Anggota Panel Ahli Komnas FBPI, Dr. IGN Mahardika untuk Jakarta Post, 23 April 2008
The nature of avian influenza A (H5N1) virus -- popularly known as bird flu -- itself brings difficulties in its control. Curbing its infection and spread needs to be well organized and concerted, nation-wide. Like a concert, there must be a single conductor.
The intrinsic nature of the virus makes it difficult to be fully controlled. The vaccine should be adjusted to the most current strains. Antiviral agents might lose their effectiveness quickly.
Moreover, a genetic makeup of that kind leads to a complex virus ecology. Considering evolution, the influenza virus is strictly species related. Avian influenza is limited to avian species only, while swine influenza to pig, equine influenza to horse, and human influenza to people.
As proven, however, the bird flu virus is capable of infecting a variety of species. It has expanded its host range from domesticated birds to wild birds and mammals, such as dogs, cats, pigs and even tigers.
Within this situation, the virus will continue to be disseminated by sick and healthy animals. It does not recognize any boundary. The risk in Aceh might be as high as in Java and Papua. It might happen in Indonesia, China, as well as in the United States. The risk level might differ in one area, depending primarily on animal and people densities. Wild bird and international travelers contribute to the globalization of the bugs.
Nowadays, the control of bird flu in Indonesia is disorganized. There is a conductor in every related ministry. Down to provincial and district level, there are other conductors. In the name of autonomy, every province or district has its own strategy to control the bug.
If we go deeper, the bird flu control does not find fertile ground within the community, private industry and government agencies. A part of the community is still unwilling to report any suspected case. People are afraid to be exposed by the media and their birds could be culled thereafter.
So far, bird flu control initiative can not penetrate giant poultry industries. Top officers in this country have said, on various occasions, the state has no access to major poultry industries, known as sector 1 and 2.
This kind of indifference is also supported by local governments. Officers try hard to keep any suspected case silent. The reasons vary. It might be for community stability, poultry industry existence, or tourism safety issues.
We are dealing with a bug that could infect anyone in the planet, rich or poor. If it would happen, there will be no mantra to stop the industry people, their workers and families from becoming infected. The magic of tourism will also lose its sorcery.
International agencies seem to work without coordination as well. Some projects sound very donor driven. Its sustainability is arguable. Some are carried out without the government and society's willingness to adopt them.
The result, not surprisingly, is disharmony. We understand a lot of things have been done and a bulk of funds have been disbursed for bird flu control. Notwithstanding effort, animal and human cases happen out of control. Outbreaks are continuously reported. The up and down pattern expresses merely that the disease is endemic with very little human intervention.
We should find a concerted action to handle this. It must be a single national task force. The National Committee on Bird Flu and Influenza Pandemic Preparedness (Komnas FBPI) was established to coordinate actions to control bird flu. Unfortunately, ego, funding, and autonomy issues have hampered its action.
To be effective, the Komnas should be led by the president or vice president. The head of executive secretary should be a ministry level. This problem of the strata of officers, known as 'eselon', will be diminished.
Komnas must be a task force that works at all level of activities, including research and surveillance, community awareness, communication, and legal and enforcement. It must work based on the best scientific evidence. All stakeholders, such as research institutes, universities, private industries, non-government organizations, lawmakers and enforcers, mass media, etc, must support the task force. All segments must work accordingly.
Available funding should go to it. International donors should work under the Komnas umbrella.
In this regard, international scientist collaboration is a must. The task force will be a port de'entre for international experts to work hand-in-hand with local counterparts.
Nothing is at stake. Neither the livelihood nor poultry industry is. Neither the tourism industry nor national dignity is. We simply save life.
The writer is a virologist at School of Veterinary Medicine, Udayana University, Denpasar, Bali. He can be reached at gnmahardika@indosat.net.id.
Tuesday, April 22, 2008
Friday, April 18, 2008
New Strategies Against Bird Flu
ScienceDaily (Apr. 17, 2008) — Multiple lethal pathogens such as H5N1 avian flu trigger acute lung injury with a high death rate. Scares of an epidemic have led to an increasing interest in understanding the molecular mechanisms that lead to this condition. Scientists have now identified oxidative stress and innate immunity as a common pathway that controls the severity of ARDS.
The Spanish flu outbreak of 1918 killed between 30 and 50 million people. In the infected patients, the ultimate cause of death was acute respiratory distress syndrome (ARDS). This fatal condition is a massive reaction of the body during which the lung becomes severely damaged. ARDS can be induced by various bacterial and viral infections, but also by chemical agents. These could be toxic gases that are inhaled or gastric acid when aspirated. Once ARDS has developed, survival rates drop dramatically. Among patients infected with H5N1 bird flu, about 50 percent die of ARDS.
An international team of scientists has been addressing the underlying disease mechanisms for the past five years. The team involved researchers from leading institutions in Vienna, Stockholm, Cologne, Beijing, Hongkong, and Toronto as well as the US-army at Fort Detrick. The international effort was coordinated by Josef Penninger and Yumiko Imai of the Institute of Molecular Biotechnology (IMBA) of the Austrian Academy of Sciences.
A first breakthrough came in 2005 when IMBA-scientists identified ACE2 as the essential receptor for SARS virus infections and showed that ACE2 can protect from acute lung failure in disease models (Imai et al. Nature 2005; Kuba et al. Nature Medicine 2005). Based on these data, ACE2 is now under therapeutic development.
In a paper recently published by Cell, the authors describe an essential key injury pathway that is operational in multiple lung injuries and directly links oxidative stress to innate immunity. They also report for the first time a common molecular disease pathway explaining how diverse non-infectious and infectious agents such as anthrax, lung plague, SARS, and H5N1 avian influenza may cause severe and often lethal lung failure with similar pathologies.
To identify these pathways, the researchers studied numerous tissue samples from deceased humans and animals. Victims of bird flu and SARS were examined in Hongkong, and the US-army provided samples from animals infected with Anthrax and lung plague. Common to all ARDS samples was the massive amount of oxidation products found within the cells. Based on these findings, the scientists showed that oxidative stress is the common trigger that ultimately leads to lung failure.
To elucidate the entire pathway, Yumiko Imai of IMBA developed several mouse models. She was now able to show that a molecule called TLR4 (Toll-like receptor 4) is responsible for initiating the critical signalling pathway. TLR4 is displayed at the surface of certain lung cells called macrophages, important players of the body's immune system. Once activated, TLR4 initiates an entire chain reaction which ends with the fatal failure of the lungs. Surprisingly, mice challenged with inactivated H5N1 avian influenza virus also dveloped the full reaction. On the other hand, mutant mice in which the function of TLR4 was genetically impaired were protected from lung failure in repsonse to the inactivated virus.
Based on these findings, the researchers can now outline a common molecular disease pathway: Microbial or chemical lung pathogens trigger the oxidative stress machinery. Oxidation products are intrepreted as danger-signals by the receptor TLR4. Subsequently, the body's innate immune system is activated. This defense machinery in turn leads to a chain of reactions with severe and often fatal lung damage as a consequence.
For Yumiko Imai, a Postdoc in Josef Penninger's team and pediatrician by training, these results are highly satisfying. Her motivation to study ARDS is based on personal experience in over 10 years at a pediatric intensive care unit. "I have seen so many children die from acute lung failure and felt utterly helpless", Imai says. "Since we found a common injury pathway, our hopes are high that we may be able to develop a new and innovative strategy for tackling severe lung infections."
The paper "Identification of oxidative stress and Toll like receptor 4 signalling as a key pathway of acute lung injury" by Imai et al. will be published on April 18 in Cell, Vol. 133(2).
Adapted from materials provided by Research Institute of Molecular Pathology, via EurekAlert!, a service of AAAS.
Monday, April 14, 2008
First Successful Libraries Of Avian Flu Virus Antibodies Created
Dikutip dari http://www.sciencedaily.com/releases/2008/04/080414174851.htm
ScienceDaily (2008-04-14) -- Scientists have created the first comprehensive monoclonal antibody libraries against avian influenza using samples from survivors of the 2005/2006 "bird flu" outbreak in Turkey. These antibody libraries hold the promise for developing a therapy that could stop a pandemic in its tracks and provide treatment to those infected, as well as potentially pointing the way towards the development of a universal flu vaccine.
ScienceDaily (2008-04-14) -- Scientists have created the first comprehensive monoclonal antibody libraries against avian influenza using samples from survivors of the 2005/2006 "bird flu" outbreak in Turkey. These antibody libraries hold the promise for developing a therapy that could stop a pandemic in its tracks and provide treatment to those infected, as well as potentially pointing the way towards the development of a universal flu vaccine.
