_for developing a pneumococcal conjugate vaccine fo的基础上开发的肺炎球菌结合疫苗的课件

Basis for Developing a Pneumococcal Conjugate Vaccine for Adults George R. Siber, MD Executive Vice President and Chief Scientific Officer Wyeth Vaccines Research VRBPAC, November 17, 2005 Summary nNeed for another pneumococcal vaccine for adults nAdvantages of the conjugate pneumococcal vaccine nPotential public health impact of adult pneumococcal conjugate nProposed regulatory basis for licensing pneumococcal conjugate vaccine for adults nFeasibility of efficacy trials for community acquired pneumonia or invasive pneumococcal disease (IPD) 2 Question # 1 Why do we need another Pneumococcal Vaccine for Adults? 3 Because there are limitations of 23vPs vaccine nAntibody titers and efficacy appear to wane after 5 years (Shapiro, et al, NEJM, 1991) nEffectiveness is very low in immunocompromised patients n23vPs induces hyporesponsiveness to either another dose of 23vPs (Torling, et al Vaccine, 2003) or to a dose of conjugate (deRoux, et al IDSA, 2005) nRe-vaccinations cause more severe adverse events (Jackson, et al JAMA, 1999, Vaccine, 2005) nTherefore, 23vPs is generally given only once, which provides only a narrow window of protection during a prolonged period of risk (ACIP recommendation: MMWR, 1997) 4 Cases Cases per 100,000 Deaths Age Group Years Estimated # of deaths Age Group Years And because there remains a substantial invasive pneumococcal disease burden in the US (2004 rates with 60% uptake of 23vPs Vaccine) CDC, ABC Surveillance 2004 (provisional) 5 Question #2 What are the advantages of a pneumococcal conjugate vaccine for adults? 6 Pneumococcal Conjugate Offers Additional Benefits over Ps Vaccine nConjugate antibody responses are significantly better or non-inferior to 23vPs 4By both ELISA and OPA nConjugate does not induce hyporesponsiveness to subsequent 23vPs or a 2nd dose of conjugate nConjugate can therefore be used to extend the age range of protection against pneumococcal disease (i.e.,50-64yo) and to provide long-term protection by repeat dosing, if needed 7 Randomized Trial in Nave Elderly 70+ years of age (Germany) PnC PnC Ps PsPnC (PnC/PnC) (PnC/Ps) (Ps/PnC) Year 1Year 2 N = 110 N = 109 Bleeds for IgG, OPA pre and 1 month post year 1 and year 2 dose N=43 N=38 N=78 8 7vPnC N = 110; 23vPs N = 104-107 * statistically significant * * * * * Immunogenicity of Prevnar vs 23vPs after Dose 1 ELISA Antibody * GMC (g/ml) 9 Immunogenicity of Prevnar vs 23vPs after Dose 1 OPA * * * OPA GMT 7vPnC N = 110; 23vPs N = 104-107 * statistically significant * 10 Randomized Trial in Nave Elderly Does Prior Ps affect the response to PnC? PnC PnC PsPnC(Ps/PnC) Year 1Year 2 N = 61 Ps N = 62 11 Prior 23vPs Blunts the Response to Subsequent Prevnar (Hyporesponsiveness) 7vPnC (N=61); 23vPs/7vPnC (N=62) * Statistically significant ELISA GMC (g/mL) * * * * * * 12 Prior Prevnar Does Not Blunt the Response to a 2nd Dose of Prevnar 7vPnC (N=61); 7vPnC/7vPnC (N=31) ELISA GMC (g/mL) 13 PnC Ps Ps PnC Randomized Trial in Nave Elderly Does prior PnC affect the response to Ps? Year 1Year 2 N=62 PnC (PnC/Ps) N = 30 14 Prior Prevnar Does Not Blunt the Response to Subsequent 23vPs ELISA Antibody 23vPS (N=62); 7vPnC/23vPs (N=30) ELISA GMC (g/mL) 15 Would Ps induced hyporesponsiveness improve with longer interval? ELISA GMC g/ml Seattle Study: 5 year interval Wyeth Study: 1 year interval Lisa Jackson, unpublished, by