Vaccines are the most efficient and cost-effective means of preventing infectious disease on a global scale. However, traditional vaccine approaches have thus far failed to provide protection against human immunodeficiency virus (HIV), tuberculosis, malaria, and many other diseases. New approaches to vaccine development are needed to address some of these intractable problems.
The first vaccine was made in 1796. Edward Jenner who took some fluid from a cowpox blister from the hand of a milkmaid and then scratched the fluid into a boy’s skin. Despite suffering a local reaction and feeling unwell for several days, Phipps made a full recovery. Two months later, in July 1796, Jenner inoculates Phipps with matter from a human smallpox sore in order to test Phipps’ resistance. Phipps remains in perfect health, and becomes the first human to be vaccinated against smallpox. The term ‘vaccine’ is later coined, taken from the Latin word for cow, “ vacca”.
Since the late 1800s, animals have been used in the industrialised production of human vaccines since vaccine farms were established to harvest cowpox virus from calves. Most vaccines are either produced by growing pathogens in live animals or by using animal cells. Researchers know that these methods are not ideal, due to the fact that research animals are costly and require extensive monitoring, both to maintain their health and to ensure the continued viability of the research. Animals may be carrying other bacteria or viruses that could contaminate the eventual vaccine. This was the case with the polio vaccines that were made with monkey cells and eventually found to contain a monkey virus called SV40, or Simian Virus 40, which is believed harmless to humans. Moreover, some pathogens, such as the chickenpox virus, simply do not grow well in animal cells.
Therefore, using cell culture techniques to produce vaccines in human cell strains is a significant advance in vaccine development. Cell cultures involve growing cells in a culture vessel.
A primary cell culture is usually taken directly from living tissue and never sub-cultivated, and may contain multiple types of cells such as fibroblasts, epithelial, and endothelial cells. A cell strain is a cell culture that contains only one type of cell in which the cells are normal and have a finite capacity to replicate. Cell strains can be made by taking subcultures from an original, primary culture until only one type remains. Human pathogens for example, viruses can be grown in cell strains to attenuate them – that is, to weaken them. Later, when it’s used in a vaccine and injected into a living human body at normal temperature, it still provokes an immune response but can’t replicate enough to cause illness.
The first licensed vaccine using a human cell strain was the adenovirus vaccine made by the US military in the late 1960s. The next one was the rubella vaccine developed in human cell strains. At the height of a rubella epidemic that began in Europe and spread to the United States in the mid-1960s, women who were infected with rubella while pregnant terminated their pregnancies due to the serious risks from CRS.
Following one such abortion, Leonard Hayflick (working at the Wistar Institute at that time) developed a cell strain called WI-38 using metal lung stem cells from an aborted fetus. He found that many viruses, including rubella, grew well in the WI-38, and showed that it proved to be free of contaminants and safe to use for human vaccines. Plotkin grew the rubella virus in WI-38 cells and the vaccine developed is still used throughout much of the world today as part of the combined MMR (measles, mumps, and rubella) vaccine.
According to Hayflick, however, the main reason for using WI-38 was the fact that it could be stored in liquid nitrogen, reconstituted, and tested thoroughly before use for contaminating viruses.
After testing, Plotkin’s vaccine was first licensed in Europe in 1970 and was widely used there, offering a strong safety profile and high efficacy. In light of that data, and of larger side effect profiles with the other two rubella vaccines, it was licensed in the United States in 1979 and replaced the rubella vaccine component that had previously been used for Merck’s MMR (measles, mumps, rubella) combination vaccine. Another human fetal stem cell strain, the MRC-5 cell strain (also started with fetal lung stem cells) 1970 at the Medical Research Center in the United Kingdom. Together these two stem cell lines WI-38 and MRC-5 cells that, while not capable of infinitely replicating like immortal cell lines, will serve vaccine production needs for several decades in the future.
The vaccines below were developed using either the WI-38 or the MRC-5 cell strains.
- Hepatitis A vaccines [VAQTA/Merck, Havrix/GlaxoSmithKline, and part of Twinrix/GlaxoSmithKline]
- Rubella vaccine [MERUVAX II/Merck, part of MMR II/Merck, and ProQuad/Merck]
- Varicella (chickenpox) vaccine [Varivax/Merck, and part of ProQuad/Merck]
- Zoster (shingles) vaccine [Zostavax/Merck]
- Adenovirus Type 4 and Type 7 oral vaccine [Barr Labs]
- Rabies vaccine [IMOVAX/Sanofi Pasteur]
It is believed that vaccines made in WI-38 and its derivatives have prevented nearly 11 million deaths and prevented (or treated, in the example of rabies) 4.5 billion cases of disease. Various other vaccines made in the US were developed using animal cell strains, primarily using cells from African green monkeys. These include vaccines against Japanese encephalitis, rotavirus, polio, and smallpox. Of these, only rotavirus and polio vaccines are routinely given.
