Controlled human infection models Andrew J Pollard FMedS ci - - PowerPoint PPT Presentation

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Controlled human infection models Andrew J Pollard FMedS ci - - PowerPoint PPT Presentation

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Controlled human infection models Andrew J Pollard FMedS ci Smallpox & variolation Lady Mary Montagu Variolation of 6 prisoners in exchange for pardon (England, 1722) Variolation of orphans to assess safety in children (London,

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Controlled human infection models

Andrew J Pollard FMedS ci

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Smallpox & variolation

  • Variolation of 6

prisoners in exchange for pardon (England, 1722)

  • Variolation of orphans

to assess safety in children (London, 1722)

Lady Mary Montagu

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Jenner & vaccination

S arah Nelmes Edward Jenner vaccinating James Phipps, 1796

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1802

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Wolfgang Casper: gonococcal vaccine

  • Rudolf Virchow Hospital, Berlin (1930)
  • 5 vaccinees & 5 cont rols
  • ‘ exposed’ to a commercial sex worker on

a hospital ward

  • Attack rates: 0/ 5 in vaccinees vs. 4/ 5 in

cont rols

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Unethical studies during WWII

  • S

tudies performed by Nazi Waffen-S S doctors in concentration camps

  • S

potted fever, also yellow fever, smallpox, cholera, tuberculosis etc.

  • High lethality in control subj ects (+/ -1000

died at Buchenwald)

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The Nuremburg Code

  • The Doctors’ Trial
  • US

A vs. Karl Brandt and others – US Milit ary Tribunal Nuremburg, 19 July 1947

  • Based on 6 initial points used to define

legitimate medical research – a further 4 were added by Nuremburg Trial verdict # 1. The voluntary consent of the human subject is absolutely essential

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Other infamous cases

  • Japanese, Unit 731 (1937 – 1945)

– Experimentation with infectious agents – Infants, elderly and pregnant women – Syphilis, gonorrhoea, plague, cholera, smallpox, botulism, typhoid, TB

  • Willowbrook State School – Hepatitis A studies

(mid 1950s – early 1970s).

– Deliberate infection of children with hepatitis A to study spread

  • Syphilis studies in Tuskegee (1932-1972)

– Natural history of syphilis in 622 Africa- Americans…naturally infected and not treated. Followed for 40 years, and not given penicillin even after it became routine treatment.

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Other challenge studies, 1950s - 1974

  • Many experimental

challenge studies performed using incarcerated prisoners

– Malaria, typhoid,

shigella, influenza, diarrhoeal E. coli, viral gastroenteritis, tularaemia

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Common Cold Unit

  • 1946 -1990, S

alisbury (UK)

  • Rhinovirus & coronavirus
  • >20,000 volunteers
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Number of trials

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Number of volunteers per trial

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22,257 and counting

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ETHICAL, LEGAL AND SAFETY CONSIDERATIONS

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https:/ / acmedsci.ac. uk/ policy/ policy- proj ects/ controlled- human-infection- models Informed consent Minimise risk

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Et hical approval

http://www.reviewingresearch.com/human-challenge-studies/

Dr Hugh Davies, Ethics committee chair “ Challenge studies should not be considered ethically unacceptable. To the contrary, they may sometimes be ethically

  • required. “
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Regulatory considerations

  • Quality – GMP
  • Trial protocol
  • Regulation in UK?
  • Environmental and Public

S afety (DEFRA)

  • Pathway to licensure

– Timing of challenge aft er

immunisation

– S

train select ion/ number of strains

– Geographic locat ion of

volunteers

– Dose of challenge strain

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Regulat ory confusion

  • FDA
  • EMA
  • WHO
  • EU directive for national regulators

– Different interpretations – MHRA

  • EU regulations coming, but still not clear
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Use and development stage

  • f some current challenge

studies

Darton, 2015

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ROLE IN VACCINE DEVELOPMENT

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Vaccine development pathway

Phase I S afe? Immune response? Phase II Best dose? S afe? Immune response? Phase III* Does it work? licensure Post approval studies (Phase IV) Discovery Pre- clinical immune response? Protect?

* Or bridging/ Phase IIb studies Which

  • Candidate?
  • Dose?
  • Formulation?

Direct measure of protective efficacy

  • nb. part icipant select ion

CORRELATES

CORRELA TES?

