Transcript 1997 PRELIMINARY RESULTS

Options for the Control of Influenza VI
June 17-23, 2007
Toronto, Ontario, Canada
Conference Summary
Overview
Disease surveillance and modeling
Virus-host interactions and pathogenesis
Seasonal influenza: vaccine evaluation
Pandemic influenza: outbreak and pre-pandemic
response
Pandemic influenza: vaccine evaluation
Antivirals
Clinical guidance and policies
Global surveillance efforts
Varies widely, resources an issue
 Africa: emerging programs
 Asia: some seasonal surveillance, focus on avian
 Oceania: little information presented
 Europe: significant national and EU efforts
 Latin America: increasing number of programs
 US & Canada: significant government, military (US)
programs
 International: WHO, collaborative groups
Surveillance: Africa
Location
Abidjan, Côte
d’Ivoire
Season
Cases
Confirmed
2002
through
2006
572 samples from
patients with flu-like
syndrome or febrile
acute respiratory
illness
Influenza: 59
Identification by passage in
MDCK cells, ELISA
immunocapture
2006-2007
ILI: 83
SARI: 104
Confirmed influenza B: 10
No influenza A
Confirmation by PCR
2006-2007
839 specimens, 67
isolates
Majority: influenza B
(Malaysia-like)
Kadjo H, abstract P146
Kenya
Muthoka P, abstract P135
Kenya
Schnabel D, abstract O3
Surveillance: Asia
Location
Jeonbuk Province,
Korea
Kim C, abstract P159
Taiwan
Chiu S, abstract P102
India
Chadha M, abstract O1
Season
Cases
Confirmed
2004
through
2007
ILI: 1313
specimens
Influenza viruses isolated: 687
Confirmed by multiplex RT-PCR
July 1999 –
November
2006
7339 influenza Yes: virus culture, RT-PCR, IFA, HI,
viruses
phylogenetic analysis
isolated
2004
through
2006
202 isolates
from 4112
patients
Virus culture, HI
• China: 197 sentinel hospitals (Zhang Y, abstract P154)
Surveillance: Europe
Location
England
Hayward A, abstract P168
Poland
Romanowska M, abstract
P107
Season
Cases
Confirmed
October
ILI: 253 nasal
2006-March swabs
2007
3 of 11 analyzed (PCR) swabs were
positive for influenza
Remainder still to be processed
2004-2005
2005-2006
2006-2007
Influenza: 63 (21%)
Influenza: 47 (5%)
All respiratory infections: 27
(analysis in progress)
ILI cases: 399
ILI cases: 949
ILI cases: 650
• Established sentinel networks in Sweden (Andersson E, abstract P136),
Portugal (Gonçalves P, abstract P147), France (Mosnier A, abstract
P166)
• Evidence of west-to-east spread through season (W Paget, abstract O4)
• Peaks: no link to prior cold weather (Mangtani P, abstract P111)
Surveillance: Latin America
Argentina: National Influenza Centre Network1
 Important peak in winter everywhere; additional
summer/autumn peaks @ extreme latitudes
Brazil:
 National Influenza Surveillance Network: 958 samples
collected in 2006 season, virus strain surveillance2
 Single-centre ILI cases 2006-2007: 115913
 Climate analysis: spread associated with rainfall in
equatorial areas, low temperatures in other areas4
Cuba:
 Laboratory surveillance of circulating strains5
1. Savy V. abstract P117, Options VI, 2007.
2. Paiva T. abstract P119, Options VI, 2007.
3. Cintra O. abstract P169, Options VI, 2007.
4. Alonso W. abstract P171, Options VI, 2007.
5. Acosta B. abstract P153, Options VI, 2007.
Surveillance: US
CDC: 122-City Mortality Reporting System1
 Provides early data on influenza mortality
 Reported area of jurisdiction covers ~69 million people
(23.2% of US population)
CDC: Sentinel Provider Surveillance Network2
 ~2500 participating physicians, weekly reports of ILI
cases
 High correlation between ILI reports and WHO lab
isolates
 Regional differences currently being addressed
1. Blanton L. abstract P118, Options VI, 2007.
2. Johnson A. abstract P132, Options VI, 2007.
Surveillance: Canada
 FluWatch programme: analysis of 11 years of data1
 Comprehensive system for timely surveillance, in line with other
international efforts
 Lacks real-time severity indicators of adult hospitalizations, mortality
 Web-based model for real-time electronic reporting2
 Currently being piloted in Atlantic Canada
 IMPACT paediatric surveillance programme:3
Season
Influenza-related admissions
2003-2004
505
2004-2005
391
2005-2006
374
2006-2007
140 (to Feb 24)
Surveillance: international efforts
US Naval Medical Research Unit 3: eastern
Mediterranean, Africa, eastern Europe, central Asia1
WHO global network: determination of vaccine strains2
 Expansion of network in collaboration w/ CDC
CDC: general guidelines for seasonal surveillance &
early pandemic detection3
 Fills gaps in WHO approach re: pandemic detection
Asian group: surveillance of online news sources4
 Development of downloadable, searchable “intelligent” Webbased surveillance system
1. Soliman A. abstract P122, Options VI, 2007.
2. Daves S. abstract P145, Options VI, 2007.
3. Ortiz J. abstract P128, Options VI, 2007.
4. Collier N. abstract P157, Options VI, 2007.
Surveillance: children & families
Location
Data
Results
England &
Wales
40 years of incidence
data on children as
drivers of community
ILI & bronchitis spread
No consistent time lags between ILI
peaks in children & others
Bronchitis always peaked in children
before elderly
Questionnaire:
families of 35 children
with confirmed
influenza
35% of adult, 63% of child household
contacts experienced ~2 days of ILI
35% of households: parental time off
work to care for ill child (mean 1.7 days)
Analysis of 1609
influenza patients
from 1234 families
Most common index cases: age 0-6
Influenza A: commonly passed from
children (any age) to mother, younger sib
Influenza B: transmitted from children 04, to wider spread of age ranges
Elliot A, abstract
P124
Leicester, UK
Democratis J,
abstract P123
Japan
Hirotsu N,
abstract O5
Surveillance: complications
Location
Data
Results
São Paolo,
Brazil
Case study: fatal
pneumonia associated
with H1 influenza in 3year-old child
Influenza A, subtype H1, clade 1
First documented case (in investigators’
experience) of fatal pneumonia due to
influenza infection
848 cases of
influenza-associated
encephalopathy
B: poorer prognosis, more abnormal
blood parameters vs AH1
Prognostic factors: elevated AST,
hyperglycemia, haematuria, proteinuria,
diclofenac
Paiva T, abstract
P106
Japan
Wada T, abstract
P109
Surveillance: comorbidities
Location
Data
Results
Canada
Patients admitted to
hospital due to
respiratory conditions
from 1994 to 2000
Overall influenza-attributable mortality
~4000/year
Schanzer D, abstract
P112

