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Immunity and how vaccines work
Immunity and how vaccines work
Introduction
Immunity is the ability of the human body to protect itself from infectious disease. The defence mechanisms of the body are complex and include innate (non-specific, non- adaptive) mechanisms and acquired (specific, adaptive) systems. Innate or non-specific immunity is present from birth and includes physical barriers (e.g. intact skin and mucous membranes), chemical barriers (e.g. gastric acid, digestive enzymes and bacteriostatic fatty acids of the skin), phagocytic cells and the complement system. Acquired immunity is generally specific to a single organism or to a group of closely related organisms. There are two basic mechanisms for acquiring immunity – active and passive.
Active immunity
Active immunity is protection that is produced by an individual’s own immune system and is usually long-lasting. Such immunity generally involves cellular responses, serum antibodies or a combination acting against one or more antigens on the infecting organism. Active immunity can be acquired by natural disease or by vaccination. Vaccines generally provide immunity similar to that provided by the natural infection, but without the risk from the disease or its complications. Active immunity can be divided into antibody- mediated and cell-mediated components.
Antibody-mediated immunity
Antibody-mediated responses are produced by B lymphocytes (or B cells), and their direct descendants, known as plasma cells. When a B cell encounters an antigen that it recognises, the B cell is stimulated to proliferate and produce large numbers of lymphocytes secreting an antibody to this antigen. Replication and differentiation of B cells into plasma cells is regulated by contact with the antigen and by interactions with T cells (a type of lymphocyte), macrophages and complement. The antibody provides immunity against infection in a variety of ways. These ways include neutralising toxins, blocking adhesion and cell entry by organisms, neutralising and preventing viral replication or complement-mediated killing.
Cell-mediated immunity
Cell-mediated immunity is controlled by a subset of lymphocytes called T lymphocytes or T cells. T cells mediate three principal functions: help, suppression and cytotoxicity. T-helper cells stimulate the immune response of other cells (i.e. T cells stimulate B cells to produce antibodies). T-suppressor cells play an inhibitory role and control the level and quality of the immune response. Cytotoxic T cells recognise and destroy infected cells and activate phagocytes to destroy pathogens they have taken up.
Immunity and how vaccines work These two components of specific immunity are closely related to each other, and T cells interact with B cells in the production of antibodies against most antigens. Specific antibodies and cell-mediated responses are induced for all infections, but the magnitude and quality of these two components vary in different infections.
Passive immunity
Passive immunity is protection provided from the transfer of antibodies from immune individuals, most commonly across the placenta or less often from the transfusion of blood or blood products including immunoglobulin. Protection provided by the cross-placental transfer of antibodies from mother to child is more effective against some infections (e.g. tetanus and measles) than for others (e.g. polio and whooping cough). This protection is temporary – commonly for only a few weeks or months.
How vaccines work
Vaccines produce their protective effect by inducing active immunity and providing immunological memory. Immunological memory enables the immune system to recognise and respond rapidly to exposure to natural infection at a later date and thus to prevent or modify the disease. Antibodies can be detected in blood or serum or other body fluids, but, even in the absence of detectable antibodies, immunological memory may still be present. Cell- mediated responses to some vaccines (e.g. BCG, see Chapter 32) may be detectable by skin testing but do not necessarily indicate protection. Traditional vaccines are made from whole pathogens, either inactivated (killed) or attenuated live organisms, secreted products including toxins or parts of the pathogen’s structure either as viral like particles or subunit vaccines. Newer vaccines are being developed and produced using recombinant viral vectors to deliver the antigen (Ewer et al. 2016). These viral vectors can either be replicating vectors where there is local replication and hence amplification in the recipient, analogous to the live attenuated vaccines, or non-replicating vectors or replication deficient vectors, that can only replicate in certain cell lines used for manufacture, and more analogous to the inactivated vaccines The newest types of vaccine use the pathogen’s genetic code as the vaccine; this then exploits the host cell’s apparatus (including enzymes and ribosomes) to translate the proteins that then act as an intracellular antigen and stimulate the immune response (van Riel and de Wit, 2020). These DNA or RNA vaccines often use a lipid outer shell to aid entry into the cell, and may have modified nucleotides or nucleosides to delay degradation by host cell machinery and to modulate the correct components of the immune system (Verbeke et al 2019). In some of these vaccines the genetic sequence can code for self- replication within the host cell to produce even more antigen and therefore induce a more robust response. mRNA is a natural component of the body, does not enter the nucleus and is processed entirely in the cytoplasm. Any mRNA that is not taken into cells is rapidly degraded by circulating ribonucleases. DNA vaccines enter the nucleus where mRNA is produced by the host cells RNA polymerase. The mRNA then passes into the cells cytoplasm to be translated into protein. DNA vaccines do not integrate into host cell DNA and are degraded by normal cellular processes.
