EINet Alert ~ Aug 24, 2007

*****A free service of the APEC Emerging Infections Network*****
APEC EINet News Briefs offers the latest news, journal articles, and notifications for emerging infections affecting the APEC member economies. It was created to foster transparency, communication, and collaboration in emerging infectious diseases among health professionals, international business and commerce leaders, and policy makers in the Asia-Pacific region.
In this edition:
- Global: Cumulative number of human cases of avian influenza A/(H5N1)
- Italy (Lugo): Low pathogenic avian influenza H5N2 detected in poultry
- Indonesia (Bali): New human case of avian influenza H5N1
- Pakistan: Avian influenza H5N1 strikes poultry again

1. Updates
- Avian/Pandemic influenza updates

2. Articles
- Journal of Wildlife diseases – Supplement on avian influenza
- Ecologic immunology of avian influenza (H5N1) in migratory birds.
- Antigen sparing and cross-reactive immunity with an adjuvanted rH5N1 prototype pandemic influenza vaccine: a randomised controlled trial.
- Neuraminidase inhibitor resistance in influenza viruses.
- How much would closing schools reduce transmission during an influenza pandemic?
- Pandemic Flu Preparedness: A Manufacturing Perspective
- Influenza Survey Uncovers Key Differences Between Bird Flu And Human Flu
- North American pandemic plan takes shape

3. Notifications
- WHO Clinical management of human infection with avian influenza A (H5N1) virus
- Roche Joins the Fifth International Bird Flu Summit as a Sponsor

Global: Cumulative number of human cases of avian influenza A/(H5N1)
Economy / Cases (Deaths)

Viet Nam / 3 (3)
Total / 3 (3)

Thailand / 17 (12)
Viet Nam / 29 (20)
Total / 46 (32)

Cambodia / 4 (4)
China / 8 (5)
Indonesia / 17 (11)
Thailand / 5 (2)
Viet Nam / 61 (19)
Total / 95 (41)

Azerbaijan / 8 (5)
Cambodia / 2 (2)
China / 13 (8)
Djibouti / 1 (0)
Egypt / 18 (10)
Indonesia / 56 (46)
Iraq / 3 (2)
Thailand / 3 (3)
Turkey / 12 (4)
Total / 116 (80)

Cambodia/ 1 (1)
China / 3 (2)
Egypt / 20 (5)
Indonesia / 30 (26)
Laos / 2 (2)
Nigeria / 1 (1)
Viet Nam 2 (0)
Total / 59 (37)

Total no. of confirmed human cases of avian influenza A/(H5N1), Dec 2003 to present: 322 (195).
(WHO 8/23/07 http://www.who.int/csr/disease/avian_influenza/en/index.html )

Avian influenza age distribution data from WHO/WPRO: http://www.wpro.who.int/sites/csr/data/data_Graphs.htm. (WHO/WPRO 8/16/07)

WHO's maps showing world's areas affected by H5N1 avian influenza (last updated 8/24/07): http://gamapserver.who.int/mapLibrary/

WHO’s timeline of important H5N1-related events (last updated 7/30/07): http://www.who.int/csr/disease/avian_influenza/ai_timeline/en/index.html.


Europe/Near East
Italy (Lugo): Low pathogenic avian influenza H5N2 detected in poultry
An outbreak of low pathogenic avian influenza (LPAI), type H5N2, has been diagnosed on a poultry farm in Lugo, Italy. This has been notified by the Ministry of Agriculture. The farm included 7000 adult ducks, 3000 geese and 150 chickens. The infection was detected within the framework of the annual, routine sero-surveillance activities. No clinical symptoms were seen. Some of the birds reportedly also had antibodies to an H7 avian flu virus. The holding was confined, and the animals will be culled. A restriction zone of 1km radius has been imposed around the site. Last week, an infected hobby-holding was found. In late Jul 2007, LPAI H7N3 was found in a holding with ornamental birds in the region of Veneto; the same strain was found earlier, in May 2007.
(Promed 8/20/07; CIDRAP 8/21/07)


Indonesia (Bali): New human case of avian influenza H5N1
As of 23 Aug 2007, the Ministry of Health of Indonesia has announced a new case of human infection of H5N1 avian influenza. A 28-year-old female from Tabanan District, in Bali Province developed symptoms 14 Aug 2007, was hospitalized 18 Aug 2007, and died in hospital 21 Aug 2007. The case was a poultry trader. The case investigation found that she collected poultry from villages where outbreaks of avian influenza in poultry had occurred and were later confirmed by rapid testing. She is the second fatal case in Bali this month. Of the 105 cases confirmed to date in Indonesia, 84 have been fatal.

