Vaccines--how and why they work.
Recent advances in vaccine development have raised hopes of more widespread use of immunisation--against non-infectious diseases such as cancer, Alzheimer's and drug addiction.
Vaccines, as with any drug, must be assessed in terms of risk vs benefit. Where fatal infections are concerned, benefits far outweigh risks, but perceptions of the benefits are changing, as experiences of childhood disease epidemics fade from living memory. It is important to use rigorous science to accurately assess the risks and benefits of vaccines. Nurses are crucial to the promotion of community health through widespread vaccination. A good understanding of the physiological effects of vaccines and the research supporting global vaccination campaigns is an essential basis for this role.
The immune system in humans is divided into two branches: innate and acquired. Acquired immunity allows the body to respond more rapidly and with greater force to second and subsequent exposures to the same pathogen, and forms the basis of vaccination. Millennia of recorded observations have noted that individuals surviving an infectious disease rarely get reinfected.
Variolation (the use of smallpox scabs from infected individuals to inoculate healthy individuals) was probably first used in China or India in the 11th century and moved to Europe via the Middle East and Turkey. (1) The pioneer of the smallpox vaccine, 18th century English scientist Edward Jenner, observed that milkmaids who had had cowpox did not get smallpox, which led to the first empirical use of vaccines, long before any understanding of microbiology or immunology. (2) Smallpox, which killed one third of its victims, and caused more than 300 million deaths in the first half of the 20th century alone, was officially declared eradicated from the world in 1979. (3)
While the eradication of smallpox is a resounding success for global health and vaccination, there remain numerous infectious diseases that are amenable to vaccines but continue to kill in large numbers. Measles was responsible for the death of 114,900 mainly under-fives in 2014, but, before the introduction of widespread vaccination, killed 2.6 million people annually. (4) Improved hygiene and the ready availability of antibiotics mean infectious diseases are rarely lethal in developed nations. But in regions where malnutrition and impaired immunity (eg due to HIV/Aids) are prevalent, measles and other infectious diseases remain deadly. Measles, in particular, can be devastating in countries experiencing or recovering from natural disaster or war. (4)
Vaccines exist for many diseases, including polio, tetanus and whooping cough (pertussis). But, despite concerted global effort, effective vaccines for other diseases such as HIV, respiratory syncytial virus, malaria and group A streptococcus (causing rheumatic fever) remain elusive. Some vaccines, due to their origins, are effective and long-lasting with a single dose, while others require repeated administration, and may lose effectiveness over time. Recently, the use of vaccines in preventing autoimmune disorders, drug addiction and cancer has become increasingly feasible. Understanding the mechanism of action of vaccines and their adjuncts, within the contexts of innate and acquired immunity, allows nurses to support clients in their decisions to vaccinate, and to participate in the vaccine debate from an informed, scientific basis.
IMMUNE FUNCTION AND THE EFFECTS OF VACCINATION
The immune system is generally divided into two branches: innate immunity and acquired (also called adaptive or humoral) immunity.
Innate immunity is the body's first defence against invading pathogens. Patrolling immune cells recognise common invaders by identifying molecular signatures on invading bacteria, viruses and fungi, etc. Innate immunity has evolved over millions of years and, unlike acquired immunity, is identical in all humans. (5) The innate immune system rapidly reacts to invading pathogens by activating the complement system, phagocytic cells (macrophages and neutrophils) and natural killer cells. These attack invading pathogens and secrete cytokines and other factors that tag invaders for destruction, while attracting other immune cells to the area.
Macrophages also act as antigen-presenting cells (APC), but the most important APCs are the dendritic cells, which provide the key link between innate and acquired immune function. Dendritic cells are found throughout the body just below epithelial barriers. They sample surrounding fluid for danger signals, such as cytokines or pathogens. Once activated, dendritic cells ingest pathogens and break them down. Protein fragments from the pathogen are then attached to a major histocompatibility complex on the surface of the dendritic cell (the class II MHC complex).