Immunity and how vaccines work Replicating vector vaccines generally use vector pathogens that are naturally of low pathogenicity and have key genetic components, including the genes for the viral vectors structural proteins removed.
Vaccine failure
No vaccine offers 100% protection and a proportion of individuals get infected despite vaccination. Vaccines can fail in two main ways – known as primary or secondary vaccine failures. Primary failure occurs when an individual fails to make an initial immunological response to the vaccine. Infection can therefore occur at any point after vaccination. A good example of primary vaccine failure is the 5–10% of children who do not respond to the measles component of the first dose of MMR. The risk of measles in such children is reduced by offering an additional dose of vaccine, usually before school entry. Secondary failure occurs when an individual responds initially but then protection wanes over time. The incidence of secondary vaccine failure therefore increases with time. Individuals who acquire infection despite vaccination may have a modified, milder form of disease and are less likely to suffer serious complications than those who have never been vaccinated. An example of secondary vaccine failure is pertussis vaccine, when protection against whooping cough after three doses is initially high but declines as a child gets older. A fourth (booster) dose is given to improve protection during the school years.
How are vaccines made
Vaccines are usually made by growing cultures of the target virus or bacterium. Viruses need to grow in cells and so vaccine viruses are often grown in eggs (e.g. influenza) or in cell-lines derived from mammals, including humans. This culture media provides numerous nutritious elements and growth factors that may have been obtained from materials of animal origin, such as serum, milk and milk derivatives, gelatine, meat extract or extracts from other muscular tissues. These components are used in the early stages of the manufacturing and should not be present, or only be present in trace amounts (residues) in the final vaccines. Animal enzymes are also used during the manufacture of vaccine viruses but subsequent washing, purification and dilution steps removes them from the final vaccine. One example is trypsin, normally derived from pigs, which is widely used during the manufacture of vaccines, usually being added to the final cell culture to activate the vaccine virus. Trypsin is also used during the manufacture of other medical products e.g. insulin and heparin.The trypsin is then eliminated during the next steps of the manufacturing process (for example by washing and filtration).
What cell lines are used for vaccines
The mammalian cell lines used to grow the virus for a vaccine will normally derive from a primary culture of cells from an organ of a single animal which has then been propagated repeatedly in the laboratory, often over many decades. For example, measles vaccine is grown in chick embryo cells and polio vaccines are grown in a mouse cell line. Another animal cell line, now being used to make egg-free flu vaccine, was derived in 1958 from the kidney of a cocker spaniel.
Immunity and how vaccines work The best-known human cell line is MRC5; these cells derive from the lung of a 14-week- old male fetus from a pregnancy that was terminated for medical reasons in 1966. This cell-line is used to grow viruses for vaccines against rubella, chickenpox and hepatitis A. Other fetal cell lines have been used for other vaccines, including influenza and some of the new COVID-19 vaccines. No fetal material is present in the final vaccine. The moral issues around the use of vaccines grown on fetal cell lines have been discussed within the Catholic church. The church distinguishes between the ethics of the initial termination, but states that acceptance of such vaccines where there is no appropriate alternative does not signify cooperation with abortion. www.academyforlife.va/content/pav/en/the-academy/activity-academy/note-vaccini.html Recombinant protein vaccines are usually also expressed in cell lines but these are less commonly of mammalian origin and may use insect cells and bacteria. For example, hepatitis B vaccine is expressed in yeast and human papillomavirus vaccine in insect cells. Vaccines based on genetic material are an exception in that the DNA or RNA can be synthesised chemically. However, for some of these vaccines, cell-lines may be required earlier in the production process and products such as enzymes and stabiliser may still be important.