permission Ps/PnC 1 yr (Wyeth) (n=62) Ps/PnC 5yr (Seattle) (n=44) Ps/Ps 5yr (Seattle) (n=44) 16 23vPS reduces the response to subsequent doses of 23vPS (Torling, Vaccine 2003) Combined geometric mean pneumococcal antibody concentration (GMC) to six antigens prior to and 4 weeks after primary vaccination and revaccination, respectively, for serotypes 1, 4, 7F, 14, 18C, and 19F. Note that the Y-axis scale for serotype 14 differs from the other serotypes. A: before vaccination; B: 4 weeks after vaccination; C: 1 year after vaccination; D: revaccination after 47 years; E: 4 weeks after revaccination. . (Torling, Vaccine 2003) 17 Prevnar Immunogenicity in the Elderly support the following nPrevnar conjugate can be used repeatedly without inducing hyporesponsiveness n23vPS can be given after pneumococcal conjugate vaccine without hyporesponsiveness nIf both vaccine are used to maximize coverage conjugate should be used first 18 Question # 3 What is the potential public health impact of pneumococcal conjugate vaccine for adults? 19 Estimated Impact on Invasive Pneumococcal Disease-Simplifying Assumptions: 23vPs13v ConjugateReference Serotype coverage 75%56%ABC surv. 2003 IPD rates See briefing package. Rates adjusted upward for effect of 23vPs (per Fry et al) ABC, 2004 US census Efficacy (immuno- competent) 88% for 5 years, declining to 0% by 15 years 88% Maintained over at -risk period Shapiro, NEJM 1991 (PS) Efficacy (immuno- compromised) 0%0%Shapiro, NEJM 1991 (PS) Vaccine uptake 60% in 65 y/o 43% in high risk 50 y/o NHIS, 2004/MMWR, 2004 20 Impact of Extending The Age Range of Protection 50 yr65 yr70 yr IPD Cases (Deaths) Preventable/yr 2979 (489) 23vPs alone 21 Impact of Extending The Age Range of Protection 50 yr65 yr70 yr IPD Cases (Deaths) Preventable/yr 2979 (489) 23vPs alone 13vPnC alone 5544 (895) 86% more than 23vPs 22 13vPnC + 23vPs566 (93) 5544 (895) 6110 (988) Impact of Extending The Age Range of Protection 50 yr65 yr70 yr IPD Cases (Deaths) Preventable/yr 2979 (489) 23vPs alone Conjugate with re-vaccination 13vPnC alone 5544 (895) 86% more than 23vPs 23 This is Conservative Estimate of Public Health Impact of PnC 1. Does not assume higher IPD efficacy, despite higher ELISA and OPA antibody responses 2. Does not assume protection of immunocompromised, although HIV (+) patients and other high risk groups respond better to PnC than Ps 3. Assumes no efficacy against pneumonia, although OPA antibody after PnC in elderly is similar to OPA post 3 doses of PnC in infants. 24 Question #4 Are serologic studies adequate to demonstrate efficacy of adult pneumococcal conjugate? 25 Historically 2 Approaches Used for Licensure of Polysaccharide-based Vaccines 1. When there is no vaccine to prevent the disease in a particular age group, an efficacy trial is required, if feasible 414vPneumococcal Ps 4Group A and C Meningococcal Ps 4Hib Ps in toddlers 4Hib conjugate in infants 4Pneumococcal conjugate in infants 2. When there is already a licensed vaccine to prevent the disease in a particular age group, immunogenicity comparison has been acceptable to extend coverage or to improve immunogenicity. 