Epstein-Barr Virus, Multiple Sclerosis and Cancer: Looking Back at 60 Years of Research
60 years on from the discovery of the Epstein-Barr virus, Professor Lawrence Young discusses current efforts to find a vaccine.
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The Epstein-Barr virus (EBV) was the first virus to be discovered that could cause human cancer. Since then, the virus has been implicated in the development of a range of different cancers and, more recently, in the development of multiple sclerosis (MS).
Studying EBV over the past 60 years has shed light on general aspects of cancer pathogenesis, the immunology of virus infections and different approaches to cancer immunotherapy.
Lawrence Young is a professor of molecular oncology and director of the Warwick Cancer Research Centre at the University of Warwick. Known for his work on the role of virus infection in the development of cancer, his research has led to several clinical trials including contributing to the ongoing development of a therapeutic EBV vaccine for MS.
In an interview with Technology Networks, Young discusses the historic discovery of EBV, the current interest in EBV vaccines and his thoughts on the future direction of virology research.
Blake Forman (BF): For our readers, who may not be familiar with the discovery of EBV, can you elaborate on the historical journey of EBV discovery and how it was first linked to cancer?
Lawrence Young (LY): During the 1950s, a young pathologist called Anthony Epstein was investigating the Rous sarcoma virus, a virus that was known to cause cancer in chickens. Epstein was interested in understanding if viruses could also play a role in human cancer.
In 1961, Epstein attended a lecture by Denis Burkitt, a surgeon working in Africa. Burkitt had discovered a lymphoma that appeared in the jaws of young children. He mapped the appearance of this lymphoma to areas where malaria was common.1 This sparked interest in Epstein who hypothesized that an infectious agent may be the cause of this lymphoma.
Following the lecture, Burkitt arranged to send tumor samples from Africa to London for Epstein to investigate further. After a few years of trying in vain to find a virus in the samples, Epstein, alongside a young researcher called Yvonne Barr, was eventually able to grow free-floating cancer cells to study.
With the help of a colleague called Burt Achong, and by studying Burkitt’s lymphoma cells with an electron microscope, the researchers were able to identify virus particles that looked like the shape of a herpes virus in the growing cancer cells. In 1965 the scientific community confirmed that Epstein and company had spotted a brand-new human virus, and it was officially christened Epstein-Barr virus.2
BF: Given the significant role of viruses in cancer development, why do you think public awareness about this link remains limited?
LY: Cancer-causing viruses are responsible for approximately 30% of cancer cases in low- and lower-middle–income countries and around 15% of cancers worldwide. Given the amount of research in this area and its applications in human health, it is surprising there is not more public awareness.
Studies into the role of viruses in cancer have led to the development of vaccines as with the human papillomavirus. Similarly, a vaccine against hepatitis B has been used to help prevent the development of liver cancer for quite some time. I think the limited public awareness of the role of viruses in cancer comes down to a lack of publicity.
BF: Can you talk about the current interest in EBV vaccines; what impact could these vaccines have on the management of associated diseases such as MS?
LY: The development of vaccines against EBV has had a somewhat checkered history. One of the problems is that more than 90% of adults globally are infected with this virus. Often, we contract the virus when we are young and there are no symptoms. Stopping the early transmission of the virus is very difficult.
Individuals who contract EBV as adults are much more likely to develop glandular fever, otherwise known as infectious mononucleosis. There has been a lot of work over the years to try and develop vaccines that might prevent this disease. This has been difficult to justify economically because of the relatively small number of people who get glandular fever. You would also ideally need to vaccinate all individuals as babies, probably at birth.
There is renewed interest in an EBV vaccine off the back of studies identifying EBV as a driving force in the origin and development of MS.3 We've learned a lot more about the different proteins that the virus produces to get into different cell types. This has made researchers more aware of the fact that if we're going to have an effective vaccine, we're going to have to use a combination of different EBV proteins as targets.
The revolution in our understanding of vaccinology, particularly as it relates to mRNA vaccines, means that we can incorporate many more elements of a virus into a vaccine. Something that we know has been very important during the COVID-19 pandemic.
Moderna is currently involved in early clinical trials looking at an mRNA vaccine for preventing EBV infection. There is hope that vaccines like this could be used not only to prevent EBV-associated diseases like MS but also to treat people with these diseases including cancer.
BF: Are there any current hurdles in the study of EBV?