Cell lines developed from past abortions are used in the testing or development of certain COVID-19 vaccines. The HEK 293 cell line was developed in Holland in the early 1970s from embryonal kidney tissue from a supposedly therapeutic abortion that was transformed by adenovirus type 5. The PER.C6 cell line was developed in 1995 from retinal tissue from an abortion in 1985 that was transformed by adenovirus type 5. The University of Oxford/AstraZeneca vaccine ChAdOX1 nCoV-19 is developed in the HEK 293 cell line and the Janssen/Johnson & Johnson vaccine Adenovirus 26 vaccine Ad26.COV2.S is developed in the PER.C6 cell line; however, the final products do not contain fetal cells. The mRNA vaccines are not manufactured in cell lines, although testing of mRNA vaccines reportedly uses cell lines.
COVID-19 and even before that, a small but growing number of parents object to vaccinating their children on religious grounds is based on the fact that vaccines are the product of cells that once belonged to aborted foetuses and that vaccines may contain fetal DNA.
These abortions, which occurred decades ago, were not undertaken with the intent of producing vaccines. The original cells were obtained more than 50 years ago and have been maintained under strict FDA guidelines by the American Type Culture Collection.
Therefore the reasoning of anti-vaccine statement: “there is fetal DNA in vaccines” is unfounded on scientifically and religious grounds; because DNA is not stable when mixed with certain chemicals, much of it is destroyed in the preparation in the final vaccine. The amount if present will be trillionths of a gram and highly fragmented. Because it is fragmented it cannot create a whole protein and cannot incorporate itself into cellular DNA. If this was the case; gene therapy would be much easier than it has been in the past 4 decades. Therefore the value of vaccines in irradicating infectious disease in humans throughout the centuries, it far outweighs the harmless fetal DNA that might be present in these vaccines.
When we further evaluate the contribution of stem cells to vaccine development; the versatile mesenchymal stem cells (MSCs) have again proven to be irreplaceable to the scientific community.
Although MSCs are unique multipotent progenitor cells that are presently being exploited as gene therapy vectors for a variety of conditions, including cancer and autoimmune diseases. Although MSC are predominantly known for anti-inflammatory properties during allogeneic MSC transplants, there is evidence that MSC can actually promote adaptive immunity under certain settings. Recently, however, MSC has also demonstrated some success in anti-cancer therapeutic vaccines and anti-microbial prophylactic vaccines. MSC can express and secrete a viral antigen that stimulates antigen-specific antibody production in vivo. This unique property of modified MSC may enable MSC to serve as an unconventional but innovative, vaccine platform. Such a platform would be capable of expressing hundreds of proteins, thereby generating a broad array of epitopes with correct post-translational processing, mimicking a natural infection. By stimulating immunity to a combination of epitopes, it may be possible to develop prophylactic and even therapeutic vaccines to tackle major health problems including those of non-microbial and microbial origin, including cancer, or an infectious disease like HIV and COVID-19, where traditional vaccination approaches have failed.
Mesenchymal stem cells are a new-found platform for designing genetically engineered cellular vaccines that hold the promise to produce efficient and safe vehicles for enhancing the host immune response.
Reference
- Hayflick, L., Plotkin, S.A., Norton, T.W., Koprowski, H. Preparation of poliovirus vaccines in a human fetal diploid cell strain. Am J Hyg. 1962 Mar;75:240-58.
- Lindquist, J.M., Plotkin, S.A., Shaw, L., Gilden, R.V., Williams, M.L. Congenital rubella syndrome as a systemic infection: studies of affected infants born in Philadelphia, USA. Br Med J 1965;2:1401-6.
- Olshansky, S.J., Hayflick, L. (2017). The role of the WI-38 cell strain in saving lives and reducing morbidity. AIMS Public Health; 4(2):137-148. Accessed 01/10/2018.
- Plotkin, S.A., Orenstein, W.A., Offit, P.A., eds. Vaccines. Philadelphia: Saunders; 2008. Plotkin, S.A. The History of Rubella and Rubella Vaccination Leading to Elimination. Clin Infect Dis. 2006 43 (Supplement 3): S164-S168.
- Sgreccia, E. (2005). Statement from the Pontifical Academy for Life, including English translation of “Moral Reflections on Vaccines Prepared from Cells Derived from Aborted Human Foetuses.” Accessed 01/10/2018.
