A CONSIDERATION OF H1N1/09pdm AND

NEW VARIANT H3N2/13 AS AGENTS FOR

HUMAN CHALLENGE TRIALS

Dr. Adrian Wildfire

Project Director; Infectious Disease and HCU

CLINICAL TRIAL SOLUTIONS SGS - World Vaccine Congress – Washington, March 30th, 2016

2

INTRODUCTION

Influenza viruses make ideal agents for study owing to the

transient yet well characterised nature of the illness

Influenza-like illnesses have been documented as causing

pandemics since 876 A.D.

H1N1 and H3N2 serotypes have caused the majority of the

pandemics in the 20th and 21st Centuries

Currently circulating H1 and H3 strains are relative of past

circulating strains e.g. A/Wuhan/359/95 (H3N2) is a drifted

distant relative of the 1968 Hong Kong H3N2 strain

Both H1 and H3 strains have epidemic and pandemic

potential – antigenic drift and shift (reassortment) cause

flares in transmission or ‘waves’ of recurrence

Using cGMP manufactured H1 or H3 viruses in Human

Challenge Trials can emulate high incidence disease

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THE ORIGINS OF INFLUENZA

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A NEW PHYLOGENETIC ANALYSIS*

New evidence suggests influenza originated in bats and

most likely spread sequentially to horses, poultry and

swine before entering humans about 6000 years ago

Reassortment of 18 HA and 11 NI genes lead to new

serotypes of influenza

Influenza strains in poultry show rapid rates of mutation

H1, H2, H3, N1 and N2 – have evolved sustained

transmission into humans

Pandemic H1N1 and H3N2 originated approximately

towards the end of the 19th century. H1N1 when a major

reassortment coincided with a horse flu outbreak

H3N2 and H1N1 have been responsible for serial

pandemics since 1900

*http://www.nature.com/nature/journal/v508/n7495/full/nature13016.html

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THREE PANDEMICS PER CENTURY

The 11 pandemics since 1700, listed by the year they started:

1729 – ?

1732 – ?

1781 – ?

1830 –

H1?

1833 –

H1?

1889 –

H3N8

1918 –

H1N1

1957 –

H2N2

1968 –

H3N2

1977 –

H1N1

2009 –

H1N1

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H1 and H3 - Serial pandemics since the 19th Century

THE PREDOMINANCE OF CIRCULATING H1

AND H3 SEROTYPES

Palese P (December 2004). "Influenza: old and new threats". Nature Medicine 10 (12 Suppl): S82–7.

doi:10.1038/nm1141. PMID 15577936.

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H1N1 AND H3N2 – GLOBAL PREVALENCE

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H1N1 AND H3N2: 2015 – 2016 FLU SEASON

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CLINICAL CHARACTERISTICS

OF H1, H3 INFLUENZA

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FLU - SIGNS AND SYMPTOMS*

(PANDEMIC H1, H3)

temperature – 102 to 104oF

sore throat

exhaustion

headache

aching limbs

bloodshot eyes

cough

nosebleeds

vomiting or diarrhoea

relapse and respiratory problems

pulmonary haemorrhages

*30-50% of influenza cases may be asymptomatic

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CASE FATALITIES

Name of pandemic Date Deaths Case Fatality

Rate Subtype involved

Pandemic

Severity Index

1889–1890 flu

pandemic

(Asiatic or Russian

Flu)

1889–1890 1 million 0.15% H3N8

2

1918 flu pandemic

(Spanish flu) 1918–1920 20 to 100 million 2% H1N1 5

Asian Flu 1957–1958 1 to 1.5 million 0.13% H2N2 2

Hong Kong Flu 1968–1969 0.75 to 1 million <0.1% H3N2 2

Russian flu 1977–1978 N/A N/A H1N1 N/A

2009 flu pandemic

(Worldwide) 2009–2010 18,000 to 284,500 0.03% H1N1/09 1

Annual flu virus

deaths (USA only) 1976-77 to 2006-07 3,000 to 46,000 N/A N/A N/A

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H1N1 vs H3N2 – SEVERITY AND SEQUELAE

Influenza A H3N2 infection infections are more severe than

A H1N1 in terms of fever, leucopoenia and CRP

Mean ages for attack are 33 +/- 8.4 years (H1N1), and 41

+/- 15.2 years (H3N2)

A greater number of hospitalisations occur during years

that influenza A(H3N2) is predominant

Pneumonia is positively associated with vaccination

Seasons with prominent circulation of influenza A(H3N2)

viruses have 2.7 times more deaths associated.

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H1, H3 AND IMMUNITY

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INFLUENZA – H1 IMMUNITY

Influenza promotes a strong protective antibody response to

surface haemagglutinin and neuraminidase antigens

Severity of disease correlates to prior exposure

Full-length H1 HA antigens induce a profound HI and NAb

response*

H1N1/09pdm immunity increases with age and does

not does not correlate to pre-seasonal HI titres

*http://jvi.asm.org/content/80/23/11628.full

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INFLUENZA – H3 IMMUNITY

Since 2010, all circulating influenza strains are showing a

decreased ability to agglutinate

H3 HA genes mutate more rapidly than H1 – H3 has a greater

propensity to vaccine failure or escape

Both full-length and secreted, transmembrane-truncated H3 HA

antigens induce high-level HI and NAb responses*

Severity of disease correlates to prior exposure

H3N2 immunity correlates to pre-seasonal HI

titres

*http://jvi.asm.org/content/80/23/11628.full

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H1, H3 AND VIRAL LOAD

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VIRAL LOAD (vAUC)

