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Naval Medical Research Unit 2 Indonesia Avian and Pandemic Influenza Activities

The Naval Medical Research Unit No. 2 (NAMRU-2), originally established during World War II in Guam and later relocated, first to Taiwan and then to the Philippines, began operating a detachment in Jakarta, Indonesia, in 1970. Its mission at that point was to investigate infectious diseases of military importance both for the U.S. Navy and for the rest of the Department of Defense (DoD) (DoD-GEIS, 2007a). It has recently played a very important role in the surveillance of avian influenza and a potential pandemic (see Figure 3-1).

Historically NAMRU-2 has focused on applied research in support of its medical mission. Its past research activities provided a strong foundation for the expanded focus of the DoD’s Global Emerging Infections Surveillance and Response System (DoD-GEIS) on surveillance and response capacity. Avian influenza highlights the issues of regional disease spread and also the significant role that NAMRU-2 plays in conducting disease surveillance, case and outbreak investigation, and diagnostic support. NAMRU-2 either identified or shared in the confirmation of all recent human cases of H5N1 infection in Indonesia, where the laboratory is recognized as one of two H5N1 reference laboratories by the Ministry of Health (MoH).

A site visit team of the Institute of Medicine (IOM) Committee for the Assessment of Department of Defense Global Emerging Infections Surveillance and Response System visited NAMRU-2 from March 4-10, 2006.1

1

Prior to the NAMRU-2 visit, the laboratory staff provided the committee with detailed background information on NAMRU-2 and the pandemic/avian influenza activities it was supporting. These materials are available from the IOM in the Public Access File.



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3 Naval Medical Research Unit 2 Indonesia Avian and Pandemic Influenza Activities T he Naval Medical Research Unit No. 2 (NAMRU-2), originally es- tablished during World War II in Guam and later relocated, first to Taiwan and then to the Philippines, began operating a detachment in Jakarta, Indonesia, in 1970. Its mission at that point was to investigate infectious diseases of military importance both for the U.S. Navy and for the rest of the Department of Defense (DoD) (DoD-GEIS, 2007a). It has recently played a very important role in the surveillance of avian influenza and a potential pandemic (see Figure 3-1). Historically NAMRU-2 has focused on applied research in support of its medical mission. Its past research activities provided a strong foundation for the expanded focus of the DoD’s Global Emerging Infections Surveil- lance and Response System (DoD-GEIS) on surveillance and response ca- pacity. Avian influenza highlights the issues of regional disease spread and also the significant role that NAMRU-2 plays in conducting disease surveil- lance, case and outbreak investigation, and diagnostic support. NAMRU-2 either identified or shared in the confirmation of all recent human cases of H5N1 infection in Indonesia, where the laboratory is recognized as one of two H5N1 reference laboratories by the Ministry of Health (MoH). A site visit team of the Institute of Medicine (IOM) Committee for the Assessment of Department of Defense Global Emerging Infections Surveil- lance and Response System visited NAMRU-2 from March 4-10, 2006.1 1 Priorto the NAMRU-2 visit, the laboratory staff provided the committee with detailed background information on NAMRU-2 and the pandemic/avian influenza activities it was supporting. These materials are available from the IOM in the Public Access File. 

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 REVIEW OF THE DOD-GEIS INFLUENZA PROGRAMS FIGURE 3-1 DoD’s regional presence in influenza surveillance (South East Asia), 2007. SOURCE: DoD-GEIS, 2007b. During the team’s visit, its members also toured a NAMRU-2 extension facility in Phnom Penh, Cambodia. A list of the people that the team met and interviewed along with the itinerary that the team followed can be 3-1 and 4-1 found at the end of this chapter. INFLUENZA IN INDONESIA Indonesia, home to 224 million people and 1.3 billion poultry, includ- ing 920 million chickens and 48 million ducks, reported its first human case of H5N1 avian influenza in July 2005 (Naipospos, 2007; WHO, 2007a). Since then it has experienced more avian flu fatalities than any

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 NAVAL MEDICAL RESEARCH UNIT  INDONESIA other country in the world, with its 97th case confirmed in late May 2007 (WHO, 2007a). In addition to Indonesia having the highest number of H5N1 AI cases worldwide, it has also experienced the largest family cluster of confirmed cases. In May 2006, seven human cases were reported in the Karo district of North Sumatra, all of whom were close relatives of the suspected initial case. Though the disease did not spread beyond the extended family, limited human-to-human transmission of the virus was not entirely ruled out. Full genetic sequencing of viruses isolated from cases in this cluster found no evidence of genetic reassortment or significant mutations, and subsequent outbreak clusters in Indonesia also failed to provide evidence of human-to- human transmission (WHO, 2006a; WHO, 2007a). In addition to Indonesia, eight countries in Southeast Asia have re- ported highly pathogenic avian influenza among poultry, namely Bangla- desh, Cambodia, India, Laos, Malaysia, Myanmar, Thailand, and Vietnam. Both Bangladesh and Myanmar reported outbreaks of highly pathogenic H5N1 in poultry in early 2007. Indonesia reported its first human case of H5N1 avian influenza in July 2005 (WHO, 2007a; WHO, 2007b). MANAGEMENT AND PLANNING Staffing DoD-GEIS projects at NAMRU-2 are overseen by the laboratory sci- ence director. At the time of the IOM visit by the site team, NAMRU-2 staff included 21 Americans. In addition, NAMRU-2 employs a staff of more than 120 foreign service nationals (FSNs). FSN staff includes labora- tory technicians and contract support personnel with expertise in areas of management and administration. All department heads have significant in- volvement in programs other than DoD-GEIS and avian influenza/pandemic influenza (AI/PI) activities, including Military Infectious Diseases Research Program (MIDRP) projects (NAMRU-2, 2007b). In fiscal year 2006, there were eight AI/PI projects being conducted by NAMRU-2 in Southeast Asia. These projects were headed up by five U.S. military staff and supported by the NAMRU-2 administrative and manage- ment staff. At the time of the visit by the site team, there was a part-time DoD-GEIS coordinator in Jakarta who is scheduled to leave NAMRU-2 circa June 2007. His replacement, a veterinarian who most recently served at NAMRU-3, had been in Indonesia for approximately five months; this replacement DoD-GEIS coordinator, who will also serve part-time, is cur- rently preparing for the transition (NAMRU-2, 2007b). In Cambodia and Laos, NAMRU-2 paid contractors to manage the AI/PI-related projects in these satellite laboratories. With the expansion of