1400 with chronic heart /respiratory conditions
Of 14000 influenza-related hospital
admissions in adults (20 years):





48% COPD patients
11% chronic heart disease
8% asthma
6% other risk factors
13% without comorbidities
Mathematical models:
influenza spread and intervention
 D Smith (Cambridge): models must be questioned & tested1
 D Shay (CDC, USA): comparison of excess mortality
modeling methods2
 All yielded similar (22000 to 34900 deaths) estimates, risk-difference w/
summer baseline higher
 Estimates varied with age group, viral type/subtype
 L Denoeud (France): validation of morbidity as mortality
predictor3
 N Ferguson (UK): current models of pandemic control4





Containment: requires early detection, antiviral stockpiles
Treatment: must be fast (12-24h) to reduce transmission
Travel restrictions: would only buy time, not contain
Social distancing: difficult to measure or enforce
Combination of strategies: could reduce attack rate by 75%
1. Smith D. TS 5, Options VI, 2007.
2. Shay D. abstract O7, Options VI, 2007.
3. Denoeud L. abstract P115, Options VI, 2007
4. Ferguson N. TS 5, Options VI, 2007.
Overview
Disease surveillance and modeling
Virus-host interactions and pathogenesis
Seasonal influenza: vaccine evaluation
Pandemic influenza: outbreak and pre-pandemic
response
Pandemic influenza: vaccine evaluation
Antivirals
Clinical guidance and policies
Pathogenesis: seasonal influenza
Seasonal factors affecting transmission (guinea
pigs)1
 varies with humidity (highest at 20-35%) and temperature
(highest at 5C)
PB1-F2 protein and pneumonia (mice)2
 “1918” version of protein associated with:
increased virulence
 heightened immunopathology
 priming for secondary bacterial pneumonia

