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

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

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

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

  2. 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

  3. 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

  4. Surveillance: Africa Location Season Cases Confirmed Abidjan, Côte d’Ivoire Kadjo H, abstract P146 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 Kenya Muthoka P, abstract P135 2006-2007 ILI: 83 SARI: 104 Confirmed influenza B: 10 No influenza A Confirmation by PCR Kenya Schnabel D, abstract O3 2006-2007 839 specimens, 67 isolates Majority: influenza B (Malaysia-like)

  5. Surveillance: Asia Location Season Cases Confirmed Jeonbuk Province, Korea Kim C, abstract P159 2004 through 2007 ILI: 1313 specimens Influenza viruses isolated: 687 Confirmed by multiplex RT-PCR Taiwan Chiu S, abstract P102 July 1999 – November 2006 7339 influenza viruses isolated Yes: virus culture, RT-PCR, IFA, HI, phylogenetic analysis India Chadha M, abstract O1 2004 through 2006 202 isolates from 4112 patients Virus culture, HI • China: 197 sentinel hospitals (Zhang Y, abstract P154)

  6. Surveillance: Europe Location Season Cases Confirmed England Hayward A, abstract P168 October 2006-March 2007 ILI: 253 nasal swabs 3 of 11 analyzed (PCR) swabs were positive for influenza Remainder still to be processed Poland Romanowska M, abstract P107 2004-2005 2005-2006 2006-2007 ILI cases: 399 ILI cases: 949 ILI cases: 650 Influenza: 63 (21%) Influenza: 47 (5%) All respiratory infections: 27 (analysis in progress) • 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)

  7. 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.

  8. 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.

  9. Surveillance: Canada Season Influenza-related admissions 2003-2004 505 2004-2005 391 2005-2006 374 2006-2007 140 (to Feb 24) • 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

  10. 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.

  11. Surveillance: children & families Location Data Results England & Wales Elliot A, abstract P124 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 Leicester, UK Democratis J, abstract P123 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) Japan Hirotsu N, abstract O5 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 0-4, to wider spread of age ranges

  12. Surveillance: complications Location Data Results São Paolo, Brazil Paiva T, abstract P106 Case study: fatal pneumonia associated with H1 influenza in 3-year-old child • Influenza A, subtype H1, clade 1 • First documented case (in investigators’ experience) of fatal pneumonia due to influenza infection Japan Wada T, abstract P109 848 cases of influenza-associated encephalopathy • B: poorer prognosis, more abnormal blood parameters vs AH1 • Prognostic factors: elevated AST, hyperglycemia, haematuria, proteinuria, diclofenac

  13. Surveillance: comorbidities Location Data Results Canada Schanzer D, abstract P112 Patients admitted to hospital due to respiratory conditions from 1994 to 2000 • 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

  14. 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.

  15. 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

  16. 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.

  17. 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.

  18. 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

  19. 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.

  20. 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.

  21. Clinical vaccine evaluation: Influvac Population Findings Children (<5 yrs) n=29927 Gerez L, abstract P703 • ILI reduction of 39% (kindergarteners) and 29% (schoolchildren) vs no vaccine • Vaccination of children reduced morbidity in household contacts, morbidity in the elderly Coronary artery disease n=658 Brydak L, abstract P708 • Placebo-controlled trial • Protection rates from 56.4% to 60.3% following vaccination, vs 6.2% to 8.2% for placebo group Non-Hodgkin lymphoma n=26 Romanowska M, abstract P707 • 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 n=597 Hak E, abstract O115 • Influvac plus pneumococcal vaccine • During flu season: 52% reduction in influenza, 24% reduction in all-cause RTI vs no-vaccine control

  22. Clinical vaccine evaluation: Fluarix (GSK) Population Findings Children with asthma n=36 Romanowska M, abstract P705 • MFI of antibody titres: 4.2 to 6.4 at 1 month post-vaccination, 3.1 to 3.9 at 3 months • Humoral response to NA component similar to that of healthy control subjects Children with inflammatory bowel disease n=29 Rybicka K, abstract P706 • MFI of antibody titres: 2.5 to 4.9 at 1 month post-vaccination, 2.7 to 4.2 at 3 months • Long-term immunosuppressive therapy: no effect on 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%