US CDC confirmed that it has received from Indonesia a sample from the woman who had the first reported H5N1 infection on Bali, a 29-year-old who died of the disease Aug 12, 2007. The CDC is a WHO collaborating center. Results of tests by the CDC would be announced by the Indonesian government. In an Aug 20 statement, Indonesia's avian flu committee said it had sent the CDC samples from the 29-year-old Bali woman and a 2-year-old girl, also from Bali, who had a suspected case but had tested negative for H5N1. The statement said the CDC had already confirmed the findings from the Indonesian labs regarding the two patients. Previous reports mentioned a 2-year-old girl with suspected avian flu who was a neighbor of the 29-year-old woman. The woman also had a 5-year-old daughter who died of pneumonia on Aug 3, but she was not tested for H5N1 (reportedly she was cremated before samples were taken), according to previous reports. The bird flu issue is sensitive in Bali, where the tourism industry is only just recovering from the 2002 and 2005 terrorist bombings. None of the recent bird flu cases, or suspected cases, was from areas close to Bali's tourist precincts.

Elsewhere, local officials on Sulawesi island said they were struggling to contain H5N1 outbreaks on farms near Palu, the capital of Central Sulawesi. Tests conducted after several chickens in Palu died confirmed the disease in 29 chickens. Infected birds have been found in 3 of 4 subdistricts in Palu, and 2 chickens in neighboring Donggala district died of the disease recently.
(Promed 8/21/07, 8/23/07; CIDRAP 8/21/07, 8/22/07)


Pakistan: Avian influenza H5N1 strikes poultry again
Government officials in Pakistan announced a recent outbreak of H5N1 avian influenza at a poultry farm in the country's northwest. The Pakistan outbreak occurred late Jul at a large farm in the town of Mansehra, about 50 miles north of Islamabad. The birds were tested for the disease after about 14,000 chickens at the farm died. After samples came back positive for the H5N1 virus, the remaining 35,000 birds were culled. A report that Pakistani officials submitted to the World Organization for Animal Health (OIE) said the outbreak affected 16-week-old breeder and broiler chickens. Pakistan has had several poultry outbreaks this year, but the latest incident is the first since May, according to OIE reports. The country has not reported any human H5N1 cases.
(CIDRAP 8/21/07)


1. Updates
Avian/Pandemic influenza updates
- UN: http://www.un-influenza.org/ : the website has been moved and updated. Also, http://www.irinnews.org/Birdflu.asp provides information on avian influenza.

- WHO: http://www.who.int/csr/disease/avian_influenza/en/index.html.

- UN FAO: http://www.fao.org/ag/againfo/subjects/en/health/diseases-cards/special_avian.html. Link to supplement to Journal of Wildlife Diseases on avian influenza.

- OIE: http://www.oie.int/eng/en_index.htm.

- US CDC: http://www.cdc.gov/flu/avian/index.htm. News on federal updates.

- The US government’s web site for pandemic/avian flu: http://www.pandemicflu.gov/. Link to North American Plan for Avian and Pandemic Influenza.

- Health Canada: information on pandemic influenza: http://www.influenza.gc.ca/index_e.html.

- CIDRAP: http://www.cidrap.umn.edu/.

- PAHO: http://www.paho.org/English/AD/DPC/CD/influenza.htm. Link to National Influenza Centers in PAHO Member States.

- US Geological Survey, National Wildlife Health Center Avian Influenza Information: http://www.nwhc.usgs.gov/disease_information/avian_influenza/index.jsp. Updated 17 Aug 2007.


