On November 24, 2009, Novartis officially opened its first, large-scale vaccine manufacturing facility in the U.S. Located in Holly Springs, North Carolina. The project is a collaborative effort between Novartis and the U.S. Department of Health and Human Services, which contributed $457M for the design, construction, and licensing of the facility.
For its part in the deal, Novartis is required to provide two commercial-scale lots of "pre-pandemic" vaccine annually for a minimum of three years. In addition, the government has the right to exercise options to purchase influenza vaccine over the next 17 years. (1) Currently, 191 employees work at the plant but that will increase to 350 persons when fully operational, anticipated to be sometime in 2011. The Holly Springs facility will be able to roll out 150 million flu shots per year.
Even though its use has not been approved by U.S. regulators, the plant will be producing MF59 as early as December 2009.(2) MF59 is Novartis' proprietary and controversial adjuvant composed of squalene and a surfactant called Tween80, also known as polysorbate 80. Back in July, 2009, the department of HHS purchased over $343.8M of "oil-in-water" adjuvant from Norvartis.(3) It looks like the government may want to take delivery on its purchase some time soon.
All flu shots used in the U.S. are made from eggs, a time- and labor-intensive process. But the new plant will provide something different. Vaccines will be brewed from animal cells mixed with viruses in six 1,320 gallon fermenters which are owned by the U.S. government and the Department of HHS, as identified by a bright yellow, plastic plaque on the sides of the giant vats. (4)
The use of human and animal cells for biological and pharmaceutical research is big business, particularly in Europe. For example, the European Collection of Cell Cultures (ECACC), established in 1984, is an international depository of cell culture collections. The ECACC describes itself as having one of the "premier collections of authenticated cell cultures in the world." It holds more than 40,000 cell lines representing 45 different species and 50 different tissue types. (5) Many of these lines are used in cancer research; some are specifically made for use with vaccines.
To replicate, influenza viruses need to be mixed with living cells and several types of mammalian cells have been used for this purpose since the 1950s. Examples include calf lymph for smallpox vaccines, African green monkey cells (AGMK cells and VERO cells) for polio vaccines, and mouse brain cells for Japanese encephalitis vaccines. In the 1960s, tissues from aborted human fetal tissue, called MRC-5 and WI-38 cells, were developed and are still used for the manufacture of rubella, hepatitis A, chickenpox, and shingles vaccines. Since 2000, new cells under investigation for making flu shots include cells derived from retinas of aborted fetuses (PER.C6), cells from ovaries of Chinese hamsters, and even cells from insects.
Perhaps even the FDA agrees that a vaccine made from infected caterpillar eggs is just a little too weird. On November 19, an FDA panel voted 6 to 11 against the approval of FluBlok, flu shots made from bugs, citing "lack of safety data" as the reason. Made by Protein Sciences Corp. of Meriden, Connecticut, FluBlok would have been the first cell-line influenza vaccine licensed in the U.S. (6) Novartis must have been thrilled that its closest U.S. cell-line competitor was knocked out of the running days before it officially announced the launch of its Holly Springs plant.
Novartis still needs approval of its cell line, MDCK cells originating from dog kidneys, before it can ramp up flu shot production. Novartis has been using MDCK cells for several years to make its European-approved influenza vaccines: Optaflu, for seasonal flu, and Celtura, for swine flu. I find it interesting that the plant has been built, the vats are in place and the opening ceremony has been announced...and yet, flu shots made from dog cells have not been approved by U.S. regulators.
Concerns about Injected Animal Cells
When viruses are combined with animal and human cells in culture, the new, "immortalized" cells can replicate in perpetuity. By their very design, the cells are neoplastic (i.e. abnormal). If these abnormal clumps cause tumors when injected into experimental animals, the cell line is called tumorigenic. If the tumors are cancerous, the cell line is labeled as oncogenic. (7)
No matter how careful manufacturers try to be, animal cells, animal DNA and culture-contaminating viruses end up in the final vials. While dog kidney cells have reportedly fewer stray viral contaminants than eggs, the injection of animal DNA could have untoward results in humans. The FDA is aware of this and is rightfully concerned. These stray proteins can be incorporated into vaccine recipient's own DNA, leading to the risk of abnormal genetic transcription. To minimize that possibility, the FDA has set manufacturing guidelines: The final vaccine product should have less than 1 million residual [animal] cells and less than 10 ng of DNA. (8) The FDA trusts that vaccine manufacturers will comply with these standards. I wonder who will be responsible for quality control and batch checking?
I find it disturbing that the FDA has been discussing cell-line concerns since 1998. Couldn't manufacturers develop something better? Less risky? Less disgusting? An even bigger question is, knowing the potential cancer-causing risks of animal cell lines, why have government regulators allowed this technology to evolve and be used at all?
Concerns about the adjuvant, MF59
An adjuvant is molecule added to a vaccine so that less antigen (virus) is needed to achieve an antibody response. This reduces vaccine production costs and when the amount of virus is in short supply, adding an adjuvant stretches the available vaccine supply. With a few exceptions, adjuvants are foreign to the body and can cause adverse reactions.
