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Vaccines

IPV Review Memo, January 11, 2010 - MenHibrix

BLA/STN Number: BLA 125363/0

Sponsor:                  GlaxoSmithKline (GSK) Biologicals’

Products:                 MENHIBRIX (Meningococcal Groups C and Y and Haemophilus b       Tetanus Toxoid                                 Conjugate Vaccine)

Purpose:                    Chemistry, Manufacturing, and Control


From:               Majid Laassri, Product Reviewer, DVP
Thru:                Steven Rubin, DVP     
Copy:               Robin Levis, PhD., Deputy Director, DVP
                        Meghan Ferris, MD, MPH, Clinical Reviewer, DVRPA
           
Memo Date:     January 11, 2010          Revision Date:  January 19, 2010         

Introduction

This Biologics License Application contains information to support the use of MenHibrix, which is a non infectious vaccine that contains Neisseria meningitidis serogroup C capsular polysaccharide (PSC), Neisseria meningitidis serogroup Y capsular polysaccharide (PSY), and Haemophilus influenzae type b capsular polysaccharide (polyribosyl-ribitol-phosphate, PRP), each covalently bound to tetanus toxoid. The vaccine formulation is a lyophilized product supplied in a (b)(4) monodose glass container, stoppered with rubber closures for lyophilization and closed with flipoff caps. The vaccine is to be reconstituted prior to intramuscular injection, with a liquid saline diluent supplied in ---b(4)----------- containing                                (b)(4) of diluent. The reconstituted product contains 2.5 μg of PRP-TT, 5 μg PSC-TT and 5 μg PSY-TT per 0.5 mL dose volume.
The proposed vaccine is for active immunization of infants and toddlers 6 weeks through 15 months of age for the prevention of invasive diseases caused by Neisseria meningitidis serogroups C and Y and Haemophilus influenzae type b.

Poliovirus Vaccines used

The sponsor conducted some studies with Pediarix or Infanrix vaccines (contain the antigens D for poliovirus type 1, 2 and 3) in combination with MenHibrix, to evaluate their immunogenicity.

This review is limited to an evaluation of the sponsor’s serological assays for measuring levels of anti-poliovirus 1, 2 and 3 antibodies in serum of vaccinees.

Anti-Poliovirus antibody assay

Standard operating procedure of -------------(b)(4)---------------- assay

In this submission the sponsor provides the standard operating procedure  (SOP) of the  -------(b)(4)---------- test that allows quantifying the anti-poliovirus antibodies. This test was adapted from the World Organization Guidelines (WHO/EPI/GEN/93.9).

-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------(b)(4)-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------.

In this SOP the sponsor describes in detail the ---------(b)(4)-------- procedure: The purpose of the assay, glossary needed for the assay, scope, responsibilities, and procedure of the assay are emphasized in this SOP. Also an annex for ---------(b)(4)--------  formula and an annex for grid of possible results are included.

Reviewer comment
The SOP was reviewed and found to be acceptable

Performance and Characteristics ------------(b)(4)--------------- assay

 The sponsor states that the performance and Characteristics document provided in this submission, is adapted from the World Health Organization Guidelines for WHO/EPI Collaborative Studies on Poliomyelitis ­Standard Procedure for Determining Immunity to Poliovirus Using the -------(b)(4)----------- Test (WH0/EPI/GEN 93.9). Its objective is to demonstrate that these ---------(b)(4)-------- procedures are adequate for their intended use.
-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------(b)(4)-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------(b)(4)------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------

Precision

To examine the repeatability series of samples representing a range of Polio 1, 2 and 3 antibody levels were assayed (b)(4) in the same test run (table below).

To examine the Intermediate Precision (within laboratory variation) several series of assays were performed with samples representing a range of Polio 1, 2 and 3 antibody levels. The influence of the number of technicians performing the assay and the number of assays performed for the same sample were taken into account as to be representative of normal operational conditions.

The presented data were calculated for positive and negative samples, a negative titer of (b)(4) included in calculations as a value of ----------(b)(4)-------. In this cell-based immunoassay, for each serum sample, the individual ratio between the maximum and minimum titers obtained for different assays/technicians were analyzed; then (table below) the value of the highest ratio (Max ratio) and the number of times the ratio was (b)(4) were recorded.