Dendritic cells remain in the tissues for about six hours after first contact with a danger signal and then travel through the lymphatic system to the nearest lymph node--a journey that takes about a day. (5) On reaching the lymph node, dendritic cells activate naive T-cells and the link between innate and acquired immunity is made.
The acquired immune system comprises B- and T-Lymphocytes, which adapt to protect against specific invading pathogens. B-cells produce antibodies, which attach to invading pathogens, labelling them for destruction by phagocytes, increasing the efficiency of this over the innate system, and identifying pathogens that might be overlooked by phagocytes acting on their own (eg many viruses).
T-cells secrete cytokines that direct activity of other immune cells (helper T-cells), recognise and destroy virus-infected body cells (killer T-cells) and prevent the immune system from over-reacting (regulatory T-cells).
Both B- and T-cells are produced in the bone marrow, but mature by separate pathways. Until they encounter their specific antigen, these are classed as naive.
A helper T-cell is presented with an antigen by an APC, which also secretes cytokines called co-stimulatory factors. The T-cell begins to proliferate, producing many clones that all respond to the same antigen, and these then mature into a variety of helper T-cells that produce the cytokines needed to oversee the rest of the immune response. This proliferation and maturation takes about a week. (5)
Naive B-cells can be activated by direct contact with their specific antigen (a fragment from an invading pathogen), but also require the presence of a co-stimulatory signal--either from activated helper T-cells or another danger signal. Once activated, B-cells, like T-cells, begin to proliferate and mature. At the end of a week, there will be thousands of B-cells programmed to respond to a specific antigen and differentiated into a variety of plasma cells (that produce antibodies) or memory cells.
Following an infection, numbers of T- and B-cells contract, leaving behind a much-reduced population of central memory cells that persist in lymphatic organs ready to respond rapidly to another attack. Memory cells replicate slowly and may persist for an entire lifetime. At the same time, some long-lived plasma B-cells also remain sequestered in the bone marrow. These produce a continuous low-level amount of pathogen-specific antibodies, ready to act immediately on reinfection. Memory B-cells are able to respond more rapidly to reinfection due to changes in receptor sensitivity and because they already know which class of antibody is required for that specific antigen. Figure 1 (p21) shows the difference in time and strength of response between initial infection and reinfection with the same pathogen/antigen.
Memory killer T-cells can also be generated, but for this to occur, the pathogen must infect an APC directly, or it must involve class I MHC complexes which are not normally involved in pathogen responses.
Due to their differing actions, B-cells and their secreted antibodies are essential for the destruction of pathogens that occur outside body cells, while killer T-cells are needed to combat intracellular pathogens, including many viruses.
In recent decades, it has become recognised that acquired immunity is driven and directed by innate immune responses. There are many different types of dendritic cells (and other APCs) with many different classes of danger receptors on their membranes. The type of APC, the receptor activated and the site of the cell when it encounters a pathogen may have a strong effect on the strength, quality and persistence of the subsequent acquired immune response. This has significant implications for vaccine development. (2,6)
Box 1. MMR and autism IN 1998, United Kingdom (UK) medical journal The Lancet published a paper by surgeon Andrew Wakefield and colleagues that linked the combined MMR (measles, mumps and rubella) vaccine to developmental disorder in children. Following an investigation into Wakefield's conduct and methods by the UK General Medical Council, The Lancet retracted the paper in 2010, describing it as "utterly false", and three months later Wakefield was struck off the UK medical register for serious professional misconduct. However, as a result of the publication of this paper and ensuing media hype, measles vaccination rates dropped dramatically: in New Zealand, the rate dropped from 100 per cent in 1997 to 68 per cent in 2007, while in the UK, from 1995 to 2005, it dropped from 92 to 81 per cent. Herd immunity requires a coverage rate of about 95 per cent to prevent measles outbreaks. Both New Zealand and Europe suffered major outbreaks of measles earlier this decade, with 30,000 cases reported in Europe for each of 2010, 2011 and 2013. In New Zealand, the outbreak occurred mainly in the 10 to 19-year-old age group--those who would have been likely to miss vaccination due to the impact of the Wakefield report. What was wrong with Wakefield? First, the sample size was very small--12 case reports, which is allowable for a rare disease but MMR vaccination