic all year round, with seasonal epidemic peaks, Faso, Cameroon, Cote d’Ivoire and Central varying in intensity from year to year. Meningococcus, Pneumococcus and Africa. The project has improved epidemiolo- gical monitoring of meningitis and capacity for Haemophilus are the three main pathogenic agents that cause acute research in molecular biology by transferring bacterial meningitis and each one has several “sub-types”. the required techniques to reference laborato- ries in countries that are partners for the majority of the RIIP member institutes. Victims of bacterial meningitis are mainly chil- dren under the age of five. Infants between 4 and 18 months are particularly vulnerable. Between 15 and 35% of children who survive Haemophilus meningitis are left with perma- nent hearing deficiencies, speech problems, visual impairment or motor defects(2). There is a lack of sufficient documentation in Africa and knowledge in this area needs to be upda- ted to facilitate more effective management of these disabilities. The CERMES is currently carrying out a study to improve identification of the nature and frequency of the long-term effects of meningitis in Niger. CERMES, Niger. THE IMPACT OF VACCINATION

Up until now, the solution for meningitis out- ponsible for carriage studies in this field for a main types of meningococcal meningitis, Bibliography breaks in Africa has been anti-meningococcal three-year period. represents a particularly effective field tool(3,4). (1) WHO, 2000. polyosidic vaccines but these have shown This simple and inexpensive test uses dips- their limits. The introduction of the new (2) WHO, Reference No. 294, 2010. ticks and can be administered at the patient’s (3) Chanteau S, Dartevelle S, Mahamane AE, Djibo S, conjugate vaccine MenAfriVac is therefore a FAST-CHANGING BACTERIAL bedside. By enabling rapid identification of the Boisier P, et al. (2006) New rapid diagnostic tests significant step in this fight, since it specifi- etiological agent in remote areas with little for Neisseria meningitis serogroups A, W135, C, and Y. PLoS Med 3(9): 1579-1586. cally targets meningococcal serogroup A, STRAINS access to molecular diagnostic techniques, it which is the primary cause of the major out- (4) P. Boisier, A. Elhaj Mahamane, A. Amadou The major fear now however is that there will would improve monitoring capabilities and Hamidou, F. Sidikou, S. Djibo, F. Nato and S. breaks observed. save precious time in terms of patient care. Chanteau. (2009) Field evaluation of rapid diagnostic be a rapid change in the bacterial strains cir- Funding is currently being sought to support tests for meningococcal meningitis in Niger. Tropical Alongside the major vaccination campaigns culating in these countries if the proportion of Medicine and International Health 14(1): 111-117. the development and field evaluation of the that began in 2010 in Burkina Faso, Mali and type A strains is reduced as these are the only required tests as part of a multi-site post-vac- Niger, the project coordinated by the London strains targeted by MenAfriVac. Other hitherto Neisseria meningitidis cination study to obtain a complete and effec- School of Hygiene and Tropical Medicine and minor “sub-types” may then become increasin- adhering to the surface of tive rapid diagnostic kit capable of detecting funded by the Wellcome Trust and the Bill and gly prevalent. epithelial cells. Melinda Gates Foundation involves seven the majority of bacterial meningitis strains in countries from within the meningitis belt. The circulation around the world. aim of the project is to study the spread of RAPID DIAGNOSTIC TESTS meningococcal meningitis in Africa and to document the impact of the MenAfriVac vac- In view of this, monitoring based on rapid dia- cine on transmission of the infection. The gnostic tests (RDT) jointly developed by the CERMES plays a significant role, being res- CERMES and the Institut Pasteur to detect the

