Fetal tissue use in vaccines
The short version: You may have heard that vaccines make use of fetal tissue in their production and this might be causing you some unease regarding whether or not it is acceptable to take these vaccines. There are a few things you should know though. Firstly, the abortions from which these cells were procured occurred decades ago and the cells themselves are many generations removed from those original fetuses. Furthermore, the elective abortions in question that gave us these cells would have occurred regardless of whether or not the cells were then used for vaccine production. In other words, it wasn’t a choice between having the cells for application to biomedical research and the pregnancies being kept, but rather a choice between using the abortions to make a positive contribution to our knowledge of biology and medicine or not. Additionally, these abortions have been able to provide enough material for the production of these vaccines that they have lasted decades and continue to serve us. The vaccine industry isn’t actively procuring tissues from abortions for the sake of their manufacturing. It doesn’t need to. The vaccines from these fetal cell strains have prevented billions of illnesses and saved millions of lives. No vaccine contains actual fetal cells or tissues within it. The only purpose of the cells is as factories to make vaccine antigens and those antigens are then purified out. There is no DNA from the cells in the vaccines either because vaccines are treated with enzymes that destroy DNA before they are ever given to the public as part of their quality control mechanisms. The history of vaccines tells us that the best cells to use to make human vaccines are human cells, and ideally cells that have not had a chance to become contaminated with other viruses, making fetal cells ideal candidates (see below for the crazy history). Multiple religious authorities have spoken on the issue and do not feel that the vaccines are morally compromised to the extent that taking a vaccine that has been made with the aid of fetal cells is unethical, among these being the Catholic church (though many feel that if alternatives which have not been produced with the technology are available those should be taken instead). I do recognize however that one’s religion may not be represented by the bodies of religious scholars who have provided their thoughts on the subject, so I have instead focused here on the facts about the use of these cells rather than the morality and I feel that it isn’t my place to opine on those aspects here as I am not a religious scholar. In the future, we will likely have alternatives to the use of fetal tissue in vaccine production, but for now those technologies are not quite ready to be the standard (mRNA vaccines for instance are very attractive in that they can be made without any cells at all, but they are extremely expensive to make and store, and they aren’t appropriate for every type of infectious disease). It is my very strong opinion that concerns about the use of fetal cells should not be used to withhold essential protection that can only be obtained by vaccination, and further that in the current situation with COVID-19 vaccines being as scarce as they are, the first vaccine available to you is the one that you should take because you don’t know when you will have the opportunity to get another. I would only encourage efforts to pursue alternative technologies that can produce vaccines that are as safe, effective, and cheap as the ones produced through human cell strains today, but for now, this is what we have to work with, and if this technology helps to eliminate COVID-19, that will only be a good thing.
The use of fetal cells in medical research generally invites many impassioned opinions because the subject is necessarily tied to people’s thoughts on abortion, which is a touchy matter that I probably won’t address in the context of this blog. Principally, I will focus here on explaining (in the most dispassionate and objective manner I am capable):
Why fetal cells are used in the first place
Why there isn’t (yet) a suitable alternative to their use (but what alternatives may appear in the future)
The relevance to specific COVID-19 vaccines
The Rationale
Firstly, vaccines against viruses require massive production of those viruses, but viruses can’t reproduce on their own- they need a host cell to provide for them so they can replicate, so clearly some kind of cell is needed (bacteria can be cultured on their own, although this does depend on the particular bacteria). Further, ideally that cell should have significant capacity to divide (depending on the virus, the replication process may result in the death of the cell and thus that cell can no longer be used for further culturing). You may at this point wonder why we couldn’t simply use animal cells to circumvent the apparent moral quandaries of fetal cell use. The first and most basic reason is that many viruses are very specific for the cell types they infect. A cell has to be both susceptible (meaning it expresses the receptors needed for the virus to be able to get inside) and permissive (meaning it has to be able to support viral replication metabolically) for any virus to be able to reproduce within it. That unfortunately means that some viruses will not grow effectively in non-human cells, even if you make them susceptible. There is further another important historical reason for the shift towards fetal cell use for the culturing of virus: SV40. SV40 (simian virus 40) is a virus that is present in monkey kidney cells which have been used to culture viruses; in the 1950s, adenoviruses type 4 and 7 were cultured for vaccine production in these monkey kidney cells, and it was later shown that the vaccines had been contaminated with SV40 as well. These cells were also used to produce virus for the inactivated polio vaccine. SV40 is known to be capable of causing cancer in rodents, and thus on discovering it had been present in vaccines for humans, and the question became whether or not the virus could potentially cause cancer in humans as well. Plotkin’s Vaccines summarizes the evidence well (emphasis mine):