2. Articles
Journal of Wildlife diseases – Supplement on avian influenza
The Wildlife Disease Association (WDA) and the Food and Agriculture Organization of the United Nations (FAO) have worked together to publish a supplement to the Journal of Wildlife Diseases on avian influenza. The supplement is comprised of 14 papers presented at an FAO/OIE international conference on avian influenza in Rome in May 2006. Articles can be viewed at: http://www.jwildlifedis.org/content/vol43/3_Supplement/index.dtl


Ecologic immunology of avian influenza (H5N1) in migratory birds.
Weber TP, Stilianakis NI. Emerg Infect Dis [serial on the Internet]. August 2007 [date cited].
Abstract: The claim that migratory birds are responsible for the long-distance spread of highly pathogenic avian influenza viruses of subtype H5N1 rests on the assumption that infected wild birds can remain asymptomatic and migrate long distances unhampered. We critically assess this claim from the perspective of ecologic immunology, a research field that analyzes immune function in an ecologic, physiologic, and evolutionary context. Long-distance migration is one of the most demanding activities in the animal world. We show that several studies demonstrate that such prolonged, intense exercise leads to immunosuppression and that migratory performance is negatively affected by infections. These findings make it unlikely that wild birds can spread the virus along established long-distance migration pathways. However, infected, symptomatic wild birds may act as vectors over shorter distances, as appears to have occurred in Europe in early 2006.
(Promed 8/20/07)


Antigen sparing and cross-reactive immunity with an adjuvanted rH5N1 prototype pandemic influenza vaccine: a randomised controlled trial.
Leroux-Roels I et al. Lancet. 2007 Aug 18;370(9587):580-9.
Abstract: BACKGROUND: Antigen sparing is regarded as crucial for pandemic vaccine development because worldwide influenza vaccine production capacity is limited. Adjuvantation is an important antigen-sparing strategy. We assessed the safety and immunogenicity of a recombinant H5N1 split-virion vaccine formulated with a proprietary adjuvant system and investigated whether it can induce cross-reactive immunity. METHODS: Two doses of an inactivated split A/Vietnam/1194/2004 NIBRG-14 (recombinant H5N1 engineered by reverse genetics) vaccine were administered 21 days apart to eight groups of 50 volunteers aged 18-60 years. We studied four antigen doses (3.8 microg, 7.5 microg, 15 microg, and 30 microg haemagglutinin) given with or without adjuvant. Blood samples were collected to analyse humoral immune response. Adverse events were recorded up through study day 51. Safety analyses were of the whole vaccinated cohort and immunogenicity analyses per protocol. This trial is registered with the ClinicalTrials.gov, number NCT00309634. FINDINGS: All eight vaccine formulations had a good safety profile. No serious adverse events were reported. The adjuvanted vaccines induced more injection-site symptoms and general symptoms than did the non-adjuvanted vaccines, but most were mild to moderate in intensity and transient in nature. The adjuvanted formulations were significantly more immunogenic than the non-adjuvanted formulations at all antigen doses. At the lowest antigenic dose (3.8 microg), immune responses for the adjuvanted vaccine against the recombinant homologous vaccine strain (A/Vietnam/1194/2004 NIBRG-14, clade 1) met or exceeded all US Food and Drug Administration and European Union licensure criteria. Furthermore, 37 of 48 (77%) participants receiving 3.8 microg of the adjuvanted vaccine seroconverted for neutralising antibodies against a strain derived by reverse genetics from a drifted H5N1 isolate (A/Indonesia/5/2005, clade 2). INTERPRETATION: Adjuvantation conferred significant antigen sparing that could increase the production capacity of pandemic influenza vaccine. Moreover, the cross-clade neutralising antibody responses recorded imply that such a vaccine could be deployed for immunisation before a pandemic.