The expanded treatment and containment options offered by Sea Lane's antibody libraries could help provide healthcare officials, researchers, and governments with unprecedented resources to combat this serious global health threat.
"Three global influenza pandemics have occurred within the past 100 years, each with devastating consequences," said Richard A. Lerner, the Lita Annenberg Hazen Professor of Immunochemistry at, and President of, the Scripps Research Institute (La Jolla, CA) who collaborated with Sea Lane on the study. "Our study holds out the hope that a new outbreak could potentially be stopped at an early stage, and that effective treatment could be available to those infected."
Libraries Have Yielded More Than 300 Antibodies Active Against Avian Influenza
So far, the new antibody libraries reported in the study have yielded more than 300 unique monoclonal antibodies that are active against H5N1 antigens--foreign substances that produce an immune system response. From this group, the authors identified several broadly neutralizing antibodies that were effective against a number of contemporary subtypes of H5 (avian) flu.
Moving Towards A Universal Influenza Vaccine
The new research reported here suggests that the antibodies recovered from the avian flu survivors may point to an exploitable weak spot in the virus, offering the tantalizing possibility that a "universal" vaccine against all strains might be made.
Remarkably, three of the more than 300 antibodies catalogued have been found to neutralize both the H1 (common seasonal flu) and H5 (avian) subtypes. "The antibodies we have isolated have the potential to be used directly as therapeutic agents against multiple influenza subtypes, permitting the resolution of infection upon administration to an infected individual," said Peter Palese, the Horace W. Goldsmith Professor & Chairman of Microbiology at The Mount Sinai School of Medicine (New York, NY), another collaborator on the project.
"Perhaps most importantly, these antibodies may be used to identify cross-reactive epitopes on the hemagglutinin protein of an influenza virus. Identification of such epitopes may allow the rational design of vaccines with cross-subtype neutralizing activity. Such vaccines would constitute a major advance on current technology, and would be a first step towards the design of a universal influenza vaccine," noted Palese.
Preventing The Worst-Case Scenario -- Another Global Influenza Pandemic
Human infection with the avian flu virus H5N1 was first reported in 1997. Since 2003, according to the World Health Organization, more than 370 confirmed cases of human infection have been reported in 14 countries.
While overwhelmingly confined to bird populations in Asia and Europe, the H5N1 avian flu virus has shown its ability to infect humans and has killed more than 230 people around the world. Epidemiologists remain concerned that the virus will one day mutate and be able to spread more readily between people, sparking a global pandemic. The 1918-1920 Spanish flu, which shows evidence of originating in birds, killed somewhere between 40 and 100 million people.
The antibodies recovered from these H5N1 survivor libraries, described in the report, provide opportunities for passive immunization with monoclonal antibodies that could help future individuals infected with H5N1 successfully overcome infection. Monoclonal antibody therapy is known as passive immunotherapy because patients are treated with antibodies that were made outside of their own immune systems instead of those actively made internally.
The potential for passive immunization against influenza has been evident since the Spanish influenza pandemic nearly a century ago, where the benefits of transfused blood reduced the risk of mortality by more than 50 percent. Additionally, the benefits of treatment with convalescent plasma have begun to be reported in instances of H5N1, while passive immunization with human and mouse monoclonal antibodies have been shown to protect animals from death, even when given after H5N1 infection.
Offers Additional Therapeutic Potential
"The antibodies we recovered from Turkey have important and broad potential," said Michael Horowitz, Chief Operating Officer for Sea Lane. "They could lead the way to providing significant protection against a broad reach of influenza--perhaps as protection to first responders and those at immediate risk, and then as treatment for those infected."
According to Ramesh Bhatt, Vice President for Research at Sea Lane, "The combination of the team's innovative antibody library techniques and tremendous scientific rigor enabled the recovery of this extensive collection of antibodies from the avian flu survivors. Because of the large number of antibodies obtained, we were able to perform a detailed immunochemical analysis of these survivors' antibody solutions against avian influenza virus during an actual outbreak."
The resulting antibody libraries--collections of genetic antibody material--were not dependent on whether an important antibody was being produced by the body at the time of the sample collection. Instead, the scientists were able to obtain the entire immunologic history of an individual's response, which offered a clearer picture of the relationships between antibodies and their relative effectiveness. These insights may help scientists determine prescient strategies for therapies as the virus mutates in the future.
