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NBSB Pandemic Influenza Working Group Detailed Report How do the findings of basic biological research apply to making a vaccine? Dr. Hackett said there is no profile of normal human immune responses. Among the many diverse populations, measuring immune parameters is difficult, and assays are needed that spare samples. Therefore, NIAID is awarding funds to establish a consortium around the Protection of Human Health by Immunology and Vaccines. The grant would include funding to develop sample-sparing assays. In December 2008, NIAID and FDA held a joint workshop on biological and regulatory issues around adjuvants. The goal was to assess the scientific knowledge base, facilitate development of a research agenda, and identify approaches to enhance nonclinical safety assessment. The transcript is available online at http://www.fda.gov/BiologicsBloodVaccines/NewsEvents/WorkshopsMeetingsConferen ces/ucm095698.htm. Essentially all successful vaccines have either naturally occurring or an added adjuvant. Adjuvant activates antigen-presenting cells, which stimulates uptake and increases migration, and causes local inflammation. Adjuvants stimulate interactions at the innateadaptive interface that initiates an adaptive immune response. Adjuvant also appears to be one of multiple signals that co-triggers antigen-dependent activation of human B cells. One way adjuvant works to increase the breadth of antibody responses is to increase the number and breadth of T helper cells. Also, there may be an additional signal in B-cell receptor-mediated responses that activates more broadly than in the absence of added adjuvants. Adjuvants have both qualitative and quantitative effects on adaptive immune response. B cells are becoming better understood in humans, but many gaps remain. Influenza has its own adjuvant activity, mostly by internal components. Innate receptors evolved to detect microbial motifs: Viral single-strand RNA recognized by toll-like receptor (TLR-7) and RIG-1 Viral ribonucleoprotein plus other virion components trigger cellular inflammasomes Influenza endogenous adjuvants are present in whole virion and to varying amounts in split vaccines; they are probably linked to the reactogenicity often observed. The goal of our adjuvant research program is to replace the toxicity-causing components with less-hazardous, quality-controlled, exogenous adjuvants. Endogenous adjuvants may not be ideal triggers for vaccine immune responses. The innate immune system not only triggers adaptive immunity but also triggers the antiviral response. Dr. Hackett said he would like to see more focus on adjuvants helping adaptive immune response and separating it from innate immune defenses. It is feasible to replace viral immunostimulatory components with defined, tested adjuvants and still meet goals. Cellmediated immunity, e.g., cytotoxicity of cells, is a good question that should be looked at, said Dr. Hackett. 34
NBSB Pandemic Influenza Working Group Detailed Report In terms of vaccine safety, research is needed on the ability to reduce or eliminate the need for nonprotein viral components, eliminate manufacturing variability of endogenous adjuvant activity, and facilitate the meta-analysis of adjuvant function and safety. Metaanalysis could compare adjuvants across platforms and demonstrate alternative uses (e.g., ALDARA (imiquimod) used to treat warts may have potential as a vaccine adjuvant). In the U.S., seasonal live attenuated vaccine and inactivated trivalent vaccine have endogenous adjuvants only. In Europe, some vaccines have added exogenous adjuvant. At present, it is not possible to look at a human profile and measure precisely what responses adjuvant triggers. The effort to create a consortium of organizations to identify normal human immune response is intended to address that barrier. Dr. Hackett concluded that NIAID hopes to have some platforms and databases on which to address some questions about safety in clinical data. Discussion Dr. Pavia: I’m gratified to see the investments in basic research on safety for the future; will any of that investment be useful this fall? Dr. Hackett: We have nothing like a chip or gene that can help you identify whom not to vaccinate, but there are investigators looking at special populations and generating data. You could get preliminary information from them on special populations. Dr. Pavia: If Dr. Salmon asked, could you identify the top 10 conditions for which we need baseline rates on, e.g., diseases or adverse events? Dr. Hackett: That’s a good question. We are always concerned that when you trigger B cells could they respond to existing antigens as auto-antigens? That’s one priority. For special populations, we are concerned about people who have had transplants and people with autoimmune disease or primary immune deficiency. Those are some groups to look at, but we can’t have that data by this fall. Dr. Schonberger: How do we get key information, such as denominators? It’s unclear to me how this vaccine will be distributed (mass campaign? private sector?). In 1976, we had available to us the results of the National Center for Health Statistics (NCHS), Health Interview Survey, Weekly report to identify the proportion of people receiving vaccine each week. I think such surveys should be conducted during the upcoming fall campaign. In 1976-77, we also had the National Influenza Immunization Program (NIIP) weekly and monthly data to evaluate how much vaccine was administered each week as well as each month by age group. In an important re-analysis of the GBS data conducted in Minnesota and Michigan by Dr. Safranek and colleagues published in 1991, the NIIP data worked well in Minnesota, so they were used to determine denominators in Minnesota. In Michigan, on the other hand, the NIIP data on vaccine administration seemed delayed, so the NCHS data were used instead for denominators. Setting up several mechanisms for determining unvaccinated and vaccinated population denominators over time in the fall could be very important for evaluating potential adverse reactions. The risk of swine flu vaccine-related GBS was not equivalent in all ages. People under 25 years were much less likely to get GBS after swine flu vaccination than older recipients. Those ages 25–44 had a higher than average risk. Among unvaccinated 35
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