Dec 22, 2008 (CIDRAP News) – An H5N1 influenza vaccine made by Baxter International could become the first cell culture–based H5N1 influenza vaccine to be approved for marketing, following its endorsement by a committee of the European Medicines Agency (EMEA) last week.
Recommendations of the Committee for Medicinal Products for Human Use (CHMP) are usually followed by the EMEA within a few months.
Most flu vaccines, including the two H5N1 prepandemic vaccines now licensed, are grown in chicken eggs, a process that takes about 4 to 6 months. Baxter's H5N1 vaccine, called Celvapan, is grown in Vero (monkey kidney) cells. Cell culture production is regarded as somewhat faster and much more flexible than the egg-based method.
Also last week, the CHMP recommended EMEA approval of a Sanofi Pasteur seasonal flu vaccine that is injected intradermally (ID)—just beneath the skin surface—instead of into muscle. "This represents the first key step toward recognition of the ID route as a promising option for vaccine administration," the company said in a news release.
Baxter vaccine called mock-up
Baxter said its cell-based production technology is faster than the egg-based method because the virus used in the vaccine does not need to be modified to grow in chicken eggs.
The company said EMEA approval of Celvapan would permit the vaccine to be used if the World Health Organization declared a pandemic. The vaccine is derived from an H5N1 strain isolated in Vietnam in 2004.
The company described Celvapan as a mock-up vaccine—one that is identical to the future pandemic vaccine in composition and manufacturing but contains an existing flu strain, since the actual pandemic strain has not emerged.
"Once a pandemic strain is declared, this licensure allows for a fast track approval of the vaccine containing the actual pandemic strain," the company said in a news release. Health officials hope that vaccines based on existing H5N1 viruses will provide some protection if H5N1 evolves into a pandemic strain.
In May 2007 the EMEA approved a mock-up flu vaccine made by Novartis, called Focetria, to permit a faster start on production in case of a pandemic. The company said that vaccine would not be manufactured until a pandemic is declared.
Baxter said the antigen composition and structure of Celvapan "are identical to the actual virus circulating in nature," which eliminates the need to use adjuvants (immune-boosting chemicals) and the resulting potential for side effects.
Clinical trial results
In a phase 3 trial, Celvapan was tested in two groups of adults, aged 18 to 59 and aged 60 and older. Two doses produced an immune response in 73% of the younger group and 74% of the older group, the company reported. Six months after the second dose, a booster vaccination with either the vaccine strain or a 2005 H5N1 strain from Indonesia induced a "substantial booster response," the company said.
The vaccine had a side-effect profile similar to that of licensed seasonal flu vaccines, Baxter reported. Celvapan is produced in Bohumil, Czech Republic, the company said.
Human H5N1 vaccines licensed to date include one in the United States and one in Europe. In April 2007 the US Food and Drug Administration approved a vaccine made by Sanofi Pasteur, and the government has been stockpiling it. In May of this year, the EMEA approved GlaxoSmithKline's H5N1 vaccine, called Prepandrix. Both are egg-based vaccines.
Though no cell-based prepandemic vaccines have been licensed yet, at least one cell-based seasonal flu vaccine has been approved. Novartis announced the European approval of Optaflu in June 2007.
Intradermal vaccine supported
The CHMP approval of Sanofi Pasteur's ID seasonal flu vaccine, called Intanza/IDflu, was announced Dec 18.
"Vaccination via the ID route involves the administration of the antigen into the dermal layer of the skin," Sanofi said in a news release. "Due to the high concentration of specialized immune cells in the skin layer and their ability to effectively stimulate an immune response, ID vaccination provides direct and efficient access to the immune system."
The vaccine is administered with the Micro Injection System made by Becton Dickinson (BD), which permits consistent and reliable ID vaccination, according to Sanofi.
The BD product consists of a prefilled syringe with a needle and a shield that allows the needle to penetrate only 1.5 millimeters into the skin, according to a 2007 report in Vaccine. Previously, ID injections were done with the Mantoux technique, developed for tuberculosis skin tests, the report said. It said the Mantoux technique is not commonly used for vaccination, because it is hard to apply reliably and efficiently.
The US flu vaccine shortage in the 2004-05 flu season stimulated interest in using ID vaccination as a way to stretch the vaccine supply, the report said.
In preparation for seeking European approval, Sanofi said it conducted clinical trials of Intanza/IDflu involving more than 7,000 adult and elderly volunteers. In a phase 3 trial involving more than 3,000 volunteers over age 60, Intanza was well tolerated and induced a stronger immune response when given intradermally than intramuscularly, according to Susan Watkins, a Sanofi spokeswoman in Swiftwater, Pa. The trial used the same dose as in licensed seasonal flu vaccines: 15 micrograms for each of three strains.
Sanofi is also developing an ID version of its US-licensed seasonal flu vaccine, Fluzone, Watkins told CIDRAP News. She said the vaccine is in "end-term" clinical development, but she was not sure when the company would apply for FDA approval.
Dec 18 Baxter news release about Celvapan
May 9, 2007, CIDRAP News story on EU approval of Novartis's mock-up pandemic vaccine
Jun 13, 2007, CIDRAP News story on European approval of Novartis's cell-based seasonal flu vaccine
December 2007 Vaccine report on BD's system for ID vaccination