is far too common to rely on so few cases. Secondly, this was not a research study but a series of anecdotes from non-randomly selected patients and should not have been used to draw such firm conclusions. While the original paper did not state a causal link between MMR and autism, subsequent press releases from Wakefield strongly emphasised the association. These were embraced by the press and reporting was largely done by journalists with no scientific or health background, who could not/did not evaluate the evidence being presented. The third issue is one of scientific fraud. It emerged that Wakefield's "research" was being paid for by a lawyer (from legal aid funds) who was bringing a class action against the manufacturers of the MMR vaccine. Wakefield himself had taken out a patent for a single measles vaccine before publishing his research. He blamed the triple vaccine as the cause of autism, and said the vaccines were safe if given individually. Evidence has shown that data in the study was falsified, including blood results and case histories that were altered to suggest onset of autism symptoms occurred within 14 days of vaccination in each case. No ethical approval was granted for the research. The role of the media in the MMR autism scandal cannot be ignored. The absence of expert reporting and critique was marked. At the height of the media frenzy, papers that refuted Wakefield's findings were ignored or received minimal coverage. Commentary by non-experts (including celebrities) was given the same or more weight than that of scientific experts and there was no discrimination between the validity of comments based on the qualifications of the person making them. Investigative journalist Brian Deer uncovered a great deal of Wakefield's fraud. You can read his articles published in the British Medical Journal at www.bmj.com/content/342/bmj.c5347. (21)
TYPES OF VACCINES
Vaccines can be divided into two broad categories--live attenuated vaccines and non-living vaccines that frequently contain adjuvants to stimulate the immune system.
Live attenuated vaccines
Louis Pasteur--the French microbiologist renowned for his discovery of the principles of vaccination--discovered the method of attenuation of live pathogens in 1881. By subjecting pathogens to high temperatures or other environmental insults, they could be rendered harmless to vaccine recipients but still trigger an immune response. Early success was seen against anthrax and rabies in the 1880s; and the first half of the 20th century saw the development of the Bacille Calmette Guerin (BCG) vaccine against tuberculosis and success in managing yellow fever outbreaks. (1)
Since the 1960s, live attenuated vaccines have been developed against polio (oral, 1962), measles (1963), rubella (1969), chickenpox (1995) and a number of other bacterial or viral pathogens. (1) For many attenuated vaccines, a single dose will confer decades-long immunity but they rely on pathogens being invariant (non- or slow-mutating) and infections largely acute. Pathogens that do not naturally trigger full immunity (eg respiratory syncytial virus), that mutate rapidly or that persist as latent infections (eg HIV or hepatitis C) pose greater challenges. (6)
Vaccines for typhoid, cholera, influenza and the plague, as well as early pertussis vaccines, use inactivated whole organisms to trigger immune reactions. Diphtheria and tetanus vaccines are manufactured from purified toxins secreted by the pathogens. The toxins (now called toxoids) are weakened by treating with aluminium salts before injection. Other non-living vaccines are constructed from extracts of pathogens, specific proteins from pathogen cell membranes, or purified and recombinant proteins that are sometimes joined to other vectors to ensure immune responses. Acellular pertussis vaccine is made by isolating the proteins the immune cells recognise and leaving behind the bacterial components that cause the symptoms of whooping cough. (5) The hepatitis B and human papilloma virus (HPV) vaccines are both made by genetic engineering; only the viral proteins necessary for immune recognition are manufactured for these vaccines, making them entirely non-infectious. (5)
Non-living vaccines will not cause the generation of memory killer T-cells, as they cannot infect APCs. This means they are ineffective for some pathogens, but determining which pathogen is often still a matter of trial and error. Triggering a sufficiently vigorous response to ensure long-lasting immunity is also difficult with non-living vaccines, so other substances may be added to the vaccine to stimulate immune activity. These adjuvants enhance the strength of the immune response and modify its quality in the direction of appropriate B- and T-cell differentiation and development of memory cells. (6)
The most commonly used adjuvant in vaccines is aluminium. Aluminium salts such as aluminium hydroxide and potassium aluminium sulphate (alum) have been included in vaccines for more than 70 years. Vaccines containing aluminium include DTaP (diphtheria, tetanus and acellular pertussis), hepatitis A and B, HPV and meningococcal B.