Neuraminidase inhibitor resistance in influenza viruses.
Reece PA. J Med Virol. 2007 Aug 17;79(10):1577-1586 [Epub ahead of print].
Abstract: Zanamivir and oseltamivir, the currentlymarketed influenza virus neuraminidase inhibitors (NAIs), are prescribed for the treatment and prophylaxis of influenza and are being stockpiled for pandemic influenza. Oseltamivir resistance has been reported in up to 2% of patients in clinical trials of oseltamivir and in up to 18% of treated children. There are also reports in at least three patients treated with oseltamivir for influenza A (H5N1) infections. At this stage, there are no reports of resistance occurring to zanamivir in immunocompetent patients. Zanamivir and oseltamivir bind differently at the neuraminidase catalytic site and this contributes to different drug resistance profiles. The magnitude and duration of NAI concentrations at the site of infection are also expected to be important factors and are determined by route and timing of drug administration, dose, and pharmacokinetic differences between patients. In addition, the type, strain, and virulence of the influenza strain and the nature of the immune response all appear to play a role in determining the likelihood of drug resistance arising. The clinical significance of a particular NAI-resistant isolate from a patient is often not clear but virus viability and transmissibility are clearly important characteristics. Early initiation of NAI treatment in suspected cases of influenza is important for maximizing efficacy and minimizing the risk of drug resistance. Higher NAI doses and longer periods of treatment may be required for patients with influenza A (H5N1) infections but further work is needed in this area.


How much would closing schools reduce transmission during an influenza pandemic?
Glass K, Barnes B. Epidemiology. 2007 Sep;18(5):623-8.
Abstract: BACKGROUND:: When deciding whether to close schools during an influenza pandemic, authorities must weigh the likely benefits against the expected social disruption. Although schools have been closed to slow the spread of influenza, there is limited evidence as to the impact on transmission of disease. METHODS:: To assess the benefits of closing schools for various pandemic scenarios, we used a stochastic mathematical model of disease transmission fitted to attack rates from past influenza pandemics. We compared these benefits with those achieved by other interventions targeted at children. RESULTS:: Closing schools can reduce transmission among children considerably, but has only a moderate impact on average transmission rates among all individuals (both adults and children) under most scenarios. Much of the benefit of closing schools can be achieved if schools are closed by the time that 2% of children are infected; if the intervention is delayed until 20% of children are infected, there is little benefit. Immunization of all school children provides only a slight improvement over closing schools, indicating that schools are an important venue for transmission between children. Relative attack rates in adults and children provide a good indication of the likely benefit of closing schools, with the greatest impact seen for infections with high attack rates in children. CONCLUSIONS:: Closing schools is effective at reducing transmission between children but has only a moderate effect on average transmission rates in the wider population unless children are disproportionately affected.


Pandemic Flu Preparedness: A Manufacturing Perspective
Aeby Thomas, Niels Guldager, Klaus Hermansen. BioPharm International, Aug 2, 2007
Abstract: In today's seasonal influenza market, vaccine manufacturers must match supply to a conservatively estimated annual demand; this estimate is typically lower than what is needed, and so it can represent lost profits. The threat of an influenza pandemic presents an unprecedented vaccine manufacturing situation in which scalability, speed, and biosafety would be key issues. An avian flu strain could mean additional biocontainment challenges. Hence, alternative technologies are being developed to address the drawbacks of traditional platforms. The ideal vaccine manufacturing facility would handle multiproduct campaigns and would include a range of production and process platforms. Vaccine manufacturers should consider how to make a good business case for new production and facility concepts.


Influenza Survey Uncovers Key Differences Between Bird Flu And Human Flu
Scientists have found key features that distinguish influenza viruses found in birds from those that infect humans. Specific mutations linked to immune suppression and viral replications differ between bird and human flu viruses could be used to monitor emerging pandemics. The St. Jude team used a mathematical technique to identify specific amino acid building blocks that are statistically more likely to appear in avian influenza virus proteins and those that are more likely to be in human influenza virus proteins. The differences in these amino acids can be used as markers to track changes in H5N1 avian influenza strains that threaten humans. "Influenza mutates rapidly, so that any marker that is not the same in bird flu but remains stable in human flu is likely to be important," said David Finkelstein, research associate at the St. Jude Hartwell Center for Bioinformatics and Biotechnology. "If human specific markers start accumulating in bird flu viruses that infect humans, that suggests that the bird flu may be adapting to humans and could spread."

