The Threat of Pandemic Influenza Are We Ready? Workshop Summary (2005) / Chapter Skim
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5 Emerging Technical Tools
5 Emerging Technical Tools
Pages 254-314
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From page 254... ...
In the first contribution to this chapter, Suzanne Epstein describes animal studies on the various means of inducing heterosubtypic immunity and explores the possibility of taking advantage of conserved features among influenza viruses to reduce mortality in a pandemic until a matched vaccine became widely available. Routine immunization could potentially be used to induce heterosubtypic immunity in advance of a pandemic, and the vaccine could also be offered early in a pandemic to those who had not received it.
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The chapter concludes with mathematical modeling of pandemic preparedness plans, showing the consequences on health economic outcomes of possible intervention strategies. This modeling helps to determine the costs and benefits of different strategies and gauges the public health benefits of optimized preparedness.
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Current vaccines focus on variable, strain-specific epitopes of circulating influenza virus strains and new viral strains require new vaccines. Here, a different approach will be considered, vaccination based on shared epitopes as an anti-infective measure that could provide broad protection against even new pandemic strains.
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257 fo al. acute are et 1983 with names Glezen A/Bangkok in persons 1 1982 Strain of B/Singapore Figure virus.
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. All these subtypes infect aquatic birds, and human pandemic viruses have arisen from avian viruses by reassortment (Webster, 2002)
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EMERGING TECHNICAL TOOLS 259 Variable surface glycoproteins (important antibody targets) : HA: Hemagglutinin NA: Neuraminidase Conserved proteins (important T cell targets)
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Influenza viruses can be adapted to Immunize with one member, challenge Protection with another: Flu types A B C Heterologous No Subtypes H1N1 H3N2 H5N1 of flu A Heterosubtypic Partial Strains within 1 2 3 Homosubtypic Often subtype Single 1 Homologous Yes strain FIGURE 5-3 Categories of influenza viruses and immunity they induce. Colors indicate similarity.
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Results in an animal model do not predict in every particular what will happen in humans, but they provide a valuable information base that can help design future studies in humans and novel approaches to vaccine development. Immunity to Influenza Virus Infection How to Analyze Mechanisms of Immunity in Animal Models The complexity and redundancy of the immune system is good for defense against pathogens but hard on those trying to interpret experiments.
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in clearing primary influenza virus infection (Doherty et al., 1997) and also in protection against challenge with homologous virus (Lu and Askonas, 1980)
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They can survive primary influenza virus infection and can mount protective immune responses to homologous and heterosubtypic challenge (Bender et al., 1994; Epstein et al., 1997)
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. Several studies have shown that such mice could clear primary influenza virus infection but less effectively than normal mice and immunization protected them at least to some extent against homologous challenge (Bot et al., 1996; Topham and Doherty, 1998; Epstein et al., 1998; Graham and Braciale, 1997)
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Heterosubtypic Immunity Induced by Vaccines Against Influenza A Subtypes Common or Novel in Humans The previous section explored Het-I induced by wild type virus infection. How can we induce it more safely?
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. Thus, it was not clear whether immunizations inducing heterosubtypic immunity effective against H1N1 and H3N2 viruses would work against H5N1 infection.
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. NP + M DNA vaccination protected against lethal challenge with the H5N1 strain HK/156 and reduced lung virus titers approximately 500-fold.
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has also been shown to induce Het-I in mice. H1N1 influenza ISCOMS protected mice against lethal challenge with H1N1, H2N2 and H3N2 and reduced lung titers of
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Recall that wild type virus infection given by TRT exposure in mice induces Het-I but virus infection confined to the URT does not (Nguyen et al., 1999)
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Furthermore, influenza virus infections were confirmed by culturing of swabs, not just based on symptoms. In this population, the incidence of cultureconfirmed influenza was much higher in children than in adults (Jordan et al., 1958)
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The Future: Vaccines and Pandemic Planning Given the extensive evidence in animals and the hints in humans, the potential of Het-I to reduce morbidity and mortality from a new pandemic strain should be explored. Strainmatched vaccines would probably not be available in time in the case of a rapidly spreading pandemic, even with new technologies for vaccine production.
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If heterosubtypic immunity could even partially control infection and thus reduce the morbidity and mortality due to a spreading pandemic, we need to study how best to induce and make use of this type of immunity. Five-Year View Many vaccine candidates will be compared in animal models for their ability to protect against potential pandemic subtypes of influenza.
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· www.cdc.gov/ncidod/diseaseslflu/fluvirus.htm Centers for Disease Control and Prevention influenza website · www.who.int/health-topics/influenza.htm World Health Organization fact sheet on influenza GENERATION OF TRANSGENIC CHICKENS RESISTANT TO AVIAN INFLUENZA VIRUS Laurence Tiley Department of Veterinary Medicine, University of Cambridge, United Kingdom and Helen Sang Roslin Institute, Midlothian, United Kingdom
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Intensively reared domestic livestock such as pigs and poultry are the prime candidates as they are permissive for avian influenza viruses, and can act as amplifier hosts. This results in the massive and prolonged exposure of humans to novel and evolving strains of virus, thus increasing the probability of successful transmission to humans.
