Successfully reported this slideshow.
We use your LinkedIn profile and activity data to personalize ads and to show you more relevant ads. You can change your ad preferences anytime.

Vaccine H3N2 H1N1 Comparison Virus Viral Challenge Testing

1,024 views

Published on

Lecture from World Vaccine Congress, Washington 2016. This presentation provides further information about different viral challenge agents and the relative merits of two common influenza serotypes for vaccine clinical trials.

Published in: Health & Medicine
  • Be the first to comment

  • Be the first to like this

Vaccine H3N2 H1N1 Comparison Virus Viral Challenge Testing

  1. 1. A CONSIDERATION OF H1N1/09pdm AND NEW VARIANT H3N2/13 AS AGENTS FOR HUMAN CHALLENGE TRIALS Dr. Adrian Wildfire Project Director; Infectious Disease and HCU CLINICAL TRIAL SOLUTIONS SGS - World Vaccine Congress – Washington, March 30th, 2016
  2. 2. 2 INTRODUCTION  Influenza viruses make ideal agents for study owing to the transient yet well characterised nature of the illness  Influenza-like illnesses have been documented as causing pandemics since 876 A.D.  H1N1 and H3N2 serotypes have caused the majority of the pandemics in the 20th and 21st Centuries  Currently circulating H1 and H3 strains are relative of past circulating strains e.g. A/Wuhan/359/95 (H3N2) is a drifted distant relative of the 1968 Hong Kong H3N2 strain  Both H1 and H3 strains have epidemic and pandemic potential – antigenic drift and shift (reassortment) cause flares in transmission or ‘waves’ of recurrence  Using cGMP manufactured H1 or H3 viruses in Human Challenge Trials can emulate high incidence disease
  3. 3. 3 THE ORIGINS OF INFLUENZA
  4. 4. 4 A NEW PHYLOGENETIC ANALYSIS*  New evidence suggests influenza originated in bats and most likely spread sequentially to horses, poultry and swine before entering humans about 6000 years ago  Reassortment of 18 HA and 11 NI genes lead to new serotypes of influenza  Influenza strains in poultry show rapid rates of mutation  H1, H2, H3, N1 and N2 – have evolved sustained transmission into humans  Pandemic H1N1 and H3N2 originated approximately towards the end of the 19th century. H1N1 when a major reassortment coincided with a horse flu outbreak  H3N2 and H1N1 have been responsible for serial pandemics since 1900 *http://www.nature.com/nature/journal/v508/n7495/full/nature13016.html
  5. 5. 5 THREE PANDEMICS PER CENTURY The 11 pandemics since 1700, listed by the year they started: 1729 – ? 1732 – ? 1781 – ? 1830 – H1? 1833 – H1? 1889 – H3N8 1918 – H1N1 1957 – H2N2 1968 – H3N2 1977 – H1N1 2009 – H1N1
  6. 6. 6 H1 and H3 - Serial pandemics since the 19th Century THE PREDOMINANCE OF CIRCULATING H1 AND H3 SEROTYPES Palese P (December 2004). "Influenza: old and new threats". Nature Medicine 10 (12 Suppl): S82–7. doi:10.1038/nm1141. PMID 15577936.
  7. 7. 7 H1N1 AND H3N2 – GLOBAL PREVALENCE
  8. 8. 8 H1N1 AND H3N2: 2015 – 2016 FLU SEASON
  9. 9. 9 CLINICAL CHARACTERISTICS OF H1, H3 INFLUENZA
  10. 10. 10 FLU - SIGNS AND SYMPTOMS* (PANDEMIC H1, H3)  temperature – 102 to 104oF  sore throat  exhaustion  headache  aching limbs  bloodshot eyes  cough  nosebleeds  vomiting or diarrhoea  relapse and respiratory problems  pulmonary haemorrhages *30-50% of influenza cases may be asymptomatic
