1

Immunological Correlates of Protection: Statistical Perspectives and Methods

Andrew J Dunning

Sanofi Pasteur

Fondation Mérieux

21 September 2009

2

Correlate of Protection

• Immunological assay whose values correlate with protection from disease

• Become „established‟, i.e. generally accepted, by

– references in standard texts (e.g. Plotkin/Vaccines; WHO Immunological Basis for Immunization Series)

– regulatory guidance (e.g. FDA/diphtheria, tetanus; FDA/influenza; WHO/pneumococcal)

– statements in vaccine package inserts/summary of product characteristics (regulatory approval)

3

Correlate of Protection – Questions

• Is a correlate of protection a level at which …– all individuals are protected? or

– 90% are protected? or

– a „population average‟ (50% protected)?

• Is it level to be achieved …– post-vaccination, when immune response is at its

highest• (possibly more relevant in vaccines research)

– or pre-exposure• (possibly more relevant in general scientific terms)?

• If an individual achieves a protective level, are they protected … – at the time the sample is taken

– for 1 year, 2 years, 5 years, 10 years

– for life

4

Correlate of Protection - Questions

• Is the threshold required for protection the same for infants, children, adolescents, adults, elderly?

• Does protective level depend on etiology of immune response being measured?

– natural infection

– killed vaccine

– live attenuated vaccine

– asymptomatic carriage

• How may these questions be answered in a quantitative sense?

5

Björkholm/diphtheria (1986)

0.01 IU/mL 0.1 IU/mL

?

1.0 IU/mL

7/10

1/7

0/6 0/21

Ppn.

Develo

pin

g D

isease

0.0

0.2

0.4

0.6

0.8

1.0

Diphtheria antitoxin IU/mL

<=0.0025 0.01 0.04 0.16 0.64 2.56

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Titer-Specific Rates of Disease

• Similar methods – inspection of titer-specific rates of disease:

– Ipsen/diphtheria 1946

– Goulon/tetanus 1972

– Neumann/measles 1985

– Chen/measles 1990

– White/varicella 1992

• See discussion in Siber 1997

• Selected level not necessarily predictive of vaccine efficacy

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Logistic regression: e.g. White/varicella

13/113

5/55 16/186

16/239

13/370

8/6175/891 3/988

Ppn.

Develo

pin

g D

isease

0.00

0.05

0.10

0.15

Six-week gpELISA Titer

<0.3 0.3-0.64

0.65-1.3

1.4-2.5

2.6-4.9

5.0-9.9

10 -19.9

>=20

8

Logistic regression - limitations

• Conclusion depends on length of surveillance and prevalence of disease

• Limited interpretability

– “for every increase of 1 in loge(gp ELISA) the risk of disease decreased by 51.7%”

• Models rate of disease, but interest is in protection

• Examples:

– Piedra (2003); Stehr (1998); Cherry (1998) Gustafsson (1996); Storsaeter (1998); Dagan (2005); Rapola (2003)

– see also Chan (2002)

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7-valent Pneumococcal Conjugate

• 7-valent pneumococcal conjugate vaccine efficacy trial (Black 2000)

– 38,000 infant subjects, randomized 1:1 to 7-valent pneumococcal conjugate vaccine or placebo

– subsets of 75 vaccinees and placebo recipients provided samples for assay

– 40 cases of invasive pneumococcal disease (none among assay subset)

• Titer-specific rates of disease cannot be used

– titers of cases not known

• Logistic regression cannot be used

– no cases in immunogenicity subset

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7v-PVC: Method of Chang & Kohberger

• Protective threshold is assay value at which relative risk of being below the value equals relative risk of disease (Jódar 2003)

• i.e. find tP such that:

threshold protective

(titer) valueassay t where

vaccinated not|DiseaseP

vaccinated|DiseaseP

vaccinated not|P

vaccinated|P:

P

P

PP

t

tt

ttt

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7v-PVC: Method of Chang & Kohberger

Cases = 39

Cases = 1

VE = 97.4%

RR = 0.026

2.3----- = 0.026

87.1

Protectivethreshold= 0.18

2.3%

87.1%

Susceptible Protected

Non-vaccinees Vaccinees

Dis

trib

ution

0.0

0.2

0.4

0.6

0.8

1.0

Pneumococcal IgG ELISA

0.001 0.010 0.100 1.000 10.000 100.000

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7v-PVC: Method of Chang & Kohberger

• Lead to adoption by WHO of 0.35 g/mL IgG reference level after pneumococcal conjugate vaccination (WHO 2005)

• Method also used for 1:8 SBA titer following meningococcal C conjugate vaccination (see Andrews 2003)

