New Vaccines for Pneumococcal Disease Prevention in Adults

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					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
Vaccines and Related Biological Products Advisory Committee CBER, FDA March 8, 2001 Point of discussion:
“ Please discuss whether non-inferiority immune response trials comparing a new pneumococcal

Bethesda, Maryland

conjugate vaccine with Prevnar are sufficient for inferring efficacy against invasive disease for the new product. “

Discussion before the VRBPAC
Point of discussion:
“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 “

Committee opinion:

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

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.

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?

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

 

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

What were the endpoints used? ENDPOINT: 90% of Immunized adults should have a four-fold or greater increase in bactericidal antibodies against 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

Hemophilus b conjugate vaccine
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.

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

An observation:

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

Why ?

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:
Any new pneumococcal vaccine is likely to

contain additional serotypes not in the currently licensed conjugate vaccine 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. But, how different are the immune

responses to individual serotypes? Use of reverse cumulative distribution curves may provide valuable information for evaluation
of the full spectrum of the immune response.

Reverse cumulative distribution curve
RCD curves used for comparison of vaccines

Conclusion:
What immune response endpoint measures could be used?
Antibody quantitation - ELISA • Geometric mean concentration (GMC)

• •

Percent seroconversion to a threshold value Reverse cumulative distribution curves

Functional activity of induced antibodies

•

Opsonophagocytosis


				
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