mRNA vaccines

Introduction

mRNA vaccines are one of many types of vaccines used to provide us with artificial active immunity. Despite having been in development for several decades, they gained traction after the use of the technology in Moderna and Pfizer-BioNTech’s COVID-19 vaccines. Following their success throughout the pandemic, clinical research into mRNA vaccines has been accelerated, with the ambition to create cancer vaccines. 

How the COVID-19 mRNA vaccine works

In the example of the COVID-19 vaccine, the genetic material that codes for the spike protein on the COVID-19 virus surface is isolated and used to create an mRNA molecule. The mRNA is then inserted into either a viral vector or a lipid nanoparticle so that once inside the body, it can enter cells. mRNA can then be translated at ribosomes to produce spike proteins, which are displayed on the cell surface membrane. Therefore, an immune response can be stimulated, producing both antibodies and memory cells, for a faster and stronger secondary immune response.¹

Using mRNA vaccines against cancer

More recently, there has been an influx in clinical trials aimed at utilising mRNA vaccines to fight cancer. Rather than preventing the development of cancer, they are aimed at helping the immune system to recognise and remove it. There have been two approaches to this, with some companies focussing on a general vaccine and others on a personalised one.

A general vaccine would contain mRNA coding for proteins found commonly in a range of cancers, stimulating an immune response against their respective antigens once they are synthesised. The two main advantages of this type of vaccine is the low cost, as well as the scope for large-scale production and distribution. Current trials involving them are targeting cancers such as advanced melanomas, prostate cancer and ovarian cancers. 

However, greater strides have been made in creating a personalised vaccine, which codes for neoantigens- proteins which are specific to an individual’s cancer. Since each cancer tends to present uniquely in different cases, it is important to identify the relevant antigens to ensure a high level of effectiveness; however this process can be expensive, costing several thousand pounds per dose. Ongoing phase two trials with personalised vaccines are targeting diseases such as melanoma and colorectal cancer.²

The image below, from BioNTech, summarises how a personalised cancer vaccine is created and subsequently stimulates an immune response:

There are numerous options for the delivery format of the mRNA vaccine, one of which is introducing mRNA into dendritic cells (DCs), in a process known as transfection, creating a cell-based cancer vaccine. Another alternative is injecting the mRNA directly into the body, without the use of a carrier. Whilst this technique is cheaper and quicker, without any protective carrier, the mRNA is prone to degradation by enzymes thus limiting their benefits. Currently, the most promising delivery method is through implementing a similar method to the COVID-19 vaccines by using lipid nanoparticles. These can be easily taken in by cells through endocytosis, followed by endosomal escape, enabling the mRNA to be translated at ribosomes and produce the desired antigen.³

Advantages and disadvantages

One of the greatest advantages of mRNA vaccines is the speed with which they can be developed, for example Moderna completed the whole process from design to manufacturing in just 7 weeks. In order to adapt the technology for other vaccines, all that would need to be changed is the mRNA base sequence to produce the desired protein. Although this makes it seem as if we could develop mRNA vaccines for every disease, it is the necessary, lengthy clinical trials which mean that very few are approved for use today.⁴

Another advantage is that such vaccines cannot be integrated into the genome, as the mRNA is broken down quickly after translation, as well as the absence of the enzyme reverse transcriptase. This reduces the risk of insertional mutagenesis (mutations in DNA caused by extra base pairs), which could otherwise have drastic effects on polypeptide synthesis and impact phenotype.⁵

However, one of the main limitations of mRNA is its lack of stability at high temperatures, and therefore the need for it to be transported in freezers. This is a major obstacle for those living in rural areas, as well as developing countries, both due to high transportation costs, as well as a lack of suitable infrastructure. Another limitation is potential long-term impacts, which are yet to be seen, due to the technology being relatively new compared to other forms of vaccines.⁴

Conclusion

Overall, the field of mRNA vaccine research is continually growing, with large strides being made towards a future where we can use it to treat a range of diseases. Although as of yet none have been approved for cancer treatment, there are several ongoing trials by a number of pharmaceutical companies, many of which are showing promising results. This technology has the potential to transform the way we tackle cancer and is definitely something to look out for in the near future.