32 INSTITUT PASTEUR INTERNATIONAL NETWORK ••• REPORT 2010 33 Research on infectious diseases

Due to its worldwide propagation and the speed nation, into the domestic environments where at which it is developing, antibiotic resistance is they were then ingested. ANTIBIOTIC currently one of the greatest public health Institut Pasteur in Dakar and Madagascar, Pas- concerns. As there is no new class of antibiotic teur Centre in Cameroon, AFSSA (French Food RESISTANCE expected in the next few years, antibiotic resis- Safety Agency) and LERQAP (Laboratory for Study tance is threatening the effectiveness of many & Research on Food Quality & Processes) drugs in use today, thus challenging significant Finally, an international study coordinated by Infections caused by antibiotic resistant bacteria are steadily increasing progress made in the fight against infectious the Institut Pasteur has recently detected a type agents. worldwide, both in the community and in healthcare institutions. Their of salmonella that has become multi-resistant consequences are often more serious than those caused by “sensitive” in the space of ten years and that is spread by bacteria, resulting in the need for second-line treatment that is generally contaminated poultry in Africa and the Middle LOW-INCOME COUNTRIES (3) more expensive, and a more intensive and costly follow-up. In 2007, East . The emergence of these bacteria, detec- OPEN TO THREAT ted by the surveillance systems of Northern the estimated cost of infections caused by antibiotic resistant bacteria In low-income countries, the use of antibiotics countries in travelers and migrants, empha- amounted to about euro 1.5 billion in Europe (including direct extra charges is often anarchic, and this has a significant sizes both the need to establish such networks and charges associated with additional days of hospitalization, ambulatory impact on the emergence and development of in the Southern countries and the fundamental role played by the RIIP institutes as sentinels care and loss of productivity due to sick leave, death, etc.)(1). bacterial resistance. The use of drugs in these countries is poorly regulated and a medical for these emerging phenomena. prescription is not required to obtain antibio- tics. The quality of antibiotics is inconsistent Bibliography due to the high volume of counterfeit drugs available. Moreover, patients often do not com- (1) ECDC/EMEA Joint Technical Report, The bacterial challenge: time to react. A call to narrow the gap plete their treatment regimen correctly. Also, a between multidrug-resistant bacteria in the EU and the lack of hygiene, vulnerability and an increase in development of new antibacterial agents. 2009. immunosuppression due to HIV infection, (2) Breurec S, Fall C, Pouillot R, Brisse S, Diene-Farr F, encourage the dynamics for resistance trans- Djibo S, Etienne J, Fonkoua MC, Perrier-Gros- Claude JD, Ramarokoto CE, Randrianirina F, mission, by placing the populations of these Thiberge JM, Zriouil SB, the Working Group on countries in constant contact with germs, some Staphylococcus aureus infections, Garin B, Laurent F. of which are resistant. Clin. Microbio. Infect. 2010. (3) S Le Hello, RS Hendriksen, B Doublet, I Fisher, EM A prospective study carried out in Africa on the Nielsen, JM Whichard, B Bouchrif, K Fashae, SA strains of methicillin-resistant Staphylococcus Granier, N Jourdan-Da Silva, A Cloeckaert, EJ Threlfall, FJ Angulo, FM Aarestrup, J Wain, and FX aureus (MRSA) has shown the alarming ability of Weill. International spread of an epidemic clone of this particularly virulent bacterium to spread over Salmonella enterica serotype Kentucky ST198 resistant a large geographic area, as well as the potential to ciprofloxacin. Journal of Infectious Diseases. 2011. role of Africa as the initial reservoir, responsible for sporadic spread to other continents(2). Institut Pasteur in Madagascar, Dakar and Morocco, Pasteur Centre in Cameroon and the CERMES Another international study has confirmed the Study program for antibiotic resistance in different parts of important role played by enterobacteria in the the world: Children’s Antibiotic Resistant infections in Low Income dissemination of antibiotic resistance, due in countries: an international cohort study (ChARLI) particular to their presence in the intestinal lumen, a preferred place for exchange of genetic Currently, surveillance networks for bacterial resistance focus mainly on industrialized countries. information between different types of bacteria. However, monitoring in low-income countries, the main environments for the origin and Pasteur Centre in Cameroon, Institut Pasteur in dissemination of resistant infections, is essential to stem their development. In December 2010, Dakar, Morocco, Algeria, Cote d’Ivoire, Madagas- the Principality of Monaco and the Institut Pasteur signed a partnership agreement to combat car, Cambodia, Ho Chi Minh City and National infant antibiotic resistant infections in low-income countries. The main objective of the Institute of Hygiene and Epidemiology in Hanoi ChARLI project is to assess the incidence and medical and economic effects of antibiotic Contamination with salmonella, the main resistant bacteria in severe infant and neo-natal infections, acquired in a healthcare cause of food poisoning in humans, has also environment or the community. An international pediatric cohort will be set up and monitored been evaluated on domestic consumption of chickens in Senegal and Madagascar. An analy- within the RIIP, with the benefit of the Network’s expertise in the field, its ideal geographical sis of the flora present on the skin of the neck presence and its effective partnerships established at local level. of thousands of chickens at the time of slaugh- www.charliproject.org ter has shown that resistant salmonella bacte- ria could have been spread, by cross-contami-