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However, there is no reason to expect that the next pandemic strain must be derived from an HPAI. The human pandemic strains H1N1, H2N2, and H3N2 all resemble low-pathogenicity avian influenza (LPAI)
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. Chick embryo fibroblast cell lines expressing Mx1 were refractory to influenza virus replication, showing reduced plaquing efficiency, multicycle yield, and viral gene expression.
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Synthetic decoys need only to mimic the binding site of the protein. The influenza virus RNA polymerase is a sequencespecific RNA-binding protein complex composed of three viral proteins, PB1, PB2, and PA (Tiley et al., 1994)
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Decoy RNAs exploit an interaction between two very highly conserved viral components, the viral polymerase and the terminal sequences of the eight viral genome segments. Thus it is very unlikely that the virus will succeed in circumventing the effect of the decoy by mutation.
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RNAi The discovery of the existence of an RNA-mediated gene silencing pathway (RNA interference or RNAi) in a wide range of species, including vertebrates, has already demonstrated enormous potential (for reviews, see
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Such short interfering RNAs (siRNAs) are unwound and become incorporated into an RNA induced silencing complex (RISC)
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The resulting birds were bred to determine the frequency of production of germline transgenic birds: the frequency achieved using high titers of virus vectors approached 100 percent and the transmission rate of the integrated viruses to the next generation was between 4 percent and 45 percent. The integrated viruses were stably transmitted on to the next generation, suggesting that transgenic lines produced using lentiviral vectors will be stable.
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A G2 G2 G1 Int Skn Liv Pan Int Skn Liv Pan Int Skn Liv Pan 250 kDa 160 kDa 105 kDa Bird no.
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The availability of the chicken genome sequence will make analysis of integration sites quite straightforward, and facilitate the elimination of transgenic birds with the most obviously undesirable gene disruptions. The great advantage of the transgenic approach is that the single desired trait (resistance to influenza virus)
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Other countries are much more pragmatic about GMO food and are likely to welcome such a development more enthusiastically. Eliminating the chicken from the pandemic influenza equation might delay or prevent the next pandemic disaster.
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Highly pathogenic avian influenza virus is on every top ten list available for potential agricultural bioweapon agents, generally following foot and mouth disease virus and Newcastle disease virus at or near the top of the list. Rapid detection techniques for bioweapon agents are a critical need for the first-responder community, on a par with vaccine and antiviral development in preventing spread of disease.
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Avian Influenza A Viruses as Potential Bioweapons Highly pathogenic avian influenza viruses are generally found on all the lists of potential agricultural bioweapons. Like virulent Newcastle disease viruses that have been weaponized in the past, the AI viruses can be highly
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For example, anecdotal evidence exists purporting that poultry farmers have used infectious virus collected from an outbreak to infect their own stock, in attempts to vaccinate or in hopes of indemnification as a result of having infected flocks. Whatever the case, the need for the capability to rapidly and accurately detect avian influenza viruses, as well as other highly infectious poultry pathogens in the environment, is growing, and new research efforts are needed to evaluate the best approaches to put into the hands of early responders to a purposeful introduction.
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The sensitivity of such immunologically based tests is generally lower than nucleic acid based tests, and costs are such that individual bird samples must be pooled before screening. A number of novel rapid detection approaches employ mass spectrometry (MS)
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and many variations on that idea have been used to unequivocally identify organisms. The same approach can be taken with RNA viruses such as influenza viruses (Offringa et al., 2000)
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In addition, the availability of dried or packaged reagents for a variety of pathogens will allow early responders to prepare a sample in the field and run FRT/PCR in place. We have prepared a number of primers and probe reagents that are specific for avian influenza viruses, and these are reported and described by Spackman et al.
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The unit on the right is Idaho Technology's RAZOR system, which cycles temperatures for the reaction by moving reaction mixtures back and forth in the plastic tubes between fixed temperature chambers and can run 12 reactions simultaneously. In each case, the nucleic acid has to be first extracted from the sample matrix before running the FRT/PCR.
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However, given the commercial success of this technology, which was used quite extensively during the anthrax attack in the fall of 2001, it is definitely worth pursuing avian influenza specific primer and probe development and validation of assays in real-world settings, such as those described in this symposium. MODELING PANDEMIC PREPAREDNESS SCENARIOS: HEALTH ECONOMIC IMPLICATIONS OF ENHANCED PANDEMIC VACCINE SUPPLY Jeroen K
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The case study for which the model has been used shows the current level of global pandemic preparedness in an assumed pandemic scenario, the health economic implications of enhanced pandemic vaccine supply and the importance of cell culture-based influenza vaccine manufacturing technologies as a tool for pandemic control. Introduction Influenza is an acute respiratory disease, which can often lead to serious and life-threatening complications in several populations, like the elderly and chronically ill.