Although concerns were raised about the carcinogenic potential of SV40 in vaccinees and their offspring, long-term follow-up studies do not support such an association. 572,573 A meeting convened at the National Institutes of Health in 1997 reexamined the available evidence and concluded that “no measurable increase in neoplastic diseases has occurred in humans exposed to SV40 contaminated polio vaccines.” 574 Subsequently, a report evaluated the cancer risks of birth cohorts potentially exposed to SV40 and concluded that these cohorts did not experience a significantly increased risk for the cancer outcomes studied. 575 Nevertheless, the question of whether SV40 exposure can increase cancer risk continues to be debated. 576,577 A review by the Immunization Safety Committee (under the auspices of the Institute of Medicine) concluded in 2002 that because the epidemiologic studies were sufficiently flawed, the evidence was inadequate to conclude whether SV40-contaminated polio vaccine caused cancer. 578 Several subsequent cohort and case-control studies using more scientifically rigorous methods failed to support a relationship between SV40 and cancer. 579, 580, 581, 582 Cell lines currently used for OPV production come from monkeys raised in colonies free of SV40 or from well-characterized continuous cell lines (Vero cells). In addition, OPV must be screened for known viruses; consequently, SV40 is not present in current lots of OPV vaccine.
In other words, thankfully, review of the evidence does not suggest that SV40 from polio vaccines contributed to a rise in the rates of cancer, or that the virus can be harmful to humans within the limits of our epidemiologic methods to detect such signals. Some have also argued that the antibodies used to identify SV40 in tumors from patients may not have been specific enough (i.e. it was binding other viruses) to demonstrate adequately that the virus was in fact present in them. IARC has a detailed monograph on SV40 for anyone interested. However, this raised important questions about which cells should be used for the production of vaccines.
Lodish H, Berk A, Kaiser CA, et al. Molecular Cell Biology. 8th ed. W.H. Freeman; 2016. Figure 4.1
In their natural history, cells will inevitably be exposed to viruses, and when you’re trying to manufacture large quantities of them, like for vaccines, it’s critical to avoid contaminants- even though we can’t demonstrate harm to human health from the presence of SV40 contaminants, the possibility exists that an alternative contaminant could be present in the vaccines and be deleterious to human health. Thus the solution is obvious: use cells which haven’t had an opportunity to become infected with virus- fetal cells.
First though, a brief detour is needed to clarify some important terminology. Often in discussions of this topic, people will use the term “cell lines” to note the specific cell types used in the manufacture of these vaccines, but this is incorrect. Cells that are isolated from human tissue go through predictable changes. Firstly, a sizeable portion of them die, but the remaining cells can be harvested and diluted and replated in dishes repeatedly for a period of about 50 cell divisions before they attain a stage called cellular senescence wherein they stop dividing (the number of divisions it takes to get to this stage is known as the Hayflick limit). The steady-state period of growth (phase II in Figure 4.1a) is a cell strain. On the other hand, as this occurs some of the cells may acquire mutations that render them immortal and incapable of senescence. This is known as a cell line. Cancer cells exhibit this property, and you may be familiar with the HeLa cells which were unethically procured from Henrietta Lacks without her consent. Cell strains, but not cell lines, are used to make vaccines, and the efforts of Hayflick have ensured that these cell strains should last us several decades for production of vaccines.
For the vaccines on the schedule, two fetal cell strains have been used: MRC-5 and WI-38, used to make vaccines for varicella, rubella, hepatitis A, and one of the rabies vaccines; both from elective abortions from the 1960s from women in Europe. In the history of their use, no evidence for viral contaminants has ever been found. I think it’s critical to note here that these were not abortions carried out for the sake of having virus-production material for vaccine manufacturing: they would have happened anyway, but this way, at least that fetal tissue could be used to positively change human health. As Hayflick and Olshansky explain:
Results indicate that the total number of cases of poliomyelitis, measles, mumps, rubella, varicella, adenovirus, rabies and hepatitis A averted or treated with WI-38 related vaccines was 198 million in the U.S. and 4.5 billion globally (720 million in Africa; 387 million in Latin America and the Caribbean; 2.7 billion in Asia; and 455 million in Europe). The total number of deaths averted from these same diseases was approximately 450,000 in the U.S., and 10.3 million globally (1.6 million in Africa; 886 thousand in Latin America and the Caribbean; 6.2 million in Asia; and 1.0 million in Europe).
