Internship presentation on case study findings for Menhibrix vaccine.

1. Immunogenicity and Safety of H influenzae Type-b-
N meningitidis C/Y Conjugate Vaccine in Infants
July 19, 2012
Sarah Hudson
BSPS 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
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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 H
influenzae Type b-N meningitidis C/Y
Conjugate Vaccine in Infants
American Academy of Pediatrics,
127.6: 1375-84
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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
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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
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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
Consistency
Method Bactericidal GMT ratio anti-PRP ≥1.0 GMC or GMT ratios
titers ≥1:8 ug/mL of lots
for C/Y
Percentage/ ≥90% ≥2 ≥-10% (0.5-2.0)
interval
American Academy of Pediatrics, 127.6: 1375-84
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13. Results
Lot-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
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14. American Academy of Pediatrics [Supplemental], 2011 14

15. Results
Immunogenicity: 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
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16. FIGURE 2
Percentage of subjects who achieved bactericidal titers 1:4 or higher or 1:8 or higher 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 16

17. Results
Immunogenicity: 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
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18. FIGURE 3
Bactericidal 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. Results
Noninferiority: 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
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20. FIGURE 4
Percentage of subjects with anti-PRP antibody concentrations above the specified cutoff 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 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
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22. TABLE 1
GSK [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
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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
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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
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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
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27. Resources
Bryant, 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/21624883
Cohn, 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.htm
Illinois Department of Public Health. (2007). Meningococcal Disease. Retrieved July 9, 2012, from
http://www.idph.state.il.us/public/hb/hbmenin.htm
GlaxoSmithKline. (2012). GSK Receives FDA Approval for Menhibrix [Press Release]. Retrieved July
9, 2012, from http://www.gsk.com/media/pressreleases/2012/2012- pressrelease-
1134059.htm
GlaxoSmithKline. (2012). Highlights of Prescribing Information. Retrieved July 17, 2012, from
http://us.gsk.com/products/assets/us_menhibrix.pdf
GlaxoSmithKline (2012). Results Summaries: Haemophilus Influenza Type b, Meningococcal CY-TT
Conjugate Vaccine. Retrieved June 16, 2012, from http://www.gsk-clinicalregister.com/
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