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Taskforce, a new pandemic discussion and collaboration platform in which all major influenza vaccine manufacturers are represented. Increased awareness has also resulted in governmental pandemic preparedness plans on national and regional levels, such as the "Influenza Pandemic Preparedness Action Plan for the United States" and "A pandemic influenza planning guide for state and local officials" by the Centers of Disease Control and Prevention (Strikas et al., 2002; Patriarca et al., 1999)
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Inputs for Intervention Scenarios The model inputs for intervention scenarios determine the availability of possible interventions, e.g., pandemic vaccine and antivirals, such as amantadine or the new neuraminidase inhibitors. These input parameters include specific vaccine production inputs, such as time to produce a suitable pandemic virus seed time to produce a batch of vaccine, availability of eggs for egg-based vaccine production and available vaccine manufacturing capacity.
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Approach One way of giving structure to conceptual pandemic preparedness plans is to evaluate these plans from a health economic perspective. Therefore the developed model is used to calculate the costs and benefits of certain intervention scenarios for different pandemic scenarios.
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To visualize the current level of pandemic preparedness, the intervention strategies that can he launched to decrease the burden of the "2004 pandemic" are based on existing egg-based influenza vaccine technologies. Currently, the estimated Northern Hemisphere influenza vaccine usage is 230 million trivalent doses, which translates to a global influenza vaccine manufacturing capacity of 22 million monovalent doses (i.e., 15 µg of pandemic strain antigen)
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35a,b Years per life lost 5c Event probabilities PCP consultations (for influenza) 6.34d Hospitalization rates due to: Influenza + pneumonia 2.52d Other respiratory disease 9.34d Congestive heart failure 1.9d Mortality rate 1.87d Vaccine effectiveness Vaccine efficacy (%)
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As vaccination is the most cost effective intervention, an improved intervention strategy from a health economic perspective would be to produce more pandemic vaccine in the available time frame. This can be achieved by increasing the time period for vaccine manufacture, by increasing the vaccine manufacturing capacity or preferably by a combination of the two.
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Compared to the assumed egg-based vaccine intervention with 17% vaccine coverage, the cell culture-based intervention strategy leads to vaccination of 37% of the population, avoiding an additional 35 million influenza cases, 2.04 million PCP consultations for influenza treatment, 3.14 million influenza-related hospitalizations and 654,500 excess deaths. The cell culture-based intervention strategy costs add up to 4.9 billion, but as this strategy leads to a reduction of 20.2 billion medical care costs, the saving on direct costs of the "2004 pandemic" is 15.3 billion, an additional 8.3 billion compared to the egg-based intervention scenario.
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However, both knowledge and surveillance of circulating influenza viruses have been well established over the last 50 years, enabling an earlier identification of potential pandemic viruses and consequently an earlier onset of intervention programs compared to 1918. Furthermore, improved influenza diagnosis and the availability of intervention enable us to significantly reduce pandemic virus spread.
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Seed preparation time for the next pandemic is unpredictable and cannot be based on experience with epidemic strains: although the H5N1-subtype that emerged in Hong Kong in 1997 appeared only a candidate pandemic virus, a suitable seed is still not available 5 years later. In case of a high pandemic threat the efforts that will be put into seed preparation will be accordingly and preparation times for pandemic seeds suitable for egg-based vaccine manufacture in general is expected to be 28 months (internal communication J
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The more vaccines, the greater the vaccination rate and the greater the opportunity to benefit from both reduced mortality and reduced total costs. This underlines the importance of cell culture-based influenza vaccine manufacturing as tool for increased pandemic preparedness.
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Cell culture-based vaccine manufacture however makes long-term advance planning obsolete, as all starting materials are in stock and readily available whenever required. This advantage however is not illustrated in the assumed "2004 pandemic", thereby underestimating the advantageous health economics of cell culture-based over egg-based intervention and thus the importance of cell culture-based vaccine manufacturing as tool for increased pandemic preparedness.
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1998. Human influenza A H5N1 virus related to a highly pathogenic avian influenza virus.
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1997. Mechanisms of heterosubtypic immunity to lethal influenza A virus infection in fully immunocompetent, T cell-depleted, beta2-microglobulin-deficient, and J chain-deficient mice.
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. Canadian Contingency Plan for Pandemic Influenza- Draft.
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2000. Strategies for inducing protection against avian influenza A virus subtypes with DNA vaccines.
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2004. Modeling pandemic preparedness scenarios: Health economic implications of enhanced pandemic vaccine supply.
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1999. Heterosubtypic immunity to lethal influenza A virus infection is associated with virus-specific CD8+ cytotoxic T-lymphocyte responses induced in mucosa associated tissues.
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2003. Avian influenza in Hong Kong 19972002.
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2002. Influenza pandemic preparedness action plan for the United States: 2002 update.
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2001. Mucosal delivery of inactivated influenza vaccine induces B-cell-dependent heterosubtypic cross-protection against lethal influenza A H5N1 virus infection.
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Proc Natl Acad Sci USA 82:17851789. Zambon M
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