"Our libraries create a roadmap for improving the efficacy and/or specificity of therapeutic influenza antibodies," Arun Kashyap, Director of Influenza and Antibody Libraries for Sea Lane said. "As a result, we might be able to engineer the best features of different antibodies into a single antibody that may not only treat contemporary strains of influenza, but also future influenza strains which normally would escape through simple mutations."
Innovative Research Driven by International Effort
"None of this research could have been accomplished without the participation of the Turkish scientists who were responsible for the processes for collection of the bone marrow and their shipment to the laboratories in the United States preserved in a way that made recovery of the antibodies possible. This shows the value of international cooperation in basic scientific research," said Lawrence Horowitz, CEO of Sea Lane. "Infectious diseases know no national boundaries and treatments will only be developed if the pooled efforts of all scientists are harnessed, regardless of where they happen to reside."
The study is being published in the Early Edition of the journal Proceedings of the National Academy of Sciences.
Other authors of the study, Combinatorial Antibody Libraries from Survivors of the Turkish H5N1 Avian Influenza Outbreak Reveal Virus Neutralization Strategies, include Michael A. Dillon, Ryann E. Swale, Katherine M. Wall, Kimberly J. Perry, and Aleksandr Faynboym of Sea Lane Biotechnologies; John Steel of The Mount Sinai School of Medicine; and Mahmut Ilhan and Ahmet F. Oner of Yuzuncu Yil University.
The study was supported by Sea Lane Biotechnologies, LLC. Partial support to Peter Palese was also provided by NIH grants.
Adapted from materials provided by Scripps Research Institute, via EurekAlert!, a service of AAAS.
Wednesday, April 2, 2008
ScienceDaily: New Approach May Lead To Effective H5N1 Influenza A Virus Vaccine
(Mar. 28, 2008) — Manipulating a previously identified protein may be the key to developing an effective H5N1 influenza A virus vaccine say researchers from the University of Wisconsin-Madison and the University of Tokyo.
Since its emergence in 1997, the highly pathogenic avian influenza virus (H5N1) has affected wild birds and poultry in more than 10 Asian countries as well as Europe and
The influenza A virus M2 protein consists of three structural domains, one of which is a 54-amino acid cytoplasmic tail domain. In a previous study the researchers demonstrated that deleting the M2 cytoplasmic tail caused a growth defect in the H1N1 influenza virus, indicating that the M2 cytoplasmic tail plays a vital role in virus replication. In the current study they created an M2 tail mutant H5N1 virus, vaccinated mice with it and challenged the mice with a lethal dose of influenza virus. Results showed that the mice were protected from death suggesting that the virus could not replicate and could therefore be used as a vaccine.
"Here, we demonstrate that an M2 cytoplasmic tail deletion mutant protects mice from lethal challenge with a highly pathogenic H5N1 virus, suggesting the potential of M2 tail mutants as live attenuated vaccines against H5N1 influenza virus infection," say the researchers.
Journal reference: T. Watanabe, S. Watanabe, J. Hyun Kim, M. Hatta, Y. Kawaoka. 2008. Novel approach to the development of effective H5N1 influenza A virus vaccines: use of M2 cytoplasmic tail mutants. Journal of Virology, 82. 5: 2486-2492.
Adapted from materials provided by American Society for Microbiology.
http://www.sciencedaily.com/releases/2008/03/080326181733.htm#Tuesday, April 1, 2008
Jakarta Post : "RI bird flu virus, Let's keep in scientific loop", Dr. IGN Mahardika, Anggota Panel Ahli Komnas FBPI
I Gusti Ngurah Mahardika, Denpasar, Sat, 03/29/2008
The Indonesian bird flu virus might not become a pandemic vaccine seed and thus it is a far-flung idea to make it into a biological weapon.
In an influenza pandemic horror vision, world health politicians and experts agree on one point, a vaccine will be the most powerful medical intervention to reduce the morbidity and mortality caused by an influenza pandemic strain.
However, if "an Indonesian" thinks the Indonesian bird flu virus will be used as a pandemic vaccine seed, the geographical and serological data show it might not be the case.
Moreover, although Indonesian bird flu cases end mostly in the death of victims, the virus has no potential to be developed into a biological weapon.
