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Menhibrix Case Study

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Internship presentation on case study findings for Menhibrix vaccine.

Internship presentation on case study findings for Menhibrix vaccine.

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  • 1. Immunogenicity and Safety of H influenzae Type-b- N meningitidis C/Y Conjugate Vaccine in InfantsJuly 19, 2012Sarah HudsonBSPS Pharmacy Intern
  • 2. Objectives• Define and differentiate between meningococcal disease and Hib disease• Identify risk factors of meningococcal disease• Discuss use of Menhibrix vaccine• Describe assessment of immunogenicity and safety of Menhibrix vaccine 2
  • 3. Meningococcal Disease• Bacterial infection caused by Neisseria meningitidis• 5 major meningococcal serogroups are A, B, C, Y, and W-135• 2 forms of disease: – meningococcal sepsis (blood infection) – meningococcal meningitis (inflammation of meninges) CDC, 2012 3
  • 4. Risk Factors of Meningococcal Disease• Disease most common in infants and toddlers• In the US alone 2,500 people are infected and 300 die each year• Spread through direct contact with infected person or salivia• Difficult to diagnose • fever, headache and stiff neck are not easily detected or present in infants Illinois Department of Public Health, 2007 4
  • 5. Hib Disease• Caused by bacterium Haemophilus influenzae• Originally the leading cause of meningitis in young children until being virtually eliminated by routine, effective Hib vaccinations• 20,000 children younger than 5 years of age contract serious Hib disease• 1,000 children age 5 and younger die each year from the disease GSK [press release], 2012 5
  • 6. Menhibrix Vaccine• Menhibrix® [Haemophilus b-Meningococcal Groups C and Y-Tetanus Toxoid Conjugate Vaccine]• Approved in the US for use in children 6 weeks to 18 months of age• Prevent invasive diseases caused by Haemophilus influenzae type b and Neisseria meningitidis serogroups C and Y GSK [press release], 2012 6
  • 7. Safety Information for Menhibrix• Contraindictions – Severe allergic reaction – Guillain-Barré syndrome – Fainting – Apnea in premature born infants – Local injection site redness, swelling, and pain – Systemic events such as irritability, fever, loss of appetite, and drowsiness GSK [press release], 2012 7
  • 8. Immunogenicity and Safety of Hinfluenzae Type b-N meningitidis C/Y Conjugate Vaccine in Infants American Academy of Pediatrics, 127.6: 1375-84 8
  • 9. Rationale• Demonstrate: – consistency of 3 lots of candidate vaccine, Hib-MenCY-TT, in terms of immunogenicity – immune response of Hib-MenCY-TT against N meningitidis serogroups C/Y – non-inferiority of Hib-MenCY-TT with respect to immunogenicity and safety compared to the control, monovalent Hib vaccine, when both co-administered with DTPa-HBV-IPV at 2, 4, and 6 months American Academy of Pediatrics, 127.6: 1375-84 9
  • 10. Study Design• Phase III, randomized, multinational study• Evaluated immunogenicity, safety, and lot-to-lot consistency of 3 Hib-MenCY-TT lots and Hib-MenCY- TT vs. control Administered: Co-administered: Age: Primary study: 3 doses of Hib- DTPa-HBV-IPV 2, 4, and 6 mo Dose 1, 2, 3 MenCY-TT Safety follow up till dose 4 Control: 3 doses of Hib-TT Fourth dose study: 1 dose of Hib-MenCY- MMR and Var 12-15 mo Dose 4 TT 6 month safety follow Control: up 1 dose of Hib-OMP American Academy of Pediatrics, 127.6: 1375-84 10
  • 11. Materials and Methods• 4,180 infants total to receive HibMenCY or licensed Hib-TT/Hib-OMP• Study period: Feb 2006 to Aug 2008• Study population: – Healthy male and female infants 6 to 12 weeks of age at the time of first dose – Free of obvious health problems – Born full term – No prior hepatitis B vaccinations American Academy of Pediatrics, 127.6: 1375-84 11
  • 12. Statistical Methods• Responses that met the criterion were demonstrated in 95% confidence intervals• Dose phases for immunogenicity and non-inferiority: postdose 3, predose 4, and postdose 4 Immunogenicity Noninferiority Lot-to-lot ConsistencyMethod Bactericidal GMT ratio anti-PRP ≥1.0 GMC or GMT ratios titers ≥1:8 ug/mL of lots for C/YPercentage/ ≥90% ≥2 ≥-10% (0.5-2.0)interval American Academy of Pediatrics, 127.6: 1375-84 12
  • 13. ResultsLot-to-Lot Consistency• Successfully demonstrated for 8 of 9 comparisons• Only one lot-to-lot comparison marginally exceeded the predefined criteria interval (1.19-2.24)• Immunogenicity for the pooled lots was met for each lot individually• Lot-to-lot consistency of the hSBA titers were met at predose 4 American Academy of Pediatrics, 127.6: 1375-84 13
  • 14. American Academy of Pediatrics [Supplemental], 2011 14
