Designer Cells as Substrates for the Manufacture of Viral Vaccines is a report that goes over the use of certain viral vectors in treatment of HIV - 1. It does support the use of Ad5 vaccine vectors, and also applies conditions to that support - in that the contributors state a belief...
...that there is an extremely low probability that residual DNA from the adenovirus 5-transformed human cells could transfer traits that could induce neoplastic development in vaccines. OVRR/CBER also believes that such cells may be considered for the development of HIV vaccines, provided that the phenotype of the cells can be documented to be of an adenovirus 5 E1 type, and that appropriate testing rules out the presence of adventitious agents within the limits of state-of-the-art technology.
The report on designer cells utilized for development of vaccines was the result of FDA initiation, in the form of an FDA inquiry, about the potential risks in using two novel cell substrates, 293 cells and PER.C6 cells. What activity is represented within development of designer cells?
These cell lines were developed by transforming human embryonic kidney cells (293) and human embryonic retinal cells (PER.C6) with the transforming early region 1 (E1) of adenovirus type 5 (Ad5). Since cell lines such as 293 and PER.C6 express the Ad5 E1 region, they are able to complement the growth of defective Ad5 vectors which have been "crippled" by deletion of E1. Defective Ad5 vectors have been engineered to express foreign genes such as those from human immunodeficiency virus (HIV), the causative agent of AIDS, and vectors of this type are thought to have significant potential for vaccine development because of their demonstrated ability to generate cell-mediated immune responses to HIV. However, a feature of regulatory importance associated with Ad5-transformed cells is their capacity to form tumors in immunodeficient animals such as nude mice.
So the subject of tumorigenicity is addressed and defined for the FDA, with the result of settling some risk assessment questions - thereby allowing for next steps in development of possible treatment for HIV. It appears that Crucell is making good on next steps in development of treatment for HIV...
Crucell announced its intention to participate in a Phase I clinical trial in the United States and Africa of a combination of two AdVac®- based AIDS vaccine candidates, Ad26.ENVA.01 and Ad35-ENV, in healthy adults who are not infected with HIV. The clinical trial, which will be led by the International AIDS Vaccine Initiative (IAVI), represents a collaboration between IAVI, Crucell, the Ragon Institute, and Beth Israel Deaconess Medical Center (BIDMC), a major teaching hospital of Harvard Medical School.
But, Designer Cells as Substrates for the Manufacture of Viral Vaccines also considers overall productive infection as a risk consideration - not just the infection that results in cancer. ...residual DNA has the potential, upon inoculation into the vaccine recipient, to produce infectious virus from this DNA and thus establish a productive infection. Assessing risks of DNA residual presence in vaccines requires some absolute knowledge with regard to the amount of residual DNA being delivered via inoculation; that absolute number allows for understanding with regard to the probable amount of oncogene (infectious agent). In the case of a finite amount of 10ng DNA residual presence, the presence of oncogene within that 10ng DNA residual is between 0.00001 and 0.0001ng. At the time of the Designer Cells FDA briefing there was no data indicating that purified isolated oncogenes or any other DNA are biologically active at these (0.0001) levels. Keeping DNA residuals at 10ng or below is constantly emphasized, but what should also be emphasized is that there is no mechanism in place to enforce the standard - it is left to those who produce vaccines to practice diligence.
The briefing also emphasized the need for assessment of Transmissible Spongiform Encephalopathy...
...it is important to consider other agents such as the agent of TSE. There are several mechanisms by which vaccine cell substrates, including neoplastic cells, could theoretically become infected with a TSE agent.
There is an the possibility of Transmissible Spongiform Encephalopathy (TSE) ... being derived from individuals with a propensity to develop sporadic or familial Creutzfeld-Jakob disease (CJD) - and this possibility is evident because CJD has already been passed on to individuals via products such as human growth hormone and dura matter grafts. Also, a variant of CJD has been transmitted to humans, from cattle, in Europe.
As far a risk assessment, assays sensitive enough to detect low levels of CJD contamination need to be available and ...a determination of the origin of the cells with respect to the possible family history and medical history of the donor regarding TSE risk factors and the identification and documentation of possible exposure of the cell line to bovine-derived materials, such as fetal bovine serum from countries with BSE needs to be made.