• Samples from subset of subjects sufficient

• Predictive of vaccine efficacy

• Population average measure

• Assumes same threshold for vaccinees and non-vaccinees

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Scaled logit model

• Bridges from disease to protection

• Incorporates exposure into logistic regression

• Useful paradigm: “Both exposure and susceptibility (i.e. lack of protection) are necessary for disease to occur, and together they are sufficient”

– (same paradigm applied in previous method)

• Refs./examples:– Dunning 2006, Forrest 2008, Nauta 2009, Coudeville

2010

ProtectedP1ExposurePDiseaseP

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Scaled Logit Model (varicella data)

exposure parameter = 0.118

logistic regression

scaled logit model

13/113

5/55 16/186

16/239

13/370

8/6175/891 3/988

Ppn.

Develo

pin

g D

isease

0.00

0.05

0.10

0.15

Six-week gpELISA Titer

<0.3 0.3-0.64

0.65-1.3

1.4-2.5

2.6-4.9

5.0-9.9

10 -19.9

>=20

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Scaled Logit Protection Curve

t_50

t_90

95% C.I

95% C.I

Pro

tection

0.0

0.2

0.4

0.6

0.8

1.0

Six-week gpELISA Titer

.13 .25 .5 1 2 4 8 16 32 64

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Scaled logit model

• Corresponds more closely to expectations in many cases

• Estimates protection rather than rate of disease

• Estimate of protection independent of length of surveillance or disease incidence

• Requires rich dataset; model fit not always achieved

• Protection curve conditional on exposure parameter; reliability of protection curve depends on small variance of estimated exposure parameter

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Principal Surrogate method

• Experimental method

• Because a subject cannot be „assigned‟ to an assay value, a designed experiment to test the relationship between assay value and disease cannot be devised

• Principal surrogate method applies causal inference methods

• Special study design or additional data needed

• Applied to „consistency‟ question – see Gilbert 2007, Follmann 2006 (and next slide)

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Classification scheme

• “Correlate of Risk” (weak) – high and low assay values associated with low and high risk of disease

• “Specific Surrogate of Protection” (medium) –reliably predicts vaccine efficacy from assay values in similar setting– relationship between assay value and protection

consistent for vaccinees and placebo recipients

• “General Surrogate of Protection” (strong) –reliably predicts vaccine efficacy from assay values in different settings– consistent for any immunological history – e.g.

different kinds of vaccine, immunity from natural infection, asymptomatic carriage, etc.

• see Qin 2007, Sadoff 2007

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Challenges: Statistical Methods

• Method for finding threshold in homogenous subjects (i.e. no vaccinee/non-vaccinee distinction)

• (see illustration next slide)

• Extension of exposure-based, continuous models (e.g. scaled logit)

– test for consistency; case-cohort design (see Qin 2008); direct method for CI for t50 and t90; tractable form of „Nauta Integral‟ (see Nauta 2009); more flexible/non-parametric models; goodness of fit

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e.g. Swedish Pertussis Pertactin data

13/26

31/53

12/18

16/27

7/18

8/12

1/15

2/15 2/17

0/6 0/1 0/1

Ppn.

Develo

pin

g D

isease

0.0

0.2

0.4

0.6

0.8

Pertussis PRN (Swedish)

.125 0.25 0.5 1 2 4 8 16 32 64 128 256

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Challenges: Statistical Methods

• Two threshold method of Chang & Kohberger

– without „same threshold‟ assumption

• Principal surrogate methodology applied to homogenous subjects (i.e. no vaccinee/ placebo recipient distinction)

• Link post-vaccination protection to pre-exposure protection

• (see illustration in following slide)

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Challenges: Post-vaccination/pre-exposure

post-vaccination assay

pre-exposure assay

disease

Assay V

alu

e

0

Time

0

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Challenges: Technical

• Protection is mediated through multiple immunological mechanisms of action, but assays only measure a single characteristic

• (see illustration next slide)

• Kinetics of immune response poorly understood• (see illustration next slide)

• Despite efforts to standardize assays, differences in immune responses to same vaccine observed in different trials

• Lack of cases among vaccinees, and lack of immune response among placebo recipients renders demonstration of consistency problematic

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Challenges: Mechanisms of action/kinetics

Assay V

alu

e

0

Time

0

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Challenges: Data

• Limited opportunities to collect data …– Both immunogenicity and disease occurrence data needed

• Vaccine licensure efficacy trial– one chance only? – may be unethical to conduct placebo-

controlled trial post-licensure

– incentivize sponsor to look for correlate

• Observational study– cost

– reliable surveillance

• Challenge study– ethical issues

• Acute-phase study– only certain diseases

– timing problematic

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Challenges: What’s possible?

