# Presentation: 521174

## Statistical Issues Related to

- Pneumococcal Vaccine Evaluation
- Brian D. Plikaytis
- Centers for Disease Control and Prevention

## Statistical Issues Related to

- Pneumococcal Vaccine Evaluation

-  Briefly summarize WHO meeting, June, 2003

-  Discuss non-inferiority in the context
-      of T-cell independent vaccines

-  Extend these points to T-cell dependent vaccines

-  Use of multiple correlate endpoints
-      to predict protection

## T-cell Independent Vaccine

- Antibody Level

- Time

- Licensed vaccine

- New vaccine

- threshold or reference

## Endpoints for Vaccine Comparison

-  Antibody response (GMC)

-  Proportion above threshold or reference level

-  Additional assays / endpoints?

-  Opsonophagocytic Titer (GMT)

-  Fold-increase in titer (% fold-responders)

## Hypothesis Testing

## T-cell Independent Vaccine

- Lic. Vac –
- New Vac

- Licensed vaccine

- New vaccine

- threshold or reference

- Antibody Concentrations or Titers

- Antibody Level

## T-cell Independent Vaccine

- Licensed vaccine

- New vaccine

- threshold or reference

- Lic. Vac –
- New Vac

- Antibody Concentrations or Titers

- Antibody Level

## T-cell Independent Vaccine

- Licensed vaccine

- New vaccine

- threshold or reference

- Lic. Vac –
- New Vac

- Antibody Level

- Antibody Concentrations or Titers

## T-cell Independent Vaccine

- Lic. Vac –
- New Vac

- Licensed vaccine

- New vaccine

- threshold or reference

- Antibody Concentrations or Titers

- Antibody Level

- Δ

- Equivalence boundary for
- testing non-inferiority (Δ)

## T-cell Independent Vaccine

- Lic. Vac –
- New Vac

- Licensed vaccine

- New vaccine

- threshold or reference

- Antibody Concentrations or Titers

- Antibody Level

- Equivalence boundary for
- testing non-inferiority (Δ)

- Δ

## T-cell Independent Vaccine

- Licensed vaccine

- New vaccine

- threshold or reference

- Proportion ≥ Threshold

- Licensed vaccine

- New vaccine

- threshold or reference

- Antibody Level

- Proportion Above Threshold

- Time

## T-cell Independent Vaccine

- Time

- Diff in Prop.
- ≥ Threshold

- Licensed vaccine

- New vaccine

- Proportion ≥ Threshold

- threshold or reference

- Proportion Above Threshold

## T-cell Independent Vaccine

- Time

- Licensed vaccine

- New vaccine

- Proportion ≥ Threshold

- threshold or reference

- Proportion Above Threshold

- Equivalence boundary for
- testing non-inferiority (Δ)

- Δ

- Δ for diff. in prop.
-  thresh. = 0.10

- Diff in Prop.
- ≥ Threshold

## Is Antibody Response an Accurate Correlate

- Antibody Level

- Licensed vaccine

- New vaccine

- Natural exposure
- or vaccine boost

- Priming Dose Series

- for T-cell Dependent Vaccines?

- threshold or reference

## Predicting Protection

- Given that we can measure more than one
-      correlate of protection ....

- How do we utilize them to predict protection
-      more effectively than each test individually?

## Predicting Protection

- Antibody Concentration

- Sn=95%
- Sp=93%

- Frequency

- Unprotected

- Protected

## Predicting Protection

- Frequency

- Sn=90%
- Sp=90%

- Titer

- 8

- 16

- 32

- 64

- 128

- 256

- 512

- 1024

- 4

- Unprotected

- Protected

## Predicting Protection

- Antibody Concentration

- Titer

- 8

- 16

- 32

- 64

- 128

- 256

- 512

- 1024

- 4

- r = 0.64
- r2 = 0.41

## Predictive Model Building

- IS =	immunologic ‘score’
- xi =	correlate data
- bi =	model coefficients
- p =	number of variables in the model

- Multiple approaches
- logistic discriminant analysis, cluster analysis, other exploratory techniques (CART, etc.)
- Logistic Discriminant Analysis
- Model relates a series of assay endpoints to protection
- Construct a discriminant function from results:

