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1 Assessment of the Effectiveness of Small Pox Vaccines: Immunogenicity Assay Considerations Freyja Lynn Division of Bacterial, Parasitic and Allergenic Products OVRR, CBER The Development and Evaluation of Next-Generation Smallpox Vaccines September 16, 2011
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2 Overview Uses of assays to provide evidence of effectiveness Smallpox immunogenicity assay issues relevant to assessment of non-inferiority of human immune response Smallpox immunogenicity assay issues relevant to assessment of animal immune response (Animal Rule)
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3 Immunoassay data to provide evidence of effectiveness Surrogate of Protection - Immune measure that explains all the protection afforded by a vaccine - Demonstrated in efficacy studies Correlate of Protection - Immune measure that correlates with but does not explain all of the protection afforded by a vaccine - Demonstrated in efficacy studies Immune measure - Immune response measured that correlates with vaccination or disease, expected to contribute to protection and indicate robustness of immunological response but not necessarily predict protective immunity
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4 Smallpox Correlate of protection for licensed vaccine is vaccine “take” - New generation vaccines do not necessarily demonstrate “take” or demonstrate a different “take” than traditional vaccine - Lack of “take” may not indicate lack of efficacy Traditional measure of immunogenicity is the PRNT - Not a correlate of protection - Variola is the human pathogen but impractical for large scale studies What was appropriate for old vaccine may not be appropriate for new vaccines.
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5 Challenge – providing evidence of effectiveness of next generation smallpox vaccines Noninferiority to licensed vaccine - Demonstrate immunologic noninferiority to ACM2000 in clinical studies Animal rule - Demonstrate efficacy in animals and bridge to immunogenicity in humans Models are imperfect but necessary Use related orthopox rather than variola
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6 Noninferiority to licensed vaccine - Comparator would be ACAM 2000 - What assay? - What are the appropriate immunogenicity endpoints? - What are the appropriate criteria for demonstration of non-inferiority?
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7 Diversity of immune responses Human antibody responses to WR proteome after immunization with MVA or Dryvax
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8 PRNT using Variola Damon, Davidson, Hughes, et al. 2009. J Gen Virol. 90:1962-1966
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9 Effect of antigen on vaccine evaluation Groups indicate different vaccination regimens with either MVA or Dryvax Frey, Newman, Kennedy, et al. 2007. Vaccine. 25:8562-8573
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10 Comparison of neutralization of WR and Dryvax in standardized PRNT Adults immunized with MVA Courtesy of BN and DMID
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11 ELISA Groups indicate different vaccination regimens with either MVA or Dryvax Frey, Newman, Kennedy, et al. 2007. Vaccine. 25:8562-8573
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12 Assessing clinical noninferiority What assay do you choose? - ELISA versus PRNT - Total antibody versus functional What antigen do you choose? - Vaccine strains - Human pathogen What difference is meaningful? - Immunologic difference versus clinical difference - Complexity of virus Mechanism of action between vaccines may be different and one assay may not measure effectiveness equally between vaccines
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13 Animal rule - Develop an animal model - Bridge animal efficacy to human dose
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14 Possible bridging strategy - Determination of a correlate of protection for the animal model - Bridging correlate of protection in animal model to immunogenicity in humans Species neutral assay
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15 Animal model Correlation between clinical outcome and immune measurement BBRC Study 1023, Courtesy of OBRA/DMID
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16 Effects of methodology on PRNT Is PRNT species neutral? Courtesy of BN
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17 Assay standardization issues for use as bridge between animal and human PRNT - Choice of virus - Methodology Methods adapted to each species – is the assay truly species neutral? - Sensitivity ELISA - Species neutrality - Choice of antigen Crude versus purified material Batch to batch consistency
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18 Additional data needed to develop model Vaccine dose ranging to identify a dose that results in both protected and unprotected animals Assessment of immunogenicity in the animal model - Assay sensitivity ELISA may be more sensitive than PRNT but which assay is more relevant? - Species neutrality Is PRNT inherently species neutral? - May be product specific
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19 Anthrax vaccine Logistic regression between survival and toxin neutralization titer Courtesy of OBRA/DMID
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20 Assessment of effectiveness of next generation small pox vaccines: Considerations Noninferiority - Based on clinical data - Comparison to licensed product - Relevance of immunogenicity measures - Selection of assay - Selection of antigen Animal Rule - Demonstrate actual efficacy in animal model - Relevant assay based on correlative data - Relevance of animal model - Assumes the immunoassay in animals and humans is equivalent biologically
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