# Presentation: 446292

## 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
- 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

**Approval of conjugate vaccine**

*ABCs Report, Emerging Infections Program Network*

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

**Decreasing rate of **
**PCN-susceptibility here**

**Indirect Impact on Rates of IPD in the Elderly**

**Increasing Rate of Non-Vaccine Serotypes **
**in Children**

## 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

- 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 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

|  | 
Group-Common Protein-based | Capsular Polysaccharide-based
(23-PS and Conjugates) |
| --- | --- | --- |
| Serotype coverage | Potentially all | Limited, geographic diversity |
| Serotype substitution | No | Demonstrated in children, importance TBD in adults |
| Escape mutants | Possible, TBD | No |
| Complexity of manufacture & release | Relatively low, single high-yield recombinant | Moderately to very high (esp. for conjugates) |
| T cell help | Intrinsic | Requires 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 | Good | Low |

## 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.**

## 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)

- 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)

- 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)

- 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