1. Lowen A. abstract O91, Options VI, 2007.
2. McAuley J. abstract O89, Options VI, 2007.
Pathogenesis: pandemic-potential influenza
Viral polymerase impact on virulence (mice, ferrets)1
 swapping polymerase gene from non-lethal CH58 into VN1203
attenuated virulence in ferrets and mice
 inhibition of polymerase by Mx1 may protect vs death
NS1 protein C-terminus and virulence (mice)2
 4-aa truncation abolishes plaque formation
 “avian-like” sequences most virulent
HPAI H5N1 and interferon response (cell culture)3
 HP virus associated with reduced & delayed IFN induction,
decreased expression of IFN-stimulated genes
1. Salomon R. abstract O92, Options VI, 2007.
2. Jackson D. abstract O90, Options VI, 2007.
3. Zeng H, abstract O93, Options VI, 2007.
Overview
Disease surveillance and modeling
Virus-host interactions and pathogenesis
Seasonal influenza: vaccine evaluation
Pandemic influenza: outbreak and pre-pandemic
response
Pandemic influenza: vaccine evaluation
Antivirals
Clinical guidance and policies
Seasonal influenza vaccines:
pre-clinical evaluation
Solvay: new cell-derived products
 Qualification of MDCK cells as safe vaccine production system1



Risk assessment
Elimination of residual cellular DNA (DNAse treatment)
MDCK cells are as safe as other cell lines
 Pre-clinical validation of Grippol TC adjuvanted cell-derived
(MDCK) vaccine2