In a meta-analysis of HCTs, viral shedding was noted in 93.1%

of H1N1/09pdm subjects and 92.5% of H3N2

Peak viral loads differ little between H1 and H3 studies

vAUC is observed to be greater in H3N2 challenge studies

No significant correlation has been observed between pandemic

(H1N1) 2009 or seasonal influenza viral loads and clinical

severity of illness

Viral loads in pandemic H1N1 viruses are characterised by lower

copy numbers than seasonal H3N2 viruses (~1 log10)

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VIRAL SHEDDING

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H1N1, H3N2 AS CHALLENGE AGENTS

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WHY H1N1pdm and H3N2? – 1

Influenza A strains show fewer GI symptoms compared to B

H1 and H3 strains have been dominant for >100 years

H1N1/09pdm has been the cause of the most recent and

most severe pandemic in the 21st C

H1N1/09pdm is associated with the greatest symptomology

of the most recently circulating H1N1 serotypes

Seasonal H3N2 demonstrates greater symptomology

compared to seasonal H1N1/09pdm*

The Northern Hemisphere showed an H3N2 new variant as

the predominant virus for 2014-2015

The Northern Hemisphere showed a resurgence of the

H1N1/09pdm as the predominant virus for 2015-2016

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WHY H1N1pdm and H3N2? – 2

H3N2 new variant has not been in circulation long enough to

attenuate (low CFR)

H3N2 new variant has low levels of natural (homotypic)

immunity

H3N2 has a good shedding profile

Challenge strains of H1N1/09pdm and H3N2 strains do not

possess the markers for highly pathogenic disease

In challenge trials, fixed effect estimates are similar for both

H1N1 and H3N2 (60%) i.e. both cause equal amounts of

disease

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H3N2 NEW VARIANT

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H3N2 SWITZERLAND 2013 – NEW VARIANT

Influenza A/Texas/50/2012 like viruses were the most

common circulating influenza (H3N2) viruses during the

2013-14 season.

New clusters of A(H3N2) were first detected through

surveillance in late March 2014

A/Switzerland/9715293/2013, a representative of one of

the new groups, predominated by the end of the 2013-

2014 season

SGS isolated an new variant of the A/Switzerland/2013

group circulating locally

This new variant is currently under manufacture for release

in 2016 as a novel challenge agent

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IDENTIFICATION OF A NEW STRAIN

PNA150487NA

GHE_150482_NA

YRO_150479_NA

KTI_13799_NA

AME_15049NA

CCA5734NA

AEL150491_NA

SVE10369NA

A/Switzerland/9715293/2013

A/Switzerland/9715293/2013

MK

SME_150477_NA

SBO6110NA

A/Texas/50/2012 | HA | 440627

A/Victoria/361/2011 | HA | 408194

A/Perth/16/2009 | HA | 307676

A/Minnesota/11/2010 | HA | 465400

89

100

100

99

68 65

83

87

100

65

45

0.01

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SGS – A VIRAL MENU

SGS is committed to providing a viral menu

including Influenza A and RSV for use in Human

Challenge Trials within its HCU/CPU for 2016

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FULL SCOPE SERVICES

Large HV recruitment database

Extensive early phase experience (>1000 studies)

Dedicated HCU (Class II, negative pressure unit) within

fully accredited CPU

x8 single-bedded isolation rooms with en suite facilities

plus x12 bed ‘ward’ style isolation unit ( = 20 bed total)

Strict IC including HEPA filtered air systems

Access to complex or innovative clinical interventions /

practices (LP; nasal washes; BAL; tissue sampling)

Full eSource capability

Biometrics; PK/PD; M&S; PM; QA; Regulatory guidance;

Laboratory Services; GMP Pharmacy; Class II safety lab

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VIRAL CHALLENGE FACILITIES AT SGS

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HUMAN CHALLENGE

CONTEXT:

“A randomized, placebo-controlled, double-blind Phase 2a trial was designed to assess

the efficacy and safety of a novel mAb in healthy human volunteers challenged with a

2009 pandemic strain of H1N1 influenza virus”

KEY CHALLENGES:

Identifying a susceptible cohort (60-80 HVs - HAI <10)

10d isolation of subjects within a specialised HCU

Intense NP swab SoA / intense pre-screen PCR schedule

OUTCOMES:

A total of 332 subjects were screened; 31 were enrolled - 20 subjects met the

definition of laboratory-confirmed infection (mAb, n=13; and placebo, n=7) (AR = 62%)

vAUC for mAb treated subjects was reduced by 92% (p=0.019); peak viral load was

reduced by 2.2 logs (p=0.009) (interim result data @ 6 months)

mAb was generally safe and well tolerated. There were no drug-related

discontinuations or serious adverse events (SAEs) reported in the study

Based on the interim results - the comparative portion of the trial was ended.

CASE STUDY: PHASE 2a STUDY IN INFLUENZA

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Agriculture, Food and Life

Adrian Wildfire

Project Director - Infectious Diseases & Viral

Challenge Unit - Clinical Research

SGS United Kingdom Limited Phone: + +44 (0)78943 92625

SGS House 217-221 London Road,

Camberley GU15 3EY E-mail : adrian.wildfire@sgs.com

United Kingdom

Web : www.sgs.com/lifescience

THANK YOU FOR YOUR ATTENTION

+ 41 22 739 9548

+ 1 866 SGS 5003

+ 65 637 90 111

+ 33 1 53 78 18 79

+ 1 877 677 2667

+ 33 1 41 24 87 87

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QUESTIONS ?

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