Options for the Control of Influenza VI June 17-23, 2007 Toronto, Ontario, Canada
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Transcript of Options for the Control of Influenza VI June 17-23, 2007 Toronto, Ontario, Canada
Options for the Control of Influenza VI
June 17-23, 2007Toronto, 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
Varies widely, resources an issueAfrica: emerging programsAsia: some seasonal surveillance, focus on avianOceania: little information presentedEurope: significant national and EU effortsLatin America: increasing number of programs US & Canada: significant government, military (US)
programs International: WHO, collaborative groups
Global surveillance efforts
Surveillance: Africa
Majority: influenza B (Malaysia-like)
839 specimens, 67 isolates
2006-2007Kenya
Schnabel D, abstract O3
Confirmed influenza B: 10No influenza AConfirmation by PCR
ILI: 83SARI: 104
2006-2007Kenya
Muthoka P, abstract P135
Influenza: 59Identification by passage in MDCK cells, ELISA immunocapture
572 samples from patients with flu-like syndrome or febrile acute respiratory illness
2002 through 2006
Abidjan, Côte d’Ivoire
Kadjo H, abstract P146
ConfirmedCasesSeason Location
Surveillance: Asia
Yes: virus culture, RT-PCR, IFA, HI, phylogenetic analysis
7339 influenza viruses isolated
July 1999 – November 2006
Taiwan
Chiu S, abstract P102
Virus culture, HI202 isolates from 4112 patients
2004 through 2006
India
Chadha M, abstract O1
Influenza viruses isolated: 687Confirmed by multiplex RT-PCR
ILI: 1313 specimens
2004 through 2007
Jeonbuk Province, Korea
Kim C, abstract P159
ConfirmedCasesSeason Location
• China: 197 sentinel hospitals (Zhang Y, abstract P154)
Surveillance: Europe
Influenza: 63 (21%)Influenza: 47 (5%)All respiratory infections: 27 (analysis in progress)
ILI cases: 399ILI cases: 949ILI cases: 650
2004-20052005-20062006-2007
Poland
Romanowska M, abstract P107
3 of 11 analyzed (PCR) swabs were positive for influenzaRemainder still to be processed
ILI: 253 nasal swabs
October 2006-March 2007
England
Hayward A, abstract P168
ConfirmedCasesSeason Location
• 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 mortalityReported 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
3912004-2005
140 (to Feb 24)2006-2007
3742005-2006
5052003-2004
Influenza-related admissionsSeason
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” Web-based 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
No consistent time lags between ILI peaks in children & othersBronchitis always peaked in children before elderly
40 years of incidence data on children as drivers of community ILI & bronchitis spread
England & Wales Elliot A, abstract P124
Most common index cases: age 0-6Influenza A: commonly passed from children (any age) to mother, younger sibInfluenza B: transmitted from children 0-4, to wider spread of age ranges
Analysis of 1609 influenza patients from 1234 families
Japan
Hirotsu N,
abstract O5
35% of adult, 63% of child household contacts experienced ~2 days of ILI35% of households: parental time off work to care for ill child (mean 1.7 days)
Questionnaire: families of 35 children with confirmed influenza
Leicester, UK
Democratis J, abstract P123
ResultsDataLocation
Surveillance: complications
Influenza A, subtype H1, clade 1First documented case (in investigators’ experience) of fatal pneumonia due to influenza infection
Case study: fatal pneumonia associated with H1 influenza in 3-year-old child
São Paolo, Brazil Paiva T, abstract P106
B: poorer prognosis, more abnormal blood parameters vs AH1Prognostic factors: elevated AST, hyperglycemia, haematuria, proteinuria, diclofenac
848 cases of influenza-associated encephalopathy
Japan
Wada T, abstract P109
ResultsDataLocation
Surveillance: comorbidities
Overall influenza-attributable mortality ~4000/year
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
Patients admitted to hospital due to respiratory conditions from 1994 to 2000
Canada
Schanzer D, abstract P112
ResultsDataLocation
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, 20074. 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 productsQualification 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 constructInduces 10-fold increase in HA antibody titre vs normal HAAntibodies 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
10/26 patients: immunosuppressive therapyInfluvac protective (antibody titres ≥40) in 69.2% to 96.2% of patients regardless of immunosuppressant use
Non-Hodgkin lymphoma
n=26Romanowska M, abstract P707
Influvac plus pneumococcal vaccineDuring flu season: 52% reduction in influenza, 24% reduction in all-cause RTI vs no-vaccine control
Children 18 to 72 months
n=597Hak E, abstract O115
Placebo-controlled trialProtection rates from 56.4% to 60.3% following vaccination, vs 6.2% to 8.2% for placebo group
Coronary artery disease
n=658Brydak L, abstract P708