Novel adjuvant: polyoxidonium
Sterile cell-derived antigens, immunogenic at 3-fold lower levels
than split or subunit vaccines
Pre-clinical validation complete, clinical trials to begin soon
1. Kersten A. abstract P1404, Options VI, 2007.
2. Nekrasov A. abstract P1433, Options VI, 2007.
Seasonal influenza vaccines:
pre-clinical evaluation
Dynavax: “universal influenza vaccine” approach1
 Conserved viral antigen (NP) with immunostimulatory DNA
 Promising results in mice; NP-ISS plus Fluzone enhanced
antibody response, viral neutralization in baboons
NIBSC: DNA vaccine with truncated HA2
 Spontaneous insertion of bacterial DNA into HA construct
 Induces 10-fold increase in HA antibody titre vs normal HA
 Antibodies to truncated HA can recognize intact virus
DelSite: dry powder (GelVac) delivery system3
 Ionic polysaccharide (nasal delivery or reconstitution for
injection); whole virion or split antigens
 Safe & tolerable through nasal route; immunogenic when injected
1. Higgins D. abstract P1419, Options VI, 2007.
2. Robertson J. abstract P1421, Options VI, 2007.
3. Ni Y. abstract P1431, Options VI, 2007.
Clinical vaccine evaluation: Influvac
Population
Findings
Children (<5 yrs)
n=29927
ILI reduction of 39% (kindergarteners) and 29%
(schoolchildren) vs no vaccine
Vaccination of children reduced morbidity in household
contacts, morbidity in the elderly
Gerez L, abstract P703
Coronary artery disease
n=658
Brydak L, abstract P708
Non-Hodgkin lymphoma
n=26
Romanowska M, abstract P707
Placebo-controlled trial
Protection rates from 56.4% to 60.3% following
vaccination, vs 6.2% to 8.2% for placebo group
10/26 patients: immunosuppressive therapy
Influvac protective (antibody titres ≥40) in 69.2% to
96.2% of patients regardless of immunosuppressant use
Children 18 to 72 months Influvac plus pneumococcal vaccine
n=597
During flu season: 52% reduction in influenza, 24%
Hak E, abstract O115
reduction in all-cause RTI vs no-vaccine control
Clinical vaccine evaluation: Fluarix (GSK)
Population
Findings
Children with asthma
n=36
MFI of antibody titres: 4.2 to 6.4 at 1 month postvaccination, 3.1 to 3.9 at 3 months
Humoral response to NA component similar to that of
healthy control subjects
Romanowska M, abstract P705
Children with inflammatory MFI of antibody titres: 2.5 to 4.9 at 1 month postbowel disease
vaccination, 2.7 to 4.2 at 3 months
n=29
Long-term immunosuppressive therapy: no effect on
Rybicka K, abstract P706
vaccine effectiveness
Antibody responses in
Taiwan, 2006
120 serum samples (30
adults, 30 elderly)
Chen C, abstract P711
Seroconversion rates >40% in adults, >30% in elderly
Exception: B/Taiwan/0050/2006
Seroprotection rates 70 to 100%
Clinical vaccine evaluation: Fluad (Novartis)
Population
Findings
Adults with underlying
chronic disease
n=359
Fluad (MF59 adjuvant) vs Novartis’ conventional
subunit vaccine Agrippal in high-risk adults
Significantly higher geometric mean titres (p<0.001),
seroprotection rates (p<0.01) with Fluad
Both well tolerated, more reactogenicity with adjuvant
Baldo V, abstract P733
Elderly subjects with
chronic disease
n=111
Fluad vs virosomal vaccine Inflexal-V
Significantly higher immunogenicity with Fluad
Some cross-protection against heterologous strains
Baldo V, abstract P714
HIV-1 seropositive and
seronegative adults
n=256
Durando P, abstract P736
Adjuvanted Fluad vs non-adjuvanted Agrippal
Generally better immunogenicity for Fluad across all
viral subtypes
No significant changes in viremia or CD4s for HIV+
Clinical vaccine evaluation:
cell culture (Novartis)
Population
Findings
Adult and elderly subjects
n=2654
Non-inferiority trial vs egg-derived Agrippal
No significant differences in immune response for
each of the three vaccine strains
No significant differences in safety profile
Groth N, abstract P716
Adult subjects
n=613
Reisinger K, abstract P717
Adult subjects
n=1200
Groth N, abstract P718
Phase II study of safety, tolerability, immunogenicity
vs egg-based subunit vaccine Fluvirin
Immune responses for MDCK-derived vaccine noninferior to those for Fluvirin
Ecchymosis, chills higher in Fluvirin group
Phase II trial of consistency of immune response
and tolerability across different vaccine lots
MDCK-derived vaccine lots bioequivalent to each
other, non-inferior to comparator Agrippal
Clinical vaccine evaluation: children
Population
Findings
6- to 59-month-old children
in 3 US communities, 20032004 season
Surveillance detected 231 influenza cases: 3% fully and
10% partially vaccinated
Vaccine effectiveness across 3 studies 43 to 54% in
spite of circulation of a drifted strain
M Iwane, abstract O49
Children <5 yrs
Gerez L, abstract P703
Children <4 yrs
n=259
Irie S, abstract P713
Children 6 to 23 months
De Serres G, abstract P723
Children 6 to 23 months
Shay D, abstract P724
Influvac field study (previously discussed): 29 to 39%
reduction in ILI vs non-vaccinated
2 doses of unspecified trivalent inactivated vaccine
failed to induce protective antibody levels in 50 to 80% of
infants <1 year and 40 to 50% of children 1 to 2 years
