1997 PRELIMINARY RESULTS
Download
Report
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.