  23. Clinical vaccine evaluation: Fluad (Novartis) Population Findings Adults with underlying chronic disease n=359 Baldo V, abstract P733 • 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 Elderly subjects with chronic disease n=111 Baldo V, abstract P714 • Fluad vs virosomal vaccine Inflexal-V • Significantly higher immunogenicity with Fluad • Some cross-protection against heterologous strains 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+

  24. Clinical vaccine evaluation: cell culture (Novartis) Population Findings Adult and elderly subjects n=2654 Groth N, abstract P716 • 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 Adult subjects n=613 Reisinger K, abstract P717 • Phase II study of safety, tolerability, immunogenicity vs egg-based subunit vaccine Fluvirin • Immune responses for MDCK-derived vaccine non-inferior to those for Fluvirin • Ecchymosis, chills higher in Fluvirin group Adult subjects n=1200 Groth N, abstract P718 • 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

  25. Clinical vaccine evaluation: children Population Findings 6- to 59-month-old children in 3 US communities, 2003-2004 season M Iwane, abstract O49 • 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 Children <5 yrs Gerez L, abstract P703 • Influvac field study (previously discussed): 29 to 39% reduction in ILI vs non-vaccinated Children <4 yrs n=259 Irie S, abstract P713 • 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 6 to 23 months De Serres G, abstract P723 • Surveillance study: no significant benefit from TIV in preventing influenza-related hospitalization in infants Children 6 to 23 months Shay D, abstract P724 • Surveillance study: 2 doses of TIV provided up to 71% effectiveness in reducing influenza-related hospitalization

  26. Clinical vaccine evaluation: elderly Population Findings 18 cohorts of community-dwelling elderly Nichol K, abstract O50 • 10-year data pooling, 713872 person-seasons of observation • Vaccination associated with significant reduction in pneumonia/influenza hospitalization (OR 0.73) and death (OR 0.52) vs no vaccination Elderly w/ chronic disease Baldo V, abstract P714 • Previously discussed Fluad study: increased immunogenicity vs non-adjuvanted, some cross-protection Subjects aged 60+ n=1107 Booy R, abstract P727 • Phase II trial of intradermally administered novel split-virion vaccine (sanofi-pasteur) vs IM Vaxigrip • Superior immune response vs all vaccine strains

  27. Clinical vaccine evaluation: altered immune response Population Findings HSCT recipients n=5 Mossad S, abstract P715 • HSCT recipients undergoing reduced-intensity conditioning • Lower rates of seroprotection, seroconversion vs controls SLE patients n=30 Crowe S, abstract P719; Air G, abstract P720 • Demographic determinants of vaccination response: • High: older age, African-American ethnicity • Low: Hispanic or Native American ethnicity, corticosteroid use • SLE patients’ T cells recognize vaccine components, undergo cell division, but fail to produce IFNγ Wegener’s granulomatosis n=35 Zycinska K, abstract P721 • Clinical/serological remission after immunosuppressive therapy • Response to vaccination comparable to that in healthy controls HIV-positive subjects Durando P, abstract P736 • Fluad: immunogenic, no effect on CD4 or viremia

  28. Clinical vaccine evaluation: strain mismatch Population Findings Healthy adult subjects n=1247 Monto A, abstract O51 • 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% Patients presenting with ILI n=442 Skowronski D, abstract P732 • 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 Elderly subjects n=100 Ansaldi F, abstract P728 • 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

  29. 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

  30. 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.

  31. 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.

  32. 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.

  33. 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.

  34. 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.

  35. 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

  36. 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

  37. 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.

  38. 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.

  39. 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

  40. 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.

  41. 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.

  42. 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.

  43. 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.

  44. 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.

  45. 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?

  46. 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.

  47. 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

  48. 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.

  49. 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.

  50. 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.

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