Surveillance study: no significant benefit from TIV in
preventing influenza-related hospitalization in infants
Surveillance study: 2 doses of TIV provided up to 71%
effectiveness in reducing influenza-related hospitalization
Clinical vaccine evaluation: elderly
Population
Findings
18 cohorts of community- 10-year data pooling, 713872 person-seasons of
dwelling elderly
observation
Vaccination associated with significant reduction in
Nichol K, abstract O50
pneumonia/influenza hospitalization (OR 0.73) and death
(OR 0.52) vs no vaccination
Elderly w/ chronic
disease
Baldo V, abstract P714
Subjects aged 60+
n=1107
Booy R, abstract P727
Previously discussed Fluad study: increased
immunogenicity vs non-adjuvanted, some crossprotection
Phase II trial of intradermally administered novel splitvirion vaccine (sanofi-pasteur) vs IM Vaxigrip
Superior immune response vs all vaccine strains
Clinical vaccine evaluation:
altered immune response
Population
Findings
HSCT recipients
n=5
HSCT recipients undergoing reduced-intensity conditioning
Lower rates of seroprotection, seroconversion vs controls
Mossad S, abstract P715
SLE patients
n=30
Demographic determinants of vaccination response:
 High: older age, African-American ethnicity
Low: Hispanic or Native American ethnicity, corticosteroid use
Crowe S, abstract P719;
Air G, abstract P720
SLE patients’ T cells recognize vaccine components, undergo cell
division, but fail to produce IFNγ
Wegener’s
granulomatosis
n=35
Clinical/serological remission after immunosuppressive therapy
Response to vaccination comparable to that in healthy controls
Zycinska K, abstract P721
HIV-positive subjects
Durando P, abstract P736
Fluad: immunogenic, no effect on CD4 or viremia
Clinical vaccine evaluation: strain mismatch
Population
Findings
Healthy adult subjects
n=1247
Absolute and relative efficacies of TIV (Fluzone) vs
LAIV (Flumist) in antigenically drifted season
Efficacy in year with 2 drifted strains: TIV 75%, LAIV
48%
Monto A, abstract O51
Patients presenting with
ILI
n=442
Skowronski D, abstract P732
Elderly subjects
n=100
Ansaldi F, abstract P728
Sentinel surveillance of ILI cases in Canadian influenza
season (2005-2006) with two circulating drifted strains
Relatively low TIV effectiveness (50 to 70%) but
evidence of cross-protection
Efficacy of adjuvanted (MF59) vs non-adjuvanted TIV
in serological tests vs heterologous strains
Adjuvanted vaccine induced higher titres vs
homologous strains, broader protection vs drifted variants
Overview
Disease surveillance and modeling
Virus-host interactions and pathogenesis
Seasonal influenza: vaccine evaluation
Pandemic influenza: outbreak and pre-pandemic
response
Pandemic influenza: vaccine evaluation
Antivirals
Clinical guidance and policies
Avian influenza: general considerations
Veterinary aspects of avian influenza1
 For every human infected, 1 million infected animals
 Spread to wild birds: unprecedented ecological & epidemiological
situation
 Should be seen as disease of animals, not just birds
Study of pathogenesis in ducks2
 Virus present 1 day post infection in nasal cavity, lungs, spleen
 Better understanding of targets for surveillance sampling
State of bird vaccines3
 Potentially useful for eradication, management, prevention
 Issues: administration & coverage, new variants
 Future directions: replaceable “cassette”, improved vectors
1. Capua I. PS 3, Options VI, 2007.
2. Banks J. abstract O95, Options VI, 2007.
3. Swayne D. PS 3, Options VI, 2007.
Avian influenza: surveillance
 Thailand1
 Zero seroprevalence of H5N1 antibodies in residents of villages with
confirmed human cases (2005)
 Inefficient poultry-to-human transmission in spite of high exposure to
backyard birds (68.1%), sick or dead poultry (33.3%)
 China2
 Retrospective study of poultry contact in 22 confirmed human H5N1 cases
(59% fatality)
 History of sick/dead poultry exposure or live market visit in all but one case
 Sudan3
 Door-to-door survey in town with avian outbreak: no human cases
 Nigeria4
 Survey of poultry workers after avian outbreak: no human cases
1. Dejpichai R. abstract O21, Options VI, 2007.
2. Yu H. abstract O97, Options VI, 2007.
3. Lado M. abstract O19, Options VI, 2007.
4. Katz M. abstract O20, Options VI, 2007.
Avian influenza: spread & control
Control in birds in SE Asia1
 Effective surveillance, rapid eradication, proper disposal,
enhanced biosecurity, vaccination
 Will need to be sensitive to regional issues/practices
Control of spread into Europe/Africa2
 No new wild cases in Europe since June 2006
 Need to enhance systems for early detection
 Establishment of protection/surveillance zones
 Increase/improve vaccination, biosecurity
1. Kalpravidh W. PS 3, Options VI, 2007.
2. Brown I. abstract PS 3, Options VI, 2007.
Avian influenza: spread & control
Control of avian/human clusters in UK:
 Feb 2007 - H5N1 outbreak on Suffolk poultry farm1
All 160000 birds culled
 Oseltamivir prophylaxis and seasonal influenza
vaccination for exposed people
 No human H5N1 cases detected