References

1. Understanding covid-19 mrna vaccines [Internet]. Genome.gov. [cited 2023Mar11]. Available from: https://www.genome.gov/about-genomics/fact-sheets/Understanding-COVID-19-mRNA-Vaccines 
2. Sanderson K. How close are we to developing an mrna cancer vaccine? [Internet]. The Pharmaceutical Journal. 2022 [cited 2023Mar11]. Available from: https://pharmaceutical-journal.com/article/feature/how-close-are-we-to-developing-an-mrna-cancer-vaccine 
3. Vishweshwaraiah YL, Dokholyan NV. MRNA vaccines for cancer immunotherapy. Frontiers in Immunology. 2022;13. 
4. MRNA vaccines – here’s everything you need to know [Internet]. World Economic Forum. [cited 2023Mar11]. Available from: https://www.weforum.org/agenda/2021/07/everything-you-need-to-know-about-mrna-vaccines/ 
5. Lorentzen CL, Haanen JB, Met Ö, Svane IM. Clinical advances and ongoing trials of mrna vaccines for cancer treatment. The Lancet Oncology. 2022;23(10). 

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The HeLa cells: Exploring Their Importance and Ethical Issues

Introduction:

Historically, scientists had attempted for many decades to create a cell line which could be multiplied indefinitely, a feat which, if achieved could revolutionise science. In spite of this, all endeavours resulted in the same futile outcome. However this was soon to change, when, in 1951, 31-year-old Henrietta Lacks visited John Hopkins for cervical cancer treatment where a surgeon took a sample of her tumour¹. Little did anyone know that this sample would grow to become the first immortal human cell line (HeLa) and contribute so much to modern medicine.

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Contributions to medicine: A timeline

Following the revelation that the HeLa cell line could multiply at a prolific rate and stayed alive in culture for long periods of time, their popularity grew. In fact, it is estimated that if all the HeLa cells ever grown were laid in a line, they would wrap around the Earth three times! Samples were sent across the globe for scientists to use in research, the results of which transformed treatment methods, many of which we still use today. Below is a short timeline covering a few of the many ways in which the cells revolutionised science.

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1953: The polio vaccine

During the development of the polio vaccine, scientists required cells which could be used to test its efficacy, and the HeLa cells were found to be more susceptible to polio infection than other cell lines. The Tuskegee institute, also the site of the infamous syphilis studies, was chosen as the location to create a factory dedicated to manufacturing the cells. Culturing of the HeLa cells occurred at a never-before-seen industrial scale, contributing to rapid subsequent clinical trials and rollout of the vaccine². Since their implementation, 2 of the 3 strains of the disease have been globally eradicated, as well as a 99% decrease in wild poliovirus cases, saving millions of lives³.

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1964: Treatment for blood disorders

Hydroxyurea is now a common treatment for a range of blood disorders, ranging from cancer to sickle cell anaemia and testing on the HeLa cells laid the groundwork for its approval. A group of researchers found that the drug was not only able to reduce cancerous growth rates, but also prevent ‘sickle-shaped’ red blood cells⁴. It achieves this by increasing the levels of foetal haemoglobin, making the erythrocytes larger and more flexible, alleviating symptoms of the disease⁵.

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1983: HPV/cervical cancer

In the 1980s, a virologist analysed the HeLa cells to find that they contained HPV-18, which caused Henrietta Lacks’ cervical cancer by switching off her tumour suppressor gene. This particular strain is considered to be one of the most dangerous, and further research enabled the development of the HPV vaccine, which is now commonly administered to teenage girls⁶.

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2020: Covid-19

To this day, the HeLa cells are being used in research, and they were particularly useful in studying the infectivity of the SARS-CoV-2 virus. It was found in a 2020 study that this form of the virus was unable to infect these cells as well as expected, which prompted research into the cause. It was previously known that other forms of coronavirus use a molecule called ACE2, commonly found on the surface of some body cells. Modification of the HeLa cells to produce and display the molecule enabled the virus to infect and therefore replicate inside the cells⁷. Studies such as this, among others, paved the way for the development of the vaccine, which was estimated to have saved 20 million lives in 1 year⁸. 

These are just a few of the many ways in which the HeLa cells have been used in scientific research in order to further develop our understanding of disease. However over the years, the HeLa cells have been subject to controversy due to ethical concerns.