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 REVIEW OF THE DOD-GEIS INFLUENZA PROGRAMS AI/PI activities in Cambodia, the NAMRU-2 laboratory in Phnom Penh had difficulty finding and hiring technical staff. Initial attempts to find competent technical personnel with training or experience in performing microbiologic techniques failed; as such individuals either were not avail- able in Phnom Penh or were already working in critical positions in other laboratories (e.g., the Pasteur Institute). Recognizing the importance of not competing for the limited local technical personnel, NAMRU-2 and col- laborating scientists from the Centers for Disease Control and Prevention (CDC) employed an innovative method to solve this problem. They hired a nongovernmental organization to search for competent, experienced techni- cians in neighboring Asian countries and imported them to live and work in Phnom Penh. The high level of competence and enthusiasm of these skilled senior technicians from Thailand and the Philippines has made its mark on the project. In order to build this capacity in Cambodia in the longer term, NAMRU-2 is also now supporting local training to increase the expertise in laboratories in the country (NAMRU-2, 2007b). Technology and Information Management In Jakarta, communications systems provide e-mail, Internet, fax, and telephone access. An onsite data center supplies computer systems support as well as data entry and analysis services. The MoH of Indonesia is in the process of developing a shared data- base. Epidemiologic information is currently maintained at a central AI Response Center at the Indonesian CDC. Other than that, each institute involved in the diagnoses of H5N1-infected samples has maintained its own database (NAMRU-2, 2007b). Conclusions The site visit team was told that single-year funds received at the end of a fiscal year are very difficult to use effectively. For example, a large por- tion of the fiscal year 2007 salaries for scientific personnel were supposed to be funded by DoD-GEIS, but by early fiscal year 2007 no (or limited) DoD-GEIS funding had been received. If NAMRU-2 were to receive fund- ing at the beginning of a fiscal year, so that it had an entire year to spend the funds, then officials at NAMRU-2 believe they would be able to plan and implement activities more effectively. The team also noted the difficulty faced by NAMRU-2 scientists and leadership in trying to plan and coordinate during a time of uncertainty. This uncertainty includes the long-term status of NAMRU-2, since a new memorandum of understanding must be completed shortly with the Indo- nesian government in order for NAMRU-2 to continue and carry out its

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 NAVAL MEDICAL RESEARCH UNIT  INDONESIA studies. Trying to undertake long-term planning in the face of such funda- mental uncertainty is difficult. A fundamental problem identified with respect to sustainability of the expanded pandemic influenza surveillance activities is this limited time period during which the one-year supplemental funds can be spent. Opti- mal expanded sustainable surveillance requires the allocation of multiple years—at least two and preferably three—of adequate support. This will allow more resources to be directed to the personnel costs of surveillance, allow local national staff to be better trained, and permit specific expanded surveillance projects to be more fully funded. The site visit team heard varying opinions as to whether the position of a full-time DoD-GEIS coordinator is critical to the efficient administra- tion and management of the DoD-GEIS program at NAMRU-2. Under any circumstances and however it is accomplished, significant administrative support is crucial to the management and overview of the various DoD- GEIS AI projects. Given the challenges associated with the AI/PI funds, NAMRU-2 would benefit from an additional administrator. A full-time dedicated administrative officer would be helpful to assure optimal use of DoD-GEIS funds and maximize productivity from the scientists. SURVEILLANCE The Influenza-Like Illness (ILI) Surveillance Project began in Indonesia in 1999. The original study, which ran from 1999 to 2004, involved six sites and was funded by DoD-GEIS. In 2004, this work was augmented with funding from the CDC, and 20 sites were subsequently established. The surveillance network was increased to 28 sites in 2005 with supple- mental funding from DoD-GEIS and the U.S. Agency for International Development (NAMRU-2, 2007b). Using the 2006 AI/PI supplemental funding, NAMRU-2’s avian and pandemic influenza surveillance program was expanded to incorporate both animal and human surveillance, including surveillance of influenza viruses in migratory birds in Java; a passive surveillance network to detect influenza viruses in humans with influenza-like illness alone or with diar- rhea and acute respiratory symptoms in Indonesia; and development of new human surveillance projects and diagnostic capabilities in Laos and Cambodia (NAMRU-2, 2007b). Specimens that come in for the detec- tion of influenza virus or other respiratory pathogens are accompanied by clinical and demographic data. There is a parallel surveillance project being carried out by Litbangkes, the National Institute of Health Research and Development Laboratory, but the clinical and demographic data collected by NAMRU-2 surveillance activities provide added value. This network regularly tests over 500 human specimens a month, and has collected 697