While addressing outright concerns with regard to cancer and some infection seems doable, the issue of testing for the presence of adventitious agents (like TSE) within the limits current understandings cannot provide complete data as far as possible risk - when one considers how material for development of vaccines is acquired.
From CJD fact sheet: There are three major categories of CJD:
- In sporadic CJD, the disease appears even though the person has no known risk factors for the disease. This is by far the most common type of CJD and accounts for at least 85 percent of cases.
- In hereditary CJD, the person has a family history of the disease and/or tests positive for a genetic mutation associated with CJD. About 5 to 10 percent of cases of CJD in the United States are hereditary.
- In acquired CJD, the disease is transmitted by exposure to brain or nervous system tissue, usually through certain medical procedures. There is no evidence that CJD is contagious through casual contact with a CJD patient. Since CJD was first described in 1920, fewer than 1 percent of cases have been acquired CJD.
Misdiagnosis might factor in with regard to understanding some cases, whereby some have been given a label such as Alzheimer's when in reality they had a form of CJD.
Other studies have challenged the assumption that sporadic CJD is a rare, "one in a million" occurrence. In 1989, a Yale University team performed autopsies on the brains of patients diagnosed with Alzheimer's disease and found that 13 percent had CJD. A similar investigation found three of 12 patients diagnosed with Alzheimer's to actually have a TSE disease. A larger University of Pittsburg study "found a misdiagnosis rate of 5 percent, and estimated there may be 200,000 cases of CJD in the U.S. each year which are misdiagnosed as Alzheimer's." (link)
There are varied presentations of CJD type infection. One variant, called kuru, was suffered in epidemic proportion by a community in Papua New Guinea. In part an article on the research reflects that...
The infection was passed on at mortuary feasts, where mainly women and children consumed their deceased relatives as a mark of respect and mourning. This practice was banned and ceased in the late 1950s.
Scientists from the MRC Prion Unit, a national centre of excellence in prion diseases, assessed over 3000 people from the affected and surrounding Eastern Highland populations, including 709 who had participated in cannibalistic mortuary feasts, 152 of whom subsequently died of kuru. They discovered a novel and unique variation in the prion protein gene called G127V in people from the Purosa valley region where kuru was most rife.
More recently, reports have indicated that the community in Papua New Guinea that suffered a major epidemic of a fatal brain disease called kuru has developed strong genetic resistance to the disease, according to new research by Medical Research Council scientists. (link)
Two cases of iatrogenic (induced inadvertently) CJD - from human growth hormone treatment are discussed - with regard to MRI imaging providing diagnostic capability in identifying cases of CJD. In one case an individual had received serial injections of human growth hormone for short stature between the ages of 16 and 17 - with the identifiable onset of CJD occurring at 31 years of age. In another case, an individual who was 31 years old showed the first signs of CJD and this person had serial injections of human growth hormone when he was 14 and 15 years of age. (Spectroscopy and serial diffusion MR findings in hGH-Creutzfeldt-Jakob disease - C Oppenheim, M Zuber, D Galanaud, M Detilleux, F Bolgert, J L Mas, J Chiras, J F Meder) If if the human growth hormone is verified to have cause CJD - I am struck by the length of time it took for the illness to progress - when caused by injections given approximately 15 years prior.
CJD can be transmitted via blood transfusion...
Scientists have confirmed that Variant Creutzfeldt-Jakob disease (vCJD) can be passed from person to person through blood transfusion. A case study published in The Lancet reports on the third person known to have contracted vCJD from blood transfusion. The patient, who has since passed away, is the first to have been diagnosed whilst still alive. Two others from a group of 66 people who received prion-infected blood from donors known to have developed vCJD, died before their illness was confirmed.
At the age of 23, the patient was given a blood transfusion from a donor who later developed vCJD. Seven and a half years later he was referred to the NHS National Prion Clinic at the National Hospital for Neurology and Neurosurgery where his symptoms were confirmed to be caused by vCJD. The patient opted to join the experimental MRC treatment trial Prion-1 which began in 2004, in which patients are given a drug called quinacrine. Sadly, he died a year later at the age of 32. (link)
The FDA had taken two separate positions on blood donor requirements. One is ...that potential donors with risk factors or a diagnosis of classical forms of CJD should be permanently excluded and that any blood products or plasma derivatives from these donors should be immediately retrieved, quarantined, and destroyed. The other is that plasma derivatives are allowed to remain, ones from donors with risk factors. The reason is that laboratory and large epidemiological studies suggest that the risk of classical CJD from plasma derivatives is extremely low. In And it would be inconvenient because a shortage in plasma derivatives might be a problem for patients in need of them...(link)
A recent finding reported on ScienceDaily indicates that following with regard to general surgery contributing to transmission of CJD.