423vPneumococcal Ps after 14vPs in adults 44vMeningococcal Ps after 2vPs in adults 4Hib conjugate after Hib Ps in toddlers 44vMening conjugate after 4vPs in adolescents 26 Proposal Licensing Criteria for Adult Pneumococcal Conjugate # 1. Based on regulatory precedents the efficacy of Pneumococcal conjugate vaccine for adults can be proven by showing serologic non-inferiority to the shared serotypes in the licensed 23vPs vaccine based on OPA # 2. Lack of hyporesponsiveness to 2nd dose of conjugate (which enables using repeated doses, if needed, to maintain protection) # 3. Lack of hyporesponsiveness to 23vPs given subsequently, (which enables extending serotype coverage in high risk groups, if desired) 27 Scientific Basis for Proving Efficacy Based on Serologic Studies 1. The efficacy/effectiveness of 23vPs is established. The capsular Ps is the protective antigen 2. Antibody is the protective mechanism against IPD (passive immunization) 3. Opsonophagocytosis is the functional mechanism whereby antibody protects 4. Induction of opsonophagocytic activity (OPA) is believed to correlate with clinical efficacy and is proposed as the primary basis for comparing adult vaccines 5. Antibody binding assays (e.g., ELISA) can be used as a surrogate when they correlate highly with OPA (e.g., in infants after conjugate vaccine.) 28 Efficacy of 23v Ps Vaccine for IPD has been established StudyPopulationVaccineEfficacy vs IPD Austrian, 1976S. African Miners6, 13 valent82% * Riley, 1977Papua New Guinea14 valent86%* StudyPopulationVaccineEfficacy vs IPD Shapiro, 1991Elderly/high risk14, 23 Overall 56% (42, 67) Immunocompetent61% (47, 72) Immunocompromised21% (-55,60) Butler, 1993Elderly/high risk Overall Immunocompetent 14, 23 valent 57% (45, 66) 75% (57, 85) Effectiveness Efficacy * By blood culture * By blood culture or lung tap 29 Rationale for OPA as a Surrogate for Clinical Efficacy in Adults nOPA in infants is high and so is efficacy, i.e., high OPA correlates with high efficacy nType 19F has lower OPA in infants than the other 6 types in Prevnar nAlthough efficacy of Prevnar is high for 19F IPD, it is low for otitis media and inhibition of colonization 30 ELISA and OPA of Infants (140-1) after 3 Doses of Prevnar (7 mos) Serotype ELISA GMC (g/ml) OPA GMT 6B5.181887.6 9V1.88 3551.3 18C2.88 1558.6 19F4.17 203.2 23F2.16 4845.5 N=33-34 31 Efficacy of Prevnar in Infants by Serotype Serotype IPD Efficacy Kaiser 1 IPD Effectiveness (ABC) 2 Otitis (Finland) 3 Colonization (Israel) 4 4-87 (39, 97)49 (-176, 91)- 6B86 (-11,100)88 (65, 96)84 (62, 93)88 (46, 91) 9V 100 (-42, 100) 100 (79, 100)54 (-48, 86)61 (17, 82) 14100 (60, 100)94 (80, 98)69 (20, 88)49 (4, 73) 18C100 (49, 100)96 (82, 99)58 (-4, 83)- 19F85 (32, 98)81 (52, 93)25 (-14, 51)21 (-17, 46) 23F100 (15, 100)96 (70, 99) 59 (35, 75)47 (12, 67) All VT97 (83, 100)92 (86, 95)57 (44, 78)50 (34, 62) 1.Black S., et al PIDJ 2000 2.Whitney C., personal communication 3.Eskola J., NEJM 2001 4.Dagan R., JID 2002 32 Low OPA explains why elderly are at risk of IPD Despite Good ELISA Antibody nThe conundrum: Elderly adults have similar ELISA antibody levels, even prior to immunization, as infants after Prevnar. Yet they are at high risk of IPD. nThe explanation: Pneumococcal Ab in the elderly have lower opsonic function relative to infant Ab 33 Pneumococcal Antibody Levels in Unimmunized Elderly vs Infants after Prevnar Infants Post 3 doses 7vPnC Elderly - Unimmunized ELISAELISA 6B5.181.04 9V1.88 0.87 18C2.88 1.15 19F4.17 1.17 23F2.16 0.95 Infants: N=33-34; Elderly: N=209-218 (7vPnC Elderly: N=209-218 (7vPnC Elderly: N=104-107 (23vPs), 110 (7vPnC) 37 OPA and ELISA Responses to Pneumococcal Conjugate Vaccine in