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0 REVIEW OF THE DOD-GEIS INFLUENZA PROGRAMS throat swab samples and 698 cloacal swab samples from 64 species of do- mestic birds, resident wild birds, and migratory birds. Human Surveillance NAMRU-2 is implementing four protocols related to human cases of highly pathogenic influenza, including medical record review (Indonesia), prevalence of avian and human influenza viruses among diarrheal pediatric cases (Indonesia), passive hospital surveillance for acute influenza-like ill- ness (Laos), and seroincidence in humans and seroprevalence in animals of avian influenza virus infections (Cambodia) (NAMRU-2, 2007b). NAMRU-2’s medical record review protocol is assessing severe respira- tory disease among hospitalized patients across Indonesia through a system- atic review of inpatient medical records. A standardized data-abstraction form, based on the common clinical manifestation of current H5N1 cases in Indonesia, was mailed to participating referral hospitals. Medical record personnel at each hospital complete questionnaires, including demographic, clinical, and laboratory data for each patient meeting the inclusion crite- ria (NAMRU-2, 2007b). By the study’s end in 2007, NAMRU-2 plans to have collected data on medical records dated from January 2003 through December 2005. In order to identify possible H5N1 infections prior to Indonesia’s first laboratory-confirmed H5N1 cases in July 2005, NAMRU- 2 extended its retrospective review to roughly one year’s worth of data prior to the first documented cases of H5N1 poultry infection in November 2003. NAMRU-2 will also use the data to determine if there was an in- crease in morbidity and mortality associated with severe respiratory disease over the same timeframe. NAMRU-2 plans to run descriptive statistics and a simple factor analysis on the data collected to identify prior H5N1 cases based on current clinical and laboratory knowledge of confirmed H5N1 cases (e.g. symptoms such as fever, pneumonia, leukopenia, lymphocytope- nia, hypoalbuminia, and elevated liver enzymes). Morbidity and mortality estimates will be established based on the catchment population of the respective hospitals. In some fatal cases of avian influenza reported in Vietnam and Thai- land, diarrhea occurred without any respiratory symptoms, and laboratory testing has found that highly pathogenic avian influenza H5N1 is pres- ent in the stool of infected patients (de Jong, et al. 2005 and Wiwanitkit, 2005). Local Indonesian laboratories have also documented that diarrhea was a common symptom reported by several patients infected with highly pathogenic avian influenza H5N1 (NAMRU-2, 2007b). NAMRU-2 has de- veloped a protocol to determine whether or not influenza A or B, especially highly pathogenic avian influenza, is shed in stool during primary influenza infections and to assess the association of viral recovery in stool versus up-

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 NAVAL MEDICAL RESEARCH UNIT  INDONESIA per respiratory specimens in the same patient. Viral RNA is extracted from stool and throat swabs collected from diarrheal pediatric patients with in- fluenza symptoms (fever and runny or stuffy nose) who are recruited from hospitals and community health centers across Indonesia. Stool specimens and respiratory specimens are examined using multiplex nested-PCR to identify influenza A and influenza B viruses in the same reaction tube, based on two unique primer pair-sets. To date, approximately 6,000 pediatric pa- tients have been enrolled, from which 364 matched stool-throat swabs have been collected. This study has found a high prevalence of human influenza A and B (12.1 percent) in pediatric diarrhea cases (NAMRU-2, 2007b). As this study continues NAMRU-2 researchers expect it will provide critical surveillance in detecting H5N1 in patients whose respiratory symptoms may be minimized in favor of more common gastroenteritis diagnoses. The Laos People’s Democratic Republic has had no human ILI surveil- lance network to identify human cases. Beginning in 2007, in conjunction with the MoH and CDC, NAMRU-2 developed a network of surveil- lance hospitals and clinics to screen and identify cases of H5N1 infections (NAMRU-2, 2007b). Using specific case definitions for selection purposes, ILI cases and controls are enrolled, throat and nasal swabs are obtained, and a study questionnaire is completed. At each hospital site at least 333 cases and 333 controls are required to be enrolled. Samples will be exam- ined locally for screening purposes using rapid influenza A&B tests. At the National Center for Laboratory and Epidemiology (NCLE) in Vientiane, specimens will be screened by a multiplex system for pathogen identifica- tion. H5N1-positive specimens will be confirmed by real-time RT-PCR (reverse transcriptase polymerase chain reaction) methodology. Positive H5N1 isolates will be shipped to and characterized at the CDC and a World Health Organization (WHO) laboratory identified by the Ministry of Health (MoH) (NAMRU-2, 2007b). NAMRU-2 expects this study to yield information about influenza in Laos, to enhance Laos’s capacity to identify potential pandemic influenza viruses and other highly pathogenic and virulent respiratory pathogens, and to provide the CDC with a broader net to identify highly pathogenic influenza viruses. Since MoH representa- tives are being trained in an extremely versatile and cost-effective diagnostic system for surveillance and outbreak investigation, NAMRU-2 also expects this project to increase the indigenous diagnostic capacity. The widespread epizootic of avian influenza A (H5N1) that has emerged among poultry since 2003 has resulted in severe and fatal H5N1 human cases in Asia, the Middle East, the Near East, and Europe, but human deaths have not always paralleled the poultry outbreaks (WHO, 2005; FAO, 2007, WHO, 2006b). It is thought that human H5N1 influenza infections (clinical and subclinical) have occurred much more frequently than suggested. In order to increase information on H5N1 prevalence and

