To successfully treat diseases their cause must be understood. All diseases are results of disruption at the cellular level, and it was said by E.B. Wilson (1925) that “the key to every biological problem must finally be sought in the cell”. It’s therefore essential that cell biology research continues to unravel the workings of cells, both in their healthy and diseased states, so new ways of preventing and treating disease can continue to be developed.
Cell biology is fundamental to a large variety of medical research areas, but this essay focuses on its importance in vaccine development. Understanding our adaptive immune response has led to development of vaccinations against a huge variety of different pathogens. Prior to vaccines infection by these pathogens may have led to serious complications or death, however vaccination programmes are now successfully able to prevent the loss of many lives.
It was first proposed by Frank Macfarlane Burnett (1957) that antibodies had a selective mechanism – the clonal selection theory. He suggested we already have many different forms of potential antibody producing cells which pre-exist within the body. Each form has different cell surface receptors specific to an individual antigen. Attachment of an antigen to its complementary receptor initiates proliferation of the cell to produce clones. These clones then secrete clonotypic antibodies which are also specific to the antigen. It was also discovered that a rat would lose all its adaptive immune responses if it had its lymphocytes removed (Gowans et al. 1952). Their immune responses returned on replacement of their lymphocyte cells, suggesting lymphocytes were responsible for secreting the clonotypic antibodies.
Following the invasion of a pathogen, the lymphocytes specific to that pathogens antigens will recognise the antigens and bind to them. This causes enlargement of the lymphocyte to become a lymphoblast. The lymphoblast’s then undergo rapid division to form many identical progenies. These progenies differentiate into different effector cells. B lymphocytes differentiate into plasma cells, which are able to secrete antibodies specific to the pathogen, while T lymphocytes become either helper or cytotoxic cells. It takes 4-5 days for clonal expansion to be completed and for all effector cells to have differentiated (Janeway et al. 2001). On the first infection of a pathogen symptoms will be experienced as it takes several days for cloning of the necessary lymphocytes to occur and for the adaptive immune response to begin. This is known as the primary adaptive response. However, some of the effector cells from the primary response go on to form memory cells and remain circulating in the lymph. On encounter of the same pathogen again a secondary adaptive response can instead be launched. The secondary response is much quicker and more effective against the pathogen, wiping it out before symptoms develop. Memory cells therefore provide an individual with lasting immunity against any pathogens they’ve previously encountered.
Understanding the workings of lymphocyte cells and the secondary immune response has been crucial in the development of modern vaccines. Researchers have exploited the way in which memory cells form to provide an individual with immunity towards pathogens they’ve never been infected with before.
The very first primitive vaccine was performed in 1796 by Edward Jenner. He took matter from cowpox lesions on the hand of dairymaid Sarah Nelmes, and rubbed this material into scratches he’d made on the arm of his subject, 8-year-old James Phipps. Phipps developed cowpox but recovered within a week. Jenner then carried out the same inoculation procedure again, but instead used matter from a smallpox lesion rather than a cowpox lesion. Phipps did not develop smallpox on any occasion of the several that Jenner repeated the smallpox inoculation to test Phipps’s immunity (The Jenner Institute ©2016). It’s now understood that the cowpox virus was also able to provide immunity against the smallpox virus due to the two viruses being so closely related. Both belong to the orthopoxvirus family, and some of the same antigens are present on surface of both viruses (Baxby 1972). Previous cowpox infection therefore gave an individual the memory cells necessary to produce antibodies against an invading smallpox virus.
Jenner’s work is considered as the first-time vaccination was deliberately used to attempt to control the spread of infectious disease. It was his primitive version of the smallpox vaccine that paved the way for modern vaccine research. The modern smallpox vaccine was developed in the 1950’s. The vaccinia virus was prepared from calf-lymph and spun in a centrifuge to produce a suspension of the virus, which was then freeze-dried, producing a heat-stable virus which could be stored for long periods without the need for refrigeration (Belongia & Naleway 2003). Despite various vaccination programmes, by 1966 there were still 33 countries in which smallpox remained endemic (Belongia & Naleway 2003). It was in 1966 that WHO (©2016) launched their global ‘Smallpox Eradication Programme’, and by 1980 they declared the SEP had been successful in eradicating smallpox. Smallpox is the only infectious disease that’s ever been successfully eradicated, and thanks must be given to the underlying cell biology research that allowed development of modern, and more effective, vaccines.
In 1976, following the last ever recorded case caused by the variola major strain in 1975, WHO requested all laboratories still in possession of stocks of the smallpox virus destroy them or hand them into either the Centre for Disease Control in the US, or the Moscow Institute in the Soviet Union. However, there’s been evidence that these smallpox stocks were used to develop a biological warfare weapon in the Soviet Union, and that they’ve since developed recombinant strains with increased infectivity (Belongia & Naleway 2003). The September 2001 terror attacks led to further research into developing more effective smallpox vaccines.
Recombinant DNA technology has led to a revolution in the way viral vaccines are produced. The original Dryvax vaccine used in the eradication of smallpox was produced in calf-skin. The new ACAM2000 smallpox vaccine, approved by the FDA in 2007, is derived from the original vaccine, but is cultured in human embryonic lung cells, allowing better control, quality and a higher purity. The use of recombinant DNA technology has allowed development of a much safer and more effective smallpox vaccine, without requiring replication of the vaccinia virus (FDA 2007). The US now holds enough stocks of this smallpox vaccine to vaccinate the entire US population in case of intentional release of smallpox as a biological weapon (Centres for Disease Control and Prevention 2016).
Without the understanding of the acquired immune response and the way in which lymphocytes respond to invading pathogens, it wouldn’t have been possible to develop the modern vaccine, which is more specific, effective and easily produced. It also wouldn’t have been possible to eradicate smallpox, an extremely infectious and virulent disease which killed and disfigured many people. It’s estimated the eradication of smallpox saves 5 million lives annually, and that all vaccines are responsible for saving 9 million lives every year across the globe (Unicef 1996).
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