34 INSTITUT PASTEUR INTERNATIONAL NETWORK ••• REPORT 2010 35 Research on infectious diseases

LEISHMANIASIS DIARRHEAL DISEASES Leishmaniasis is a chronic disease which may be cutaneous and/or In low-income countries, diarrhea is the third main cause of death in visceral, caused by protozoan parasites belonging to the genus children under the age of 5 (18%). This percentage is slightly lower than Leishmania. The parasites are transmitted by the bite of an insect for respiratory infections (19%), but higher than the one for malaria (8%). vector, the phlebotomine sandfly. According to the World Health Organization (WHO), gastrointestinal infections that cause diarrhea still kill approximately 2.2 million people each year, mainly due to contaminated food or water, or transmission THE EXTENT between humans resulting from poor hygiene. OF THE PROBLEM Leishmaniasis occurs in many tropical and subtropical countries, as well as in areas The first phase of the project in Bangui will around the Mediterranean Basin. It is conside- FIGHTING INFANT DIARRHEAL DISEASES involve improving infrastructures, equipment red endemic in 88 countries, 72 of which are Sandfly. and knowledge at the operational level. Plans developing countries. Leishmaniasis is a IN BANGUI for a second phase involve launching a case- poverty-related disease. Leishmaniasis threa- At the Pediatric Complex in Bangui, severe control epidemiological study necessary for tens about 350 million men, women and chil- diarrhea is responsible for 13% of hospitaliza- developing, establishing and supporting an dren around the world. As many as 12 million tions and causes 5.4% of infant deaths. The epidemiological and operational-style pro- people are believed to be currently infected, • Epidemiology of leishmaniasis, including Institut Pasteur in Bangui, the Pediatric Com- gram as a basis for fundamental research. with around 1 to 2 million estimated new cases diagnosis, population genetics and risk plex in Bangui and the Saint Joseph Health This project in the Central African Republic is occurring every year. assessment • Study of climate change‘s effect and its Center in Ouango are working with the Institut funded by the Total Foundation which has impact on infection in the Mediterranean Pasteur on a research program focusing on worked with the Institut Pasteur for several RIIP’S STUDY OF Basin severe infant diarrhea in developing countries years to fight infant diarrheal diseases through a similar project in Madagascar. LEISHMANIASIS • Study of new anti-parasitic strategies invol- with the aim of: ving testing of natural products and study of • improving management of cases of severe Among the institutes of the RIIP, at least 9 are resistance to treatments using preclinical and child diarrhea by diagnosing them earlier on FIGHTING INFANT located in endemic countries, namely Morocco, clinical therapeutic trials and adapting medical care to local working DIARRHEAL DISEASES Algeria, Tunisia, Italy, Greece, Iran, Brazil, • Vaccine development. conditions. IN MADAGASCAR French Guiana and France. • developing and improving epidemiological conducts advanced research on the acute and Recently a network working on leishmaniasis knowledge. This field project involving the Institut Pasteur chronic complications of severe diarrhea. The European project Leishdrug, funded by has been set up (LeishRIIP Network) to • answering fundamental questions regarding in Madagascar and Paris concerns a new inte- Leishmania major in the European Union’s Seventh Framework improve interaction between the various RIIP physiopathology, immunity, the infected host’s grated treatment and research facility in scanning microscopy. Programme, is an example of a collaborative groups working on this pathology. (http://www. Bibliography response and prevention through vaccination Moramanga. The center provides diagnosis, Network project on leishmaniasis. It involves pasteur.fr/infosci/conf/leishriip-TMP/index. in endemo-epidemic regions. treatment and prevention programs, but also Randrianasolo L., BMC Public Health 2010 21:10-31. 13 teams, including four RIIP institutes (Insti- html). tut Pasteur in Paris, Korea, Tunis and Monte- video). Its main objective is to exploit parasite- specific pathways for anti-leishmanial drug LEISHMANIASIS/HIV development and overcome current limita- CO-INFECTION tions in anti-leishmanial therapy. Visceral leishmaniasis is a serious opportu- The main strength of the consortium lies in nistic infection sometimes associated with the complementary expertise in imaging and HIV. A concomitant HIV infection increases the Total Foundation cell biology, peptide biochemistry, genomics risk of developing active visceral leishmania- Following an initial corporate funding agreement signed in 2005, and proteomics, drug development and struc- sis by between 100 and 2,320 times. In tural biology, and finally in vivo assessment of the Total Foundation renews its continued commitment Southern Europe, an increase of 70% in the leishmanicidal activity and pharmacokinetics to the Institut Pasteur in the fight against infectious diseases. number of cases of visceral leishmaniasis in of lead compounds. (www.leishdrug.org). This new agreement, signed on June 15, 2010, highlights the common adults is associated with HIV infection. Other topics of research on leishmaniasis desire of the Total Foundation and the Institut Pasteur to pursue a within the RIIP include: quality partnership in the fight against infectious diseases. The Total Bibliography • Study of key determinants of the natural his- Foundation will help to fund research programs, in particular transversal tory of L. major infection –Ben-Othman R et al, Mol Immunol 2009, programs involving several Institut Pasteur teams, as well as the group 46(16) :3438-44. • Study of animal reservoirs, particularly wild research of young researchers. rodents –Ben Salah A. et al, PLos Neg Trop Dis 2009, 3(5) e432. –Ben Hadj Ahmed S. et al., J. Med Entomol. 2010, 47(1): • Study of transmission and of virulence fac- 74-9. tors in host-pathogen interaction –Meddeb-Garnouai A. et al., Vaccine 2010 28(7): 1881-6.

36 INSTITUT PASTEUR INTERNATIONAL NETWORK ••• REPORT 2010 37 The Institut Pasteur International Network (RIIP) strives to improve scientific capabilities and human resources around the world. To achieve this, the RIIP develops training programs in partnership with universities and International local stakeholders. Although primarily aimed at staff from member institutes, the programs are also open to external researchers, technicians and students. Over 100 RIIP trainees come every year to complete their trai- ning by taking courses or serving traineeships in Paris. The Institut Pasteur and the Institut Pasteur International Teaching Network provide international grants for traineeships and courses taken in Paris. and Training