Several types of adjuvants are used today. The most common are aluminum hydroxide, aluminum phosphate and calcium phosphate. There are a number of others under investigation: oil-based emulsions, products from bacteria, liposomes, endotoxins, and aliphatic amines. (9) Of these, oil-in-water adjuvants are at the forefront because they have been added to several of the pandemic swine flu vaccines.
Scientific data in peer-reviewed journals show that ingested squalene, available as shark liver oil in health food stores, passes easily through the digestive tract. It is a very different story when squalene is injected into the arm. Pearson and his associates at UCLA injected dozens of oils, including squalene, into rats and found that all the oils were toxic, inducing arthritis with varying degrees of severity. Based on their ability to cause join pain, the oils were assigned "arthritis scores," ranging from (+), considered to be mildly toxic, to (++++), which was "guaranteed to cripple." Squalene was given a score of (+++). In addition, all rats injected with squalene developed symptoms that, in humans, would look very much like Guillain-Barre syndrome: the animals were crippled and paralyzed, dragging their hindquarters across their cages. (10)
Squalene stimulates an excessive and nonspecific immune response. A study using electron microscopy was undertaken to examine neurological tissue of mice after they had been given 20g/kg of squalene for four days. The devastating effects squalene were seen in both the central and peripheral nervous system. Researchers documented swollen astrocytes (brain cells) and disintegration of myelin sheath throughout the brain. Peripherally, the myelin sheaths were destroyed and the nerves were compressed. It was concluded that squalene "produces characteristic pathological changes in both the central and peripheral nervous systems. (11)
Granted, this is a very large dose of squalene. However, even a trace amount is not harmless. In immunology, parts-per-billion is a substantial dose. A mere 10 ppb concentration of squalene translates into approximately 184 trillion molecules of squalene and an equal number of potentially destructive immune responses. (12) More than two dozen peer-reviewed scientific papers from ten different laboratories throughout the U.S., Europe, Asia, and Australia have published studies documenting autoimmune disease in animals injected with squalene-based adjuvants.
A convincing proposal for how this occurs can be explained through the concept of "molecular mimicry." Squalene is a normally occurring molecule within the body. It is a precursor of cholesterol and it is on the surface of most cells, particularly throughout the nervous system. The squalene droplets from the vaccine are transported by immune cells to the lymphatic system where antibodies against them are formed. Later, the squalene antibodies can cross react with squalene found normally throughout the body, leading to debilitating autoimmune and nervous system diseases.
MF59 - like similar oil-in-water adjuvants - is capable of an accelerated activation of the immune system. Once "turned on," there is no switch to turn it off. The results of long-term reactions are unknown and most likely will remain unknown. Following patients for an extended period to look for the development of serious reactions is not what the vaccine industry is interested in studying.
Despite substantial evidence--and even admissions of concern--the FDA and the government are moving forward with its celebrated relationship with Novartis. If there is any doubt, there should be no doubt. These concerns, and others outside the scope of this article, deserve an in depth investigation prior to proceeding. Let the buyer - and the vaccine recipient - beware.
(1) "Novartis Partners with U.S. Government for Faster Flu Vaccine Manufacturing," http://seekingalpha.com/article/175396-novartis-partners-with-u-s-government-for-faster-flu-vaccine-manufacturing
(2) Novartis press release. "Novartis inaugurates large-scale US based cell-culture influenza vaccine manufacturing facility." November 24, 2009. http://www.novartis.com/newsroom/media-releases/en/2009/1356789.shtml
(3) "HHS Purchases Additional H1N1 Vaccine Ingredients." July 13, 2009. http://www.hhs.gov/news/press/2009pres/07/20090713b.html
(4) "Novartis 'Cells' Its Flu Vaccine Technology," November 24, 2009. http://www.cnbc.com/id/34130982
(5) The Health Protection Agency Culture Collections of the Health Protection Agency (HPA), UK. http://www.hpacultures.org.uk/aboutus/index.jsp
(6) FDA panel votes against new bug-based flu vaccine. Reuters. Nov. 11, 2009.
(7) FDA: "Use of MDCK Cells for Manufacture of Inactivated Influenza Vaccines" by Philip R. Krause, M.D., FDA. www.fda.gov/OHRMS/DOCKETS/AC/05/slides/5-4188S1_1.PPT
(8) FDA: Use of MDCK Cells for Manufacture of Inactivated Influenza vaccines," by Philip R. Krause, M.D., FDA
(9) "Adverse Effects of Adjuvants in Vaccines", by Dr Viera Scheibner. http://www.whale.to/vaccine/adjuvants.html#ADJUVANTS,_PRESERVATIVES_AND_TISSUE_FIXATIVES_IN_VACCINES_
(10) Matsumoto, Gary. Vaccine A: The Covert Government Experiment That's Killing
Our Soldiers and Why GIs Are Only the First Victims Vaccine, 54 (New York: Basic
Books). p 54-55.
(11) Gajkowska B, et al. "The experimental squalene encephaloneuropathy in the rat." Exp Toxicol Pathol. 1999 Jan;51(1):75-80. http://www.ncbi.nlm.nih.gov/pubmed/10048717
(12) Ibid. Matsumoto. p 203.