For type 1, type 2 and type 3, ------(b)(4)------------- of the respective ratios were (b)(4).

Type 1

 

Number of assays done for each sample

Sample assayed

Max. Ratio

# ration > 4

Repeatability
Duplicate

 

(b)(4)

 

(b)(4)

 

(b)(4)

 

(b)(4)

Reproducibility
--b(4)---------

 

 

--b(4)------

 

(b)(4)
(b)(4)
(b)(4)
(b)(4)

(b)(4)
(b)(4)
(b)(4)

 

(b)(4)
(b)(4)
(b)(4)
(b)(4)

(b)(4)
(b)(4)
(b)(4)

 

(b)(4)
(b)(4)
(b)(4)
(b)(4)

(b)(4)
(b)(4)
(b)(4)

 

(b)(4)
(b)(4)
(b)(4)
(b)(4)

(b)(4)
(b)(4)
(b)(4)

 

Type 2

 

Number of assays done for each sample

Sample assayed

Max. Ratio

# ration > 4

Repeatability
Duplicate

 

(b)(4)

 

(b)(4)13

 

(b)(4)

 

(b)(4)

Reproducibility
--b(4)----

 

 

--b(4)------

 

(b)(4)
(b)(4)
(b)(4)
(b)(4)

(b)(4)
(b)(4)
(b)(4)

 

(b)(4)
(b)(4)
(b)(4)
(b)(4)

(b)(4)
(b)(4)
(b)(4)

 

(b)(4)
(b)(4)
(b)(4)
(b)(4)

(b)(4)
(b)(4)
(b)(4)

 

(b)(4)
(b)(4)
(b)(4)
(b)(4)

(b)(4)
(b)(4)
(b)(4)

Type 3

 

Number of assays done for each sample

Sample assayed

Max. Ratio

# ration > 4

Repeatability
Duplicate

 

(b)(4)

 

(b)(4)

 

(b)(4)

 

(b)(4)

Reproducibility
--b(4)----

 

 

--b(4)------

 

(b)(4)
(b)(4)
(b)(4)
(b)(4)

(b)(4)
(b)(4)
(b)(4)

 

(b)(4)
(b)(4)
(b)(4)
(b)(4)

(b)(4)
(b)(4)
(b)(4)

 

(b)(4)
(b)(4)
(b)(4)
(b)(4)

(b)(4)
(b)(4)
(b)(4)

 

(b)(4)
(b)(4)
(b)(4)
(b)(4)

(b)(4)
(b)(4)
(b)(4)

 

Accuracy

Accurate results are obtained by standardization of the ------(b)(4)------- assay using WHO/EPI guidelines (Guidelines for WHO/ collaborative studies on poliomyelitis: WHO/ EPI/ GEN/ 93.9).

Antiserum ------------------------------(b)(4)---------------------------------------- each time; the mean titre was calculated for each Polio serotype. The sponsor states that the results were within one (b)(4) dilutions of the published results (The second international standard for anti-poliovirus sera type 1, 2 and 3. D.J. Wood and B. Heath. Biologicals, 20, 203-211, 1992) for all 3 types.

Interferences

IMPACT OF –b(4)------- CYCLES
-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------(b)(4)-------------------------------------------------------------------------------------------------------------------------------------------------
----------------------------------------------------------------------------------------------------------------------------------------------------------------(b)(4)----------------------------------------------------------------------------------------------------------------------------

[(b)(4)]

 

 

---(b)(4)--
----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------(b)(4)----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------


Reviewer comment


Based on the Performance and Characteristics document provided in this submission; This  --------(b)(4)----------- test is adapted from World Organization Guidelines, and was shown to be reproducible and accurate when implemented in-house, Therefore, this assay is acceptable for use in support of the MenHibrix vaccine.

Questions to sponsor

None

Internal notes for discussion

1.  ----------(b)(4)------- test cut-off: (b)(4) for anti-polio type 1, 2 and 3
2.  In clinical reports (section 5.3.5.1.3): 792014/001 (Hib-MenCY-TT-001) and 792014/002 (Hib-MenCY-TT-002), in paragraph of “criteria for evaluation”, in pages 8 and 4 respectively, the sponsor mentioned that (b)(4) was used for measurement of antibodies, if it is not a typo. The sponsor has to send to CBER the detailed description of the (b)(4)-- used for measurement of poliovirus antibodies.