Ethical issues:

The story of Henrietta Lacks was largely unknown until it was brought to public attention by author Rebecca Skloot through her bestseller ‘The Immortal Life Of Henrietta Lacks.’ The book raised awareness about informed consent in scientific research, since when the tissue sample was taken from Lacks, there was no legal or ethical requirement for doctors to obtain permission from the patient¹. As a result, it was only 25 years after Henrietta Lacks’ death that her family found out about the cell line, at which point the cells had contributed to the polio vaccine, cancer research and even been sent to space!

Since the 1950s, the situation with informed consent has vastly improved, with much tighter regulation on a patient’s rights. Yet, this leads one to think of what would have happened if informed consent had been required at the time. If Henrietta had the choice and declined scientists taking a sample, would we be living in a very different world? Would some of the advancements that we take for granted today not exist? The tradeoff between ethics and public benefit remains controversial, but further awareness enables better decisions to be made. 

Additionally, there stands the question as to who should benefit financially from the cells. Whilst large pharmaceutical companies profited off of the research on HeLa cells, the Lacks family remained in poverty, unable to afford proper health coverage and support themselves. Whether the family should profit from the cells remains controversial, however in 2013 a stride was made by the NIH (the National Institute of Health), which meant that two members of the Lacks family are now involved in deciding who is permitted to use the HeLa cells⁹.

Conclusion:

Overall, the HeLa cell line has played a major developmental role for modern medicine, aiding us in curing and alleviating a range of diseases. Whether it be helping to eradicate polio or treat blood disorders, there is no doubt that many lives have been saved. However, this does not mean that the ethical issues should be overlooked, and although informed consent has come a long way since the 1950s, we still face several challenges. Notably, in developing countries there have been cases of violation of consent, often with regard to misinforming patients of potential dangers associated with procedures and trials. As we look into the future, we need to aim for a balance between obtaining tissues ethically, but still having a supply large enough to conduct meaningful research. Whether this can be achieved remains unknown, but at least we are taking strides in the right direction.

Nyneisha Bansal, Youth Medical Journal 2023

References:

1. Skloot R. The immortal life of Henrietta Lacks. New York: Crown Publishers; 2010.

2. Turner T. Development of the Polio Vaccine: A Historical Perspective of Tuskegee University’s Role in Mass Production and Distribution of HeLa Cells. Journal of Health Care for the Poor and Underserved. 2012;23(4a):5-10.

3. Poliomyelitis (polio) [Internet]. Who.int. [cited 24 August 2022]. Available from: https://www.who.int/health-topics/poliomyelitis#tab=tab_1

4. Significant Research Advances Enabled by HeLa Cells [Internet]. Office of Science Policy. [cited 24 August 2022]. Available from: https://osp.od.nih.gov/scientific-sharing/hela-cells-timeline/

5. [Internet]. Hematology.org. [cited 24 August 2022]. Available from: https://www.hematology.org/-/media/Hematology/Files/Education/Hydroxyurea-Booklet.pdf

6. Samuel L. 5 important ways Henrietta Lacks changed medical science [Internet]. STAT. 2017 [cited 24 August 2022]. Available from: https://www.statnews.com/2017/04/14/henrietta-lacks-hela-cells-science/

7. Jackson N. Vessels for Collective Progress: the use of HeLa cells in COVID-19 research – Science in the News [Internet]. Science in the News. 2020 [cited 24 August 2022]. Available from: https://sitn.hms.harvard.edu/flash/2020/vessels-for-collective-progress-the-use-of-hela-cells-in-covid-19-research/

8. COVID-19 vaccines saved an estimated 20 million lives in 1 year [Internet]. CIDRAP. 2022 [cited 24 August 2022]. Available from: https://www.cidrap.umn.edu/news-perspective/2022/06/covid-19-vaccines-saved-estimated-20-million-lives-1-year

9. Frequently Asked Questions | Johns Hopkins Medicine [Internet]. Hopkinsmedicine.org. [cited 26 August 2022]. Available from: https://www.hopkinsmedicine.org/henriettalacks/frequently-asked-questions.html#:~:text=How%20is%20consent%20different%20today,Federal%20law%20requires%20informed%20consent.