31 international 165 fellowships courses in 2009 and 2010 in 2009 and 2010

38 INSTITUT PASTEUR INTERNATIONAL NETWORK ••• REPORT 2010 39 International Teaching and Training

Saint Petersburg, Institut Pasteur in Mada- STUDENTS FROM AROUND gascar and Institut Pasteur in Tunis in par- THE WORLD WELCOMED AT THE Teaching – tnership with the World Health Organization INSTITUT PASTEUR IN PARIS (WHO) and the Centers for Disease Control and Prevention (CDC) in the US. Each year, the Teaching Center at the Institut a priority for the RIIP • Bioinformatics and comparative Genome Ana- Pasteur in Paris organizes 29 advanced theoreti- lyses - North Africa, Asia and Latin cal and practical courses rooted in scientific Training activities are not just intended for staff from member America research that are taken by students and resear- institutes but also for external personnel, technicians and students, chers from around the world (500 students each who may then use their experience in other national, regional or year from more than 48 nationalities). REGIONAL COURSES Funded by the Institut Pasteur’s Calmette and international bodies. Yersin program of study grants, the 2010-2011 AFRICA session brought together 31 RIIP students and West-African anti-biology program - Institut seven Amsud-Pasteur students. INTERNATIONAL RIIP COURSES Pasteur in Cote d’Ivoire >> www.pasteur.fr/enseignement • A Call for Proposals is issued every year THE AMERICAS The specialized Master’s program of School • The courses are run every year or every two Macromolecular Crystallography: Introduction ADDITIONAL TRAINING COURSES sponsors, the Institut Pasteur and CERMES Pasteur-Cnam of Public Health years and Applications – Institut Pasteur in Montevideo. Amsud-Pasteur courses in Niger. Certain forms of training provide students who • Each course is awarded funding of between in Latin America • In 2010, the Institut Pasteur in Bangui orga- are interested in doing so with the opportunity to nized its first workshop on writing and obtain a Master’s in public health, specializing in 10,000 and 30,000 euros (including grants for ASIA-PACIFIC The Amsud-Pasteur partnership organizes editing scientific publications for its resear- “risk of infection” at the School Pasteur-Cnam RIIP members) provided from the combined Pasteur Immunology Course – Hong Kong Uni- regional courses in Argentina, Brazil, Chile, chers. of Public Health. budget of the Institut Pasteur International versity-Pasteur Research Centre Paraguay and Uruguay. Eight Amsud-Pasteur • The Institut Pasteur in Montevideo organizes >> http://school-pasteur.cnam.fr/ Network and the Institut Pasteur. Pasteur-Areva Anti-Viral Immunity Course – courses were run in 2009 and 2010. a program of courses for the Latin-Ameri- Institut Pasteur of Shanghai Pasteur-Paris University International Doctoral can scientific community that includes theo- TOPICS Training funded as part of projects Program In 2009 and 2010, • Training for local personnel: quality approach, retical and practical courses on new techno- • Malaria, cell imaging, immunology, biosafety, NORTH AFRICA - IRAN An international program welcoming PhD stu- 31 courses in French laboratory techniques, good clinical research logies. virology, epidemiology, monitoring, etc. Analysis of data using STATA software - Institut dents at the Institut Pasteur in life sciences and practice (CAMELIA clinical trial: Cambodian and English were run Pasteur in Tunis biomedicine. Early vs. Late Introduction of Antiretroviral in various RIIP institutes in EXAMPLES Course on immunophysiology of infections - Ins- >> http://www.pasteur.fr/ip/easysite/pasteur/ drugs) and SISEA (Surveillance and Investi- DISTANCE TEACHING proteomics, genomics, • The Malaria workshop - Institut Pasteur in titut Pasteur in Algeria en/teaching/overview-teaching Madagascar gation of Endemic Situations in Southeast bioinformatics, biostatistics, PARTNERSHIP WITH AUF • HKU-Pasteur Cell Biology Course, Virology Asia) project (FRANCOPHONE UNIVERSITY AGENCY) epidemiology, genetics, Course and Immunology Course – Hong Kong Regional courses are also held • Theoretical and practical workshop: “Setting molecular biology, new vaccine University-Pasteur Research Centre on various subjects up an intervention unit”, (diagnostics, war- The CCSTVN (Committee for Scientific and Technical Cooperation with Vietnam), the Asia- strategies, etc. • Global Foodborne Infectious Network (GFN) Infectious diseases ning plan, communication) with the CIBU, Courses on salmonellosis monitoring - Pas- (research and public health) designed for RIIP researchers working on Pacific bureau of the Francophone University teur Centre in Cameroon, Institut Pasteur in • Pertussis and Diagnostic Techniques (molecu- influenza Agency (AUF) and the Institut Pasteur in Paris lar and classical) - Institut Pasteur in Iran • Regional workshop on virology in Cambodia signed an agreement on October 7, 2008 to • Avian Flu Training - Institut Pasteur in Cambo- define the terms of their cooperation on a series of video conferences. dia Initial and Continuous professional • New Development in Rabies Epidemiology, development: strengthening Topics include Diagnosis and Control – Institut Pasteur in Ho of capabilities • Resistance of bacteria to antibiotics Chi Minh City Several RIIP institutes are laboratories that • Cholera: epidemiological aspects • Virological monitoring within the framework of welcome university students, both national and • Rabies: clinical and epidemiological aspects the Polio Eradication Program - Institut Pas- international, particularly for Licence (Bache- >> http://cstvn.free.fr/html/visioconferences. teur in Saint Petersburg in partnership with lor’s degree), Masters and PhD. In addition, html WHO they provide supervision for national and Continuous professional Biosafety, hygiene, foreign trainees as part of the continuing trai- development in Medical Biology quality assurance ning of specialist doctors and laboratory tech- This interactive continuous professional deve- • Biosafety and BSL-3 level pathogenic agents - nicians. Researchers of the RIIP institutes are lopment course by internet covers hematology Institut Pasteur of Shanghai involved in training specialists through courses (e-HEMATimage), parasitology, mycology and • Regional workshop on BSL-2/BSL-3 biosafety and seminars in postgraduate teaching. pathological cytology with a multilingual pro- - Institut Pasteur in Cambodia Examples include: gram, e-MEDICINimage. Funding is provided as Bioinformatics Training school for health and medical techni- part of the Institut Pasteur’s continuous profes- • Advanced course on Bioinformatics and Com- cians, medical analyses option at the Pasteur sional development for expatriates and potential parative Genome Analysis – Fiocruz, Brazil Centre in Cameroon funding is available from the institutes for local • Bioinformatics and Comparative Genome • Construction of an Education Center and a researchers. Analysis – Institut Pasteur in Tunis Hall of Residence for trainees, funded by >> www.e-hematimage.eu