ILI reduction of 39% (kindergarteners) and 29% (schoolchildren) vs no vaccineVaccination of children reduced morbidity in household contacts, morbidity in the elderly
Children (<5 yrs)
n=29927
Gerez L, abstract P703
FindingsPopulation
Clinical vaccine evaluation: Fluarix (GSK)
Seroconversion rates >40% in adults, >30% in elderlyException: B/Taiwan/0050/2006Seroprotection rates 70 to 100%
Antibody responses in Taiwan, 2006
120 serum samples (30 adults, 30 elderly)Chen C, abstract P711
MFI of antibody titres: 2.5 to 4.9 at 1 month post-vaccination, 2.7 to 4.2 at 3 monthsLong-term immunosuppressive therapy: no effect on vaccine effectiveness
Children with inflammatory bowel disease
n=29Rybicka K, abstract P706
MFI of antibody titres: 4.2 to 6.4 at 1 month post-vaccination, 3.1 to 3.9 at 3 monthsHumoral response to NA component similar to that of healthy control subjects
Children with asthma
n=36
Romanowska M, abstract P705
FindingsPopulation
Clinical vaccine evaluation: Fluad (Novartis)
Adjuvanted Fluad vs non-adjuvanted AgrippalGenerally better immunogenicity for Fluad across all viral subtypesNo significant changes in viremia or CD4s for HIV+
HIV-1 seropositive and seronegative adults
n=256Durando P, abstract P736
Fluad vs virosomal vaccine Inflexal-VSignificantly higher immunogenicity with FluadSome cross-protection against heterologous strains
Elderly subjects with chronic disease
n=111Baldo V, abstract P714
Fluad (MF59 adjuvant) vs Novartis’ conventional subunit vaccine Agrippal in high-risk adultsSignificantly higher geometric mean titres (p<0.001), seroprotection rates (p<0.01) with FluadBoth well tolerated, more reactogenicity with adjuvant
Adults with underlying chronic disease
n=359
Baldo V, abstract P733
FindingsPopulation
Clinical vaccine evaluation: cell culture (Novartis)
Phase II trial of consistency of immune response and tolerability across different vaccine lotsMDCK-derived vaccine lots bioequivalent to each other, non-inferior to comparator Agrippal
Adult subjects
n=1200Groth N, abstract P718
Phase II study of safety, tolerability, immunogenicity vs egg-based subunit vaccine FluvirinImmune responses for MDCK-derived vaccine non-inferior to those for FluvirinEcchymosis, chills higher in Fluvirin group
Adult subjects
n=613
Reisinger K, abstract P717
Non-inferiority trial vs egg-derived AgrippalNo significant differences in immune response for each of the three vaccine strainsNo significant differences in safety profile
Adult and elderly subjects
n=2654
Groth N, abstract P716
FindingsPopulation
Clinical vaccine evaluation: children
Surveillance study: 2 doses of TIV provided up to 71% effectiveness in reducing influenza-related hospitalization
Children 6 to 23 monthsShay D, abstract P724
Surveillance study: no significant benefit from TIV in preventing influenza-related hospitalization in infants
Children 6 to 23 monthsDe Serres G, abstract P723
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
Children <4 yrs
n=259Irie S, abstract P713
Influvac field study (previously discussed): 29 to 39% reduction in ILI vs non-vaccinated
Children <5 yrsGerez L, abstract P703
Surveillance detected 231 influenza cases: 3% fully and 10% partially vaccinatedVaccine effectiveness across 3 studies 43 to 54% in spite of circulation of a drifted strain
6- to 59-month-old children in 3 US communities, 2003-2004 seasonM Iwane, abstract O49
FindingsPopulation
Clinical vaccine evaluation: elderly
Phase II trial of intradermally administered novel split-virion vaccine (sanofi-pasteur) vs IM VaxigripSuperior immune response vs all vaccine strains
Subjects aged 60+
n=1107Booy R, abstract P727
Previously discussed Fluad study: increased immunogenicity vs non-adjuvanted, some cross-protection
Elderly w/ chronic diseaseBaldo V, abstract P714
10-year data pooling, 713872 person-seasons of observationVaccination associated with significant reduction in pneumonia/influenza hospitalization (OR 0.73) and death (OR 0.52) vs no vaccination
18 cohorts of community-dwelling elderly
Nichol K, abstract O50
FindingsPopulation
Clinical vaccine evaluation: altered immune response
Fluad: immunogenic, no effect on CD4 or viremiaHIV-positive subjectsDurando P, abstract P736
Clinical/serological remission after immunosuppressive therapyResponse to vaccination comparable to that in healthy controls
Wegener’s granulomatosis
n=35Zycinska K, abstract P721
Demographic determinants of vaccination response: High: older age, African-American ethnicityLow: Hispanic or Native American ethnicity, corticosteroid use
SLE patients’ T cells recognize vaccine components, undergo cell division, but fail to produce IFNγ
SLE patients
n=30
Crowe S, abstract P719; Air G, abstract P720
HSCT recipients undergoing reduced-intensity conditioningLower rates of seroprotection, seroconversion vs controls
HSCT recipients
n=5Mossad S, abstract P715
FindingsPopulation