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 REVIEW OF THE DOD-GEIS INFLUENZA PROGRAMS incidence in humans and animals, NAMRU-2 will attempt to calculate the baseline seroprevalence and annual seroincidence of H1, H3, and H5 influ- enza virus infections in adults and animals living in a rural village in Kandal Province, Cambodia, and the seroprevalence of H5, H7, and H9 influenza virus in poultry, swine, and felines in a rural village also in Cambodia (NAMRU-2, 2007b). More than six hundred adults 18 years of age and older residing in adjacent villages in Kandal Province will be enrolled in this program. In each household, one adult will be randomly selected for enroll- ment. Animals—one chicken, one pig, and one cat per household—will be bled at baseline to determine seroprevalence in the same villages. Animal Surveillance The prevalence of the H5N1 and other avian influenza viruses in migra- tory birds and other animal reservoirs in Indonesia is unknown. In order to address this gap in knowledge, NAMRU-2 is supporting a multi-pronged animal influenza surveillance program in Indonesia. This program has three main objectives: to develop and conduct surveillance of avian influenza vi- ruses in migratory and wild birds; to train Indonesian government scientists in field and laboratory techniques for collecting and testing for virus; and to use remote sensing to determine environmental correlates for transmission (NAMRU-2, 2007b). Routine sampling of migratory and wild birds and domestic waterfowl has begun at two sites on the island of Java. Samples taken from these speci- mens are tested for the presence of H5N1 and other influenza A viruses. As of October 2006, NAMRU-2 had collected 695 serum samples, 697 throat swab samples, and 698 cloacal swab samples. Of these, 585 serum samples have been tested so far, and four domestic Muscovy ducks (Cairina mos- chata), 2 plovers (Charadrius spp.), and samples from a purple swamphen (Porphyrio porphyrio) have been found to be presumptively positive for HA antibodies, that is, antibodies against influenza virus hemagglutinin. RT-PCR tests on throat and cloacal swab samples are ongoing to identify possible viruses (NAMRU-2, 2007b). NAMRU-2 is working with the University of Iowa to coordinate train- ing for relevant Indonesian government experts. From September 18-29, 2006, three scientists from Indonesia’s Ecology and Health Status Research and Development Center, National Institute of Health Research and Devel- opment (Litbangkes) participated in didactic and laboratory training at the University of Iowa’s Center for Emerging Infectious Diseases. This training focused on collection, proper handling, and testing techniques for emerging zoonotic diseases, including avian influenza. NAMRU-2 is also collaborating with the government of Indonesia to plan for studies involving remote sensing and environmental correlates of

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 NAVAL MEDICAL RESEARCH UNIT  INDONESIA avian influenza virus transmission. A seminar was held for the Litbangkes institute outlining the role of remote sensing in infectious disease research and control. Two of the three objectives of this study have been met. The third, involving remote sensing of environmental parameters, has been planned, and a protocol is with the Indonesian MoH awaiting approval. NAMRU-2 expects that this project will begin in fiscal year 2007. Conclusions The committee was impressed with the surveillance protocols imple- mented at NAMRU-2, particularly those involving the University of Iowa and AFRIMS, and it encourages additional collaborative activities and initiatives between DoD laboratories. In addition, the committee concluded that NAMRU-2’s work with novel findings will greatly contribute to knowl- edge of the H5N1 influenza virus. RECOMMENDATION 3-1. NAMRU-2 should vigorously pursue work with novel findings, e.g., influenza/diarrheal studies, which have the potential to contribute to surveillance and improve understanding of how the virus spreads. LABORATORY NAMRU-2 Laboratory in Indonesia NAMRU-2 Jakarta is located in 62,000 square feet of laboratory, of- fice, and storage spaces in three buildings within the Indonesian Ministry of Health, National Institutes of Health Research and Development (Lit- bangkes) compound (DoD-GEIS, 2007a). The facilities are well equipped, and the animal facility is accredited by the American Association for the Accreditation of Laboratory Animal Care. The virology laboratory capacity at NAMRU-2 includes tissue culture capabilities along with serological and molecular biological testing technologies (NAMRU-2, 2007b). As of March 2007, there was no biosafety level-3 (BSL-3) laboratory available to NAMRU-2 or the National Institute of Health Research and Development (Litbangkes) scientists in which to attempt to culture H5 vi- ruses under appropriate biosafety and physical containment. Consequently, there is currently no ability to do microneutralization assays for measuring anti-H5 antibody or to test the susceptibility of local H5N1 viral isolates to oseltamivir or other antiviral drugs. However, largely as a response to the H5N1 pandemic threat, two BSL-3 laboratories are expected to come online within the next two years. These include the Ejikman Institute (ex- pected to be online by the middle of 2007) and the Litbangkes BSL-3 (which

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 REVIEW OF THE DOD-GEIS INFLUENZA PROGRAMS could be online in 2008). The Litbangkes leadership, NAMRU-2 scientists, U.S. embassy officials, and WHO work together closely to make arrange- ments for NAMRU-2 scientists to use the Litbangkes BSL-3 facility and to contribute to its maintenance. The IOM site visit team asked whether there is an equivalent in Indone- sia of a CDC BSL-3 inspection team or any established criteria to determine the suitability of the BSL-3 physical plant, its intended procedures, the cre- dentials of proposed investigators, and the training procedures. The answer given to the site visit team was that the NAMRU-2 staff was unaware of any such controls. During a meeting with the US Embassy staff, the site visit team learned that there will be some U.S. guidance and assistance for this with respect to the Litbangkes BSL-3, but no one knew the answers to the analogous questions regarding the Ejikman BSL-3. NAMRU-2’s H5 surveillance sample testing is based mainly on RT-PCR methodology. This is done using real time RT-PCR and multiplex RT-PCR. The relative utility of these RT-PCR methodologies depends on the specific project. For example, multiplex RT-PCR is a state-of-the-art diagnostic technology that can be adapted to allow multiple important human respi- ratory pathogens (viral and bacterial) to be identified simultaneously. With appropriate primers encoding antigens specific for various pathogens, more than 20 individual pathogens can be identified simultaneously. As such, multiplex RT-PCR is particularly suited to broad epidemiologic studies of acute respiratory disease. Moreover, it is an extraordinarily useful tool for simultaneously determining the seasonality of an array of respiratory pathogens. However, the multiplex RT-PCR device is relatively expensive to operate. The committee was informed that the cost of processing each microtiter plate is approximately $5,262 (NAMRU-2, 2007c). Thus, the annual costs of studying seasonality by running one plate per day, five days per week, as the laboratory is currently doing, costs more than $1 million per year. At present, presumptive H5 antibody in animal and human sera is detected at NAMRU-2 by the hemagglutination inhibition method; until a BSL-3 is available, microneutralization tests cannot be performed. The site visit team drew attention to the complexity of detecting antibodies to avian influenza viruses in mammalian sera. The NAMRU-2 laboratory also cultures H3 and H1 influenza A as well as influenza B viruses by cell-culture methods. Specimens are shared with the MoH. The team was informed that Indonesian veterinarians working for NAMRU-2 have the capability to perform autopsies on dead birds, cats, and other animals suspected of having succumbed to H5N1 (or other) influenza viruses and that they can perform sophisticated histopathologic examinations. The technical level of competence for these pathological examinations at NAMRU-2 is high.

