By Sandy Lunoe, Guest Author
Do the amounts of residual cancer DNA present in the vaccines vary between batches?
What genetic mutations could occur should the residual cancer DNA enter a human cell and begin reproducing?
Will manufacturers be obliged to conduct adequate safety studies before these vaccines are licensed?
The truth is no one knows.
Never before have cells that are derived directly from human cancer tumors been considered for use in vaccine production. Incredibly, this method has been approved despite the fact that it cannot be guaranteed that the vaccines will not induce cancer tumors in recipients.
Based on the approval by FDA (Food and Drug Administration) millions of vaccines which may induce cancer tumors will be produced. Where are the protests?
From a salvaged transcript (1) of the several hour long meeting in September 2012 between FDA and vaccine manufacturers some of the statements which jumped out of the page are quoted in this article.
Details regarding the meeting:
FOOD AND DRUG ADMINISTRATION (FDA). Center for Biologics Evaluation and Research (CBER). Meeting of the Vaccines and Related Biological Products Advisory Committee (VRBPAC). September 19, 2012.
Agenda Item: Topic: Consideration of the Appropriateness of Cell Lines Derived from Human Tumors for Vaccine Manufacture (excerpts below)
The meeting commenced with waivers granted for financial conflicts of interest.
Congress has authorized FDA to grant waivers to Special Government Employees and regular government employees who have financial conflicts, when it is determined that the agency’s need for a particular individual service outweighs his or her potential financial conflict of interest.
Dr. K (CBER) began with what appears to be the mantra regarding vaccines which is that irrespective of the particular issue, the potential benefits of vaccines are always emphasized. He stressed the importance of retaining public confidence:
Vaccines are among the very most effective ways to control infectious diseases. And the effectiveness of vaccines is often enhanced by herd immunity.
The safety record of vaccines is excellent, but nonetheless the maintenance of public confidence in vaccines is critical to public health.
Advantages of the new cell substrates
…there are a number of advantages to contemplating the use of additional cell substrates. One of them is that there can be a virus growth advantage. The yield of virus may be greater. There may in fact be such a difference that a vaccine could be made in a new cell substrate but not in the previously used ones. With new cell substrates there can be more rapid scale-up.
….but there are concerns about tumors caused in vaccine recipients
So the big question… Is there a potential risk for making vaccines in tumor derived cells?
… And that then leads to the question of whether residual cellular components from tumor-derived cells could pose a safety concern.
We have really identified three major factors that could potentially convey risk from tumor derived cells. And these include the cells themselves ….and if they were tumor-derived cells then maybe they themselves could form tumors in a vaccine recipient…
Cell DNA also is a theoretical concern, both because cell DNA could contain infectious genomes …. DNA can be picked up by cells and… then could lead to initiation of an infection — as well as a theoretical oncogenic risk. And then there is the question of adventitious agents.
Potentially cancer causing SV40 was discovered in polio vaccines
And so millions received SV40 contaminated vaccines in the late 1950s and early 1960s. The cell supernatants of these cells actually did cause tumors in laboratory animals and cytopathic effect in primary African green monkey kidney cells.
…. the concern from the fifties had been that vaccines shouldn’t be made in human cells because of a theoretical concern that there might be human adventitious agents, as well as the concern that perhaps human cells might be more likely to have some oncogenic risk.
The agency (FDA) is here to help the vaccine industry
Dr. D (Chair, VRBPAC):
….but we are here to consider the issues that we would like to advise the agency to consider in helping the company continue the manufacturing process, what should they be concerned about, what should they be watching for.
Concern about public opinion
… And what do you think of the risk-benefit and public perception issues?
Dr. P (CBER):
… concerns with the use of tumorigenic cells or cells derived from human tumors are really… the possible presence of tumorigenic cells in the vaccine, the presence of adventitious agents, particularly oncogenic viruses, and oncogenic materials derived from the cell themselves.
Limit for DNA residue in the vaccines is questioned
Dr. H (Univ. N .Carolina):
I had a question about …the importance of achieving DNA levels below a specified threshold ….. 10 nanograms. And I think that comes from a calculation that was done by the WHO in the 1980s…. And I know there are some assumptions underneath that calculation.
And I was just wondering…. whether or not we should revisit that calculation.
Dr. P (CBER):
And so you are asking why was it changed to 10 nanograms from 100 picograms? … But one of the considerations was that many manufacturers could not meet that criterion…
(Note: The previous ‘limit’ of 100 picograms is the equivalent of 0.1 nanograms. By changing the limit to 10 nanograms, the FDA increased the ‘allowable amount’ to 10,000 picograms. The current allowable limit of 10 nanograms is only a recommendation, so the FDA is unable to enforce it. Vaccine manufacturers may reduce the DNA contaminants only if they wish) (2)
FDA is positive towards manufacturers who do unusual things!
Also, of course, we welcome conversations with manufacturers who are contemplating doing things which are unusual, and we will give them advice on their specific set of circumstances as well.
Doubt regarding choice of test animals for assessing oncogenicity
Dr. C (Giesel School of Medicine):
….. you have the rat, you have the hamster, and you have the nude mice. Do you think those are reasonably accurate to reflect what’s going on? Do you have a plan to develop other animal models, such as transgenic, that might more mimic human conditions?
… we are trying to evaluate these rodent models to find out whether they are appropriate…..but it’s really only now that we can start to assess whether these particular recommendations are sensible. We need to determine whether they are detecting oncogenic activity of DNA, which genes they are detecting, and what the sensitivity is of these. If they are not sensitive enough to detect DNA, whether it’s amplified ….. or not, then it doesn’t make any sense to use them.
…… I’m not optimistic that we’re going to find animal models to assess oncogenicity of DNA. That’s why I’m feeling that maybe it’s the clearance aspect that we have to deal with, with respect to DNA
We do understand, or do we?
Dr. W (CDC):
… there is a level of concern that comes with using a human tumor cell line that is not necessarily based on science, that’s based on the fact that it just seems like there could be something there that maybe we don’t understand. That’s why I think understanding everything about this that we can is really important
“Things turn up” long after vaccines have been in use…
Dr. G (Nat. Vaccine Program Office, HHS):
…..There was this SV40 and, more recently, the porcine circovirus, where, because of technology, things showed up and then there had to be an assessment of what it meant when products had already been in use. …… But ultimately you’re not going to know 100 percent. Therefore, emphasize the need to continue to have systems in place to continue to look to see whether or not something has turned up.
We saw that clearly with SV40 long after… We have a similar conversation with the porcine circovirus.
Many unknown issues after vaccines are licensed
So just remember that there is so much that can happen pre-licensure, but there need to be some mechanism in place to continue to look because of the kinds of questions that will come up because of the nature of the cell line.
“Pretty poor” testing for prions including for mad cow disease
Dr. P (Baylor College of Medicine:
….. I don’t believe the mouse is an appropriate model for prion….. from what I have seen here, the sensitivity didn’t seem very satisfying. One would need to think about sensitive models, and they take time. I don’t think they are four to seven months. They may be one to two years.
There are a lot of things to be done in post-licensure. The field of the BSE (Bovine Spongiform Encephalopathy, mad cow disease) prion is really, in terms of sensitivity, of detection, is pretty poor.
More concern about public opinion
Dr. B (private practice):
How is this going to be able to be accepted by the consumers as far as — I think it goes back some of what you were saying earlier. As soon as you hear “a tumor-derived cell line,” how do you explain that, put the public at ease?
Concerns about length of time and cost of testing to find tumors
…. safety concerns with respect to these vaccines. Are they watching these animals long enough? Should it be longer? Should the manufacturers be doing more extended studies?