  11. 11. 11 CASE FATALITIES Name of pandemic Date Deaths Case Fatality Rate Subtype involved Pandemic Severity Index 1889–1890 flu pandemic (Asiatic or Russian Flu) 1889–1890 1 million 0.15% H3N8 2 1918 flu pandemic (Spanish flu) 1918–1920 20 to 100 million 2% H1N1 5 Asian Flu 1957–1958 1 to 1.5 million 0.13% H2N2 2 Hong Kong Flu 1968–1969 0.75 to 1 million <0.1% H3N2 2 Russian flu 1977–1978 N/A N/A H1N1 N/A 2009 flu pandemic (Worldwide) 2009–2010 18,000 to 284,500 0.03% H1N1/09 1 Annual flu virus deaths (USA only) 1976-77 to 2006-07 3,000 to 46,000 N/A N/A N/A
  12. 12. 12 H1N1 vs H3N2 – SEVERITY AND SEQUELAE  Influenza A H3N2 infection infections are more severe than A H1N1 in terms of fever, leucopoenia and CRP  Mean ages for attack are 33 +/- 8.4 years (H1N1), and 41 +/- 15.2 years (H3N2)  A greater number of hospitalisations occur during years that influenza A(H3N2) is predominant  Pneumonia is positively associated with vaccination  Seasons with prominent circulation of influenza A(H3N2) viruses have 2.7 times more deaths associated.
  13. 13. 13 H1, H3 AND IMMUNITY
  14. 14. 14 INFLUENZA – H1 IMMUNITY  Influenza promotes a strong protective antibody response to surface haemagglutinin and neuraminidase antigens  Severity of disease correlates to prior exposure  Full-length H1 HA antigens induce a profound HI and NAb response*  H1N1/09pdm immunity increases with age and does not does not correlate to pre-seasonal HI titres *http://jvi.asm.org/content/80/23/11628.full
  15. 15. 15 INFLUENZA – H3 IMMUNITY  Since 2010, all circulating influenza strains are showing a decreased ability to agglutinate  H3 HA genes mutate more rapidly than H1 – H3 has a greater propensity to vaccine failure or escape  Both full-length and secreted, transmembrane-truncated H3 HA antigens induce high-level HI and NAb responses*  Severity of disease correlates to prior exposure  H3N2 immunity correlates to pre-seasonal HI titres *http://jvi.asm.org/content/80/23/11628.full
  16. 16. 16 H1, H3 AND VIRAL LOAD
  17. 17. 17 VIRAL LOAD (vAUC)  In a meta-analysis of HCTs, viral shedding was noted in 93.1% of H1N1/09pdm subjects and 92.5% of H3N2  Peak viral loads differ little between H1 and H3 studies  vAUC is observed to be greater in H3N2 challenge studies  No significant correlation has been observed between pandemic (H1N1) 2009 or seasonal influenza viral loads and clinical severity of illness  Viral loads in pandemic H1N1 viruses are characterised by lower copy numbers than seasonal H3N2 viruses (~1 log10)
  18. 18. 18 VIRAL SHEDDING
  19. 19. 19 H1N1, H3N2 AS CHALLENGE AGENTS
  20. 20. 20 WHY H1N1pdm and H3N2? – 1  Influenza A strains show fewer GI symptoms compared to B  H1 and H3 strains have been dominant for >100 years  H1N1/09pdm has been the cause of the most recent and most severe pandemic in the 21st C  H1N1/09pdm is associated with the greatest symptomology of the most recently circulating H1N1 serotypes  Seasonal H3N2 demonstrates greater symptomology compared to seasonal H1N1/09pdm*  The Northern Hemisphere showed an H3N2 new variant as the predominant virus for 2014-2015  The Northern Hemisphere showed a resurgence of the H1N1/09pdm as the predominant virus for 2015-2016
  21. 21. 21 WHY H1N1pdm and H3N2? – 2  H3N2 new variant has not been in circulation long enough to attenuate (low CFR)  H3N2 new variant has low levels of natural (homotypic) immunity  H3N2 has a good shedding profile  Challenge strains of H1N1/09pdm and H3N2 strains do not possess the markers for highly pathogenic disease  In challenge trials, fixed effect estimates are similar for both H1N1 and H3N2 (60%) i.e. both cause equal amounts of disease