What do vaccines contain?
As vaccines are generally complex biological products, a number of substances are used to ensure the quality of the final product. These substances perform an important function in ensuring the vaccine is safe and effective and are classified as excipients. Constituents that are intended to be in the final product, are listed on the SmPC. Further information on commonly used vaccine ingredients can be found on these public websites. https://www.fda.gov/vaccines-blood-biologics/safety-availability-biologics/common- ingredients-us-licensed-vaccines http://vk.ovg.ox.ac.uk/vk/vaccine-ingredients Highly processed derivatives of animal materials are occasionally used, in the finished vaccine product and are classified as excipients. Gelatine is an example of an animal product used in a very wide range of medicines, including many capsules and some vaccines. Gelatine is used in vaccines as a stabiliser – to ensure that the vaccine remains safe and effective during storage. Unlike the gelatine used in foods, the product used in vaccines is highly purified and broken down into very small molecules called peptides. The presence of porcine gelatine in vaccines has raised issues around acceptability to some faith groups which is discussed in this leaflet. https://www.gov.uk/government/publications/vaccines-and-porcine-gelatine Some really important chemicals – called adjuvants – are used to improve the immune response to vaccines. The most commonly used adjuvants are aluminium salts. Aluminium salts, such as aluminium hydroxide, aluminium phosphate, and aluminium potassium sulphate have been used safely in vaccines for more than 70 years. Aluminium salts were initially tested in the 1930s-1950s with diphtheria and tetanus vaccines and it was shown that they improved the immune response to these vaccines by ensuring that the vaccine remains at the site of injection to be taken up by the cells of the immune system. They are thought to be particularly effective at stimulating humoral immunity (Brewer, 2006). Research has shown the amount
Immunity and how vaccines work Specific immunoglobulins are available for tetanus, hepatitis B, rabies and varicella zoster. Each specific immunoglobulin contains antibodies against the target infection at a higher titre than that present in normal immunoglobulin. Specific immunoglobulins are obtained from the pooled blood of donors who: ● ● (^) are convalescing from the target infectious disease, or ● ● (^) have been recently immunised with the relevant vaccine, or ● ● are found on screening to have sufficiently high antibody titres Recommendations for the use of normal and specific immunoglobulins are given in the relevant chapters.
Immunity and how vaccines work References Brewer JM, (How) do aluminium adjuvants work? (2006), Immunology Letters, 102(1),: 10-15, https://doi. org/10.1016/j.imlet.2005.08.002. Ewer KJ, Lambe T, Rollier CS, Sp[encer AJ, Hill AVS and Dorrell L (2016). Viral vectors as vaccine platforms: form immunogenicity to impact. Curr Op Immunology: 47- Hviid A, Wohlfahrt J, Stellfeld M and Melbye M (2005) Childhood vaccination and non- targeted infectious disease hospitalization. JAMA 294(6): 699–705. Miller E, Andrews N, Waight P and Taylor B (2003) Bacterial infections, immune overload, and MMR vaccine. Measles, mumps, and rubella. Arch Dis Child 88(3): 222–3. Mitkus RJ, King DB, Hess MA, Forshee, RA, Walderhaug MO, Updated aluminum pharmacokinetics following infant exposures through diet and vaccination, Vaccine, Volume 29, Issue 51,2011, Pages 9538-9543, https:// doi.org/10.1016/j.vaccine.2011.09.124. Offit PA, Quarlest J, Gerber MA et al. (2002) Addressing parents’ concerns: Do multiple vaccines overwhelm or weaken the infant’s immune system? Pediatr 109(1): 124–9. Van Riel D and de Wit W. Next generation vaccine platforms for COVID-19 (2020). Next generation vaccine platforms for COVID-19 Nat Materials 19:810-812. Verbeke R, Lentacker I, de Smedt, SC and Dewitte H (2019) Three decades of messenger RNA vaccine development. Nano Today 100766