Clinical vaccine evaluation: strain mismatch
Efficacy of adjuvanted (MF59) vs non-adjuvanted TIV in serological tests vs heterologous strainsAdjuvanted vaccine induced higher titres vs homologous strains, broader protection vs drifted variants
Elderly subjects
n=100
Ansaldi F, abstract P728
Sentinel surveillance of ILI cases in Canadian influenza season (2005-2006) with two circulating drifted strainsRelatively low TIV effectiveness (50 to 70%) but evidence of cross-protection
Patients presenting with ILI
n=442Skowronski D, abstract P732
Absolute and relative efficacies of TIV (Fluzone) vs LAIV (Flumist) in antigenically drifted seasonEfficacy in year with 2 drifted strains: TIV 75%, LAIV 48%
Healthy adult subjects
n=1247Monto A, abstract O51
FindingsPopulation
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 animalsSpread to wild birds: unprecedented ecological & epidemiological
situationShould be seen as disease of animals, not just birds
Study of pathogenesis in ducks2
Virus present 1 day post infection in nasal cavity, lungs, spleenBetter understanding of targets for surveillance sampling
State of bird vaccines3
Potentially useful for eradication, management, preventionIssues: administration & coverage, new variantsFuture 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 2006Need to enhance systems for early detectionEstablishment of protection/surveillance zonesIncrease/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 responsesNeeds: detailed implementation plan; strategies for risk
communication, stockpiling, essential service continuity
Importance of stockpilingAntivirals, 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?
US, stockpilingH5SubunitEggssanofi-pasteur
EUH5MF59 adjuvantMDCK cellsNovartis
EU, stockpilingH5, H9Subunit, MF59 adjuvant
EggsNovartis
Not yetH5, H9Live attenuated, no adjuvant
EggsMedImmune
Under EU review
H5Subunit, AS03 adjuvant
EggsGSK
Not yetH5Whole virus, no adjuvant
Vero cellsBaxter
Approval status
AntigensVaccine/
adjuvant
ProductionManufacturer
Pandemic influenza vaccines: clinical evaluation
CSL Limited: aluminium-adjuvanted inactivated split-virion A/Vietnam/1194/2004NIBRG(H5N1) vaccinePhase 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 adjuvantDose-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 carrierAntibody 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
developmentPhase III trial in 5071 subjects: safety profile of 15 mcg
dose vs seasonal vaccine FluarixSignificantly 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 strategiesBerna: 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 vaccinesDevelopment of cell culture systems
Rapidly expandable Enhanced immunogenicity? Reverse genetics
Use of adjuvantsAntigen sparingIncreased immunogenicity in elderlyCross-protection?
Pandemic influenza vaccines:future directions
Restricted applicability (high-risk groups)
Safety concerns?
Antigen-sparing
Broad response
Early protection with 1 dose?
Live attenuated virus
High reactogenicity (especially in children)
Antigen-sparingWhole virus
Cost
Developing safety profile
High reactogenicity
Antigen-sparing
Higher immunogenicity?
Adjuvanted
2 doses required
Higher antigen dose required
Safety
Broad response
Subunit
ConsProsVaccine type
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 seasons133 A(H1N1), 186 A(H3N2), 118 BAll susceptible to oseltamivir and zanamivir, one exception: B
virus, R371K active site substitutionAnother B mutant (H274Y) detected: susceptible to oseltamivir &
zanamivir, peramivir-resistant
A Hurt (WHO, Australia): mutations in N14 A(H1N1) strains detected with reduced NAI sensitivity3 novel mutations in NA gene: Q136K, K150T, K143RAll 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 miceremoves sialic acids from respiratory epithelium70% prevention of infection, 100% prevention of deathPhase I imminent (NexBio)
E Gorovkova (USA): effectiveness of oseltamivir vs H5N1 in ferrets5 mg/kg/day within 4 hours of infection: protection vs death from
VM/1203Treatment delay to 24 hours: 25 mg/kg/day requiredAll 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: 150-cavity, 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 replicationeffector 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
Seasonal vaccination coverage rates
0% 20% 40% 60% 80% 100%
all children/adolescents
high-risk children/adolescents
all adults
high-risk adults
diabetes patients
dialysis patients
asthma patients
overall
elderly
overall
elderly
overall
elderly
Kor
eaK
orea
Ger
man
yU
KIt
aly
Germany, UK, Italy: Szucs et al, abstracts P1321, P1323, P1324, Options VI, 2007.Korean studies: Kee et al., abstracts P1301, P1302, Options VI, 2007.
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 driftthe greater the likelihood of drift, the more cost-effective MF59-
adjuvanted vaccine isbecomes 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.