Menhibrix Case Study

July 19, 2012Sarah HudsonBSPS Pharmacy Intern

Immunogenicity and Safety of H influenzae Type-b-N meningitidis C/Y Conjugate Vaccine in Infants

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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

CDC, 2012 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)

Illinois Department of Public Health, 2007

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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

GSK [press release], 2012 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


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


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

8

American Academy of Pediatrics, 127.6: 1375-84

Immunogenicity and Safety of H influenzae Type b-N meningitidis C/Y

Conjugate Vaccine in Infants

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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


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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:Dose 1, 2, 3Safety follow up till dose 4

3 doses of Hib-MenCY-TT

DTPa-HBV-IPV 2, 4, and 6 mo

Control: 3 doses of Hib-TT

Fourth dose study:Dose 46 month safety follow up

1 dose of Hib-MenCY-TT

MMR and Var 12-15 mo

Control:1 dose of Hib-OMP

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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


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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 titers ≥1:8 for C/Y

GMT ratio anti-PRP ≥1.0 ug/mL

GMC or GMT ratios of lots

Percentage/interval

≥90% ≥2 ≥-10% (0.5-2.0)

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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


14American Academy of Pediatrics [Supplemental], 2011

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Results

Immunogenicity: N meningitidis Antibody Responses• All criteria for MenC and MenY were met after doses

3 and 4


Bactericidal titers 1:8 or higher:

MenC MenY

After dose 3 98.8% 95.8%

Before dose 4 96.0% (retained) 92.8% (retained)

One month after dose 4

98.5% 98.8%

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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)


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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


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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).

FIGURE 3


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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


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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)

FIGURE 4


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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


22GSK [Highlights of Prescribing information], 2012

TABLE 1

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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


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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


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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


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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


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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.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.htmGlaxoSmithKline. (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/

http://www.ncbi.nlm.nih.gov/pubmed/21624883

http://wwwnc.cdc.gov/travel/yellowboock/2012/chapter3-infectious-diseases-

http://www.idph.state.il.us/public/hb/hbmenin.htm



http://www.gsk.com/media/pressreleases/2012/2012-

http://www.gsk.com/media/pressreleases/2012/2012-

http://www.gsk-clinicalregister.com/

Menhibrix Case Study

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