 H7N2 outbreak in north Wales2
Several infected premises, all traced to same vendor
 Flu-like symptoms in exposed people; 4 H7N2 cases (2
serious)
 Prophylaxis offered to all exposed

1. Van Tam J. abstract O18, Options VI, 2007.
2. Van Tam J. no abstract available, Options VI, 2007.
Pre-pandemic planning: initiatives
EU assessment1
 All member states: good start on planning surveillance, outbreak
control, non-pharma strategies, public education
 More support needed on: integration across agencies, seasonal
flu control, research
Chinese assessment2
 Good coverage of alert phase, pandemic phase responses
 Needs: detailed implementation plan; strategies for risk
communication, stockpiling, essential service continuity
Importance of stockpiling
 Antivirals, pre-pandemic vaccines once available
1. Kreidl P. abstract O23, Options VI, 2007.
2. Peng Z. abstract P324, Options VI, 2007.
Pre-pandemic planning: challenges
 Alignment of pandemic plans with rapidly evolving knowledge
& technology (especially developing countries)
 Allocation of adequate resources & facilities to underserved
countries (Africa, Asia)
 Communication & collaboration among different nations &
agencies
 Modification of human attitudes and risk behaviours
 Retaining adequate capacity for response to other
emergencies
 Ensuring prompt & equitable distribution of available
antivirals & vaccines
PS 1, Options VI, 2007
Overview
Disease surveillance and modeling
Virus-host interactions and pathogenesis
Seasonal influenza: vaccine evaluation
Pandemic influenza: outbreak and pre-pandemic
response
Pandemic influenza: vaccine evaluation
Antivirals
Clinical guidance and policies
Pandemic influenza vaccines:
pre-clinical evaluation
Validation of ferrets as appropriate model for human
H5N1 disease1
 Response to seasonal H1N1 vaccine strain in animals previously
exposed to H3N2
 Used as baseline for tests of adjuvanted & non-adjuvanted H5N1
candidates
Adjuvanted, split-virus vaccines
(H5N1/A/Vietnam/1194/2004)
 GSK: protection vs death for ferrets vaccinated with adjuvanted
doses of 5 or 15 mcg2
 sanofi-pasteur: protection vs death for monkeys vaccinated with
adjuvanted doses of 30 mcg; lower pneumonia with new adjuvant
formulation3
1. Kersten A. abstract P1403, Options VI, 2007.
2. Baras B. abstract P1412, Options VI, 2007.
3. Caillet C. abstract P1443, Options VI, 2007.
Pandemic influenza vaccines:
pre-clinical evaluation
Live attenuated vaccines (MedImmune)
 Reverse genetics – HA and NA genes from
A/HK/213/2003(H5N1) in cold-adapted donor strain:
protects ferrets vs homologous challenge after 1 dose,
cross-protects with 2 doses1
 Same technique, A/VN/1203/2004(H5N1) strain:
homologous and heterologous protection in ferrets after 1
dose2
1. Suguitan A. abstract P1430, Options VI, 2007.
2. Jin H. abstract P1436, Options VI, 2007.
Pandemic influenza vaccines:
who’s working on what?
Manufacturer
Production
Vaccine/
adjuvant
Antigens
Approval
status
Baxter
Vero cells
Whole virus, no
adjuvant
H5
Not yet
GSK
Eggs
Subunit, AS03
adjuvant
H5
Under EU
review
MedImmune
Eggs
Live attenuated,
no adjuvant
H5, H9
Not yet
Novartis
Eggs
Subunit, MF59
adjuvant
H5, H9
EU, stockpiling
Novartis
MDCK cells
MF59 adjuvant
H5
EU
sanofi-pasteur
Eggs
Subunit
H5
US, stockpiling
Pandemic influenza vaccines:
clinical evaluation
CSL Limited: aluminium-adjuvanted inactivated
split-virion A/Vietnam/1194/2004NIBRG(H5N1)
vaccine
 Phase I, II in healthy adults: adequately immunogenic
(MN ≥1:20 for 73% of subjects at 30 or 45 mcg), generally
safe/well tolerated1
 Serological analysis: clade 1 vaccine gives some limited
cross-protection against clade 2 viruses2
1. Nolan T. abstract P7266, Options VI, 2007.
2. Hoschler K. abstract P729, Options VI, 2007.
Pandemic influenza vaccines:
clinical evaluation
sanofi-pasteur: inactivated subvirion
rgA/VN/1203/2004(H5N1), aluminium adjuvant
 Dose-ranging in healthy adults: dose relationship
observed but antigenicity low after 2 doses at all dose
levels (3.75 to 45 mcg); little to no effect from adjuvant1
 2 similar studies in elderly: still limited antigenicity after 2
doses (35-37% of subjects achieving HAI titers ≥40)2,3
 Use of a 3rd (unadjuvanted) dose 6 months later induces
higher antibody levels that persist after a further 6
months; support for “prime-boost” strategy4
1. Keitel W. abstract P722, Options VI, 2007.
2. Brady R. abstract P739, Options VI, 2007.
3. Treanor J. abstract P731, Options VI, 2007.
4. Zangwill K, abstract P737, Options VI, 2007.
Pandemic influenza vaccines:
clinical evaluation
sanofi-pasteur: PER.C6-derived H7N1 inactivated split
reverse genetics vaccine1
 HPAI A/Chicken/Italy/13474/99(H7N1) in PR8 carrier
 Antibody responses in 21 of 54 participants; best responses in
high-dose (24 mcg HA) aluminium-adjuvanted group
 Priming may be necessary given weak immunogenicity
Value of pre-pandemic priming2
 Single dose of A/VN1203/2004(H5N1) vaccine given to
individuals with 2 previous doses of A/HK/156/1997(H5N1)
vaccine
 Robust increases in H5 HA-specific B-cell response
1. Cox R. abstract O56, Options VI, 2007.
2. Topham D. abstract O55, Options VI, 2007.
Pandemic influenza vaccines:
clinical evaluation
GSK: split-virus H5N1 candidate vaccine with
novel oil-in-water adjuvant system (AS03)
 3.8 mcg dose established as effective, chosen for further
development
 Phase III trial in 5071 subjects: safety profile of 15 mcg
dose vs seasonal vaccine Fluarix
 Significantly higher levels of solicited AEs with H5N1
vaccine; medically acceptable reactogenicity
Ballou W. abstract O54, Options VI, 2007.
Pandemic influenza vaccines:
clinical evaluation
Antigen-sparing strategies
 Berna: intradermal administration of virosomal adjuvanted
seasonal vaccine1