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 NAVAL MEDICAL RESEARCH UNIT  INDONESIA In briefly inspecting the laboratories, it was apparent to the IOM team that NAMRU-2 also has well-equipped and well-staffed bacteriology laboratories which can perform, as necessary, studies of secondary bacte- rial infections that may complicate H5 viral infections. Should pandemic disease occur, the capability to do good bacteriologic studies in patients with H5N1 disease could be extremely important since, even if a pandemic H5N1 virus were commonly to cause primary viral pneumonia (as in the 1918 pandemic), the possibility of a bacterial dimension to pulmonary infections remains. On average, NAMRU-2 tests specimens from approximately 100 sus- pected H5N1 cases a month for rapid laboratory diagnosis along with other samples with suspected respiratory pathogens. Virus-positive blood or respiratory samples are shipped to the CDC for verification, genetic se- quencing, sharing with the Indonesian MoH, and use in assay and vaccine development. NAMRU-2 Laboratory in Cambodia NAMRU-2 has a well-equipped, well-fitted physical plant for labora- tory research in Phnom Penh. The NAMRU-2 building is located on the National Institute of Public Health (NIPH) campus, where several other agencies also have their administrative and technical operations. These in- clude the Pasteur Institute of Phnom Penh, the CDC unit’s offices and labo- ratories, and the National Institute of Public Health (NAMRU-2, 2007b). During the IOM team’s site visit, the laboratory’s influenza capacity was still being established. Active training was going on and the team was able to view a training session that involved the multiplex RT-PCR machine provided to the laboratory by the DoD-GEIS supplemental funding. This laboratory is primarily responsible for providing microbiologic support to field studies. Also included in the laboratory is a DNA/RNA extractor paid for by DoD-GEIS influenza surveillance supplemental funds. NAMRU-2 Laboratory in Laos The site visit team did not visit Vientiane but was informed that NAMRU-2 has been working in Laos for eight years, with influenza-specific work being done in the past year and a half. This work began with regular DoD-GEIS funding, but supplemental AI monies have allowed the initiation of a new influenza surveillance study and the hiring of additional staff. Influenza surveillance activities in Laos involve close collaboration with the NCLE in Vientiane. Specimens from patients with respiratory infections are being collected in Savannakhet and two other towns and then flown to Vientiane (NAMRU-2, 2007b).

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0 REVIEW OF THE DOD-GEIS INFLUENZA PROGRAMS gies well in place to handle such an outbreak. NAMRU-2 would have much to offer in its ability to cope with a surge situation, especially in the early stages of a pandemic. There do not appear to be too many other ways that NAMRU-2 can assist the health systems to respond to an influenza pandemic. There are few clinicians on the NAMRU-2 staff and little equipment that would be relevant. Its support would be provided mainly through technical assis- tance, and clinical training. More importantly, NAMRU-2 could provide diagnostic input to let the ministry know that the epidemic to which their health systems must respond is in fact pandemic influenza. The commit- tee would see this as valuable input from NAMRU-2 in the event that this does occur, and deeper links with the ministry could be forged as part of a significant contribution to influenza pandemic preparedness. CAPACITY BUILDING NAMRU-2 has purchased equipment and supplies for its laboratory and collaborating laboratories in Southeast Asia in order to support ongo- ing surveillance activities, increase surge capacity, augment molecular diag- nostic capability, and provide the means to rapidly test multiple specimens for influenza A H5N1 and to rapidly sequence samples from patients with confirmed H5N1 infection. An automated nucleic acid extractor was purchased for the NAMRU-2 laboratory in Indonesia to assist in sample processing. Additional thermo- cyclers have allowed for the simultaneous amplification of multiple targets for hundreds of samples at the same time. An ABI 3300 gene sequencer has been added to the new molecular virology laboratory, and, in addition, funds provided for this project have supported the purchase of reagents and the hiring of two technicians to oversee activities. NAMRU-2 has provided the laboratory in Phnom Penh, Cambodia, with significant support in the form of equipment, supplies, and personnel with which to conduct avian influenza projects in the country. Examples include an automated nucleic acid extractor to assist in sample processing and a real-time RT-PCR machine for the analysis of multiple targets and samples; a multiplex instrument, installed and commissioned in the NIPH/ NAMRU-2 laboratory in Phnom Penh; temperature-sensitive reagents to run about 1,000 samples; the hiring of a contract laboratory technician, trained by NAMRU-2 staff, as well as equipment distributor staff; and the purchase of proficiency panels in collaboration with the Naval Health Re- search Center (NHRC), which will be used to establish a quarterly quality assurance/quality control (QA/QC) program for the laboratory. In Vientiane, Laos, NAMRU-2 has provided the same as it has in Phnom Penh, with the exception of the nucleic acid extractor.

