# Presentation: 627363

## New Vaccines for Pneumococcal Disease Prevention in AdultsA Regulatory viewpoint on Laboratory Endpoints needed for licensure

**Carl E. Frasch**
- Center for Biologics Evaluation and Research, Bethesda, Maryland

## Use of immunological endpoints was a Discussion topic presented to

-           “ Please discuss whether non-inferiority immune      response trials comparing a new pneumococcal      conjugate vaccine with Prevnar are sufficient      for inferring efficacy against invasive disease      for the new product. “

- Point of discussion:

- Vaccines and Related Biological Products Advisory Committee CBER, FDA
- March 8, 2001               Bethesda, Maryland

## Discussion before the VRBPAC

-    The majority of the committee members agreed   that non-inferiority studies comparing a new    pneumococcal conjugate vaccine with Prevnar would be   sufficient for inferring efficacy

- Point of discussion:

- Committee opinion:

## Another consideration from

-  the VRBPAC discussion

- While efficacy studies for additional serotypes not included in Prevnar would be ideal, the committee
- concluded that such studies would not be feasible.

- They therefore concluded that immunological parameters  [endpoints] could be used to infer efficacy of additional serotypes.

## But what Endpoints?

-  the VRBPAC discussion

- While efficacy studies for additional serotypes not included in Prevnar would be ideal, the committee
- concluded that such studies would not be feasible.

- They therefore concluded that immunological parameters  [endpoints] could be used to infer efficacy of additional serotypes.

## Polysaccharide containing vaccineshave been licensed by the FDA basedupon immunological endpoints

- The vaccines:
-   Quadrivalent meningococcal polysaccharide vaccine
-   23-valent pneumococcal polysaccharide vaccine
-   Haemophilus b conjugate vaccine (PRP-T)

## Meningococcal ACYW135 quadrivalent polysaccharide vaccine replaced the AC polysaccharide vaccine

- What were the endpoints used?

-   Earlier studies had clearly shown that protective    immunity resulted from induction of bactericidal antibodies
-   The AC polysaccharide vaccine was licensed on basis of     clinical efficacy

- ENDPOINT: 90% of Immunized adults should havea four-fold or greater increase in bactericidal antibodiesagainst each of the four serotypes

## Pneumococcal 23-valent polysaccharide vaccine replaceda 14-valent polysaccharide vaccine based upon immunological endpoints

- Basis for licensure by the FDA

- Know that one mode of protection is presence of serotype specific anti-capsular opsonic antibodies
- The present 23-valent vaccine was licensed and replaced the earlier 14-valent vaccine based upon demonstration of:
-    Induction of increased opsonic antibody titers to       each serotype
-    Two-fold or greater increase in antibody      concentration to each pneumococcal type

## PRP-T was licensed based upon Immunological endpoints rather than a classical clinical efficacy trial

**1.****  ****Randomized comparative immunogenicity**
**      ****in infants with a similar currently approved****       vaccine****.**
**2.****  ****Persistence of antibody after the primary**
**     ****immunization series up to the time of the****     recommended booster dose.**

- Hemophilus b conjugate vaccine

## Immunological endpoints used for approval of PRP-T

- 3**.****  Priming of infants by conjugate for a****     subsequent booster response to the native****     *****H.influenzae *****type b polysaccharide given six****     to nine months after the primary immunization.**

**   ****Simulates natural exposure**
**   ****Demonstrates immunologic memory**

- 4.** ****Functional capacity of the conjugate-induced****     antibodies measured by  bactericidal  activity.**

## Immunological endpoint considerations for a new  pneumococcal conjugate vaccine for adults

-   Measure IgG antibody concentration 1 month after     immunization in comparison with licensed product
-   Use 22F polysaccharide or comparable absorption of sera     from adults used in the ELISA quantitation
-   Use a single conservative threshold antibody concentration     for all pneumococcal types
-   Demonstrate induction of opsonic antibodies against all     serotypes in the vaccine
-   _Immunologic memory_:  Demonstration in adults will not be     useful, because of repeated prior exposure to pneumococcal     and cross-reactive polysaccharides

## Why ?

- Use of seroconversion to an agreed upon threshold
- value for each serotype, may be preferable to using GMC as the primary endpoint comparison

## Use of geometric mean versus proportion of responders greater than a threshold

-    Comparisons between vaccines based upon their geometric mean shows    which vaccine induces the highest overall antibody concentrations
-   Use of a threshold provides information on the proportion of vaccinees who     achieve an antibody response predicted to be protective
-    Use of percent of vaccinees over a threshold may provide a more accurate     indication of vaccine effectiveness, if a protective level is known
-    Should use a threshold that is predictive of long term protection
-    A point for consideration:  Is it useful to have two threshold values, predictive of     short and long term protection?

## Use of geometric mean versus proportion of responders greater than a threshold

**Important Caveats:**
-    The level that predicts protection against invasive disease may not predict    protection against pneumonia
-    A threshold value derived from studies in *young children* may not to be      a useful vaccine comparator for adults, since most adults,  pre-immunization,     are above this threshold:

- Study of 140 blood donors conducted at CBER
-   Type	   Percent > 0.35 mg/ml
-    4			88.6 %
-    6B			66.4 %
-    9V			66.4 %
-   19F			90.0 %
- Used 22F absorption

## Concerning new serotypes:

- In place of clinical efficacy for such serotypes it will be important to demonstrate  that:
-   Antibodies induced to these additional serotypes    are opsonophagocytic
-   These serotypes have immunogenicity    comparable to present serotypes

## In contrast to the earlier monovalent Haemophilus b conjugate vaccines,

- Pneumococcal conjugate vaccines are a combination of 7 to 11 different immunogens

- We must therefore consider this greater complexity in our analysis of the antibody response to immunization

## The antibody response to some serotypes in thenew vaccine may be superior or inferior comparedto that of the licensed product.

- Use of reverse cumulative distribution curves may provide valuable information for evaluation of the full spectrum of the immune response.

- But, how different are the immuneresponses to individual serotypes?

## Reverse cumulative distribution curve

- RCD curves used for comparison of vaccines

## Conclusion:

**Antibody quantitation - ELISA**
-    Geometric mean concentration (GMC)
-    Percent seroconversion to a threshold value
-    Reverse cumulative distribution curves

**Functional activity of induced antibodies**
-    Opsonophagocytosis