The researchers also found that various strains of the H5N1 that have infected humans are more likely to contain human markers than are H5N1 strains that have not infected humans. Only occasionally have H5N1 samples obtained from human patients shown any of these markers, and no H5N1 strain has permanently acquired any of them. The investigators cautioned that there is no proof yet that the human markers in H5N1 and other avian influenza viruses directly contribute to the ability of these viruses to cause pandemics among humans; and H5N1 is not any more adapted to humans today than in the past. However, the fact that the bird viruses accumulate and retain these markers after infecting humans suggests that these changes are important. Therefore, scientists should monitor avian influenza viruses to see if they are acquiring human markers.

The St. Jude team identified 32 specific locations in proteins where a gene mutation caused the existing amino acid to be substituted with a different amino acid. What made these 32 changes special was that influenza from birds differed from the influenza that was in humans. After the avian influenza infected humans, the amino acid changes are stable in the proteins and remain stable over time. Therefore, these markers can be used to distinguish influenza viruses that infect birds from those that infect humans. The researchers identified 32 persistent markers that exist in 5 bird and human virus proteins: PA, NP, M1, NS1 and PB2. These markers stand out as obvious differences between bird and human viruses, and many appear in regions where host protein and viral replication occur. The researchers did not determine what functional role the markers play in the life of the viruses.

For example, 26 of the 32 markers discovered are found in NP, PB2 and PA, which help to form a complex of proteins critical for the replication of virus genes. The other 6 persistent host markers are in M1 and NS1 proteins. M1 is known to bind to a protein in cells that enhances the replication of viruses; and NS1 plays a role in suppressing the host immune response. Therefore, the markers in M1 and NS1 might represent key mutations needed to improve the ability of the virus to suppress the immune system and enhance viral replication.

The St. Jude team also studied markers in influenza viruses that caused pandemics in 1918, 1957 and 1968 -- outbreaks thought to have been caused by avian influenza viruses that adapted to humans. The study focused on the viruses isolated from humans early in each pandemic in order to determine which markers the viruses had recently acquired just before they sparked the outbreak. The researchers showed that 13 of the 32 markers identified by their survey had remained stable in these viruses, and, like the other viruses, these markers were distributed among PB2, PA, NP and M1 -- the proteins linked to virus replication. "This suggests that these 13 sites are required for pandemic influenza to fully function," Finkelstein said.

The researchers also showed that the H1N1 virus that caused the 1918 pandemic already contained 13 of the 32 markers early in the outbreak; and acquired the other 19 markers within 10 to 20 years, acquiring the preferred human influenza amino acids in stages. Eventually, descendents of the pandemic virus became the seasonal flu outbreaks rather than deadly pandemics. "While we can't directly estimate how long it would take an avian virus such as H5N1 to acquire these traits, we can use these markers to roughly measure the distance between an avian influenza and a pandemic," said Clayton Naeve, St. Jude Hartwell Center director and the paper's senior author.

Persistent Host Markers in Pandemic and H5N1 Influenza Viruses. Finkelstein DB, Mukatira S, Mehta PK, Obenauer JC, Su X, Webster RG, Naeve CW. J Virol. 2007 Jul 25; [Epub ahead of print] http://jvi.asm.org/cgi/content/abstract/JVI.00921-07v1
(Promed 8/21/07)


North American pandemic plan takes shape
Leaders of Canada, Mexico, and the United States who met at a security summit in Montebello, Quebec, Aug 21, 2007 unveiled a North American pandemic influenza plan designed to share expertise, coordinate public health messages, and overcome anticipated obstacles at national borders. The plan evolved from the Security and Prosperity Partnership of North America, a trilateral effort launched in 2006 to enhance collaboration on security and economic issues. At the 2006 summit, leaders vowed to develop a pandemic plan and establish a senior-level coordinating body to work on preparedness issues. Though the plan covers traditional areas such as information sharing, surveillance, and medical resources, it emphasizes preserving the 3 countries' economies in the event of an influenza pandemic.