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 NAVAL MEDICAL RESEARCH UNIT  INDONESIA In addition, NAMRU-2 is funding the development of a Singapore location in order to attract potential research partners based in Singapore, establish a base for diagnostic and training operations, enhance logistical capabilities and operational agility for surveillance activities in Cambodia, Laos, and Indonesia, and serve as a strategic training unit, capable of pro- viding training to NAMRU-2 regional partners. As part of the establish- ment of this platform, NAMRU-2 expects to install a multiplex system at the Defense Science Organization (DSO) National Laboratories at Kent Ridge in Singapore. Furthermore, NAMRU-2 sponsored a symposium at DSO National Laboratories, which brought together delegates from the Indonesia, Laos, Cambodia, and Singapore ministries of health to discuss disease surveillance and evaluation of detection platforms. This project is ongoing. Conclusions NAMRU-2 has invested in building the capacity of all three of their partner facilities. The IOM site visit team learned that the large items of equipment purchased with supplemental influenza surveillance monies, including the multiplex PCR apparatus installed in Cambodia and Laos, represent Department of the Navy equipment that would not be left behind should the influenza surveillance budget be severely curtailed. IOM site visitors were informed that this lack of transfer of ownership of the equip- ment to host country institutions was clearly explained to host country collaborators. Moreover, even if the expensive pieces of equipment, such as the multiplex system, were transferred to the host country institutions, the cost of operation of these machines is almost certainly too prohibitive to be sustained by the local authorities. For example, the IOM committee was in- formed that one 96-well plate tested in the multiplex system at NAMRU-2 in Jakarta costs $5,262 to process (NAMRU-2, 2007c). Importantly, with respect to both running the current projects and capacity building, these experienced senior technical staff are training a cadre of Khmer technicians. The site visit team watched a training session in which Khmer trainees were being taught to operate a multiplex ap- paratus. During the site visit to Phnom Penh, the IOM team learned that within the local technical school some Cambodian students are trained each year as laboratory technicians. However, the training is in French, and these graduates, who speak only Khmer and French, would have dif- ficulty communicating in a laboratory where the technical supervisors and investigators speak English but not Khmer or French. For some projects this would not be a major problem, but because of the diagnostic ramifications of H5 surveillance there has been reluctance to hire non-English speaking technical staff.

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 REVIEW OF THE DOD-GEIS INFLUENZA PROGRAMS COLLABORATION AND COORDINATION Collaborative relationships between organizations and agencies with public health interests in Indonesia (including agencies of the Indonesian government, the U.S. government, and international organizations) are quite complex. Within Indonesia, NAMRU-2 has been working closely with Litbangkes and the Ministry of Agriculture and Fishery with respect to influenza surveillance. While relationships on a technical level are col- laborative, there have been a couple of issues related to the flow of results and samples which, at the time of the IOM visit, had recently affected both NAMRU-2’s relationship with the government and the laboratory’s ability to function effectively. While these issues appear to have been resolved, they highlight the importance of transparency and of collaboration with host governments. One of these issues was related to the flow of samples and results to reference laboratories outside of Indonesia. Respiratory specimens collected by NAMRU-2 were conventionally split into several aliquots, one of which was sent to Litbangkes for testing there. In addition, specimens that tested positive for H5 in the NAMRU-2 laboratory were sent to the CDC in At- lanta, a WHO international reference center, for confirmation and sequence analysis. Prior to March 2006, the CDC standard operating procedure was to send confirmation and sequence information only to the laboratory that provided the specimen and not routinely to the ministry of health of the host country where the submitting laboratory resided. Because NAMRU-2 was inadvertently receiving information before the Indonesia MoH, this created a delicate situation. The issue was resolved when CDC agreed to report results simultaneously to NAMRU-2 and to Litbangkes. The other issue related to another CDC standard operating procedure, which was to make viral isolates available upon request to manufactur- ers of influenza vaccines for humans and to make the sequences publicly available to everyone in Genbank. This was in accordance with the rules of the WHO International Influenza Reference Laboratories, but the In- donesian government was unhappy with the way its viruses and sequences were being handled, and it argued that a lack of respect was being shown for the needs of Indonesia as a sovereign government. This issue became complicated when CSL (the Australian producer of influenza vaccines) pre- pared a candidate H5N1 vaccine, based on an Indonesian isolate sequence obtained from GenBank, by using reverse genetics to create a vaccine seed virus strain expressing the hemagglutinin antigen of this recent Indonesian virus that could be grown to high titer in eggs. When CSL announced the development of the vaccine and this was brought to the attention of Indone- sia’s MoH, the information was misinterpreted, and it was concluded that

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 NAVAL MEDICAL RESEARCH UNIT  INDONESIA somehow CSL had physically obtained Indonesian H5 isolates without the knowledge of the Indonesian government. These vaccine-related points of contention were aggravated by several other instances, described to the team by senior MoH officials, in which Indonesian isolate sequence data were presented at international confer- ences without Indonesian scientists or the Indonesian government being informed. Collectively, these incidents led the MoH of Indonesia to declare that the country would no longer send H5 isolates to WHO reference labs, nor would it share sequence data. This created an international crisis with respect to surveillance activities for H5 in Indonesia (currently the site of most reported human cases globally), and it also seriously impaired surveil- lance activities at NAMRU-2. The site visit team was in Indonesia in the midst of this very complicated, difficult situation with its implications for global surveillance for H5. An important clarification was provided to the site visit team when it visited with the WHO country representative in Jakarta. He indicated that at the highest levels of WHO there was involvement and discussions with the Minister of Health of Indonesia and with her associates over the issues of sending virus isolates to a WHO influenza reference laboratory and sharing strains and sequence data. The site visit team was told that in early March the Director General of WHO sent a letter to the Minister of Health of Indonesia clearly stating WHO’s position that the specimens of Indonesian origin would be used only for risk assessment and not vaccine manufacture (i.e., for non-commercial purposes) and strongly urging the country to once again send strains to a WHO international influenza refer- ence laboratory. The IOM team was informed that a letter of reply from the Indonesian government to WHO had been sent but WHO had not yet seen it. However, it was implied that the basic agreement was in place to allow resumption of the export of H5 isolates to WHO influenza reference laboratories. A high-level technical conference was being convened on an urgent basis for the week of March 27, and it was expected that this confer- ence would accomplish useful technical exchange. In response to the Indonesian government’s concerns, WHO held a two- day meeting in March 2007. According to WHO, the meeting discussions focused on striking a balance between the need to continue the sharing of influenza viruses for risk assessment and for vaccine development and the need to ensure that developing countries benefit from sharing. The WHO collaborating centers will continue to perform risk assessment on H5N1 virus samples and to transform virus into seed virus suitable for vaccine production. Following discussion with representatives of the Indonesian MoH, these processes will be documented in a revised terms of reference for the WHO laboratories. Following this meeting, the MoH of Indonesia an- nounced that the country would immediately resume the sharing of H5N1