40 INSTITUT PASTEUR INTERNATIONAL NETWORK ••• REPORT 2010 41 International Teaching and Training

• in any other course recognized by the Interna- tional Division. Support for scientists Calmette and The training must be closely related to the appli- cant’s research subject and must supplement Yersin program - GRANTS FROM THE PIERRE their initial training and strengthen their skills in Study and LEDOUX - JEUNESSE their research fields. Traineeship grants INTERNATIONALE FOUNDATION In 2009 and 2010, the Traineeship grants International Division awarded Biomedical research grants for traineeships Aimed at the employees of the RIIP institutes 64 study grants for training in the laboratories of the Institut Pasteur (researchers, technicians or students) to com- and 44 grants for internships, International Network for students of French plete an internship in a laboratory of the Network nationality from Universities and Schools carried out in France or at another research institution. (biologists, doctors, pharmacists, veterinary and within the RIIP. surgeons or young researchers) (under the Each year, the International Division launches age of 35). The traineeships last from 3 to 12 two calls for applications for traineeship grants. months. There are two calls for applications per year. Doctoral grants Within the framework of the RIIP Doctoral Pro- A three-year doctoral grant funded by the Insti- gram that was created in 2010, the first docto- CALMETTE AND YERSIN tut Pasteur allowing a student to carry out their ral grant funded by the International Division of PROGRAM OF THE INSTITUT PhD traineeship in an RIIP institute (outside of the Institut Pasteur has been awarded by the PASTEUR Paris). selection committee to a French student, who Objective: to encourage and enable French and complete a three-year PhD at the Institut Pas- The Pierre Ledoux - Study grants foreign researchers to carry out a PhD internship teur of Shanghai and in partnership with the Jeunesse Internationale Grants funded by the International Division of in an RIIP laboratory. Institute for Glycomics at Griffith University in the Institut Pasteur, to promote and facilitate the Australia, on the subject of “Drug Discovery: Foundation and the Institut participation of scientific personnel (students, The traineeship can be conducted in any topic Virology, Systems Biology, Biochemistry”. Pasteur (International Division) researchers, engineers and licensed techni- developed in the laboratories of the RIIP member jointly provided 10 grants cians) from the RIIP: institutes, whether in infectious diseases (physio- per year. • in courses run by the Institut Pasteur in Paris, pathology of infections, immunology, microbiolo- GRANTS FROM THE INSTITUT • in training workshops organized at an RIIP gy, epidemiology, virology, parasitology) or public PASTEUR INTERNATIONAL member institute, health activities (monitoring, resistance). NETWORK Traineeship grant as part of a PhD These RIIP-funded grants aim to encourage and enable students to carry out traineeships, as part of their PhD, at an RIIP institute or at ano- ther research institution. These can be co- supervised PhDs (North/South) or PhDs without co-supervision.

Conference grant These RIIP-funded grants aim to make it pos- sible for the RIIP’s young scientists to take part in international conferences.

AMSUD-PASTEUR GRANTS For regional exchange programs Amsud-Pasteur is a network of 62 research ins- 12 Amsud-Pasteur grants between 2009 and titutes in Latin America. 2010 for regional exchange programs. 2009 8 grants (5 PhDs and 3 conferences). For courses at the Institut Pasteur in Paris 2010 10 grants per year 13 grants (9 PhDs and 4 conferences). 2 calls for proposals per year 2 students per country (Argentina, Brazil, Chile, Uruguay and Paraguay)

42 INSTITUT PASTEUR INTERNATIONAL NETWORK ••• REPORT 2010 43 These platforms are a set of equipment and technology techniques required to carry out research projects, Technical particularly in the area of infectious diseases. platforms