## Immune Response vs. Protection  Model Building  

- 1

- 0

- Protected

- Unprotected

- Immune Response vs. Protection  Model Building

- Antibody Concentration

- (Protected)

- (Unprotected)

## Predicting Protection

- Antibody Concentration

- Titer

- 8

- 16

- 32

- 64

- 128

- 256

- 512

- 1024

- 4

- r = 0.64
- r2 = 0.41

## Predicting Protection

- Antibody Concentration

- Titer

- 8

- 16

- 32

- 64

- 128

- 256

- 512

- 1024

- 4

- Sn=97%
- Sp=97%

## Predicting Protection

- Antibody Concentration

- Sn=95%
- Sp=93%

- Frequency

- Unprotected

- Protected

## Predicting Protection

- Immunologic Score

- Sn=97%
- Sp=97%

- Frequency

- Unprotected

- Protected

## Limitations

-      acquired from vaccine evaluation studies.

-  Protected/unprotected status must be determined
-      using criteria independent of the analysis
-      variables

-  If more than two correlates exist, one of them may
-      serve to define protected/unprotected status

-  For this to work, multiple lab tests will need to be
-      run on all specimens (assay multiplexing?)

-  For highly efficacious vaccines, pool of unprotecteds
-      will be small

## RCD Curves for Vax and Control Groups at 4 Weeks Post Dose 3†

- 100

- 0

- 20

- 40

- 60

- 80

- 0.01

- 0.1

- 1

- 10

- 100

- Ab Concentration

- % >= Ab Conc

- Vaccine

- Control

- RCD Curves for Vax and Control Groups at 4 Weeks Post Dose 3†

- †Jódar, L., *et al.,* Vaccine, 21:3265-3272, 2003.

## Schematic RFD Curves for Vax and Control Groups at 4 Weeks Post Dose 3

- Schematic RFD Curves for Vax and Control Groups at 4 Weeks Post Dose 3

- Ab Concentration

- Relative
- Frequency

- Vaccine

- Control

## Conclusions / Questions

-  T-cell dependent vaccines complicate using
-      circulating antibody levels as a sole correlate
-      for protection (develop new correlates?)

-  Study endpoints need to be carefully selected
-      to fully optimize group comparisons

-  Two or more correlates may be utilized to better
-      predict vaccine protection (aid in licensure?)

## Slide 29

## Serological Criteria for the Evaluation and Licensure of New 

- Pneumo. Conj. Vaccine Formulations for Use in Infants

-  IgG [Ab] measured by ELISA from sera collected
-      4 weeks after 3 dose primary series

-  Single threshold or reference level of 0.35 μg/ml

-  Threshold defined using ELISA without 22F
-      absorption

-  ELISA should be calibrated against reference
-      assay (standardization)

-  Threshold not necessarily predictive of protection
-      in an individual

## Serological Criteria for the Evaluation and Licensure of New 

- Pneumo. Conj. Vaccine Formulations for Use in Infants

-  Alternative assays should be bridged to derive
-      equivalent threshold concentration

-  Proportion of responders above threshold
-      should be used to determine noninferiority

-  Noninferiority for each serotype in the registered
-      vaccine desirable but not required.

-  New serotypes compared to aggregate response
-      of serotypes in registered vaccine

-  Head-to head comparison with registered
-      vaccine preferred

## Serological Criteria for the Evaluation and Licensure of New 

- Pneumo. Conj. Vaccine Formulations for Use in Infants

-  Demonstrate functional activity of antibody using
-      opsonophagocytic assay

-  Opsono. assay should be comparable to
-      reference assay (standardization)

-  Avidity of antibodies also a useful marker for
-      immunological memory

-  Evidence of memory should be demonstrated
-      using a booster dose of pneumo. PS vaccine

## Further Information:

- and Prevention

- Plikaytis, B.D., Carlone, G.M., Statistical Considerations for Vaccine Immunogenicity Trials, in *Carbohydrate Based Vaccines,* Chris Jones and Neil Ravenscroft, editors,  Blackwell Science, Ltd., Oxford, submitted.

- World Health Organization

- Sponsors: