ORIGINAL ARTICLE: Vaccination of children – a systematic review
2010; Wiley; Volume: 99; Issue: s461 Linguagem: Inglês
10.1111/j.1651-2227.2010.01823.x
ISSN1651-2227
AutoresAnne K. Örtqvist, Mats Blennow, R M Carlsson, Hanson La, Anders Lindberg, L Lindqvist, Maria Magnusson, Lennart Nilsson, Anders Norlund, Olof Nyrén, Per Olcén, P Olin, Sven‐Arne Silfverdal, Juliette Säwe, Ann Söderström, Birger Trollfors,
Tópico(s)Virology and Viral Diseases
ResumoVarious cultures have practised immunization against a range of infectious diseases for many centuries, but the principles began to gain general acceptance in 1796 when Edward Jenner showed that vaccination against cowpox provided protection against smallpox, which was the most common cause of death among young children at the time. Sweden adopted compulsory vaccination against smallpox in 1816. While vaccination eradicated smallpox in many countries, the need to vaccinate entire populations remained as long as the infection could still be found anywhere in the world. As recently as the early 1960s, a Swedish sailor brought the disease back to the country and gave rise to a national smallpox epidemic. A global vaccination campaign launched against smallpox by the World Health Organization (WHO) in 1967 eradicated the disease within 10 years. Thus, Sweden stopped administering the vaccine in 1976. The experience with smallpox was the first illustration of the ability of vaccination to eliminate a serious disease. Experts are optimistic that polio will soon be eradicated as well, while major progress has been made around the world in controlling measles and tetanus. The WHO website states that ‘Immunization is a proven tool for controlling and eliminating life-threatening infectious diseases’ and that is considered to be ‘one of the most cost-effective health investments, with proven strategies that make it accessible to even the most hard-to-reach and vulnerable populations.’ Like many other countries, Sweden launched its child vaccination programme in the 1940s. It started off with tuberculosis (only for certain risk groups after 1976), diphtheria and tetanus, followed by pertussis and polio some 10 years later. Measles and rubella were included as of the 1970s. Since the early 1980s, Sweden has administered measles-mumps-rubella (MMR) combination vaccine. The latest additions to the programme are vaccine against Haemophilus influenzae type b (1992), followed by hepatitis B (1996) for certain risk groups. A more detailed account of the Swedish routine vaccination programme appears in Chapter 1.2. In Sweden, as in many countries with high vaccination coverage, the frequency of the diseases included in Sweden’s vaccination programme has decreased sharply, often by 98–99%. Families rarely have personal contact with someone who has had one of the old childhood diseases, much less suffered complications. Because the risk of any particular child developing the disease is so low, parents question whether vaccination is actually necessary. All healthcare initiatives must weigh the benefits of each measure (such as diagnostic examination, surgery or drug therapy) against the possible risks (radiation exposure, nosocomial infections, drug adverse effects, etc.). Such considerations are even more important when it comes to prevention interventions, such as vaccines, as they are given to healthy people in order to protect them against disease later in life. Parents are most concerned about the efficacy of vaccination for their own child, comparing it with the chance that the child will develop the disease if not vaccinated and the possibility of adverse effects. The problem is complicated by the fact that the risk of developing most diseases included in the child vaccination programme is also a function of herd immunity, the percentage of the population that has been immunized (either by vaccination or natural infection). For instance, the risk of a measles epidemic increases as soon as the percentage of an age group that has been vaccinated goes below 90%. Vaccination involves administering all or part of a pathogen that has been rendered harmless in various ways in order to stimulate the immune system to form antibodies and protective white blood cells (leucocytes), as well as memory cells for both categories, against natural infection (see Chapter 1.1). Activation of the immune system commonly leads to local reactions such as redness, swelling and tenderness at the injection site, as well as more generalized fever on occasion. These natural reactions usually go away quickly and are well-known to the healthcare profession, but it is extremely important that parents be informed about them in advance. Some vaccines have been demonstrated to cause uncommon and more serious adverse effects, such as hypersensitivity reactions and central nervous system effects. Particularly if an adverse effect develops a long time after vaccination, the correlation may be difficult to establish. Given that nearly all children participate in the vaccination programme, some of them develop a serious disease shortly after vaccination even though there is no correlation. A suspected correlation between MMR vaccine and autism was reported in the late 1990s. As a result, MMR vaccination coverage of 2-year-olds declined throughout Sweden, quite sharply in some areas. After a number of large, well-conducted studies found that no such correlation existed, coverage virtually returned to previous levels. The experience illustrates the central role that public confidence in various vaccines plays when it comes to achieving the goals of a vaccination programme, i.e. ensuring high vaccination coverage in order to control and eventually eradicate the pathogen. Compiling sound research data based on the best possible evidence with regard to both the efficacy and adverse effects of the vaccines included in the current child vaccination programme is needed in order to provide factual information to parents. The task that SBU assigned to the project group in 2003 was to conduct a systematic review of the research on the vaccines included in the Swedish child vaccination programme. The main goal was to methodically identify the evidence for the efficacy of each vaccine that was studied and to describe the magnitude of vaccination risks. The project was structured to address a number of specific