The original assay is maybe a three-week assay. It was clear that not all tumors came down in a tumorigenicity assay in that. So then we extended it for cells that take longer to form tumors. But there’s a limit to what you can do. The lifetime of a nude mouse is probably two years, at the very outside. But then you are asking sponsors to keep these animals on for many years. The cost may not be commensurate with the reward here.
…..the Vero cells that did sometimes take a year or even longer — eight months to a year or more — to come down with tumors.
…… Is it relevant to safety that a cell forms a tumor after a year, a year and a half?
The four to seven months was really a compromise between people not wanting to spend the money looking after the animals for long and getting an answer where you can think that’s the window when those tumors are going to come down.
More concern about suitability of the test animals
Dr. C (Loyola Medical Center):
….. if you get nude mice from different sources, you can get different results.
…. Actually, it’s even worse than that, because with at least two of the major nude mouse colonies, the animals you get are deliberately outbred. So even two mice that you buy at the same time will have some genetic differences between them
Concern about doctors’ opinions and what can be done to convince them
Dr. M (Pediatric Clinician and Epidemiologist):
The key point to me is the gap between this science and the knowledge base of most clinicians and the need to begin to bridge that gap long before licensure and, in fact, create a basis for understanding.
There’s just a desperate need for a Scientific American type of article that summarizes what we have heard today that is made available to clinicians who will use these products.
More concern regarding prions
I would to hear a similar session as today’s on TSE (transmissible spongiform encephalopathies, also known as prion diseases) agents. That kept being alluded to, and I got a sense that there was not nearly so robust an approach. That is concerning to me.
Tumors may occur even decades after vaccinations
… I’m guessing the safety concerns we have are ones that you typically wouldn’t observe in humans on the time scale that a Phase I trial takes place on.
…We are worried about these vaccines causing cancer in people many years down the road, well beyond the conclusion of the Phase I study.
…But certainly, if you are going to address this question about tumor risk of vaccines made in tumor cell lines, it’s going to have to be a decade’s question …
… it probably can’t be a Phase I question
Why these vaccines should not be given to newborns
… it’s perception of risk-benefit. I think it will be much more difficult if the first tumor cell-derived vaccines were intended for newborns as opposed to older children or adults.
…… if you are giving a vaccine on the first day of life, you are dealing with a different immune system, in addition to the obvious issue of length of time that the individual will survive with the agent. I think that’s something that one just has to be cognizant of.
“It’s sort of a brave new world”
I think the best we’re going to be able to do is tell the agency that the risk appears to be very, very low, and secondly, that you are obviously on top of this and doing the right kind of approach and the right kind of testing and, perhaps more importantly, revising it as new technology becomes available.
So I’m not sure that we can give a certainty — there’s no risk, don’t worry about this.
… It’s sort of a brave new world. We’re all doing it together. But I think you are doing a beautiful job.
“Tumor cell lines can cause tumors”
Dr. L (Nat. Cancer Inst):
What I think is qualitatively different about the tumor cell lines is the fact that they can cause tumors.
“We don’t always know the dose of vaccine made in a cell line”
… I agree about trying to make the calculation for how much per dose you are giving them. In fact, we are trying to do that, but it’s not so easy because we don’t always know the dose of vaccine made in a cell line. So I think that’s important, what we think.
“Doctors and the public may say Oh, my God”
… the scientific community’s perception, including the practicing medical community, and also the lay public. They are going to hear that we are recommending …..or that the manufacturers are making vaccines with tumorigenic cell lines and say, oh, my God, even if there’s no scientific basis to say, oh, my God.
“We were lucky that HIV was not present in the polio vaccine”
… we are extraordinarily lucky that HIV was not present in the monkey kidneys that were used to grow polio vaccine.
We are indeed.
Had we been using HeLa cells at that time — which we could have been, actually, I think — to make vaccine, we would have been much safer than, in fact, we were.
