Options for the Control of Influenza VI June 17-23, 2007 Toronto, Ontario, Canada Conference Summary.

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


• 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


• 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



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



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



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



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.


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.


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.


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



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



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.

Options for the Control of Influenza VI June 17-23, 2007 Toronto, Ontario, Canada Conference Summary.

Documents

abstract p135 influenza

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abstract o3

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