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 REVIEW OF THE DOD-GEIS INFLUENZA PROGRAMS avian influenza virus samples. In addition, the World Health Assembly in May of 2007 reiterated the importance of sharing virus samples as well as ensuring that developing countries are involved in and benefit from the global surveillance network (WHA, 2007). As demonstrated by the handling of the recent problem with the Indo- nesian government, NAMRU-2 works closely with WHO. During the IOM team’s visit, its members met with officials from the WHO, who confirmed that NAMRU-2 is well coordinated with and closely linked with WHO activities. As mentioned previously, specimens positive for H5N1 and other in- fluenza viruses are shipped immediately to the CDC for confirmation and genetic analysis, if applicable. In collaboration with the National Aero- nautics and Space Administration, data from animal surveillance will be coordinated with satellite data to determine environmental correlates for transmission of AI. NAMRU-2 creates weekly updates on H5N1 in Indonesia, which are made available to the DoD-GEIS Headquarters and the U.S. embassy in Jakarta. In the last two years, this program has received funding from DoD- GEIS, CDC, and the U.S Agency for International Development. Sources at the U.S. embassy were highly complimentary of the NAMRU- 2 influenza surveillance system and overall technical capabilities, and they specifically mentioned how embassy officials have repeatedly received phone calls and cables from congressional offices asking specific questions about the H5 situation in Indonesia. The NAMRU-2 staff have been invaluable in providing up-to-date, objective responses on a round-the-clock basis. Therefore the NAMRU-2 surveillance system and the NAMRU-2 technical personnel have been an extremely useful resource to the U.S. embassy. Finally, in collaboration with the Armed Forces Research Institute of Medical Sciences (AFRIMS), NAMRU-2 scientists are involved in influenza surveillance activities in Thailand. In undertaking this collaboration, the scientists provided training in influenza A H5N1 diagnostic assays to the AFRIMS laboratory personnel in Bangkok to establish and standardize these tests. Conclusions GEIS is integrated with current, ongoing activities within Indonesia’s public health infrastructure. Within-country relationships are largely person based and proximity driven, and strong partnerships have resulted over the years. NAMRU-2 DoD-GEIS staff seemed very well known and respected by the national health authorities. The interaction between NAMRU-2 and the Litbangkes staff is strong. The Ministry of Health, primarily Lit-

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 NAVAL MEDICAL RESEARCH UNIT  INDONESIA bangkes, approves all projects funded by GEIS. DoD-GEIS activities are transparent to the Indonesian Ministry of Health, and most projects are jointly conducted. NAMRU-2 also works closely with relevant government agencies on influenza surveillance activities in Cambodia and Laos. The site visit team felt that NAMRU-2 was working well in all of its locations, even in the face of serious challenges to coordination. In spite of the period of uncertainty with respect to a new long-term memorandum of understanding with the government of Indonesia, the committee supported NAMRU-2’s continued support and expansion of influenza surveillance activities in neighboring countries. NAMRU-2’s ongoing collaboration with AFRIMS allows for improved utilization of AI/PI resources as well as redundant coverage for each of the laboratories in the event of a crisis (political, geologic, etc.) that might close one and not the other during a pandemic. RECOMMENDATION 3-2. NAMRU-2 should continue to strengthen its relationship with AFRIMS and to coordinate DoD-GEIS influenza activities in the region. REFERENCES DoD-GEIS (Department of Defense Global Emerging Infections System). 2007a. U.S. Naval Medical Research Unit No. . http://www.geis.fhp.osd.mil/GEIS/Training/namru-2asp. asp (accessed June 12, 2007) DoD-GEIS. 2007b. Department of Defense influenza surveillance sites worldwide, 00 (unpublished). de Jong, M. D., Cam, B. V., Qui, P. T., Hien, V. M., Thanh, T. T., Hue, N. B., Beld, M., Phuong, L. T., Khanh, T. H., Chau, N. V. V., Hien, T. T., Ha, D. Q., Farrar, J. 2005. Fatal avian influenza A (H5N1) in a child presenting with diarrhea followed by coma. New England Journal of Medicine 352:686-691. FAO (Food and Agricultural Organization of the United Nations). 2007. Combining poultry vaccination with other disease control measures to combat HN. http://www.fao.org/ newsroom/en/news/2007/1000527/index.html (accessed June 12, 2007). Naipospos, T.S.P. 2007. The Indonesian response plan to avian influenza. PowerPoint pre- sented at Seasonal and Pandemic Influenza Meeting, February 1. Arlington, VA. NAMRU-2 (Naval Medical Research Unit No. 2). 2007a. Sample surge capacity plan (unpublished). NAMRU-2. 2007b. Fiscal year 00 AI/PI GEIS project information (unpublished). NAMRU-2. 2007c. Estimated Cost of Assays (unpublished). WHA (World Health Assembly). 2007. Pandemic influenza preparedness: Sharing of influenza viruses and access to vaccines and other benefits (WHA0.). World Health Organiza- tion Geneva, Switzerland. WHO (World Health Organization). 2005. Avian influenza frequently asked questions. http:// www.who.int/csr/disease/avian_influenza/avian_faqs/en/index.html (accessed June 12, 2007).