"Although influenza will not physically damage critical infrastructure, systems may be weakened by the absence of essential personnel in the workplace or the diversion of resources," the 44-page report states. "The Plan, therefore, extends beyond health and medical sectors to include provisions in relation to critical infrastructure and the movement of goods and services across our borders." Kim Elliott, deputy director of Trust for America's Health (TFAH), a nonprofit public health advocacy group, said TFAH welcomes the release of the pandemic flu plan. A pandemic plan is meaningless unless it stipulates that participants hold exercises to test it, Elliott said. The North American plan includes provisions for bilateral and trilateral pandemic response exercises, with a target date of Dec 2008. Among the challenges North American pandemic planners will face, Elliott said, is vastly different healthcare systems—particularly Canada with its more centralized approach, and the US with a more privatized healthcare model. "So it's good to test operations and different strategies," she said.

The plan spells out the triggers that would prompt one of the 3 countries to request assistance from its neighbors: when human or material resources are scarce, when a pandemic event in one country threatens the others, and when an outbreak requires robust coordination of responses by all 3 countries. In several areas, the plan calls on the countries to address obstacles that could hamper outbreak containment. For example, authorities should ensure rapid cross-border movement of diagnostic materials and reagents, as well as specimens, isolates, and vaccines. Also, the document specifies that countries should ease the way for veterinary and medical personnel to respond to emergencies in other countries.

Sharing information and best practices is another theme of the plan. For example, it says countries should share information about how they plan to use nonpharmaceutical interventions and communicate public health messages to their citizens. Regarding stockpiling of vaccines and drugs, planners acknowledge that though the countries have different goals, it is useful for them to share their strategies for shelf-life extension, vaccine and antiviral allocation, and mass distribution. Though border restrictions are not a centerpiece of the plan, the document does address international arrivals. The 3 countries will share and coordinate triggers, criteria, and protocols for screening international travelers. The plan advises countries to adopt a layered passenger-screening approach consisting of predeparture, en route, and arrival checks. Because the infrastructures of the 3 countries are highly interrelated, the plan suggests that infrastructure sectors in each country, such as agriculture, transportation, and utilities, join with their counterparts in the other countries to assess their risks and share their resiliency strategies. The US has already identified how it would protect critical infrastructure and key resource sectors, and Canada and Mexico are both finalizing similar plans.

North American plan for avian and pandemic influenza: http://www.state.gov/g/avianflu/91242.htm
(CIDRAP 8/23/07)


3. Notifications
WHO Clinical management of human infection with avian influenza A (H5N1) virus
This document replaces the WHO interim guidelines on clinical management of humans infected by influenza A(H5N1) published Mar 2004. The present advice is applicable for the current situation with sporadic A(H5N1) virus human infection. As more data become available or if the disease patterns change, this advice will be modified as appropriate. At the below URL you can also find: WHO H5N1 Clinical Case Summary Form and Supplementary WHO H5N1 Clinical Case Data.
(WHO 8/15/07 http://www.who.int/csr/disease/avian_influenza/guidelines/clinicalmanage07/en/index.html )


Roche Joins the Fifth International Bird Flu Summit as a Sponsor
New-Fields Exhibitions announces the inclusion of F. Hoffman-La Roche, a leading healthcare company, among the platinum sponsors of the Fifth International Bird Flu Summit (IBFS) to be held on Sep 27 and 28 this year in Nevada USA. The 2-day event will cover an integrated approach to the bird flu threat and will have discussions on pandemic prevention, preparedness, response, and recovery. The IBFS will feature public and private sector leaders addressing the threat of a bird flu pandemic and a possible human-to-human transmission. Participants will include distinguished scientists, public health officials, law enforcers, first responders and other experts. The event is open to all interested businesses and organizations from all countries. Few remaining slots for other types of sponsorship are still available. Information for the conference and sponsorship can be readily obtained at 202.536.5000 or visit us at www.new-fields.com. The Fifth international bird flu summit is part of New-Field Exhibition's continuing commitment to helping communities respond to various modern-day threats and issues, including a possible bird flu pandemic. Three past summits were held successfully in Washington, and one was held in Geneva, Switzerland.
(Bird Flu Summit bfsummit@bfsummit.com 8/21/07)