• Sufficient assays cannot be conducted to fully describe immune response

• “Specific” correlates should be sought, specific to

– assay timing … (post-vaccination, pre-exposure)

– stimulus … (type of vaccine, etc.)

– population … (infants, adults, elderly, etc.)

• and

– case definition

– surveillance period (for post-vaccination assays)

• as well as the assay itself

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Questions?

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Acknowledgements/Collaboration

• Dr. Lennart Gustafsson, for making available the Swedish pertussis datasets

• Dr. Jo White, for assistance with the varicella dataset

• Cindy Chen, Hexin Zhang, Li Qin, Kamal Desai and Fabrice Bailleux - Threshold Methods for Immunological Correlates of Protection Research Group

• Jennifer Kensler, Laurent Coudeville, Amit Bhaumik and Fabrice Bailleux - Extensions to the Scaled Logit Model for Immunological Correlates of Protection Research Group

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References

• Plotkin SA, Orenstein WA, Offit PA. Vaccines (5th edition). Elsevier 2008.

• World Health Organization, Department of Immunization, Vaccines and Biologicals. Immunological basis for immunization series; accessed at http://www.who.int/vaccines-documents/DoxTrng/h4tibi.htm

• U.S. Department of Health and Human Services, Food and Drug Administration. Biological Products; Bacterial Vaccines and Toxoids; Implementation of Efficacy Review; Proposed Rule. Federal Register 1985; 50(240):51002-51117.

• U.S. Department of Health and Human Services, Food and Drug Administration, Center for Biologics Evaluation and Research. Clinical Data Needed to Support the Licensure of Seasonal Inactivated Influenza Vaccines, May 2007

• World Health Organization. Recommendations for the production and control of pneumococcal conjugate vaccines. Published as Annex 2 to WHO Technical Report Series, No. 927 2005;64-98.

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References

• Björkholm B, Böttiger M, Christenson B, Hagberg L. Antitoxin antibody levels and the outcome of illness during an outbreak of diphtheria among alcoholics. Scandinavian Journal of Infectious Diseases 1986; 18(3):235-9

• Ipsen J. Circulating antitoxin at the onset of diphtheria in 425 patients. Journal of Immunology 1946; 54:325-347

• Goulon M, Girard O, Grosbuis S, Desormeau JP, Capponi MF. Antitetanus antibodies: Assay before anatoxinotherapy in 64 tetanus patients. Nouveau Presse Medicin 1972; 1(45):3049-50.

• Neumann PW, Weber JM, Jessamine AG, O'Shaughnessy MV. Comparison of measles antihemolysin test, enzyme-linked immunosorbent assay, and hemagglutination inhibition test with neutralization test for determination of immune status. Journal of Clinical Microbiology 1985; 22(2):296-8

• Chen RT, Markowitz LE, Albrecht P, Stewart JA, Mofenson LM, Preblud SR, Orenstein WA. Measles antibody: reevaluation of protective titers. Journal of Infectious Diseases 1990; 162(5):1036-42.

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References

• White CJ, Kuter BJ, Ngai A, Hildebrand CS, Isganitis KL, Patterson CM,Capra A, Miller WJ, Krah DL, Provost PJ, Ellis RW, Calandra GB. Modified cases of chickenpox after varicella vaccination: correlation of protection with antibody response. Pediatric Infectious Disease Journal 1992; 11:19-23

• Siber GR. Methods for estimating serological correlates of protection. Developments in Biological Standardization 1997; 89:283-296

• Piedra PA, Jewell AM, Cron SG, Atmar RL, Glezen WP. Correlates of immunity to respiratory syncytial virus (RSV) associated-hospitalization: establishment of minimum protective threshold levels of serum neutralizing antibodies. Vaccine 2003; 21(24):3479-3482.

• Stehr K, Cherry JD, Heininger U, Schmitt-Grohé S, Überall M, Laussucq S, Eckhardt T, Meyer M, Engelhardt R, Christenson P, the Pertussis Vaccine Study Group. A comparative efficacy trial in Germany in infants who received either the Lederle/Takeda acellular pertussis component DTP (DTaP) vaccine, the Lederle whole-cell component DTP vaccine, or DT vaccine. Pediatrics 1998; 101(1):1-11.

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References

• Cherry JD, Gornbein J, Heininger U, Stehr K. A search for serologic correlates of immunity to Bordetella pertussis cough illnesses. Vaccine 1998; 16(20):1901-1906.