Framing information to convince doctors and the public
Framing a discussion, as we have learned, is everything. This discussion has to be framed by what the potential for new vaccines that require human cells is. You have to start with the positive here, which is what impact we can have with new tools, and then get into how we will mitigate theoretical risks.
You need to have people who are going to be in the clinics every week talking to their patients or to the parents of their patients, explaining to them why they think this is a good idea. And they are going to have to be convinced.
.. because it’s a discussion of how one communicates these issues and how the public will perceive them. But I’m not completely sure that we have a complete answer on the fundamental scientific question.
So how can you communicate a scientific consensus that the product is safe unless we’re sure that you, the experts we are asking to advise us, are convinced that it’s safe?
FDA cannot be completely sure about safety
…then we get into the situation…… that we are in where the FDA does have to make decisions, and you cannot have 100 percent certainty that something is safe, but you are sure that you evaluated something to within the best limits that one can and the limits of the current technology.
A brave new world aspect – and how to convince consumers
I think there’s a brave-new-world aspect to this that we have to deal with….we have to tell providers about it in a way that they get it. I think we have to tell the public about it in a way that they get it. But I’m convinced after hearing the data today and the discussion today that these cell lines are important in continued development of vaccines.
“I’m a vaccine guy,” then he suggests approval
Dr. D (Chair, VRBPAC):
I’m a vaccine guy. They are wonderful to prevent infectious diseases, and they may turn out to be wonderful to treat infectious diseases…. That remains to be seen, in my opinion.
I hope I’m speaking for everybody when I say that that’s the answer to your question. If not, please chime in now.
Public opinion concerns and suggestion for omitting information from package inserts
…. the issue of public perception. At the end of the day, information will need to be included in the vaccine safety information and the package insert.
Dr. G (Dir. Office of Vaccines):
…The minute you describe something in the package insert in terms of potential clinical safety concerns, I think that really precludes using these cell substrates…
When it gets right down to what’s in the vial and what the patient is going to ask me about, whether it’s safe, I’m not going to back and say, well, you know, HeLa cells kill nude mice.
…You don’t want to go to somebody and say, “You know, botulinum kills people. It can paralyze you. It’s really dangerous,” or, “Anthrax kills people,” when you are trying to make some kind of an antibody against protective antigen or lethal factor.
The method of manufacturing vaccines from human cancer tumors was then formally approved
To come back to the agency’s question of whether this Committee believes it’s correct scientifically to go forward with the development of these vaccines, our answer is yes.
New discussion is necessary regarding how to formulate the information
… I think we need to work out some of these communication issues and education issues. It’s, to some extent, a whole new discussion. I’m not sure we can resolve it easily today.
… I don’t know that our charge is to micromanage the package insert today. As I said, I think that’s a new discussion, with lots of issues that we haven’t really aired completely.
FDA does its best and will learn more about the risks as time goes by
Dr. M (Nat. Inst. Of Health):
I think for all vaccines and the way FDA regulates them, we have always embraced every practical technique to minimize the risk of transferring infectious factors in vaccines. Now we’re sort of expanding that to minimize oncogenic factors by vaccines. The practical technique is important because there are lots of theoretical things that might not be feasible.
But I think you take pragmatically what we know and we build on that as time goes by.
….. even though there are challenges to using the new technologies, they have to be embraced and we have to continue to try to learn from them and struggle through that learning curve.
But I think the guiding principle remains that we need to do everything we can to minimize the risk of transferring infectious and oncogenic factors by vaccines. That is the best that I feel I can contribute.
As a result of the approval which is based on documented uncertainty regarding safety, millions of potentially cancer causing vaccines will be produced.
The cost of manufacture based on human cancer tumors is cheaper and faster than breeding lab animals for the culture media. Millions of dollars will be made by vaccine promoters.
Symbolically, the method paints a dire picture: tumors caused by vaccines being used to make more vaccines. Like a sort of vaccine-cancer-vaccine merry-go-round. But not so merry.