44 INSTITUT PASTEUR INTERNATIONAL NETWORK ••• REPORT 2010 45 Technical platforms

OTHER TECHNICAL robotic platform for high-throughput screening; • Hellenic Institut Pasteur: Imaging, DNA PLATFORMS IN THE RIIP histocompatibility laboratory microarrays and molecular epidemiology Biosafety level 3 (BSL3) microarrays, recombinant protein production, • Institut Pasteur in Guadeloupe: Pesticide and Several institutes have equipment for imple- molecular diagnosis menting cellular and molecular biology tech- heavy metal analyses facilities in the RIIP niques: • Institut Pasteur in Lille: Transcriptomics, • Institut Pasteur in French Guiana: Equipment genomics, bioinformatics, DNA microarrays • Flow cytometry (Algeria, Bulgaria, Cameroon, enabling implementation of molecular biology • Scientific Institute of Public Health - Brussels: Canada, Hong Kong, French Guiana, Montevi- techniques of immunology, identification and deo, Shanghai, Tunis) chemical dosage of substances; sequencer ; Mass spectrometry and chromatography plat- liquid chromatography; gas chromatography, form • Traditional and real-time PCR (Bangui, Bulga- mass spectrometry • Stephan Angeloff Institute - Bulgaria: Elec- ria, Cameroon, CERMES, Greece, Guadeloupe, tron, confocal laser scanning and fluorescence French Guiana, Madagascar, Montevideo, New • Institut Pasteur in Montevideo: bioinforma- microscopy; liquid chromatography Caledonia) tics, protein crystallography, biophysics and pro- duction, analytical biochemistry, proteomics, • Institut Pasteur in Tunis: Protein analyses, • Recombinant protein purification (Algeria, genomics, mass spectrometry, DNA microar- sequencers, electron microscopy, liquid chroma- Montevideo) rays, confocal microscopy, epifluorescence tography, irradiator, metrology, bio-fermentation LAVAL LILLE BRUSSELS BUCHAREST microscopy PARIS In addition, several institutes have biobanks (cell and genetic sequencing units banks, collections of viruses, microorganisms TEHRAN SEOUL • Institut Pasteur in Cambodia: Automated and cell cultures) and epidemiological tools mycobacteria culture system, Gen-Probe system ATHENS (cohorts, sentinel sites, hospital partnerships). CASABLANCA ALGIERS TUNIS for identification of mycobacteria • Institut Pasteur Korea: Cell biophysics; dia- HANOI OTHER TECHNICAL gnoses using microfluidics; dynamic imaging DAKAR with ultrafast Multi-D imaging and imaging pro- PHNOM PENH PLATFORMS AVAILABLE cessing; screening and pharmacology through BANGUI • Pasteur Centre in Cameroon: Liquid chroma- automated confocal microscopy; robotics, drug CAYENNE tography, ion chromatography development and chemical genomics, high- ABIDJAN YAOUNDÉ throughput visual screening programs • CERMES: Immunochromatography, cell cultures • Institut Pasteur in New Caledonia: Technical platform for dengue fever (automated system) ANTANANARIVO • Institut Pasteur in Madagascar: anatomopa- thology, production of reagent strips for rapid • Institut Pasteur of Shanghai: Scientific and diagnosis virological imaging (proteomics and genomics); microinjection into the oocytes of frogs; radioiso- • Institut Armand Frappier: Confocal microsco- tope, ion exchange py, digital imaging and electron microscopy, Cen- ter of experimental biology; mass spectrometry; • Institut Pasteur - Cenci Bolognetti Foundation: proteome analysis; biostatistics consultation; transcriptomics, bioinformatics Several BSL-3 facilities are equipped with modules for mosquito infection (Dakar, French Guiana, Madagascar and Paris).

Construction of BSL-3 and BSL-2 laboratories at the Institut Pasteur in Bangui “The Institut Pasteur in Bangui* in the Central African Republic, located at the heart of Central Africa and characterized by a distinctive equatorial and intertropical ecosystem, is a preferred facility for microbiological monitoring. The recent concept of emerging diseases and the arrival of new resistant strains have led this institute to dedicate a significant part of its research to microbiological monitoring. With the support of the French Ministry of Health and the Institut Pasteur in Paris, the Institut Pasteur in Bangui is therefore building two new safety level 2 (bacteriology) and level 3 (virology) laboratories to strengthen diagnostic capabilities and allow for on-site development of research projects on microbiological monitoring in this region of the world, in collaboration with other teams from the Institut Pasteur and the RIIP.” (Interview with Mirdad Kazanji, Head of the Institut Pasteur in Bangui). * In 2011 the Institut Pasteur in Bangui will celebrate its fiftieth anniversary in the Central African Republic. This BSL-3 laboratory will be opened in June 2011.