I am not here to answer the question of what constitutes a human life ( as well as whether or not that question is relevant to this discussion, and the corollary of when and whether it is appropriate to end) to answer whether this justifies the use of fetal cells in vaccine manufacturing, but it cannot be ignored that whatever one’s views on the procurement of those cells, they have had an enormous positive impact on public health. Multiple religious authorities have stated that in spite of their moral oppositions to abortion and the use of fetal cells generally, they do not feel that it is morally compromising for recipients of vaccines to receive vaccines produced within these cells. Prominent bioethicists on the subject matter generally don’t agree that the abortions make the vaccines morally corrupt.
PER.C6 is also a cell line (not cell strain) relevant to vaccine manufacturing belonging to Janssen, which is a retinal cell that comes from an aborted fetus from 1985. Another very common cell line used in biomedical research is the HEK.293 cell line which comes from a fetus aborted in 1972. These two cells are ideal for the production of replication-deficient adenoviruses, and the mRNA vaccines were tested in HEK.293 cells preclinically, but they are not used in the production of the vaccines. Replication-deficient adenoviruses are very useful for the production of vectored vaccines and because they cannot replicate (they have deletions in essential genes required for that) they can even be given safely to people who are immunocompromised. The cells express the genes essential to the replication of the virus in trans (meaning that the genes are not part of the virus’s genome but rather expressed by the cell) but the final product lacks the instructions to make them, producing a replication-deficient adenovirus vector.
Regarding the possible health effects from the use of fetal cells in vaccine production, truthfully I struggle to think of any barring the presence of contaminants (but of course, these are screened for very thoroughly and the cell strains in question have failed to show any). As part of the quality control processes any remnant DNA from the cells is destroyed by enzymes called nucleases, and the antigens are purified out to exclude anything other than residual, trace quantities of culturing media.
Alternatives
Moremen KW, Tiemeyer M, Nairn AV. Vertebrate protein glycosylation: diversity, synthesis and function. Nat Rev Mol Cell Biol. 2012;13(7):448-462 Box 1 demonstrating the major types of glycosylation patterns observed from vertebrates.
One of the amazing things about the mRNA vaccines is that they can be made entirely without the use of cells. All you need is a DNA sequence for the RNA you want, an RNA polymerase, and a bunch of ribonucleotides and you have yourself a vaccine manufacturing vessel (of course, it’s not quite that simple as the RNA has to be edited to control how strong an immune response it will produce and it has to be packaged into very specially formulated lipid nanoparticles). The issue here principally is twofold. Firstly, mRNA vaccines are extremely expensive to make relative to other types, and extremely difficult to store, meaning that as things are currently, they are not viable options for lower and middle income countries (LMICs). mRNA vaccines may also encounter struggles in dealing with non-viral pathogens. Proteins that are destined for secretion outside the cell get modified with trees of sugars called glycans in a process called glycosylation. Viruses that infect humans do this in human cells, so glycosylation of viral proteins from an mRNA vaccine does a fantastic job of reproducing what happens in an actual infection. However, for something like a parasite or bacteria, the manner in which they get glycosylated can be starkly different from what a human cell might do, which could be a serious problem for the immune system in recognizing the antigens.
Another option that has become more attractive in more recent years is plant-based vaccines. This is where the vaccine antigens are manufactured, literally, inside a plant. This has a lot of advantages:
Plant expression systems have several intrinsic advantages vis-á-vis bacteria, yeast, insect or mammalian systems in terms of speed, costs, scalability and safety [5, 6]. In addition, plants have the capacity to perform post-translational changes which are important in protein folding, trafficking, stability and biological activity [7, 8]. Plant-derived antibodies (PDAbs) have been developed for protection against different pathogens, including viruses, bacteria and fungi [9, 10].
