Close on the heels of the FDA’s approval of four H1N1 vaccines, the European Medicines Agency (EMEA) has recommended to the European Commission that two H1N1 vaccines be granted marketing authorisation. The EMEA’s Committee for Medicinal Products for Human Use (CHMP) expedited its assessment ofthe two vaccines. The data that allowed replacement of the strain in the mock-up vaccine with the H1N1strain was reviewed as a variation to the previously issued Marketing Authorisation (MA). The core pandemic dossiers had already been evaluated by the EMEA and the associated mock-up vaccine had been granted Marketing Authorisations, although the final vaccine could only be used during an officially declared pandemic.
The CHMP have provided details of the scientific rationale they used in order to reach the conclusions on the benefit-risk balance for the two H1N1 vaccines that led to the positive opinion. Simply put, they employed the “proof of principle” approach by which safety and immunogenicitydata were generated with the mock-up vaccine containing subtypes of influenza A (H5N1) to which the majority of the population is naive. These data were then extrapolated to the current vaccine containing the A(H1N1) pandemic strain.
The two EMEA-approved vaccines are Focetria (Novartis) and Pandemrix (GSK). The CHMP is currently recommending a two-dose vaccination schedule at an interval of three weeks for adults, pregnant women, and children over 6 months old.
Focetria is an inactivated purified subunit vaccine composed of 7.5 mcg of hemagglutinin and the MF59C.1 adjuvant. MF59C.1 is a submicron oil-in-water emulsion, comprising squalene, sorbitan trioleate, and polysorbate80. Stay tuned for a future entry with more details on MF59C.1.
Pandemrix is an inactivated purified subunit vaccine composed of 3.75 mcg of hemagglutinin and the ASO3 adjuvant. AS03 is also a submicron oil-in-water emulsion, comprising squalene, alpha-tocopherol (Vitamin E), and polysorbate 80.
The differences between the EMEA innoculation recommendations for the H1N1 vaccines and those approved by FDA are quite dramatic. Most strikingly, FDA recommended a single dose of the inactivated H1N1 influenza vaccines while EMEA recommended a two-dose vaccination schedule, 21 days apart, for adults, pregnant women, and children over six months of age. The EMEA did note that future data from ongoing clinical trials may result in these recommendations being updated.
FDA approved a single 15 mcgdose of H1N1 vaccine; EMEA recommended both a 7.5 mcg and 3.75 mcg dose. The effectiveness of the lower dose is probably due to the use of the adjuvantwhich typically stimulates the immune responses to the antigen components of the vaccine, and can generate a higher immune response with lower amounts of antigen when compared to the unadjuvanted vaccine formulation.
This adjuvant effect can decrease the amount of antigen required in a dose and hence potentially increase the number of vaccine doses that can be produced. Obviously the current recommendation for two doses of Focetria at 7.5 mcg of viral antigen per dose dose not save antigen when compared to a single unadjuvanted 15 mcg dose, but if, as Novartis have indicated, just one dose of this vaccine can protect healthy adults, the number of people that can be immunised with Focetria significantly increases. The same reasoning applies to Pandemrix.
GSK has received and agreed to orders from governments and health authorities around the world for 440 million doses of their H1N1 vaccines, which include Pandemrix and an unnamed vaccine produced by ID Biomedical (owned by GSK) in Quebec. GSK is planing to fill these orders through the first half of 2010.
The capacity advantages of a 3.75 mcg Pandemrix dose can but put into clear perspective. The GSK Dresden manufacturing facility, which produces the antigen for Pandemrix, is advertised as having a capacity of approximately 60 million doses of seasonal flu vaccine, which contains 45 mcg of antigen per dose. Therefore, at 3.75 mcg per dose, the available GSK Pandemrix capacity translates to 720 million doses. If the yield of the H1N1 strain is approximately 30-50% of that routinely obtained for a seasonal strain then the number of doses drops to 240-360 million, a significant proportion of the doses ordered from GSK. In contrast, if Pandemrix contained a 15 mcg dose, the capacity of the Dresden facility would decrease to 60-90 million doses.
As discussed on this blog back on May 18th, an adjuvant may become mandatory for translating the available flu vaccine manufacturing capacity into sufficient doses to meet global demand. GSK and Novartis have clearly travelled down this pathway and have been able to produce H1N1 vaccines that look like they will be effective and safe at one half to one quarter of the antigen dose required for a single strain in a seasonal flu vaccine.
[...] As described here in earlier blogs about the European pandemic vaccine approval process, Canada employed the mock vaccine approach, developing an H5N1 vaccine in the pre-pandemic period. Health Canadainspected the antigen manufacturing facilities, evaluated data from the process, and reviewed both animal and human data from studies performed with the mock vaccine. Safety and effectiveness of the AS03 adjuvant was also evaluated and deemed acceptable. [...]
[...] authorise the product, effectively resulting in a marketing authorisation for all 27 countries. As discussed in earlier blog entries the vaccines were all granted authorizations under strain change variances to their original [...]