Friday, April 06, 2007

Human Technology Manufacturing Platforms Part III: Human Technology Manufacturing Platforms.

In addition to the vaccines already discussed, several other vaccines dependent on human diploid cell cultures are on the horizon. The polio vaccine currently used in the United States, IPOL (Aventis-Pasteur)[1] is comprised of three strains of polio grown in monkey kidney cultures. However, the same manufacturer has another polio vaccine, Poliovax, which is cultured in the MRC-5 human diploid cell line. Although not yet widely distributed in the United States, this vaccine has been licensed by the FDA.[2]

Smallpox was declared eradicated from the planet in 1980, with the last reported natural case occurring in Somalia in 1977. Routine smallpox vaccination was discontinued in the United States in 1971, though it continued in the U.S. military until 1990.[3] However, subsequent to 9/11 it was reintroduced in selected groups of the military, usually those who were in, or scheduled to go to, the Middle East. The current smallpox vaccine, DRYVAX (Weyth)[4] was prepared from the traditional New York Board of Health vaccinia strain prepared in calf lymph, and stored as a freeze dried product. Although this freeze dried strain presents no moral problem, it is no longer manufactured in the United States[5] and aggressive development of a 2nd generation smallpox vaccine is underway using the MRC-5 cell line.[6] It's worth looking at this situation a little more closely. In October, 2001, the Washington Post reported that the British company Acambis, PLC, had been awarded a contract from the Department of Health and Human Services (DHHS) to develop 54 million doses of smallpox vaccine using the MRC-5 line. This information was picked up by the organization Children of God for Life, as well as the online news daily, WorldNetDaily, and these outfits conducted a poll of over 3,300 persons. Their findings were that 56% of those polled would refuse a smallpox vaccine manufactured using lines derived from aborted fetuses. In addition, a letter writing campaign to the DHHS was organized, and the result was that in December, 2001 DHHS modified the contract such that doses subsequent to the initial 54 million would be manufactured using the Vero monkey kidney line.[7] Currently, both MRC-5 and Vero are being used to develop the vaccine.[8]

At least two more human cell lines have been developed. The 293 cell line was developed from fetal kidney, and the PER.C6 line was developed in 1995 from embryonic retinal cultures obtained in 1985.[9] The reasons for the abortion of the baby which resulted in the 293 cell line were not clear, but that cell line was intended only for basic research.[10] However, many medical details regarding the 1985 abortion are thoroughly documented. This is because, from the beginning, the intent was to develop this line as a base for vaccine and pharmaceutical manufacturing, and since the researchers knew that the line would sooner or later be submitted for FDA licensure, they needed scrupulous documentation. The abortion was done in France on an 18 week unborn child, and the abortion was performed solely because "the woman wanted to get rid of the fetus."[11] There were no medical problems with the parents or with the unborn child. Indeed, the researchers wanted a healthy fetus; an unborn child with medical problems, or from parents with medical problems or with a family history of medical problems, would not be acceptable as a source of material for cell lines which were to be submitted for regulatory approval.. The abortion was performed, the cells were procured from the retina, frozen, and ten years later thawed for the development of the PER.C6 line, a cell line developed “just for pharmaceutical manufacturing..."[12] The researcher responsible for developing the PER.C6 cell line made this observation regarding the development of the line: "(a)nd then (there is) the pharmaceutical industry standard. I realize that this sounds a bit commercial, but PER.C6 were (sic) made for that particular purpose. Also, as far as I know, more than fifty different companies have taken license for PER.C6."[13] The company which developed and licensed the line is the Dutch biotechnology company, Crucell N.V.

Crucell originated in 1993 as company called IntroGene, which was formed with the intent of using stem cell technology to develop gene therapies.[14] However, the company recognized that existing technologies were primarily for research, and would not meet pharmaceutical industry standards, so, in 1995, IntroGene entered into formal collaboration with Leiden University to develop the PER.C6 line, "initially intended for the production of virus-based products."[15] The PER.C6 cell line ("PER.C6" is a registered trademark of Crucell) was introduced in 1997 for the commercial production of gene therapies, and in 1999 the line's use was expanded. In 2000, IntroGene and a company called U-Bisys merged, forming Crucell, N.V. By 2001 the PER.C6 line was being reported in the literature as a "new manufacturing system for the production of influenza vaccines."[16] In 2002 the PER.C6 line was further expanded onto a commercial scale as one of the company’s two "broadly applicable human technology platforms"[17] for developing pharmaceuticals. PER.C6, according to Crucell, will be used as a manufacturing system "on which a wide range of biopharmaceuticals can be developed and manufactured, such as vaccines, antibodies, therapeutic proteins and gene therapy products."[18] In addition to licensing the PER.C6 line to other vaccine manufacturers, Crucell purchased the Swiss vaccine company Berna Biotech AG in February, 2006, making Crucell "the world's leading independent vaccine company."[19] In August, 2005, the company had a market capitalization of EURO 735 million (this is prior to the Berna acquisition) and listed over 40 licensees of the PER.C6 line.[20] We will look briefly at some of the companies and products using this human technology manufacturing platform, but first, next week we need to say a few words about the flu.

Next week: The flu and Crucell.

[1] Package insert, IPOL, Aventis-Pasteur, 1999. Institute for Vaccine Safety.
[2] "Vaccines Licensed for Immunization and Distribution in the US." U.S. Food and Drug Administration, Center for Biologics Evaluation and Research, updated 9/2005.
[3] Infectious Diseases, 3rd Ed. Gorbach, S. et al, Lippincott, Williams & Wilkins, 2004. Pg. 376.
[4] Package insert, DRYVAX, Wyeth Pharmaceuticals, 2004. Institute for Vaccine Safety.
[5] "Regulatory Requirements for the Historical and New Smallpox Vaccines: Review of U.S. Regulations." K. Midthun, M.D., Center for Biologics Evaluation and Research, U.S. FDA, G7+ Workshop, Langen, Germany, 5-6 September, 2002.
[6] ibid.
[7] "Update 12-03-01: Acambis/Baxter announces second contract for 155 million doses of the new smallpox vaccine will use Vero cell lines - not MRC-5." Children of God for Life,
[8] "Smallpox vaccination and adverse events training module." CDC Emergency Preparedness & Response, Smallpox, About the Vaccine.
[9] Transcriptions of the U.S. FDA Center for Biologics Evaluation and Research, Vaccines and Related Biological Products Advisory Committee Meeting, Wednesday, 16 May, 2001. pg. 77ff.
[10] ibid, pg 94.
[11] ibid, pg.91.
[12] ibid, pg 94, my emphasis.
[13] ibid, pg. 95. My emphasis. The researcher narrating this portion of the transcript is Dr. Alex van der Eb of the University of Leiden, The Netherlands. Dr. van der Eb also disclosed at the "Disclosure" section of the transcript that he has received consulting fees from Crucell (the company sponsoring the development of the PER C6 line) for "scientific advice" on human cell lines.
[14] This synopsis is developed from the "Corporate History" section of Crucell's website,
[15] ibid. Please note that "PER.C6" is a registered trademark of Crucell, N.V.
[16] Pau, M.G. et al, "The human cell line PER.C6 provides a new manufacturing system for the production of influenza vaccines." Vaccine 21 Mar 2001, 19 (17-19):2716-2721.
[17] "Crucell's PER.C6 Cell-Line Used in Merck's HIV-1 Vaccines Research Program." United Business Media PR Newswire, 3 April 2001, My emphasis.
[18] "About Crucell.," corporate website, ibid. My emphasis.
[19] ibid.
[20] Crucell website, "Factsheet"

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