This can even be taken further in some cases to make edible vaccines, which is a fantastic solution for LMICs, wherein the plants literally contain the vaccine antigens and people eat the plants, which may represent a viable path to immunity for pathogens that infect the digestive tract like poliovirus or rotavirus. There have also been attempts to make plant-based influenza vaccines which will likely come to fruition soon. Of course, it’s not as though this approach is without its problems. For one thing, vaccine antigens are based on human or animal pathogens, so finding a plant that can reliably produce them is not at all a simple task. Furthermore, tissue choice matters as well: leaves for instance have high expression of proteases and are generally poorly enriched in proteins overall which means they could destroy antigens that they produce. It can also be a challenge to achieve consistent dosages (indeed, this issue extends infamously to herbal medicines). There are also concerns about how to ensure that patients generate good immune responses to the antigens, rather than learning to tolerate them. Furthemore, there are more general concerns about how using non-human cells could also affect glycosylation (proteins are adorned with sugars as part of their quality control measures before secretion but the manner in which this is done is very specific) as this could affect the immune system’s ability to recognize and respond to them- plants in particular do not make sialic acid residues that are very common in mammals and can be critical for immune recognition, and they produce sugars which humans do not make at all that can potentially trigger reactions from the immune system. There are attempts to make a plant-based COVID-19 vaccine.
There are also insect vector based approaches. This is actually what Novavax has done. The potential drawbacks here are similar to those of using plants, in particular with respect to glycosylation. Insects tend to have less elaborate, trimmed glycosylation patterns on their proteins relative to humans, which could be meaningful for the ability of the immune system to recognize them. They also express some sugars like plants which are not found in humans and thus could set off immune reactions. However, more recent work has enabled for the production of more humanized glycosylation systems within insect cells.
None of this is to say that these alternative approaches cannot work (after all, polio vaccines were made with monkey kidney cells with great success for vaccination campaigns), especially with the possibility of generating humanized glycosylation systems, and in fact most of the drugs we have that require cell-based expression systems do not use human cells, but when dealing with the immune system, it’s important to be as precise as possible (consider for instance that type A and type B blood differ by a single acetyl group and yet the immune system mounts very potent responses against a mismatched blood type) and these other medications are typically not designed with the purpose of eliciting a reaction from the immune system as vaccines do (in fact care is often taken to try to prevent this from happening). For now, cell strain-based approaches using human cells are still the standard, but this will be worth examining further as the technology evolves. I have no qualms with the use of alternative technology provided it is shown to be as or more safe and effective.
References
Lodish H, Berk A, Kaiser CA, et al. Molecular Cell Biology. 8th ed. W.H. Freeman; 2016.
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Henrietta Lacks: science must right a historical wrong. Nature. 2020;585(7823):7.
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Ward BJ, Makarkov A, Séguin A, et al. Efficacy, immunogenicity, and safety of a plant-derived, quadrivalent, virus-like particle influenza vaccine in adults (18-64 years) and older adults (≥65 years): two multicentre, randomised phase 3 trials. Lancet. 2020;396(10261):1491-1503.
Laere E, Ling APK, Wong YP, Koh RY, Mohd Lila MA, Hussein S. Plant-based vaccines: Production and challenges. J Bot. 2016;2016:1-11.
Pau MG, Ophorst C, Koldijk MH, Schouten G, Mehtali M, Uytdehaag F. The human cell line PER.C6 provides a new manufacturing system for the production of influenza vaccines. Vaccine. 2001;19(17-19):2716-2721.
How plants could produce a COVID-19 vaccine. Nature.com. Accessed March 9, 2021. https://www.nature.com/articles/d42473-020-00253-2
Takeyama N, Kiyono H, Yuki Y. Plant-based vaccines for animals and humans: recent advances in technology and clinical trials. Ther Adv Vaccines. 2015;3(5-6):139-154.
HEK293 cell line. Hek293.com. Published July 25, 2014. Accessed March 9, 2021. https://www.hek293.com/
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Moremen KW, Tiemeyer M, Nairn AV. Vertebrate protein glycosylation: diversity, synthesis and function. Nat Rev Mol Cell Biol. 2012;13(7):448-462.
Palmberger D, Wilson IBH, Berger I, Grabherr R, Rendic D. SweetBac: a new approach for the production of mammalianised glycoproteins in insect cells. PLoS One. 2012;7(4):e34226.
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