Aluminium salts are emulsified with an antigen to create a gel-like solution for injection. This is commonly thought to create a depot effect, releasing the antigen slowly to cause sustained presentation to the immune system. Alum triggers increased antibody production and differentiation of helper T-cells. (6,7) There has been controversy about the use of aluminium salts in childhood vaccines, due to concern about their potential toxic effects. However, aluminium is abundant and pervasive in our environment, and the amount contained in vaccines is less than an infant receives in a daily dose of milk formula. Orally ingested aluminium is largely passed through to the faeces, but the kidneys are able to excrete absorbed aluminium. There is no established link between aluminium-containing vaccines and neurological disorders. The only adverse effect of aluminium is due to its depot action, which can cause redness and swelling, and occasionally the development of a hard lump at the injection site (granuloma), particularly if intradermal injection occurs.
Oil and water emulsions are also used as adjuvants. These act as a depot in the same way as aluminium salts. When used in the influenza vaccine, they generate stronger immune responses (especially in older adults) and increased memory responses. (7) Some adjuvants are derived from pathogens themselves--eg lipopolysaccharide and synthetic viral RNA (ribonucleic acid) or bacterial DNA (deoxyribonucleic acid) strands--and directly target signalling molecules on APCs to trigger increased immune responses. (6)
Advantages of using adjuvants: (7,8)
* They reduce the amount of antigen required, thus increasing the number of available vaccine doses where antigen is scarce.
* They reduce the number of doses an individual may require to achieve full immunity.
* They enhance effectiveness in the very young, older adults and the immuno-compromised by boosting antigen responses.
* They increase effectiveness of newer vaccines comprised of purified or genetically-engineered single proteins.
* They may broaden some vaccine protection to related strains of a pathogen.
* They increase the speed of response to a vaccine--important in pandemic outbreaks.
Occasionally, live vectors are used to carry recombinant genes from the desired pathogen--for example a vaccine against dengue fever is being developed that incorporates specific dengue genes with attenuated yellow fever pathogen. (1,9)
For vaccines to work effectively within a community, sufficient people must be immune to a disease so an infected person or carrier is unlikely to encounter someone who has no immunity. Vaccination coverage rates to provide herd immunity depend on the infectiousness of the specific disease. For example, measles is highly contagious with one individual able to infect up to 20 others in susceptible communities. The World Health Organisation (WHO) recommends 93-95 per cent vaccination cover to provide herd immunity against measles. (10) Pertussis is a particular issue since immunity fades over time and if vaccination rates in the community fall, people who have been vaccinated become more susceptible. (11)
Vaccination programmes are a social contract--an individual is vaccinated to protect the community as a whole from a contagious, potentially life-threatening disease. The very young, the elderly and those who have compromised immunity especially benefit from this, but even where vaccines against, for example, rotavirus are only administered to children, rates of disease in adults are also reduced. (12)
ADVERSE EFFECTS OF VACCINES
Vaccines developed from inactivated whole organisms (eg the seasonal influenza vaccine) may occasionally contain viral particles that have not been killed. There is a risk that someone receiving the vaccine could be infected and fall ill. The live attenuated oral polio vaccine can cause the disease in roughly one per 2.4 million doses, usually in those with impaired immunity, and may be a danger to those in contact with the vaccinated child's faeces, but most countries now use a safer inactivated vaccine. (13)
Local reactions occur in up to 80 per cent of vaccinations, causing swelling, pain and redness at the injection site. They occur within a few hours of the injection and are mild, resolving with no treatment.