It is true that the latest bird flu virus, a popular name for avian influenza virus of H5N1 subtype, cases in Indonesia are increasing a pandemic worry.
The sheer number of human cases and fatalities is steadily increasing. In 2005, 13 out of 20 (65 percent) cases were fatal. The rate has become 82, 88 and 83 percent in 2006, 2007 and until February 2008, respectively. The figure is the highest in the world. The overall fatality of world bird flu cases is only 63 percent.
Although the Indonesian virus seems to be "super" pathogenic, it does not automatically mean that the Indonesian virus is the most harmful in the world. It might simply be a matter of victims being late to seek medical help.
Moreover, pathogenecity is not the most important criteria in selecting a pandemic vaccine seed. The selection is especially based on the geographical distribution, epidemiology and genetic and antigenic character of a virus candidate.
The Global Influenza Program of World Health Organization (WHO) is continuously evaluating all influenza viruses -- not only H5N1 -- and selecting appropriate vaccine seed candidates as a part of pandemic preparation plan.
Based on the state of knowledge at this time, experts do not know whether the next pandemic will be caused by an H5N1 virus or other subtype. They mostly agree that the pandemic is a matter of when, not if.
The H5N1 virus is indeed a strong candidate. Therefore, international communities via the WHO need to analyze the dynamics of the bug. Selected vaccine candidates will be changed as needed.
In 2006, the WHO selected three viruses as candidates. They were A/Indonesia/5/2005-like, A/Bar headed goose/Qinghai/1A/2005-like, and A/Anhui/1/2005-like viruses. In 2006, the number became eight strains.
Given current geographical distribution and genetic characteristics, the Indonesian bird flu virus -- so-called Clade 2.1 -- will find its best use in
However, in case the pandemic epicenter is somewhere in
The steady increasing number of human cases in
Carrier fowl continuously contaminate the environment. Available data throughout
These animals can be clinically healthy due to vaccination or naturally resistant. Water fowl -- such as ducks and geese -- have long been known to be resistant to any influenza virus infection.
They can carry the virus without being sick. They act as a reservoir of the virus and continuously transmit it to other animals and humans. Village chickens seem to act the same role, to a somewhat lesser extent.
The ecology of the virus can be more complex than the current idea that the source of infection is mainly fowl. The role of human beings and other animals as silent disseminators can not be ignored.
In the case of silent infection, a human being and other animals such as dogs and cats can be infected and carry the bug in a tiny number before it will find a genetically susceptible human host. The level of infection is so low that it can not produce disease, nor an antibody response, in the carrying person or animal.
An environment of that kind is a paradise for the emergence of pandemic strain. The bug can reproduce and replicate continuously, which gives it the chance to mutate into what it will.
The answer to the question, can an Indonesian H5N1 virus be a pandemic vaccine, is "maybe yes or maybe no". It will definitely be yes if the pandemic is caused by H5N1 virus and starts here.
Although the virus is very fatal -- killing most sick people -- it absolutely can not be used as a biologic weapon.
It would be laughable if one put an effort into developing a biological weapon based on the bird flu virus.
The bug has the biggest potential to disseminate globally. There will not be any country in the world out of the line of its fire, including the country that some thought is developing this virus into a weapon.
At this pre-pandemic stage, it is global task to prepare for a potential pandemic caused by bird flu virus. Any development of the bug should be studied intensively to detect a pandemic at the earliest moment. This effort will save millions of human lives.
In strictly contained facilities -- known as bio-safety level 3 or higher laboratories -- every virus will be propagated before its molecular, antigenic and biological characteristics are unfolded. In case it shows its adaptability to mammals and humans, the influenza alert system will be rung. If the virus does not match antigenically with standard viruses, a new vaccine seed will be developed thereafter.
To my knowledge, there is no plausible reason not to send any Indonesian human viruses to a WHO network laboratory. Such state-of-the-art facilities are not available in
If the benefit-sharing issues are the main reason to keep the virus, such a facility here should be accelerated. Based on global interest, we can not rely on global vaccine manufacturers in stockpiling pandemic vaccine to be used in
Upgrading influenza vaccine manufacturers for fowls into human influenza vaccine producers is one short-cut alternative to be considered.
Human resources are available. We could propagate the resources if we need them. Trust to national resources should be given.
The writer is a virologist and staff member of the
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