  22. 22. 22 H3N2 NEW VARIANT
  23. 23. 23 H3N2 SWITZERLAND 2013 – NEW VARIANT  Influenza A/Texas/50/2012 like viruses were the most common circulating influenza (H3N2) viruses during the 2013-14 season.  New clusters of A(H3N2) were first detected through surveillance in late March 2014  A/Switzerland/9715293/2013, a representative of one of the new groups, predominated by the end of the 2013- 2014 season  SGS isolated an new variant of the A/Switzerland/2013 group circulating locally  This new variant is currently under manufacture for release in 2016 as a novel challenge agent
  24. 24. 24 IDENTIFICATION OF A NEW STRAIN PNA150487NA GHE_150482_NA YRO_150479_NA KTI_13799_NA AME_15049NA CCA5734NA AEL150491_NA SVE10369NA A/Switzerland/9715293/2013 A/Switzerland/9715293/2013 MK SME_150477_NA SBO6110NA A/Texas/50/2012 | HA | 440627 A/Victoria/361/2011 | HA | 408194 A/Perth/16/2009 | HA | 307676 A/Minnesota/11/2010 | HA | 465400 89 100 100 99 68 65 83 87 100 65 45 0.01
  25. 25. 25 SGS – A VIRAL MENU SGS is committed to providing a viral menu including Influenza A and RSV for use in Human Challenge Trials within its HCU/CPU for 2016
  26. 26. 26 FULL SCOPE SERVICES  Large HV recruitment database  Extensive early phase experience (>1000 studies)  Dedicated HCU (Class II, negative pressure unit) within fully accredited CPU  x8 single-bedded isolation rooms with en suite facilities plus x12 bed ‘ward’ style isolation unit ( = 20 bed total)  Strict IC including HEPA filtered air systems  Access to complex or innovative clinical interventions / practices (LP; nasal washes; BAL; tissue sampling)  Full eSource capability  Biometrics; PK/PD; M&S; PM; QA; Regulatory guidance; Laboratory Services; GMP Pharmacy; Class II safety lab
  27. 27. 27 VIRAL CHALLENGE FACILITIES AT SGS
  28. 28. 28 HUMAN CHALLENGE CONTEXT: “A randomized, placebo-controlled, double-blind Phase 2a trial was designed to assess the efficacy and safety of a novel mAb in healthy human volunteers challenged with a 2009 pandemic strain of H1N1 influenza virus” KEY CHALLENGES: Identifying a susceptible cohort (60-80 HVs - HAI <10) 10d isolation of subjects within a specialised HCU Intense NP swab SoA / intense pre-screen PCR schedule OUTCOMES: A total of 332 subjects were screened; 31 were enrolled - 20 subjects met the definition of laboratory-confirmed infection (mAb, n=13; and placebo, n=7) (AR = 62%) vAUC for mAb treated subjects was reduced by 92% (p=0.019); peak viral load was reduced by 2.2 logs (p=0.009) (interim result data @ 6 months) mAb was generally safe and well tolerated. There were no drug-related discontinuations or serious adverse events (SAEs) reported in the study Based on the interim results - the comparative portion of the trial was ended. CASE STUDY: PHASE 2a STUDY IN INFLUENZA
  29. 29. 29 Agriculture, Food and Life Adrian Wildfire Project Director - Infectious Diseases & Viral Challenge Unit - Clinical Research SGS United Kingdom Limited Phone: + +44 (0)78943 92625 SGS House 217-221 London Road, Camberley GU15 3EY E-mail : adrian.wildfire@sgs.com United Kingdom Web : www.sgs.com/lifescience THANK YOU FOR YOUR ATTENTION + 41 22 739 9548 + 1 866 SGS 5003 + 65 637 90 111 + 33 1 53 78 18 79 + 1 877 677 2667 + 33 1 41 24 87 87
  30. 30. 30 QUESTIONS ?
  31. 31. 31

×