A Consideration of H1N1 2009pdm and New Variant H3N2 2013 for Viral Challenge Trials

A CONSIDERATION OF H1N1/09pdm
AND NEW VARIANT H3N2/13 AS
AGENTS FOR HUMAN CHALLENGE
TRIALS
Adrian Wildfire
Project Director; Infectious Disease and HCU
SAFETY & EFFICACY CLINICAL TRIAL SOLUTIONS
SGS Life Science Services Biopharm Day Seminar – Antwerp, October 29, 2015

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SGS LIFE SCIENCE SERVICES BIOPHARMA DAY – OCTOBER, 29 2015
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: 2014 – 2015 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

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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 generally more
severe than A H1N1 (or Flu B) in terms of fever,
leucopoenia and C-reactive protein.
 Mean ages for attack are 33 +/- 8.4 years (H1N1), and 41
+/- 15.2 years (H3N2)
 A greater number of hospitalizations occur during years that
influenza A(H3N2) is predominant.
 During seasons with prominent circulation of influenza
A(H3N2) viruses, 2.7 times more deaths occurred than
during seasons when A(H3N2) viruses were not prominent.

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H1, H3 AND IMMUNITY

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INFLUENZA – IMMUNITY
 Influenza promotes a strong protective antibody response
due to surface antigens – haemagglutinin and neuraminidase
 The prevalence of Influenza A, H1N1/09 circulating in the
community has fallen over the past five years
 H1N1/09pdm immunity increases with age but not with pre-
seasonal HI titres
 H3N2 immunity does correlate to pre
-seasonal HI titres
 Since 2010 circulating influenza
strains are showing a decreased ability
to agglutinate
 Severity of disease correlates to both
vaccination and prior infection/s

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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 percent of participants infected with A/H1N1, 92.5
percent with A/H3N2
 Peak viral loads differ little between H1 and H3 studies
 vAUC is observed to be greater in H3N2 challenge studies
 Viral RNA concentration at presentation positively
correlates with symptom scores
 Patients with major comorbidities have higher viral RNA
titres even when presenting >2 days after symptom onset
 Viral loads in pandemic H1N1 viruses are characterised by
lower copy numbers than seasonal H3N2 viruses

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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 shows an H3N2 new variant as
the predominant virus for 2014-2015

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WHY H1N1pdm and H3N2? – 2
 H3N2 new variant has not been in circulation long enough to
attenuate (low CF)
 H3N2 new variant has low levels of natural (homotypic)
immunity
 H3N2 has a superior shedding profile
 Current, circulating H1N1/09pdm and H3N2 strains do not
possess the potential for highly pathogenic disease
(immune deregulation and lower-lung epitope binding)
 In challenge trials, fixed effect estimates are similar for both
H1N1 and H3N2 (60%) i.e. both cause equal amounts of
disease
 Wild-type challenge agents may attenuate during the
manufacturing process giving a good safety profile

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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 groups of A(H3N2) viruses that became predominant
during the 2014-15 season 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)
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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Life Science Services Adrian Wildfire
Project Director - Infectious Diseases & Viral
Challenge Unit
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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A Consideration of H1N1 2009pdm and New Variant H3N2 2013 for Viral Challenge Trials

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A Consideration of H1N1 2009pdm and New Variant H3N2 2013 for Viral Challenge Trials