Basis for Developing a Pneumococcal Conjugate Vaccine for Adults

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 • Need for another pneumococcal vaccine for adults • Advantages of the conjugate pneumococcal vaccine • Potential public health impact of adult pneumococcal conjugate • Proposed regulatory basis for licensing pneumococcal conjugate vaccine for adults • Feasibility of efficacy trials for community acquired pneumonia or invasive pneumococcal disease (IPD)

Question # 1 Why do we need another Pneumococcal Vaccine for Adults?

Because there are limitations of 23vPs vaccine • Antibody titers and efficacy appear to wane after 5 years (Shapiro, et al, NEJM, 1991) • Effectiveness is very low in immunocompromised patients • 23vPs induces hyporesponsiveness to either another dose of 23vPs (Torling, et al Vaccine, 2003) or to a dose of conjugate (deRoux, et al IDSA, 2005) • Re-vaccinations cause more severe adverse events (Jackson, et al JAMA, 1999, Vaccine, 2005) • Therefore, 23vPs is generally given only once, which provides only a narrow window of protection during a prolonged period of risk (ACIP recommendation: MMWR, 1997)

And because there remains a substantial invasive pneumococcal disease burden in the US (2004 rates with 60% uptake of 23vPs Vaccine) Cases Cases per 100,000 Age Group Years Deaths Estimated # of deaths CDC, ABC Surveillance 2004 (provisional) Age Group Years

Question #2 What are the advantages of a pneumococcal conjugate vaccine for adults?

Pneumococcal Conjugate Offers Additional Benefits over Ps Vaccine • Conjugate antibody responses are significantly better or non-inferior to 23vPs • By both ELISA and OPA • Conjugate does not induce hyporesponsiveness to subsequent 23vPs or a 2nd dose of conjugate • Conjugate 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

Randomized Trial in Naïve Elderly 70+ years of age (Germany) Year 1 Year 2 PnC (PnC/PnC) N=43 PnC Ps (PnC/Ps) N = 110 N=38 Ps PnC (Ps/PnC) N=78 N = 109 Bleeds for IgG, OPA pre and 1 month post year 1 and year 2 dose

Immunogenicity of Prevnar vs 23vPs after Dose 1 – ELISA Antibody * * * * GMC (µg/ml) * * 7vPnC N = 110; 23vPs N = 104-107 * statistically significant

Immunogenicity of Prevnar vs 23vPs after Dose 1 – OPA * * OPA GMT * * 7vPnC N = 110; 23vPs N = 104-107 * statistically significant

Randomized Trial in Naïve Elderly Does Prior Ps affect the response to PnC? Year 1 Year 2 PnC PnC Ps N = 61 Ps PnC (Ps/PnC) N = 62

Prior 23vPs Blunts the Response to Subsequent Prevnar (Hyporesponsiveness) * * * * ELISA GMC (g/mL) * * 7vPnC (N=61); 23vPs/7vPnC (N=62) * Statistically significant

Prior Prevnar Does Not Blunt the Response to a 2nd Dose of Prevnar ELISA GMC (g/mL) 7vPnC (N=61); 7vPnC/7vPnC (N=31)

Randomized Trial in Naïve Elderly Does prior PnC affect the response to Ps? Year 1 Year 2 PnC PnC (PnC/Ps) Ps N = 30 PnC Ps N=62

Prior Prevnar Does Not Blunt the Response to Subsequent 23vPs – ELISA Antibody ELISA GMC (g/mL) 23vPS (N=62); 7vPnC/23vPs (N=30)

Would Ps induced hyporesponsiveness improve with longer interval? Seattle Study: > 5 year interval Wyeth Study: 1 year interval Ps/PnC 1 yr (Wyeth) (n=62) Ps/PnC >5yr (Seattle) (n=44) Ps/Ps 5yr (Seattle) (n=44) ELISA GMC µg/ml Lisa Jackson, unpublished, by permission

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 4–7 years; E: 4 weeks after revaccination. . (Torling, Vaccine 2003)

Prevnar Immunogenicity in the Elderly support the following • Prevnar conjugate can be used repeatedly without inducing hyporesponsiveness • 23vPS can be given after pneumococcal conjugate vaccine without hyporesponsiveness • If both vaccine are used to maximize coverage conjugate should be used first

Question # 3 What is the potential public health impact of pneumococcal conjugate vaccine for adults?

Estimated Impact on Invasive Pneumococcal Disease-Simplifying Assumptions:

Impact of Extending The Age Range of Protection IPD Cases (Deaths) Preventable/yr 23vPs alone 2979 (489) 50 yr 65 yr 70 yr

Impact of Extending The Age Range of Protection IPD Cases (Deaths) Preventable/yr 23vPs alone 2979 (489) 50 yr 65 yr 70 yr 13vPnC alone 5544 (895) 86% more than 23vPs

Impact of Extending The Age Range of Protection IPD Cases (Deaths) Preventable/yr 23vPs alone 2979 (489) 50 yr 65 yr 70 yr 13vPnC alone 5544 (895) Conjugate with re-vaccination 86% more than 23vPs 13vPnC + 23vPs 566 (93) 5544 (895) 6110 (988)

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.

Question #4 Are serologic studies adequate to demonstrate efficacy of adult pneumococcal conjugate?

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 • 14vPneumococcal Ps • Group A and C Meningococcal Ps • Hib Ps in toddlers • Hib conjugate in infants • Pneumococcal 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. • 23vPneumococcal Ps after 14vPs in adults • 4vMeningococcal Ps after 2vPs in adults • Hib conjugate after Hib Ps in toddlers • 4vMening conjugate after 4vPs in adolescents

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)

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.)