The most serious adverse effect with vaccines is anaphylaxis. This is extremely rare, occurring in less than one case per million vaccine doses. (14) Previous exposure to an allergen can cause an allergic response following vaccination. Gelatin, latex and egg proteins (in influenza and yellow fever vaccines) are often considered the most likely causes. Onset of anaphylaxis is usually within minutes of exposure.
Delayed reactions to vaccines include the development of a mild fever or a mild form of the disease vaccinated for, with a similar incubation period--this can occur with live attenuated vaccines only, eg MMR. Sometimes people experience symptoms such as malaise, myalgia, fever headache and anorexia. These may be due to vaccination or a coincidental viral infection. (15,16)
Rubella vaccine has been associated with the bleeding disorder idiopathic thrombocytopenic purpura, in about one in every 24,000 doses of MMR. This tends to be mild and self-limiting. (16)
The number of parents refusing to vaccinate their children, or choosing to vaccinate to a schedule that leaves children underprotected, is increasing worldwide. While in the past this has been mainly due to religious beliefs, now refusal to vaccinate can be attributed to inaccurate and highly publicised stories about the danger of vaccination. In truth, vaccines are among the most monitored medications in the world today, facing much tougher regulation since they are given to healthy people, and mainly children. (13) Adverse events do occur, but the risk is very low and often cannot be detected during initial trials. For this reason, WHO and many world governments actively and closely monitor vaccination campaigns and require rapid reporting of any suspected adverse event.
Guillain-Barre syndrome was associated with the 1976 swine flu vaccine, with five to nine cases per one million vaccinations occurring. Since then, all flu vaccines have been intensively monitored. During the 2009 swine flu pandemic, clusters of narcolepsy arose in Finland and other European centres, with 1300 people affected, out of 30 million vaccinations. A link has since been found to a specific brand of vaccine, Pandemrix, which triggers production of antibodies that can bind to brain sleep receptors, inducing narcolepsy in genetically susceptible individuals. (17)
The link between the MMR vaccine and autism has been well and truly debunked (see Box 1, p22), but fears still linger about a supposed link between autism and thiomersal (a preservative found in some vaccines) as well as other, generally unsubstantiated, claims by anti-vaccination activists. Cherry-picking of data, the use of anecdote in place of risk ratios, and celebrity "expert" opinion have caused dangerous reductions in immunisation rates in a number of nations in the last decade, with subsequent outbreaks of disease. (18)
For modern parents, the stories of terrible outcomes of vaccination are more immediate than the dangers of contagious diseases they have never seen--in this way, vaccination has been a victim of its own success. Unfounded scares about vaccines can be fatal: in Japan in the 1970s, two children died (of unrelated causes) following DTP (diphtheria, pertussis, and tetanus) vaccination. The programme was suspended, then reinstated but with a starting age of two years, rather than three months. In the subsequent epidemic of whooping cough, 13,000 children were infected and 41 died. (19)
Public confidence in vaccines is easily dented and hard to repair once damaged. Primary care providers are a key player in promoting and supporting vaccination in the community. It is important that nurses deliver information about vaccination with confidence in a way that supports parents, addresses their concerns and provides factual information about the risks and benefits of this important health intervention.
After reading this article and completing the accompanying online learning activities, you should be able to:
* Explain the role of innate and acquired immunity in defence against infectious disease.
* Describe the impact of various forms of vaccines and their adjuvants in the development of immunity.
* Discuss key myths about vaccination and research related to these.
* Describe adverse effects associated with vaccination.
Earn two hours of CPD
By reading this article and doing the associated online learning activities, you can receive a certificate for two hours of continuing professional development (CPD).
Go to www.cpd4nurses.co.nz to complete the learning activities for this article. The online service costs $19.95 per article.
These articles are supplied by CPD4nurses, an independent education company. CPD4nurses is not an NZNO service.
* References for this article can be found at www.cpd4nurses.co.nz.
Georgina Casey, RN, BSc, PGDipSci, MPhil (nursing), is the director of CPD4nurses.co.nz. She has an extensive background in nursing education and clinical experience in a wide variety of practice settings.
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|Publication:||Kai Tiaki: Nursing New Zealand|
|Date:||Feb 1, 2016|
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