46 INSTITUT PASTEUR INTERNATIONAL NETWORK ••• REPORT 2010 47 Technical platforms

HYGIENE, QUALITY AND Fish Processing Industries as the reference Hygiene, quality, ENVIRONMENT: laboratory for the detection of marine toxins. A SHARED CONCERN The LSAHE is still a laboratory for bacteriolo- gy, but water analysis work has given way to environment and The Hygiene and Environment department at food analyses. The LSAHE is associated with the Pasteur Centre in Cameroon conducts two projects within the framework of Inter- more than 10,000 tests each year in microbio- Pasteurian Concerted Actions (ACIP), the first sustainable development logy (water, food, cosmetic products) and phy- of these focusing on quantitative evaluation of sicochemistry (water, food, toxicological the risks associated with salmonella and with assessments). Several projects on the monito- Campylobacter through domestic consumption Studying the dynamics of transmission of infectious agents from the ring of legionellosis; pathogenic flora present of chickens at two pilot sites, namely Dakar environment involves field monitoring of populations of pathogenic agents, on table chickens at the time of slaughter in 11 (Senegal) and Antananarivo (Madagascar), vectors and potential reservoirs (e.g. animals, foods, soil, water, sediments, towns located across 4 continents, in Cayenne and the second focusing on legionellosis that and in New Caledonia; the FRAT (Fortification in turn associates Cameroon and Cambodia. etc.). In addition, understanding these dynamics is essential for developing Rapid Assessment Tool) study as part of the The Institut Pasteur in Dakar is also working effective alert and counter strategies in the fight against infectious diseases. National Food-Fortification Program; evalua- to characterize the isolated strains of Vibrio Within the RIIP, these studies are carried out thanks to the existence of tion of the exposure of Yaoundé’s food chain to parahaemolyticus in fishing products and in heavy metals and training workshop on the the marine environment in Senegal. specialized hygiene and environment laboratories. “Regional Total Diet Study for Sub-Saharan The Institut Pasteur in Guadeloupe is equip- Africa” are linked to this department. ped with an environmental hygiene and agri- The Institut Pasteur in Cambodia is involved food laboratory that develops tests for pesti- in monitoring legionellosis in water supplies cides and metals. The institute therefore helps and cooling towers in tropical areas in order to to control environmental quality by ensuring Institut Pasteur in Madagascar. establish the current situation and to study the that drinking and bathing water is analyzed feasibility of setting up a monitoring strategy (bacteriological quality and physicochemical at the national level. Another study focuses on quality, microbiological risk) and that indus- the sociocultural aspects of hygiene in health- trial matter and effluent from treatment SUSTAINABLE DEVELOPMENT: red for implementing a strategy that is realistic care in Cambodia given that hospital plants are monitored (organic load and patho- A VOLUNTARY APPROACH and respectful to both humans and the environ- employees are frequently becoming infected genic agents). TO SOCIAL RESPONSIBILITY ment. with diseases through blood pathogens in the A mission that is in keeping with the RIIP insti- The Hygiene and Environment Laboratory Southeast regions of Asia. This study has Sustainable development satisfies current tutes’ support for the management of their (LHE) at the Institut Pasteur in French Guiana prompted reconsideration of the importance needs without compromising the ability of future waste was conducted in May 2010 at the Institut provides public health services and expert of hygiene, with precautions taken to improve generations to satisfy theirs. It incorporates the Pasteur in Cambodia; this country being the pilot assessments, involving microbiological and practices to control infections in Cambodian necessity to combine the fulfillment of needs, site. At the moment, there are no regulations in chemical tests on water and microbiological medical environments. particularly the basic needs of the most impove- Cambodia, but they are currently being drafted tests on foods. The laboratory’s main activity rished to whom the greatest priority should be by the Ministries for Environment and Health. The Institut Pasteur in Cote d’Ivoire gives involves sanitary control of water; additional given, with the preservation of the environment. Waste management at the Institut Pasteur in priority to research and initiatives associated activities include food hygiene in the agri-food The Institut Pasteur, whether as part of its work Cambodia will be carried out according to the with controlling and improving the environ- and catering industries, hospital hygiene and in Paris or in its international connections, aims same principles as those in force in Paris. ment, with a particular focus on food safety also tests on residual water. Finally, the LHE to integrate the principles of sustainable deve- and the various ecosystems, especially the carries out unprecedented work for the RIIP, Since 2010, the Institut Pasteur has adhered to lopment in a number of ways: lagoon ecosystem. The main issues are still known as “space” microbiology, performed for the United Nations Global Compact and to its the conditions for persistence and emergence the company Arianespace. • at its Paris site via the “Green Campus” ten principles relating to human rights, labor of pathogenic infectious agents for humans in Since 2008, the LHE has been accredited by approach that specifically aims to step up mea- rights, environmental protection and the fight the environment, microbial population biology the French Committee for Accreditation sures to reduce the impact of its work on the against corruption. Finally, as part of a voluntary and microbial ecology. The ecological (COFRAC) within the field of water microbio- environment. measure based on the evaluation method AFAQ approach and the microbial biodiversity logy and physicochemistry of water. This 26000 (AFNOR Certification), the Institut Pasteur • internationally, via collaborations initiated approach are those used. Two programs are accreditation has led to the laboratory being has also undergone a social responsibility audit within the RIIP to optimize local management of run by the Institut Pasteur in Cote d’Ivoire and approved by the French General Directorate of which served to highlight its strengths and harmful waste. A guide called “For sustainable focus on the pathogens responsible for Health for sanitary control of water. The LHE’s weaknesses in this area. and responsible management of waste from diseases associated with food and the envi- employees are on duty around the clock and healthcare and laboratory activities” has been ronment. can intervene in cases of water pollution or to published, with the aim of providing the RIIP ins- handle any suspicious letters or parcels, in The Institut Pasteur in Dakar is equipped with titutes and their partners with assistance in defi- collaboration with the other units of the Insti- a food safety and environmental hygiene labo- ning and implementing a sustainable manage- RÉSEAU INTERNATIONAL DES INSTITUTS PASTEUR • RAPPORT 2010 tut Pasteur in French Guiana. ratory (LSAHE), accredited by the French ment strategy for waste produced during Committee for Accreditation (COFRAC) since The Institut Pasteur in Tunis has a water and healthcare and laboratory activities which is 2009, according to ISO 17025. This laboratory food-control laboratory that is a WHO national adapted to local policies and conditions. The is affiliated with Senegal’s Food Safety Autho- reference center for salmonellosis, shigella guide is a simple and practical tool, offering rity and is considered by the Department of and the bacterium Vibrio cholerae. information and decision-making criteria requi-