• Gustafsson L, Hallander HO, Olin P, Reizenstein E, Storsaeter J. A controlled trial of a two-component acellular, a five-component acellular, and a whole-cell pertussis vaccine. New England Journal of Medicine 1996; 334(6):349-55.

• Storsaeter J, Hallander HO, Gustafsson L, Olin P. Levels of anti-pertussis antibodies related to protection after household exposure to Bordetella pertussis. Vaccine 1998; 16:1907–16.

• Dagan R, Givon-Lavi N, Fraser D, Lipsitch M, Siber GR, Kohberger R. Serum serotype-specific pneumococcal anticapsular immunoglobulin g concentrations after immunization with a 9-valent conjugate pneumococcal vaccine correlate with nasopharyngeal acquisition of pneumococcus. Journal of Infectious Diseases 2005; 192(3):367-76.

• Rapola S, Jäntti V, Eerola M, Mäkelä PH, Käyhty H, Kilpi T. Anti-PsaA and the risk of pneumococcal AOM and carriage. Vaccine 2003; 21:3608-3613.

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References

• Black S, Shinefield H, Fireman B, Lewis E, Ray P, Hansen JR, Elvin L, Ensor KM, Hackell J, Siber G, Malinoski F, Madore D, Chang I, Kohberger R, Watson W, Austrian R, Edwards K. Efficacy, safety and immunogenicity of heptavalent pneumococcal conjugate vaccine in children. Pediatric Infectious Disease Journal 2000; 19(3):187-95.

• Jódar L, Butler J, Carlone G, Dagan R, Goldblatt D, Käyhty H, Klugman K, Plikaytis B, Siber G, Kohberger R, Chang I, Cherian T. Serological criteria for evaluation and licensure of new pneumococcal conjugate vaccine formulations for use in infants. Vaccine 2003; 21(23):3265-72.

• Andrews N, Borrow R, Miller E. Validation of serological correlate of protection for meningococcal C conjugate vaccine by using efficacy estimates from postlicensure surveillance in England. Clinical & Diagnostic Laboratory Immunology 2003; 10(5):780-6

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References

• Dunning AJ. A model for immunological correlates of protection. Statistics in Medicine 2006; 25:1485-97

• Forrest BD, Pride MW, Dunning AJ, Capeding MR, Chotpitayasunondh T, Tam JS, Rappaport R, Eldridge JH, Gruber WC. Correlation of cellular immune responses with protection against culture-confirmed influenza virus in young children. Clinical and Vaccine Immunology 2008 Jul;15(7):1042-53.

• Nauta JJ, Beyer WE, Osterhaus AD. On the relationship between mean antibody level, seroprotection and clinical protection from influenza. Biologicals 2009; 37(4):216-21.

• Coudeville L, Bailleux F, Riche B, Megas F, André P, Ecochard R. Relationship between haemagglutination-inhibiting antibody titres and clinical protection against influenza: development and application of a bayesian random-effects model. BMC Medical Research Methodoogy 2010; 10(1):18

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References

• Follmann D. Augmented designs to assess immune response in vaccine trials. Biometrics 2006; 62(4):1161-9.

• Gilbert PB, Qin L, Self SG. Evaluating a surrogate endpoint at three levels, with application to vaccine development. Statistics in Medicine 2008; 27(23):4758-78.

• Qin L, Gilbert PB, Corey L, McElrath MJ, Self SG. A framework for assessing immunological correlates of protection in vaccine trials. Journal of Infectious Diseases 2007; 196(9):1304-1312

• Sadoff JC, Wittes J. Correlates, surrogates, and vaccines. Journal of Infectious Diseases 2007; 196(9):1279-81.

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Backup slides

37

Correlate of Protection – Uses

• Protective thresholds used for

– assessment of individual protection

– as alternative to vaccine efficacy trial

– as means of quantifying response to new vaccine candidate

– to compare immunogenicity of two vaccines – non-inferiority trial

– vaccine non-interference trial

– vaccine lot consistency trial

– estimation of duration of protection

38

Other approaches

• Surrogate endpoint (Prentice criteria)

• Diagnostic testing (sensitivity and specificity)

Surrogate Endpoint Correlate of Protection

True endpoint Disease

+ +

+ 0 t < tP

Surr

oga

te

endp

oin

t

0 t tP 0

39

Interpretation: Stephen Senn

0.0 0.4 0.8 1.2

standard error

-2

-1

0

1

2

3

4

log-o

dds r

atio

31 Placebo-Controlled Trials of Cimetidine

Significant (Yates)

Not-significant

Upper control limit

Lower control limit

significance boundary