Identification of endpoints & diagnostics Bridging Cross protection Identification

  • f possible

candidates

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Regulat ory issues

  • Don’ t get hung up…

.it is j ust a model

  • Is it the right target population
  • Naïve or immune
  • Dose/ Route of challenge agent
  • Manufacturing quality: To GMP or not to

GMP?

  • Wild-type or attenuated strain
  • Which strain and how many strains?
  • What endpoints are relevant?
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Children

  • S

cient ific j ustification

  • Ethical j ustification
  • Regulatory j ustification
  • It is j ust a model
  • Never say never?
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Licensure pathway

  • Considerable attention to licensure
  • Perhaps greater role envisaged

– S

upporting data for licensure

– Confidence to move forwards – Down selection – correlates

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Up to 90% efficacy The vaccine's efficacy was demonstrated in a randomized, placebo-controlled human challenge study of 197 US volunteers 18 to 45 years of age, the agency reported. Of the 197 volunteers, 68 Vaxchora recipients and 66 placebo recipients were challenged by oral ingestion of V cholerae. Vaccine efficacy was 90% among those challenged 10 days after vaccination and 80% in those challenged 3 months after vaccination.

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Andrew J Pollard

Department Away Day 20/8/18

Mogasale 2014

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No efficacy data

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A controlled human infection model in Oxford established 2011

Progress to date

Funded by

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Typhoid attack rates

Waddington, Clin Infect Dis, 2014

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Relative efficacy Correlates Persistence S hedding B cell repertoire

Vi conjugate vaccine

Celina Jin

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Study Recruitment

Recruitment perio iod August 2015 to November 2016 Unblinding 5th January 2017

ENROLMENT VACCINATION CHALLENGE

Yes responses (n=1486) Medical screening (n=207) Enrolled and Randomised (n=11 112)

Did not respond (n=120,750) Return to sender (n=1431) Declined participation (n=1051) Not eligible (n=639) Declined further participation (n=640) Excluded at screening (n=73) Declined further participation (n=22)

Invitation letter sent (n=124,718) Vi-T

  • TT (n=41)

Vi-P

  • PS (n=37)

Cont

  • ntrol (n=34)

Withdrew (n=4) Withdrew (n=2) Withdrew (n=2)

Challenged (n=37) Challenged (n=35) Challenged (n=32)

Excluded (n=1)

Completed Challenge (n=37) Completed Challenge (n=35) Completed Challenge (n=31)

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VE 54-87%

Cumulative proportion of participants with fever 38.0 C followed by positive S. Typhi culture

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Anti-Vi-TT higher than anti-Vi-PS

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Persistence of antibody good for 7 months

Log10 anti-Vi IgG (ELISA units/ml)

Challenge timing?

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Herd immunity?

Odds of shedding overall are 3 t imes higher if unvaccinat ed (averaged across all 14 days)

Vaccin e Comparato r OR (95% CI) P Cont rol Vi-PS 3.28 (1.31, 8.19) 0.0111 Cont rol Vi-TCV 2.88 (1.18, 7.06) 0.0208 Vi-PS Vi-TCV 0.88 (0.37, 2.11) 0.7729

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Pre-existing estimates of correlates of protection for Vi-vaccines exist, but are difficult to reproduce

Vaccine, 1996 Vaccine, 2014

1.4– 2.0µg/ml 0.6– 1.2µg/ml

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Probabilit y of t yphoid infect ion

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Bivalent

  • Typhoid (Vi) –

Paratyphoid (LPS )

  • Efficacy trials for paratyphoid bordering
  • n unlikely to be feasible
  • Licensure on typhoid component with

supporting data on paratyphoid component?

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  • G. Dougan
  • J. Choudhary

S . Mukhopadhyay S . Clare

  • M. Duque
  • F. S

chreiber

  • M. Levine
  • M. S

zt ein

(Para)Typhoid team

  • V. Cerundolo
  • A. S

immons

  • L. Preciado-Llanes
  • G. Napolitani
  • P. Kurupati

Oxford Tom Darton, Claire Jones, Helene Juel, Celina Jin, Helena TB, Liqing Zhou, S

  • nu

S hrestha, Malick Gibani, Hazel Dobinson, Claire Waddington

Neelam Adhikari, S hrij ana S hrest ha, Imran Ansari, Meeru Gurung, S t ephen Thorson, Buddha Basnyat, Mila S hakya and many more… . Kat hy Neuzil Tony Marfin