Efficacy of 23v Ps Vaccine for IPD has been established Efficacy Effectiveness * By blood culture ** By blood culture or lung tap

Rationale for OPA as a Surrogate for Clinical Efficacy in Adults • OPA in infants is high and so is efficacy, i.e., high OPA correlates with high efficacy • Type 19F has lower OPA in infants than the other 6 types in Prevnar • Although efficacy of Prevnar is high for 19F IPD, it is low for otitis media and inhibition of colonization

ELISA and OPA of Infants (140-1) after 3 Doses of Prevnar (7 mos) N=33-34

Efficacy of Prevnar in Infants by Serotype • Black S., et al PIDJ 2000 • Whitney C., personal communication • Eskola J., NEJM 2001 • Dagan R., JID 2002

Low OPA explains why elderly are at risk of IPD Despite Good ELISA Antibody • The conundrum: Elderly adults have similar ELISA antibody levels, even prior to immunization, as infants after Prevnar. Yet they are at high risk of IPD. • The explanation: Pneumococcal Ab in the elderly have lower opsonic function relative to infant Ab

Pneumococcal Antibody Levels in Unimmunized Elderly vs Infants after Prevnar Infants: N=33-34; Elderly: N=209-218 (7vPnC & 23vPS Combined)

After a single dose of Prevnar, the elderly increase OPA antibody titers to levels similar to infants after 3 doses

OPA and ELISA Responses to Pneumococcal Conjugate Vaccine in Elderly vs Infants Infants: N=33-34; Elderly: N=104-107 (23vPs), 110 (7vPnC)

Proposed Licensing Criteria for Adult Pneumococcal Conjugate • Demonstrate non-inferiority of the immune response of the shared serotypes in the 13 valent conjugate and 23vPs vaccines • Primary comparison is based on OPA • Demonstrate no hyporesponsiveness to 2nd dose of 13vPnC • To support repeat dosing with 13vPnC for long term protection, if needed • Demonstrate no hyporesponsiveness to subsequent dose of 23vPs • To support extending serotype coverage with 23vPnC in high-risk groups, if desired

Question #5 Is an Efficacy Trial Feasible for Invasive Pneumococcal Disease or Community Acquired Pneumonia?

Constraints on Performing Pneumococcal Conjugate Vaccine Efficacy Trials in Adults for CAP or IPD • Placebo-controlled trial is necessary to assess efficacy of 13vPnC • Placebo is not possible in high risk adults who are currently recommended to receive 23vPs • > 65 year olds • < 65 year olds with high risk conditions • Therefore, only healthy <65 y/o can be studied • In this age-group 72% of all invasive disease occurs in high-risk groups (2004 ABC Surveillance). • Therefore, IPD rates in healthy <65 y/o are much lower than the published rates for this age group overall

Pneumococcal Conjugate Vaccine Efficacy Trials • Studies of IPD or CAP in healthy <65y/o would require enormous sample sizes (>100,000/limb) for adequate power • Alternative 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 • Post-marketing effectiveness studies are the only feasible way to assess impact of 13vPnC on IPD and CAP

What is the Sample Size to Show IPD Efficacy Trial in 50-64 y/o Healthy Adults? Assumptions: • Incidence 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) • 56% of IPD covered by 13vPnC • True VE of 70%, 80% or 90% for vaccine type IPD • 90% power • Lower 95% confidence interval of > 30% • Trial length of 3 yrs: 1 yr enrollment, 2 yrs follow-up

Invasive Disease Efficacy Trial in 50-64 y/oSample Size Calculations

Demonstration of Efficacy against CAP is Risky and/or Impractical • Can ethically study only < 65 y/o without underlying conditions   low CAP risk  very large sample sizes • Proportion of all CAP due to pneumococcus is not known, making required trial size uncertain   risk • Etiologic diagnosis of pneumonia would enable smaller trial size, but no validated techniques exist (sensitivity and specificity unknown)   risk: Lack of validated outcome is “show-stopper” for VT-specific CAP efficacy trial • Ability to enroll large numbers of healthy, low risk adults and to ascertain outcomes by non-routine methods is uncertain   risk

Conclusions • The 13v pneumococcal conjugate vaccine has the potential for a significant public health impact because it can extend the duration of protection throughout the high risk period • The 23vPs vaccine may be given after the 13vPnC to expand serotype protection in high-risk patients • Efficacy of a conjugate vaccine in adults can be proven by showing non-inferiority of the immune response to the licensed polysaccharide vaccine for the serotypes in the conjugate vaccine • Placebo controlled efficacy studies in the adult population are not feasible due to ethical considerations and size • Effectiveness against IPD can be confirmed by post marketing studies

BACK-UPS

HIV+ Study: PS can be given after PnC if desired PnC/23vPS at least as good as or better than 23vPS alone GMCs after PS P<0.05 for all serotypes except 6B 1 month interval between vaccines Conducted under the auspices of the Agence National de Recherches sur le SIDA (ANRS)

OPA and ELISA Responses to Pneumococcal Conjugate Vaccine in Elderly vs Infants Infants: N=33-34; Elderly: N=104-107 (23vPs), 110 (7vPnC)

Pneumococcal Antibody Levels in Unimmunized Elderly vs Infants after Prevnar Infants: N=33-34; Elderly: N=209-218 (7vPnC & 23vPS Combined)

Basis for Developing a Pneumococcal Conjugate Vaccine for Adults