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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
3
THE ORIGINS OF INFLUENZA
4
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
5
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
6
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.
7
H1N1 AND H3N2 – GLOBAL PREVALENCE
8
H1N1 AND H3N2: 2015 – 2016 FLU SEASON
9
CLINICAL CHARACTERISTICS
OF H1, H3 INFLUENZA
10
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
11
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
12
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.
13
H1, H3 AND IMMUNITY
14
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
15
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
16
H1, H3 AND VIRAL LOAD
17
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)
18
VIRAL SHEDDING
19
H1N1, H3N2 AS CHALLENGE AGENTS
20
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
21
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
22
H3N2 NEW VARIANT
23
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
24
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
25
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
26
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
27
VIRAL CHALLENGE FACILITIES AT SGS
28
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
29
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 : [email protected]
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
30
QUESTIONS ?
31