LY: There is a current lack of funding for fundamental research and there is still a lot we need to learn about the virology of EBV and similar viruses. The focus is now on developing better approaches to treating EBV-associated malignancies. That shift is understandable when resources are limited, but one concern I have is that we still need to fund basic virology. Due to COVID-19 people are now more aware that we must not be complacent about viruses. I would hope that some of that would translate into more funding for fundamental research into virology.
BF: Are there any novel technologies or methodologies that you think will help progress studies further?
LY: It has been difficult to manipulate the viral genome of EBV due to its large size. We've now got much better methodologies for studying genomes of this size. This means that we can now make recombinant forms of EBV so that we can study the function of individual virus genes in the context of the whole virus.
Separating viral DNA from human DNA to sequence it has also been challenging but new technology is now providing us with better ways of doing this. EBV was first sequenced in 1984, which was when I first started in the field. At that time, it was the largest piece of DNA ever sequenced. We now have access to better techniques that are helping us determine whether there are different varieties of EBV. We know there is some variation (polymorphisms) in the EBV genome. Studying this further will help us understand if there is a specific variant of EBV that might be more associated with MS.
BF: How do you envision EBV research evolving in the next few years?
LY: EBV research has led the way in the development of early diagnostics for cancer. Measuring EBV DNA in the blood is a good indicator when investigating if an individual might go on to develop EBV-associated cancer. Alternatively, when an individual has EBV-associated cancer, measuring EBV DNA levels in the blood can tell you whether they're responding well to therapy and if the cancer recurs. More generally, studying tumor DNA in the blood as a liquid biopsy for cancer is an exciting and expanding area of research.
Understanding the virus at the epidemiological level is another continuing avenue of investigation. Some of the most common EBV-associated malignancies occur in specific parts of the world. For example, EBV-associated nasopharyngeal cancers are particularly common within the Chinese population.4 Further research is still needed to understand why this is. A combination of the underlying genetics of the individual, environmental factors and the genetics of the virus itself may contribute.
All monkeys have a version of EBV so it may have helped our immune systems to develop from an evolutionary perspective. One of the big questions is if you completely eradicated EBV from your body, would it mean you are more susceptible to other infections? There is evidence, for instance, that EBV is important as we get older in that it helps tweak our immune system.
One interesting aspect that hasn’t been studied enough is understanding why a small percentage of people don’t ever contract EBV. Is there anything different about them in terms of their susceptibility to disease or other diseases that could be harnessed?
Studies have demonstrated that when individuals are infected with SARS-CoV-2, EBV reactivates, and replication increases. A proportion of individuals with long COVID appear to have more EBV floating around in their bodies.5 This is interesting as there has been a long history of EBV and its potential role in chronic fatigue syndrome. Studying how EBV interacts with other viruses will also be vital to better understanding these conditions and to developing improved therapies.
Professor Lawrence Young was speaking to Blake Forman, Senior Science Writer & Editor for Technology Networks.
About the interviewee:
Lawrence Young is a professor of molecular oncology and director of the Warwick Cancer Research Centre at the University of Warwick. Young is internationally recognized for his work on the role of virus infection (Epstein-Barr virus and human papillomavirus) in the pathogenesis of various tumors.
References
1. Burkitt D. A tumour syndrome affecting children in tropical Africa. Postgrad Med J. 1962;38(436):71-79. doi: 10.1136/pgmj.38.436.71.
2. Epstein MA, Henle G, Achong BG, Barr YM. Morphological and biological studies on a virus in cultured lymphoblasts from Burkitt’s lymphoma. J Exp Med. 1965;121(5):761-770. doi: 10.1084/jem.121.5.761.
3. Bjornevik, K, Cortese, M, Healy, BC, et al. Longitudinal analysis reveals high prevalence of Epstein-Barr Virus associated with multiple sclerosis. Science. 2022. doi: 10.1126/science.abj8222
4. Tsao SW, Tsang CM, Lo KW. Epstein–Barr virus infection and nasopharyngeal carcinoma. Philos Trans R Soc Lond B Biol Sci. 2017;372(1732):20160270. doi: 10.1098/rstb.2016.0270
5. Gold JE, Okyay RA, Licht WE, Hurley DJ. Investigation of long COVID prevalence and its relationship to Epstein-Barr Virus reactivation. Pathogens. 2021;10(6):763. doi: 10.3390/pathogens10060763
