1 Pneumococcal Immunization in the Elderly

2 U.S. Burden of Pneumococcal Disease in the Elderly Invasive disease (IPD = bacteremia, pneumonia with bacteremia, uncommonly meningitis) –38 / 100,000 person years –Mortality = 7.2 / 100,000 persons years –Disproportionate impact among Blacks –Increased rate in patients with DM, cardio-pulmonary disease, solid tumors, EtOH abuse. Community-acquired pneumonia (CAP) – ,000 hospitalizations per year in elderly –20-60% pneumococcal (25-30% best estimate)

3 Impact of Conjugate Vaccine in the Elderly Approval of conjugate vaccine ABCs Report, Emerging Infections Program Network Huang SS, et al. Pediatrics 2005; 116:e Decreasing rate of PCN-susceptibility here Indirect Impact on Rates of IPD in the Elderly Increasing Rate of Non-Vaccine Serotypes in Children

4 Impact of Conjugate Vaccine in the Elderly IPD in the elderly has dropped sharply in conjugate era, but some subsets show less marked effect. Absolute rate of pneumonias with invasive disease and non-conjugate serotypes has increased 11.6% Bacteremia/meningitis + Pneumonia in the Elderly Lexau CA, et al. JAMA 2005; 294:2043

5 Evidence Regarding Pneumococcal Vaccines in the Elderly Invasive pneumococcal disease: –No compelling evidence from RCTs (low power), –Meta-analyses are heterogeneous and still underpowered, but –Observational cohort and case-control studies monotonously show 45-65% efficacy and are really the basis of current recommendations. Community-acquired pneumonia: –No evidence from RCT –Observational studies are heterogeneous, but often (not always) are quite underpowered –Meta-analyses aren’t helpful.

6 Cost-Effectiveness 23-PS vaccine is generally believed to be acceptably cost-effective in the elderly. Multiple analyses in different countries –Typically acceptably cost-effective, in some cases cost-saving; but critically dependent on assumptions. –Earlier analyses more dramatic, but assumed efficacy against pneumococcal CAP, –More recent estimates reverse this trend and focus on IPD, but still show acceptable cost-effectiveness even considering IPD costs alone.

7 ID Biomedical Approach to Pneumococcal Vaccine ID Biomedical candidate is a chimeric protein representing immunodominant and surface- exposed domains of two conserved pneumococcal proteins. Current configuration is a aluminum-adjuvanted injectable. Possible developments include: –Aqueous formulation, especially for the elderly who may respond well, and/or –Potential for mucosal formulations.

8 Protein vs. Polysaccharide -based Vaccines for S. pneumo Group-Common Protein- based Capsular Polysaccharide-based (23-PS and Conjugates) Serotype coverage Potentially allLimited, geographic diversity Serotype substitution NoDemonstrated in children, importance TBD in adults Escape mutants Possible, TBDNo Complexity of manufacture & release Relatively low, single high- yield recombinant Moderately to very high (esp. for conjugates) T cell help IntrinsicRequires conjugation Boosting Early data suggest effective boosting with good safety Mediocre for 23-PS, w/some safety concerns, prob. better for conjugates Potential for mucosal immune response GoodLow

9 Animal Protection by ID Biomedical Protein Vaccine Bacteria in lungs decreased up to 10,000-fold in immunized animals on days 2 or 3. Similar results can be seen with bloodstream infections. Animals can be protected passively by transfer of immunized human sera. Basic mechanisms of protection appear to be similar to those induced by current vaccines. Lethal Pneumonia Model Balb/C mice immunized SC x 3, challenged with ~ 10 3 LD 50 S. pneumo 14 d later.

10 Challenges in the Development of a Pneumococcal Group Common Protein Vaccine Paucity of data regarding the prevalence of protein antibodies and their relation to disease. Current assays of functional antibodies are optimized for polysaccharide antibodies. There is no “consensus” regarding protective pneumococcal protein antibody levels. Clinical efficacy trials for the elderly, will require new thinking about endpoints to be feasible: –Trials targeting IPD will be huge because IPD is rare. –Trials targeting all-cause CAP will be large because of limited efficacy attainable (pneumococci cause only a fraction of CAP). –Trial size and duration are fungible, but any trial must make sense from a corporate perspective.

11 Issues (1) CAP with a presumptive etiologic diagnosis represents an endpoint that: –Is of clinical interest and not a rare phenomenon, –Leads to a feasible clinical trials strategy Requires regulatory assessment of non-cultural diagnostic modalities now licensed for clinical diagnostic use. –Is current validation sufficient? –If not, discussion of validation strategies in the face of a poorly sensitive “gold standard” is needed.

12 Issues (2) IDB presumes a placebo-controlled trial cannot be done in the U.S. in the elderly, 23-PS is little used in many countries with good clinical trials and eldercare infrastructure, so trials can presumptively be done elsewhere, but: What is the immunogenicity dataset to support U.S. licensure presuming ex-U.S. efficacy? Would it necessarily require functional assays? Why? Would it require that the preceding efficacy trial establish a clear-cut protective antibody level to be exceeded? Would equivalent immunogenicity in the U.S. population not suffice?

13 Issues (3) How would U.S. licensure for the elderly be approached in the presence of current pneumococcal vaccines? –Would a head-to-head trial of the protein vaccine vs. 23-PS or a conjugate be required? For IPD, this is in practical terms impossible. For CAP, the potential comparators have no demonstrated efficacy in RCTs, or consistent effect even in observational studies. IBD sees no clear requirement for a head-to-head comparison