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 REVIEW OF THE DOD-GEIS INFLUENZA PROGRAMS WHO. 2006a. Avian influenza—situation in Indonesia—update . http://www.who.int/csr/ don/2006_05_23/en/index.html (accessed June 12, 2007). WHO. 2006b. Influenza research at the human and animal interface. Report of a WHO working group. Geneva, Switzerland 21–22 September 2006. http://www.who.int/csr/ resources/publications/influenza/WHO_CDS_EPR_GIP_2006_3C.pdf (accessed July 30, 2007). WHO. 2007a. HN avian influenza: Timeline of major events. http://www.who.int/csr/ disease/avian_influenza/Timeline_2007_03_20.pdf (accessed September 5, 2007). WHO. 2007b. Avian influenza outbreaks in South-East Asia. http://www.searo.who.int/EN/ section10/section1027.htm (accessed June 12, 2007). Wiwanitkit, V. 2005. Diarrhoea as a presentation of bird flu infection: A summary on its cor- relation to outcome in Thai cases. Gut 54: 1506-1506.

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 NAVAL MEDICAL RESEARCH UNIT  INDONESIA LIST OF CONTACTS DoD-GEIS NAMRU-2 Assessment: Indonesia Patrick Blaire, Viral Disease Program, Naval Medical Research Unit No. 2, Jakarta, Indonesia Timothy Burgess, Naval Medical Research Unit No. 2, Jakarta, Indonesia Jonathan Glass, Naval Medical Research Unit No. 2, Jakarta, Indonesia Herman Kosasih, Naval Medical Research Unit No. 2, Jakarta, Indonesia Craig Stoops, Naval Medical Research Unit No. 2, Jakarta, Indonesia Agustinalka Susanti, Luminex System, Naval Medical Research Unit No. 2, Jakarta, Indonesia Steven Tobias, Naval Medical Research Unit No. 2, Jakarta, Indonesia William A. Heidt, Economic Section, Embassy of the United States, Jakarta, Indonesia Colette Marcellin, Environment, Science, Technology, and Health, Embassy of the United States, Jakarta, Indonesia Lisa Kramer, Office of Health Population and Nutrition, United States Agency for International Development, Jakarta, Indonesia Sardikin Giriputro, Sulianty Saroso Infectious Disease Hospital, Republic of Indonesia Ministry of Health, Jakarta, Indonesia Triono Soendoro, Republic of Indonesia Ministry of Health, National Institute of Health Research and Development, Jakarta, Indonesia Endang R. Sedyaningsih Mamahit, Center for Biomedical and Pharmaceutical Research and Development, National Institute of Health Research and Development, Jakarta, Indonesia Georg Peterson, World Health Organization, Jakarta, Indonesia Kumara Rai, World Health Organization, Jakarta, Indonesia Helen Louise Taylor, World Health Organization, Jakarta, Indonesia DoD-GEIS NAMRU-2 Assessment: Cambodia Shannon Putnam, Director, Bacterial Diseases Program, Naval Medical Research Unit No. 2, Phnom Penh, Cambodia Thomas Wierzba, Phnom Penh Laboratory, Naval Medical Research Unit No. 2, Phnom Penh, Cambodia Bill Brady, Avian Influenza Country Coordination, National Institute of Public Health, Phnom Penh, Cambodia Ung Sam Un, National Institute of Public Health, Phnom Penh, Cambodia

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 REVIEW OF THE DOD-GEIS INFLUENZA PROGRAMS SCHEDULE OF EVENTS DoD-GEIS NAMRU-2 Assessment Jakarta, Indonesia and Phnom Penh, Cambodia Participants: Dr. Myron M. Levine Dr. Kennedy Shortridge Kimberly Weingarten March 5, 2007–March 10, 2007 Monday, March , 00 In-brief with command and scientific director 0830-0900 Overview of GEIS/NAMRU-2 programs 0900-0930 Dr. Jonathan Glass Dr. Steven Tobias Meeting with individual projects’ primary investigators 0930-1200 for 45 minutes each, including tour Dr. Jonathan Glass and Dr. Steven Tobias, Emerging Diseases Ika Susanti, Immunology Dr. Craig Stoops and Dr. Steven Tobias, Entomology and Zoonotic Diseases 1200-1300 Lunch Meeting with individual projects’ primary investigators 1300-1500 for 45 minutes each, including tour Dr. Patrick Blair and Dr. Timothy Burgess, Virology Meeting 1515- Dr. Endang R. Sedyaningsih Mamahit, National Institutes of Health Research and Development 1900- Dinner Tuesday, March , 00 Meeting 0900-1100 Dr. Kumara Rai, World Health Organization Dr. George Peterson, World Health Organization Meeting 1100-1230 Colette Marcellin, U.S. Embassy Avian Influenza Working Group 1230-1400 Lunch Rumah Sakit Pneyakit Infeksi Sulianti Saroso Hospital 1400- for Influenza site visit

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 NAVAL MEDICAL RESEARCH UNIT  INDONESIA Wednesday, March , 00 0930-1715 Travel to Phnom Penh, Cambodia 1900- Dinner Thursday, March , 00 Meeting 0800-0845 Dr. Shannon Putman, Bacteriology 0845-0915 Travel to NAMRU-2 laboratory at the National Institutes of Public Health In-brief 0915-1000 Dr. Thomas Weirzba, Laboratory Director Tour of facility 1000-1100 Meeting 1100-1200 Dr. Bill Brady, Coordinator of Avian and Pandemic Influenza 1200-1300 Lunch Site visit to Chey Chummas Referral Hospital (Kandal 1300-1400 Province) Visited family farm south of Phnom Penh 1430-1600 1900- Dinner Friday, March , 00 0830-1600 Fly to Bangkok, Thailand Saturday, March 0, 00 1000-1640 Departure

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