  • 15. ResultsImmunogenicity: N meningitidis Antibody Responses• All criteria for MenC and MenY were met after doses 3 and 4 Bactericidal titers 1:8 MenC MenY or higher: After dose 3 98.8% 95.8% Before dose 4 96.0% (retained) 92.8% (retained) One month after dose 98.5% 98.8% 4 American Academy of Pediatrics, 127.6: 1375-84 15
  • 16. FIGURE 2 Percentage of subjects who achieved bactericidal titers 1:4 or higher or 1:8 or higher aftercompletion of primary vaccination (after dose 3) before and 1 month after the fourth dose (before and after dose 4) American Academy of Pediatrics, 127.6: 1375-84 16
  • 17. ResultsImmunogenicity: N meningitidis Antibody Responses• Geometric mean antibody titers (GMTs) for bactericidal activity for postdose 4: – Rose by 12.0-fold against MenC – Rose by 11.8-fold against MenY American Academy of Pediatrics, 127.6: 1375-84 17
  • 18. FIGURE 3Bactericidal GMTs against MenC and MenY 1 month after completion of primary vaccination (after dose 3), before and 1 month after the fourth dose (before and after dose 4). American Academy of Pediatrics, 127.6: 1375-84 18
  • 19. ResultsNoninferiority: Hib Antibody Responses• Percentage of subjects reaching protective anti-PRP levels was statistically significantly higher in HibMenCY group than Hib-TT/Hib-OMP group• One month after dose 4, 99.2% of subjects achieved anti-PRP concentrations ≥1.0 ug/mL American Academy of Pediatrics, 127.6: 1375-84 19
  • 20. FIGURE 4 Percentage of subjects with anti-PRP antibody concentrations above the specified cutoff aftercompletion of primary vaccination (after dose 3), before and 1 month after the fourth dose (before and after dose 4) American Academy of Pediatrics, 127.6: 1375-84 20
  • 21. Reactogenicity and Safety Results• Most Common solicited local and general symptoms: – Injection site pain and irritability• Injection site redness and swelling tended to increase with additional vaccinations – Irritability, drowsiness, and loss of appetite did not• Reports of at least 1 serious adverse event: – 5.2% of subjects in HibMenCY group – 6.2% of subjects in Hib group American Academy of Pediatrics, 127.6: 1375-84 21
  • 22. TABLE 1GSK [Highlights of Prescribing information], 2012 22
  • 23. Discussion• Reached the noninferiority criteria in terms of immunogenicity to licensed Hib vaccines• Showed robust immune responses of MenC and MenY antigens• HibMenCY could be another source of Hib vaccine – 3 doses of HibMenCY induced anti-PRP responses that were significantly higher than those of Hib-TT American Academy of Pediatrics, 127.6: 1375-84 23
  • 24. Disscussion• HibMenCY showed to have a safety profile that was similar to licensed Hib-TT and Hib- OMP vaccines• Fewer local reaction than licensed vaccines – May be related to decreased TT or lower PRP in the HibMenCY vaccine American Academy of Pediatrics, 127.6: 1375-84 24
  • 25. Limitations• Number of evaluable subjects (695) was lower than planned (920)• Investigators were not blinded due to them assigning causality for adverse events – Possible bias and systemic failure to attribute AE to investigational vaccine American Academy of Pediatrics, 127.6: 1375-84 25
  • 26. Conclusion• MenC and MenY serogroups most often cause invasive meningococcal disease in the US• Highest burden is infants and young children• HibMenCY Vaccine – highly immunogenic and noninferiority – Safety profile comparable licensed Hib vaccines – May be effective in preventing invasive meningococcal diseases – Decreases shot burden American Academy of Pediatrics, 127.6: 1375-84 26
  • 27. ResourcesBryant, Kristina A., et al. (2011). Immunogenicity and Safety of H influenzae Type-b-N meningitidis C/Y Conjugate Vaccine in Infants. Pediatrics, 127.6 . 1375-84. Retrieved June 16, 2012, from http://www.ncbi.nlm.nih.gov/pubmed/21624883Cohn, Amanda, & Jackson, Michael. (2012). Meningococcal Disease. Retrieved July 9, 2012, from http://wwwnc.cdc.gov/travel/yellowboock/2012/chapter3-infectious-diseases- related-to-travel/meningococcal-disease.htmIllinois Department of Public Health. (2007). Meningococcal Disease. Retrieved July 9, 2012, from http://www.idph.state.il.us/public/hb/hbmenin.htmGlaxoSmithKline. (2012). GSK Receives FDA Approval for Menhibrix [Press Release]. Retrieved July 9, 2012, from http://www.gsk.com/media/pressreleases/2012/2012- pressrelease-1134059.htmGlaxoSmithKline. (2012). Highlights of Prescribing Information. Retrieved July 17, 2012, from http://us.gsk.com/products/assets/us_menhibrix.pdfGlaxoSmithKline (2012). Results Summaries: Haemophilus Influenza Type b, Meningococcal CY-TT Conjugate Vaccine. Retrieved June 16, 2012, from http://www.gsk-clinicalregister.com/ 27