Pneumococcal immunization in the elderly
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Pneumococcal Immunization in the Elderly. 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

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U s burden of pneumococcal disease in the elderly
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)

    • 350 - 620,000 hospitalizations per year in elderly

    • 20-60% pneumococcal (25-30% best estimate)

Impact of conjugate vaccine in the elderly
Impact of Conjugate Vaccine in the Elderly

Indirect Impact on Rates of IPD in the Elderly

Increasing Rate of Non-Vaccine Serotypes

in Children

Approval of conjugate vaccine

Decreasing rate of

PCN-susceptibility here

ABCs Report, Emerging Infections Program Network

Huang SS, et al. Pediatrics 2005; 116:e408-414

Impact of conjugate vaccine in the elderly1
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

Evidence regarding pneumococcal vaccines in the elderly
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.

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.

Id biomedical approach to pneumococcal vaccine
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.

Protein vs polysaccharide based vaccines for s pneumo
Protein vs. Polysaccharide-based Vaccines for S. pneumo

Animal protection by id biomedical protein vaccine
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 ~ 103 LD50S. pneumo 14 d later.

Challenges in the development of a pneumococcal group common protein vaccine
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.

Issues 1
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.

Issues 2
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?

Issues 3
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