Elderly vs Infants Infants (140-1) (post 3 doses PnC) Elderly (166-508) (post 1 dose PnC) TypeELISAOPAELISAOPA 6B5.181888 8.021351.2 9V1.88 3551 9.822914.6 18C2.88 1559 12.971317.5 19F4.17 203 5.5182.2 23F2.16 4845 12.41309.3 Infants: N=33-34; Elderly: N=104-107 (23vPs), 110 (7vPnC) 38 Proposed Licensing Criteria for Adult Pneumococcal Conjugate nDemonstrate non-inferiority of the immune response of the shared serotypes in the 13 valent conjugate and 23vPs vaccines 4 Primary comparison is based on OPA nDemonstrate no hyporesponsiveness to 2nd dose of 13vPnC 4To support repeat dosing with 13vPnC for long term protection, if needed nDemonstrate no hyporesponsiveness to subsequent dose of 23vPs 4To support extending serotype coverage with 23vPnC in high-risk groups, if desired 39 Question #5 Is an Efficacy Trial Feasible for Invasive Pneumococcal Disease or Community Acquired Pneumonia? 40 Constraints on Performing Pneumococcal Conjugate Vaccine Efficacy Trials in Adults for CAP or IPD nPlacebo-controlled trial is necessary to assess efficacy of 13vPnC nPlacebo is not possible in high risk adults who are currently recommended to receive 23vPs 4 65 year olds 4100,000/limb) for adequate power nAlternative designs (e.g., sequential 13vPnC/23vPs vs 23vPs alone in high risk groups) cannot demonstrate the efficacy of 13vPnC alone and would be even larger than placebo controlled trials nPost-marketing effectiveness studies are the only feasible way to assess impact of 13vPnC on IPD and CAP 42 What is the Sample Size to Show IPD Efficacy Trial in 50-64 y/o Healthy Adults? Assumptions: nIncidence rate of 25 per 100,000 (high), 15 per 100,000 (intermediate) or 7.5 per 100,000 (low) Note: CDC estimates pre Prevnar (99-00) are 9.9/100,000 in healthy 50-64 y/o. (Kyaw et al. JID 2005) n56% of IPD covered by 13vPnC nTrue VE of 70%, 80% or 90% for vaccine type IPD n90% power nLower 95% confidence interval of 30% nTrial length of 3 yrs: 1 yr enrollment, 2 yrs follow-up 43 Invasive Disease Efficacy Trial in 50-64 y/o Sample Size Calculations 44 Demonstration of Efficacy against CAP is Risky and/or Impractical nCan ethically study only 0% (and 30% for VTCAP) 4Trial length of 3 yrs: 1yr enrollment, 2yrs mean follow-up 52 Community Acquired Pneumonia Efficacy Trial: Sample Size Calculation (50-64 y/o) nWith these assumptions 4Event rate for CAP due to vaccine types is 58.8 / 100,000 (350 x 0.3 x 0.56) 4Effectiveness against all CAP is 11.8% (.70 x .30 x .56) nSample size per group for average 2 years of follow-up No. of cases in placebo gp. No. of subjects per gp. All CAP (LCI95 0)2,676199,123 VT CAP (LCI95 0) (LCI95 30) 35 69 20,420 41,691 (assuming 100% specificity and 100% sensitive assay) 53 nREACTOGENICITY OF Prevnar vs 23vPs in elderly adults 54 Local Reactions* within 7 Days of Prevnar or 23vPs Swelling at injection sitePain at injection siteRedness at injection site * More severe reactions in red 55 Systemic Reactions* within 7 Days of Prevnar or 23vPs 0 10 20 30 40 50 60 70 7vPnC 23vPs 7vPnC -23vPs 23vPs -7vPnC 7vPnC -7vPnC % Subjects Dose 1Dose 2 * NS NS * Fever 38C, fatigue, headache, chills, rash, vomiting, decreased appetite, muscle and/or joint pain. Marks significant differences compared to group following hyphen (-). 56 Seattle Study: PnC and Ps as a second dose after Ps 5 years previous Redness Arm Mvt Limited PainSwelling Jackson, L., Neuzil, K., Whitney, C. et al Vaccine