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Release of information relating to the approval process for the meningococcal B vaccine (MeNZB) application

Minutes of the Vaccine Sub-Committee Teleconference Meeting 15 December 2005

Welcome and Apologies

The meeting opened at 8.20am.

Present: Associate Professor Richard Robson (Chair), Dr Tim Blackmore, Associate Professor David Holdaway, Dr Rod Ellis-Pegler, Dr Stewart Reid, Professor Jeff Weston, Alison MacDonald (Secretary), Observers: Marie Prescott, Rob Allman and Stewart Jessamine.

NEW MEDICINE APPLICATIONS UNDER SECTION 23
MeNZB (Meningococcal B) injection suspension 25mcg/0.5mL TT50-7090

Conflict of interest statement

As with earlier applications for this vaccine Dr Reid stated a conflict of interest, as he had been a member of the Meningococcal B Vaccine Project Committee for the past five years. The committee noted his declaration and confirmed its earlier decision that Dr Reid could participate in the meeting, but that Dr Reid would abstain from the decision making process.

OBJECTIVE: To further consider the application to the Minister to introduce a fourth dose of Meningococcal B (MeNZB) Vaccine for children who received their first dose of vaccine when aged less than six months.

The committee discussed additional data from the V60P6 study supplied by Chiron on 25th November 2005 in response to the questions raised by the Committee during its previous consideration of this application. Other data present included a graphical summary of earlier immunogenicity data examining serum bactericidal activity (SBA) responses in different age groups after 3 vaccinations and the impact of a fourth dose on SBA levels and on adverse reactions to vaccination. The sponsor also submitted new data examining the pattern of vaccine breakthrough cases categorised by age, sex, and time since vaccination.

On review of these data the committee noted that the sponsor’s response focussed on the immunogenicity of three doses of vaccine in infants under six months of age. The committee agreed that children in this age group had the highest risk of contracting meningococcal B disease, and unfortunately had the poorest response to vaccination in that a lower percentage demonstrated an immune response to the vaccine when assessed by SBA.

The committee confirmed their prior view that, for the consideration of MeNZB for licensure under section 23 of the Medicines Act, the percentage of individuals who mount a fourfold rise in SBA is an acceptable measure of efficacy for the purpose of epidemic management. NB in this context efficacy is taken to mean that there is an indication from the immunogenicity data that clinical protection will be seen following vaccination, though this remains to be proven.

The committee noted that the percentage of infants who mount a fourfold rise in SBA following three doses is lower than that of the other age groups in which SBA has been assessed. However, following the fourth dose, the percentage of responders increases to a level similar to that seen in older age groups: 48% of 42 subjects {95% CI 32%-64%} were sero-responders following three doses whilst 69% of 45 subjects {95% CI 53% -82%} were sero-responders following a fourth dose.

The effect of the fourth dose, therefore, is to increase the percentage of sero-responders. It is probable that the duration of any protection will be extended as well. These considerations are important as these very young infants are at the highest historical risk of the disease.

The committee noted with concern, however, that in all age groups following three doses of MeNZB there was a rapid fall in the percentage of individuals who sustained a fourfold rise over the baseline titre and of those who sustain a titre of > 1/4. This means that if the SBA response is the correlate of clinical protection such protection may be very short lived, a few months only. Accordingly, the committee were concerned about the continued use of the SBA response as the putative correlate of protection without evidence of protection against clinical disease and its duration.

For further applications concerning this vaccine, of which close to 3 million doses have now been administered under section 23 of the Medicine’s Act, it is important that data indicating protection against clinical disease and its duration are presented. The committee acknowledged that data were presented indicating a decline in the number of cases occurring. However this decline started in 2002, prior to the introduction of the vaccine, as case numbers were already falling.

The Committee found that, while reactogenic, administration of a fourth dose of vaccine was not associated with any increased rate of adverse reactions.

The Committee were reassured by the data presented as it provided further evidence demonstrating that administration of meningococcal B vaccine did not appear to interfere with the immune responses to other childhood vaccines administered concurrently.

The committee discussed that there are insufficient data to assess the efficacy (protection against clinical disease) of the vaccine, and it is not possible at this stage to determine whether or not vaccine breakthrough was occurring more frequently in younger than older children. This meant the application for a fourth dose in younger children was assessed in terms of immunogenicity comparisons with older children.

Having considered all of the issues, the VSC agreed that in terms of epidemic control, the benefits of a 4th dose of MeNZB for infants who received their first dose when aged less than six months, outweighed the risks.

Committee recommendations:

That the application of Chiron to licence the administration of a fourth dose of MeNZB (Meningococcal B) vaccine to infants who received their first dose when aged less than six months be approved under Section 23 of the Medicines Act 1981:

This approval is subject to the following:

• The datasheet is to contain a statement advising that whilst the immunogenicity of the vaccine gives an indication that clinical protection is likely, this is not yet proven.
• Further data are required to demonstrate that vaccination with MeNZB provides clinical protection against meningococcal B disease, and the duration of such protection.

The Committee advised that for full approval under Section 21 of the Medicines Act 1981 the company would be required to provide

• Evidence of efficacy in the community across all vaccinated age groups.
• The duration of such protection.
• Post-licensure safety surveillance data.

The meeting closed at 9.00 am