questions for each vaccine. To allow the group to conclude the project in a reasonable amount of time, the number of vaccines to be studied was limited. Thus, we focused on a systematic examination of the efficacy and adverse events of the tuberculosis (Bacille Calmette-Guérin or BCG), MMR, pertussis, Haemophilus influenzae type b and hepatitis B vaccines. We also methodically examined the adverse events of current combination vaccines that contain tetanus, diphtheria, polio, pertussis and Haemophilus influenzae type b vaccines, either with or without hepatitis B vaccine. Incorporating questions about adverse effects into available models is a difficult challenge. There are essentially no sufficiently large prospective randomized studies with high quality and relevance that can rule out or confirm the correlation between a vaccine and an uncommon adverse effect. Despite temporal correlations between vaccination and adverse events, the causal relation is often very hard to assess. The project also covered health economic analyses of the three vaccines for which they were available: pertussis, Haemophilus influenzae type b and hepatitis B. Also included was a short description of the natural course of each disease, as well as a section that looked at ethical considerations related to benefits and risks for individuals and the community. The report does not contain a systematic review of diphtheria, tetanus or polio vaccines. Nor did we review additives such as thimerosal and aluminium, or new vaccines such as the pneumococcal conjugate vaccine that now is since January 1, 2009 adopted by the Swedish child vaccination programme. Finally, we did not assess how well Sweden’s child vaccination schedule works – in how many doses, at what point in time and in what combinations the vaccines are administered – because the systematic methodology that we employed did not so permit. Thus, the report should be viewed neither as a comprehensive overview of the Swedish child vaccination programme nor a manual on how the various vaccines are to be used. The body hosts many microorganisms, including bacteria and viruses that live with or off it. Most bacteria do not cause any problems. The vast majority of the bacteria normally found in the intestines are harmless, and many serve a vital function by competing with more harmful ones for room and nourishment. Thus, a newly arrived bacterium has difficulty in surviving. But the protective effect of the normal bacterial flora in the mouth, throat, lower urinary tract, intestines and vagina can be compromised by antibiotic therapy and similar substances. Viruses, bacteria and parasites can cause infections. The body has a very well-developed immune system and in order to counter attacks by many very different pathogens, the system has become very complex. Over thousands of years, the pathogens have developed mechanisms to survive in the body. While some microbes are harmless, others have the ability to invade tissues and mucous membranes. Invasion of tissues normally gives rise to symptoms of infections, often caused by releasing harmful substances such as soluble toxins. Tetanus toxin is a dramatic example of a substance that can cause severe symptoms. Researchers have shown in recent years that the symptoms of most infections – local pain, soreness, heat sensation, redness, fatigue, fever and loss of appetite – are all signs of inflammation. Thus, protection against infection should stop the pathogen’s attack at the mucous membrane if at all possible. As soon as mucosal cells and deeper tissue are involved, inflammatory symptoms automatically appear. The immune system has then been activated. The innate and adaptive immune system Individual pathogens can make their way through undamaged skin. Others have developed special mechanisms for attaching to mucous membranes and subsequently permeating them (Fig. 1.1.1). The flow of saliva and intestinal juice, as well as coughing, intestinal activity and acidic pH, are among the innate defence mechanisms that act in the mucous membranes. In the tissues, the invading pathogens are exposed to various white blood cells (phagocytes) – neutrophils, macrophages and monocytes – that have the ability to provide protection by ingesting and killing them. The surface of phagocytes has receptors that protect against infection by recognizing specific groups of related microorganisms. (a) The left image shows how bacteria – pneumococci that can cause respiratory infections, including pneumonia, sinusitis and otitis – attach themselves to a human throat cell. (b) The right image shows normal throat cells without bacteria. (Images and cells obtained from Bengt Andersson, Senior Lecturer, Gothenburg). In addition to the innate immune system, the body has an adaptive immune system that specifically targets each pathogen and is able to quickly increase the number and efficacy of white blood cells when necessary. The benefit of the system is that it can develop a defence against the pathogens that permeate the tissues and often have many different virulence factors that enable them to multiply faster than the immune system can eliminate them. One such factor may be that the carbohydrate capsule of bacteria makes it difficult for phagocytes to hold onto them when trying to absorb them in order to kill them. Bacteria can also produce toxic substances that interfere with the ability of phagocytes to kill them. Some highly virulent bacteria such as Salmonella and tubercle bacilli, can even survive and multiply inside of phagocytes, where they are protected against other defence mechanisms. The question is how the adaptive immune system identifies pathogens in order to build a sufficiently strong defence against them. Research of recent years has made major strides in understanding how the adaptive immune system works (1). The phagocyte receptors are apparently capable of recognizing any potential pathogen. Thus, a pathogen is bound to such receptors as soon as it permeates the tissues, activating the phagocytes that ingest and kill it. The activated phagocytes produce a series of signal substances, leading to multiple consequences. They stimulate additional white blood cells to try to ingest and kill the pathogen by means of phagocytosis (Fig. 1.1.2a). The activated phagocytes produce special substances called cytokines, which stimulate