Highly immunogenic, well tolerated at a five-fold reduced
dose compared to IM administration
 Novartis: non-inferiority of low-dose MF59-adjuvanted
H5N1 vaccine2
2 doses of 7.5 (low) vs 15 mcg (standard) of
A/Vietnam/1194/2004like(H5N1) antigen with MF59
 Low-dose: non-inferior, may be a valid dose-sparing
candidate, pre-priming agent

1. Kunzi V. abstract P704, Options VI, 2007.
2. Banzhoff A. abstract P734, Options VI, 2007.
Pandemic influenza vaccines:
future directions
No chickens = no eggs = no vaccines
 Development of cell culture systems
Rapidly expandable
 Enhanced immunogenicity?
 Reverse genetics

Use of adjuvants
 Antigen sparing
 Increased immunogenicity in elderly
 Cross-protection?
Pandemic influenza vaccines:
future directions
Vaccine
type
Pros
Cons
Subunit
Safety
Broad response
2 doses required
Higher antigen dose required
Adjuvanted
Antigen-sparing
Higher immunogenicity?
Cost
Developing safety profile
High reactogenicity
Whole virus
Antigen-sparing
High reactogenicity (especially in
children)
Live
attenuated
virus
Antigen-sparing
Broad response
Early protection with 1 dose?
Restricted applicability (high-risk
groups)
Safety concerns?
Keitel W. TS 4, Options VI, 2007.
Overview
Disease surveillance and modeling
Virus-host interactions and pathogenesis
Seasonal influenza: vaccine evaluation
Pandemic influenza: outbreak and pre-pandemic
response
Pandemic influenza: vaccine evaluation
Antivirals
Clinical guidance and policies
Antivirals and seasonal influenza
L Gubareva (CDC, USA): antiviral resistance of >1500
isolates from last 3 seasons
 133 A(H1N1), 186 A(H3N2), 118 B
 All susceptible to oseltamivir and zanamivir, one exception: B
virus, R371K active site substitution
 Another B mutant (H274Y) detected: susceptible to oseltamivir &
zanamivir, peramivir-resistant
A Hurt (WHO, Australia): mutations in N1
 4 A(H1N1) strains detected with reduced NAI sensitivity
 3 novel mutations in NA gene: Q136K, K150T, K143R
 All affect the recently identified ‘150-cavity’
1. Gubareva L. abstract O66, Options VI, 2007.
2. Hurt A. abstract O67, Options VI, 2007.
Antivirals and seasonal influenza: children
 N Sugaya (Japan): effectiveness of oseltamivir vs zanamivir
in children with influenza A
 H1N1:

total febrile period, duration of fever after treatment initiation: no difference
 H3N2:



total febrile period: oseltamivir 1.7 days, zanamivir 2.3 days (p = 0.01)
duration of fever after treatment initiation: no difference
survival of virus in throat @ day 5: zanamivir 8%, oseltamivir 47%
 R Dutkowski (Roche, Switzerland): earlier (<24h) vs later
(≥24h) initiation of oseltamivir in children
 time to freedom from illness: 78.8% absolute improvement
 duration of fever: 25.4% absolute improvement
 resistance: 5.5% overall; fewer cases in early initiation group; no impact on
illness duration
1. Sugaya N. abstract O65, Options VI, 2007.
2. Dutkowski R. abstract O98, Options VI, 2007.
Antivirals and H5N1
J Belser (CDC, USA): novel sialidase (DAS181,
Fludase) vs H5N1 in mice
 removes sialic acids from respiratory epithelium
 70% prevention of infection, 100% prevention of death
 Phase I imminent (NexBio)
E Gorovkova (USA): effectiveness of oseltamivir vs
H5N1 in ferrets
 5 mg/kg/day within 4 hours of infection: protection vs death from
VM/1203
 Treatment delay to 24 hours: 25 mg/kg/day required
 All animals protected on homologous re-challenge (21 days)
1. Belser J, abstract O71, Options VI, 2007.
2. Gorovkova E. abstract O72, Options VI, 2007.
Antivirals and H5N1
Decreased oseltamivir sensitivity among
Indonesian H5N1 isolates1
 clade 2: 25- to 30-fold decrease in sensitivity compared to
clade 1
 zanamivir should be incorporated into all stockpiles
Clinical experience in Thailand2
 oseltamivir used in 16/25 human H5N1 cases
5 of 8 surviving patients had received it
 earlier treatment associated with higher survival
probability?

