John R. La Montagne Memorial Symposium on Pandemic Influenza Research Meeting Proceedings (2005) / Chapter Skim
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8 Working Groups, Day 2
8 Working Groups, Day 2
Pages 137-164
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From page 137... ...
We focused on improving neutralization assays for antibodies against avian strains; standardizing protocols; engineering an inoculum so it could be used in a Biosafety lab 2 setting; and boosting automation, which might include robotics but also new reagents such as fluorescentated or luciferase tagged inocula. Improving HAI methods for detecting H5 antibodies is also important..
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From page 138... ...
We conclude that it is important to use the many new methods now available to probe human immune responses against primary and secondary flu infections with non-pandemic strains. These studies would give us a repertoire of methods to apply immediately to evaluate host responses in a pandemic setting.
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From page 139... ...
Finally, it is important to generate experience with multiple pandemic vaccines to assess reactogenicity, immunogenicity, optimal dose, and route of administration. In our final analysis, gaining a broad understanding of the immune response to both natural infection and vaccines for as many different HA and NA viruses is a priority, as is looking not just at the standard serologic responses but also at cellular immune responses.
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From page 140... ...
140 PANDEMIC INFLUENZA RESEARCH Working Group 5 Presentation Slides: Immunology, Assay Standardization, and Correlates of Protection-Ann Arvin, Rapporteur (Slides available on accompanying CD)
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From page 141... ...
· Illness with titers >105 shed by 24 hrs after giving 105 pfu of wt virus. · titers 102 to 103 = asymptomatic or URI · Immune responses on board at time of exposure · titers of 107 = 104-105°F fever major players in resistance · peak titer achieved early after infection · Immune factors, either cellular or humoral, · job of immune system is to keep peak titer < generated from memory that require infection to be initiated make minor contributions to peak titer 103 achieved · live att vaccines replicate to < 103 III Lessons learned from experiments of nature IV Lessons learned from experimental challenge of · 1977 H1N1 long duration of HA specific humans with wt or att viruses immunity · Immunological correlates largely defined · Antigenic drift virus selected based on ability · four major contributors to immunity to escape antibody serum IgG Ab to HA major player in LRT · 1968 level of serum antibody to NA correlated mucosal IgA to HA Major player in URT with illness/peak virus titer serum IgG to NA · 1957 - Severe disease despite multiple mucosal IgA to NA (assumed)
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From page 142... ...
Otherwise, there is no market for such vaccines, and thus no surge capacity. Improving the efficacy, effectiveness, ease of administration and production, and routine use of all influenza vaccines is the technical framework for influenza pandemic preparedness.
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From page 143... ...
We also need to improve immunogenicity by improving heterosubtypic potency. One approach that is furthest off and highest risk -- but potentially high payoff -- is the common protein vaccine, with clinical data from one candidate pending.
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From page 144... ...
A priority is to create the infrastructure for the human challenge model using pandemic HAs and NAs on the challenge virus, including finding locations, critical reagents, and funding for these studies. We also see validating surrogate markers as a priority, particularly in the context of a priming dose for a population.
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From page 145... ...
· Access to critical IP and know-how · Platform technologies: reverse genetics, adjuvants, delivery systems · Shared tools: isolates, shared/validated assays, reagents, serum panels · Processes for manufacturing · Clinical trial tools... · As a result, true pandemic planning requires a quiet revolution in influenza vaccines.
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From page 146... ...
-- Others have advantages of being approved but are not as good candidates than these 2 above -- MDCK safety of cell substrate can develop scientific criteria rather than a generalized concern · Research to facilitate evaluation of characterized cell line in context of new understanding of factors that influence growth Long term research priorities- >10 years · Research to develop a totally new way of producing influenza vaccine (i.e., e coli)
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From page 147... ...
· Urgent Research: Need to know more about immune response to wild type H5 · Research on role of other proteins in pathogenesis Long term research priorities- >10 years · Common protein vaccine -- Existing preclinical data more related to severity/death than prevention of infection -- lower priority for public sector -- Would benefit from reviewing all potential proteins for systematic analysis particularly if role in pathogenesis is not understood
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From page 148... ...
Improved Clinical Evaluation -- general issues Create infrastructure for human challenge models Comparisons head-to-head Criteria and methods for safety, efficacy, and immunogenicity Short term research priorities - < 2 year · Create infrastructure for challenge model using pandemic HAs/NAs on the challenge virus. Could evaluate new candidates.
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From page 149... ...
WORKING GROUPS, DAY 2 149 Working Group 6 Briefing Slides: Pandemic Vaccines-Assessment, Development and Production Strategies-Dr. Harry Greenberg, Briefer
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From page 150... ...
3. What research is needed to assess the relative role of model building based analyses of previous epidemics (SARS, previous influenza outbreaks )
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From page 151... ...
Input from colleagues in Vietnam and other Asian countries could prove especially valuable. Another priority is designing studies for seasonal influenza, to help us establish research protocols and clarify the kinds of data we
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From page 152... ...
152 PANDEMIC INFLUENZA RESEARCH want to collect before a pandemic hits. Widespread use of antivirals and vaccines will require a slightly longer timeframe.
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From page 153... ...
WORKING GROUPS, DAY 2 153 Working Group 7 Presentation Slides: Strategies to Contain Outbreaks and Prevent Spread-Dr. Nicole Lurie, Rapporteur
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From page 154... ...
154 PANDEMIC INFLUENZA RESEARCH Working Group 7 Briefing Slides: Strategies to Contain Outbreaks and Prevent Spread Dr. Neil Ferguson, Briefer
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From page 157... ...
WORKING GROUPS, DAY 2 157 (Slides available on accompanying CD)
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From page 158... ...
We know a lot about the receptor specificity of influenza viruses: sialic acid which is bound in 2-3 linkage to galactose is preferentially present in avian cells and a 2-6 linkage, in which the sialic acid is bound to the six position of galactose, is the more common structure for receptors of human influenza viruses. Hemagglutinins from avian viruses thus preferentially recognize 2-3
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From page 159... ...
Mice have been very helpful so far, but ferrets provide another model, and we should not forget about simple systems such as organ cultures, which can shed light on which cells become infected. We can now make influenza viruses that express a green fluorescing protein, so studying animal infections with these reporter viruses will be very important.
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From page 160... ...
Our fifth question -- concerning what studies we need to identify measures that can alter intra-species virus transmission, and the possible side effects or consequences of these measures -- was probably the most hotly debated. Some colleagues felt that social controls among both animals and humans would be quite useful in reducing spread, while others felt that they would be less effective.
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From page 161... ...
WORKING GROUPS, DAY 2 161 Working Group 8 Presentation Slides: Viral Transmission: Understanding and Predicting Pandemic Risk-Dr. Peter Palese, Rapporteur
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From page 162... ...
162 PANDEMIC INFLUENZA RESEARCH Working Group 8 Briefing Slides: Viral Transmission: Understanding and Predicting Pandemic Risk-Dr. Daniel Perez, Briefer
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From page 164... ...
164 PANDEMIC INFLUENZA RESEARCH (Slides available on accompanying CD)
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