48 INSTITUT PASTEUR INTERNATIONAL NETWORK ••• REPORT 2010 49 Thanks… Abbreviations We would like to offer special thanks to a large number of collaborators for their help in writing, editing and AFD Agence française de développement (French development agency) producing this Report 2010 of the International Network. ANRS Agence nationale de recherche sur le sida et les hépatites virales (French National Agency for Resesarch on AIDS and Viral Hepatitis ) BCG Bacille Calmette-Guérin (vaccine against tuberculosis) BSL-3 Biosafety Level 3 laboratory INSTITUT PASTEUR INSTITUT PASTEUR AND ALSO CERMES Centre de recherche médicale et sanitaire (Niamey, Niger) (Medical and health research center) INTERNATIONAL NETWORK • Hervé Bourhy, Agata Budkowska, Nathalie Des- The Agency of translation id2m and the Agency CDC American Centers for Disease Control and Prevention All the Directors of institutes as well as the com- noyés, Marc Grandadam, Nathalie Pardigon, Avantgarde. ChARLI Children’s Antibiotic Resistant infections in Low Income countries: an international cohort study munication ‘s correspondents, Benoit Garin (Ins- Pascal Pineau, Anavaj Sakuntabhai, François- CIBU Laboratory for Urgent Response to Biological Threats (Institut Pasteur) titut Pasteur in Madagascar), Chokry Bahloul Xavier Weill, Yu Wei. CIRAD Centre de coopération internationale en recherche agronomique pour le développement (International Cooperation Center of Agricultural (Institut Pasteur in Tunis), Philippe Dussart (Ins- • International Division: Guillaume Castel, Eliane Research for Development) titut Pasteur in French Guiana), Mathurin Tejio- Coëffier, Magali Herrant, Marc Jouan, Aurélien CNR National reference center kem (Pasteur Centre in Cameroon), Eric Nerrie- Lambert, Ronald Perraut, Olivier Rescanière, DHHS Department of Health and Human Services/ASPR – Département américain de la Santé net (Institut Pasteur in Cambodia), Ke Lan Jérôme Salomon, Maud Seguy, Kathleen Victoir. (Institut Pasteur of Shanghai), Richard Njouom DNA Deoxyribonucleic Acid (Pasteur Centre in Cameroon). • All collaborators at the Institut Pasteur. EPI United Nations Expanded Program on Immunizations All collaborators and the populations of the FACS Fluorescence Activated Cell Sorting RIIP. FAO Food and Agriculture Organization of the United Nations FIOCRUZ Oswaldo Cruz Foundation (Rio de Janeiro, Brazil) FSP Priority Solidarity Fund GLODEN Global Network for Dengue Research HPLC High-performance liquid chromatography system …and partners IMMI Institut de microbiologie et des maladies infectieuses (Institute of Microbiology and Infectious Diseases) INSERM Institut national de la santé et de la recherche médicale (French National Institute of Health and Medical Research) NCLE National Center for Laboratory and Epidemiology (Vientiane, Laos) FRENCH AND INTERNATIONAL INTERNATIONAL • Fondation Total NGO Non Governmental Organizations MINISTRIES AND AGENCIES ORGANIZATIONS • Francophone University Agency (AUF) NIH National Institutes of Health (Bethesda, United States) • Medical Research Council NIHE National Institute of Health and Epidemiology (Hanoi, Vietnam) • World Health Organization (WHO) • Multilateral Initiative on Malaria (MIM) • French Agency for Development (AFD) OIE World Organisation for Animal Health • European Union (EU) • Rockefeller Foundation • American Centers for Disease Control (CDC) PCR-(RT) (Real-time) Polymerase Chain Reaction • Department of Health and Social Services • National Health Institutes (NIH) • Wellcome Trust • European & Developing Countries Clinical PDVI Pediatric Dengue Vaccine Initiative (DHSS)/ASPR Trials Partnership (EDCTP) PTR Transversal research program • U.S. Agency for International Development • Global Alliance for Vaccines and Immunization RIIP Institut Pasteur International Network (USAID) PRIVATE SECTOR (GAVI) RIKEN Japanese Research Institution for Science and Technology • French Ministry of Foreign and European • Air France Supranational reference laboratories Affairs (MAEE) • Areva SRL TDR Rapid diagnostic test • French Ministry of Higher Education and FOUNDATIONS, ASSOCIATIONS, • AXA • EDF TDR Special United Nations tropical disease research and training program Research (MESR) AND NON-GOVERNMENTAL • Ministries from the countries of RIIP • Institut Mérieux WHO World Health Organization ORGANIZATIONS • Sanofi-Pasteur • French Ministry of Health • Veolia • Union for the Mediterranean (UPM) • Bill and Melinda Gates Foundation • Mexican National Council for Science and • Doctors without Borders (MSF) Technology (CONACYT) • Drugs for Neglected Diseases Initiative (DNDi) • Friends of the Global Fund • French Association for Preventive Medicine International Division, Institut Pasteur • Design and production: avantgarde – tel: 01 45 74 61 61 (AMP) • RIKEN (Japanese research institution for • Printing: Galaxy Imprimeurs – tel: 02 43 47 03 30 • Copyrights: Institut Pasteur • Institut Pasteur International Network • Fondation de France nd science and technology) • William Beaucardet : cover, 2 cover, Alice Dautry (p. 02), Françoise Barré-Sinoussi (p. 03) and pipette (p. 29). • Fondation Pierre Ledoux Jeunesse Internationale Numerous French national research institutions • Fondation BNP Paribas - CEA, CIRAD, CNES, CNRS, IFREMER, INRA, • Fondation EDF INRIA, INSERM, InVS, IRD, IRES, IMMI - and • Fondation Mérieux agencies - ANR, ANRS, AIRD • Fondation Sanofi Espoir This report was printed on recycled paper. June 2011

50 INSTITUT PASTEUR INTERNATIONAL NETWORK ••• REPORT 2010 51 International Division, Institut Pasteur 25-28, rue du Docteur-Roux – 75724 Paris Cedex 15 Tel: +33 (0)1 40 61 36 92 – Fax: +33 (0)1 45 68 89 52 [email protected]