1. McKimm-Breschkin J, abstract O69, Options VI, 2007.
2. Chotpitayasunondh T. TS 3, Options VI, 2007.
Overcoming antiviral resistance:
new directions
New methods of targeting NA1
 potential for design of conformation-specific drugs (group 1: 150cavity, group 2: closed)
 further studies of existing agents: combinations, multimers
HA as antiviral target1
 block receptor binding, inhibit membrane fusion
NS1 as antiviral target2
 RNA-binding domain: required for replication
 effector domain: interferes with IFN mRNA processing
M1 and PB1 gene silencing by catalytic nucleic acids3
 DNAzymes and ribozymes both effective; different cleavage sites
= more effective when combined
1. Hay A. TS 2, Options VI, 2007.
2. Krug R. TS 2, Options VI, 2007.
3. Khanna M. abstract O70, Options VI, 2007.
Overview
Disease surveillance and modeling
Virus-host interactions and pathogenesis
Seasonal influenza: vaccine evaluation
Pandemic influenza: outbreak and pre-pandemic
response
Pandemic influenza: vaccine evaluation
Antivirals
Clinical guidance and policies
Clinical guidance and policies:
recurring themes
 Need for a universal seasonal vaccination recommendation :
 current age-based and disease-based recommendations can be
confusing/inconsistent
 Need to increase seasonal vaccine use:
 for its own sake (reduced morbidity/mortality from seasonal influenza)
 as a means of increasing production capacity, to be converted to pandemic
vaccine production when required
 as a catalyst for developing more effective/antigen-sparing vaccines
 Need to ensure reliable and rapid communication during a
pandemic:
 within an affected areas
 across different jurisdictions
UK
Italy
Seasonal vaccination coverage rates
elderly
overall
elderly
Germany
overall
elderly
overall
Korea
asthma patients
dialysis patients
diabetes patients
Korea
high-risk adults
all adults
high-risk children/adolescents
all children/adolescents
0%
20%
40%
Germany, UK, Italy: Szucs et al, abstracts P1321, P1323, P1324, Options VI, 2007.
Korean studies: Kee et al., abstracts P1301, P1302, Options VI, 2007.
60%
80%
100%
Factors influencing vaccine uptake
in health care providers
 Survey of determinants/deterrents of choice to receive
vaccination1
 103 health care workers in BC, Canada
 77% vaccinated
 Vaccination seen as “personal” choice



perceived risks/benefits to self & family
workplace policy (where overlap with personal considerations)
access to in-depth, personalized education
 Survey of vaccination uptake by vaccination providers2
 335 nurses, 343 physicians in BC, Canada
 89% intended to receive vaccine, 78% received it ≥75% of the time
 Drivers for vaccine use: positive direct attitudes to vaccination (2.5 times
more likely), direct social norms (3.2 times more likely)
1. Masaro C. abstract P1303, Options VI, 2007.
2. Buxton J. abstract P1304, Options VI, 2007.
Vaccination issues in the elderly
Timing of vaccination in elderly patients in
France1
 Median time of vaccination: weeks 43 to 44 (end of
October), consistent across years
Controversy over mortality benefits of influenza
vaccination2
 Weaknesses of some analyses:
frailty selection bias
 non-specific endpoints
 insufficient adjustment approaches

1. Mosnier A. abstract P1315, Options VI, 2007.
2. Simonsen L. abstract P1317, Options VI, 2007.
Cost-effectiveness of
seasonal influenza vaccination
Systematic review of vaccine cost-effectiveness in
50- to 64-year-olds1
 Few age-based recommendations include 50- to 64-year-olds on
basis of age alone
 Across 4 studies , favourable QALY ratio for vaccination of 50- to
64-year-olds regardless of risk factors
Incremental cost-effectiveness of adjuvanted
vaccine in France2
 adjuvanted vaccines: more effective in case of drift
 the greater the likelihood of drift, the more cost-effective MF59adjuvanted vaccine is
 becomes cost-saving at drift rate of 0.5 (1 mismatch/2 years)
1. Nichol K. abstract O101, Options VI, 2007.
2. Piercy J. abstract O102, Options VI, 2007.
Trends and future issues
T Tam (Canada): macroepidemiology of vaccination in
70 countries1
 Despite H5N1 concern, little change in global vaccine use
between 2002 and 2005
 9 major vaccine-producing countries: 12% of world’s population,
~60% of total vaccine use – political & public health implications
M Miller (NIH, USA): prioritization of pandemic
vaccines2
 YLL models: largest impact in younger age groups with 1918-like
outbreak, older groups with 1957- or 1968-like
 Outcomes depend on prior exposure/immunity
1. Tam T. abstract O103, Options VI, 2007.
2. Miller M. abstract O104, Options VI, 2007.