"Based on the monitoring records of spongiform encephalopathy in two Nordic countries, we studied the possibility of transmission of the sporadic form of CJD through general surgery," explains Jesús de Pedro, main author of the study and head of prion monitoring in patients at the National Epidemiology Centre of the Carlos III Health Institute.
In the case of the above finding, the evidence of having contracted the sporadic form of CJD manifested at least 20 years after the medical procedure, with few exceptions. Operation on the retina with reused equipment seems to result in identifiable symptoms of CJD, within ten years - for those who have been exposed. From the above linked ScienceDaily report is the question - Why is the idea of transmission through surgery important? Followed by the conclusion that it might cause a shift in our understanding of neurodegenerative diseases.
(As I look into all of this, my mind meanders with thoughts of my own daughter's autism. She had to have surgery for pyloric stenosis at three weeks of age. She was labeled autistic at three years of age, moderate to severe on the scale, but she was manageable and happy with all the best supports. However, at ten years of age she presented with a worsening - that many doctors feared was a result of onset of neurodegenerative process. Her presentation is so hard to describe, and not suited to this writing.)
All things considered, genetic susceptibility seems to factor in to vCJD outbreaks. The Medical Research Council Prion Unit, University College London, searched for variations in DNA that might influence a person’s risk of developing variant Creutzfeldt-Jakob disease (vCJD). Their researched had controls who were excellent candidates for involvement in prion pathology.
“...Our data lend considerable support to the hypothesis that genetic susceptibility in addition to SNP variation in the PRNP gene has contributed significantly to the outbreak of vCJD to date. Whether these effects are on the incubation period rather than susceptibility, such that further waves of BSE-associated prion disease with longer incubation periods might occur in the years ahead, is unknown.” (link)
A recent study indicates that prion diseases can be divided into two groups: those with plaques that destroy brain blood vessels and those without plaques that lead to the sponge-like damage to nerve cells. The manner in which the prion protein anchor appears determines how the disease develops.
It really appears that CJD is part of a bigger pandora's box scenario, and researchers work hard to discern, even as understandings are emerging in a fast paced - ongoing manner. One article emphasizes that... Due to the strong influence of host factors on the characteristics of the disease, diversity of prion agents responsible for CJD remains extremely difficult to investigate. (link)
One source who lost a love one to CJD expresses a real life scenario from their neck of the woods, where...171 people have died of vCJD from infected meat, contaminated vaccines and blood donation. 18 blood donors have since died of vCJD and their blood was used to make 83,500 doses of polio vaccine for Ireland. It was also used to provide human albumin which is another blood product present in many vaccines. And, if this is true - we have a problem. The source points to the use of bovine serum in vaccinations and questions why it would not have been phased out in light of the BSE crisis. As of 2008, IPV vaccines, MMR 2, varicella, Rotateq oral rotavirus vaccine and Pediacel 5 in 1 vaccine all have bovine serum in them...(link)
Researchers have established a link between HIV and Creutzfeldt-Jakob and the onset of dementia, and dementia is proposed to have a number of possible causes including; infectious viruses, bacteria, disease-carrying parasites and fungi. The Center For Prions and Protein Folding Diseases in Alberta finds that... there may be common factors between prion diseases and other human diseases such as autism and Alzheimer’s.
Recent investments by the Alberta Prion Research Institute (APRI), and the Alberta Ingenuity Fund (AIF), which total nearly $15 million, have been committed to support new research infrastructure, university and industry-led research projects, and the recruitment of new prion researchers to Alberta. Support from APRI and AIF has attracted additional funding from industry and other provincial and federal agencies, amounting to $26 million, for basic pre-commercial research and development across the province.
Will this prion research eventually indicate that vaccinations - in part - have had something to do with autism and other illnesses? I don't know. I am just a mom who likes to write and I have a daughter who gives me a lot to think and write about... I REALLY have more questions than answers.