the formation of antigens that present parts of the dead, broken down pathogen to the cells of the adaptive immune system (Fig. 1.1.2b). The antigens may consist of the pathogen’s toxins or its various surface structures, such as a carbohydrate capsule. The cytokines also stimulate the immune system to produce antibodies and T-lymphocytes, both of which have receptors that specifically recognize the antigens. (A) If pathogens such as bacteria are able to permeate the tissues, they encounter a rapidly increasing number of white blood cells, particularly neutrophil granulocytes (neutrophils) and monocytes. The cells try to ingest and kill the pathogens by binding them to receptors that are specific to their particular group. They produce a series of signalling proteins called cytokines that induce various inflammation symptoms in the infected tissues: local soreness and pain, swelling, redness, fever, fatigue and loss of appetite. While the symptoms may be local and inconsequential, they can also be general and protracted, with serious consequences such as pronounced local tissue damage, high fever and loss of appetite. (B) The cytokines that are induced as in Figure 1.1.2a activate white blood cells referred to as antigen-presenting because they ingest the pathogens and present parts of them to T-lymphocytes (T cells). Some circulating T cells that already have receptors suited to the presented antigen are stimulated and activate other T cells to produce receptors that are even more specific to the antigen presented in this example. The specific T cells circulate, recognizing and reacting with the antigen that induced the antigen presentation. They are called cytotoxic T cells, as opposed to natural killer cells. If they target a pathogen, they can kill the infected cell, which they recognize from the antigens that it expresses from the pathogen on its cell surface. Other white blood cells, such as cytokine-activated natural killer cells and macrophages (monocytes that are found in tissues), as well as circulating antibodies, help them neutralize and eliminate the pathogens that escape from the dead, infected tissue cells. The cytokines also activate the adaptive immune system to target the infectious microorganism. That way the adaptive immune system can selectively expand without inhibiting other parts (see Fig. 1.1.2b). The adaptive immune system can grow exponentially by rapid division of T cells and antibody-forming cells (B lymphocytes or B cells), thereby improving the body’s ability to eliminate the pathogen. Though inhibited by the various virulence factors of the pathogens, the phagocytes are activated by the antibodies to increase their protective capacity through different components of the blood and tissues that are part of the immune system. The immune system has a very great ability to simultaneously protect against multiple microorganisms and their many different antigens. The cytokines that are formed when the immune system is activated give rise at the same time to the symptoms that are typical of infection and inflammation (Fig. 1.1.2a). The appearance of such symptoms generally means that the immune system has been activated. Like the receptors on the T cell surface that specifically recognize structures on pathogens to which the body has previously been exposed (Fig. 1.1.2b), antibodies have a receptor that fits the microorganism that induced the specific immune response. There are five different classes of immunoglobulins (antibodies) – IgA (IgA1 made in the serum and IgA2 made in the mucosae), IgG, IgM, IgD and IgE – but the receptor for a particular microorganism is the same (Fig. 1.1.2b). When T cells or antibodies are first exposed to a micro organism; their receptors are not a perfect fit but are sufficient to induce an immune response. During the course of the infection, or when next exposed to the same microorganism, the immune system starts to adapt the receptors. As a result, the specific T cell or immunoglobulin and the microorganism bind more and more strongly. Thus, an infectious virus or bacterial toxin can be bound and neutralized more effectively, ensuring better and more reliable protection. The functional binding strength or affinity of antibodies is called avidity and may serve as a good measure of the immune system’s effectiveness. The immune system develops an immunological memory to be used when the body is exposed to the same pathogen again. A small number of memory cells may remain for decades after an initial exposure (2, 3) and recognize the pathogen with a high degree of specificity. The memory cells meeting the microbe again are stimulated to quickly divide and ensure that specific antibodies and/or T cells are produced to fight the infection. If the body retained all specific T cells and antibody-forming cells that develop during each infection, it would carry a very large number of lymphocytes. They would compete for space and nourishment with other types of cells. Thus, a limited number of memory cells can effectively monitor the reappearance of pathogens to which the body was previously exposed. Why vaccinate? The ability to develop protection against infection without adverse effects or the necessity to experience the infection would provide substantial benefits. That is particularly true when it comes to pathogens that give rise to serious disabling diseases and death, or that can cause major epidemics(4). A number of such vaccines have been discovered and widely introduced. Generally speaking, the vaccines also give rise to memory cells, ensuring long-term protection. That kind of approach has completely eradicated smallpox. Polio has almost been eradicated worldwide. Diphtheria, tetanus, measles, mumps and rubella have been largely eliminated in countries with high vaccination rates (4). Children’s immune system Because children have not been exposed to as many pathogens as adults, their adaptive immune system is not fully developed. Thus, they have fewer B cells, T cells (Fig. 1.1.2b) and immunoglobulins, and they develop more infections. Contact with various microorganisms in the environment stimulates their adaptive immune system to develop specific responses. Although there are only a few innate lymphocytes specific to particular antigens, they rapidly become more numerous, specific and effective with each exposure. The major expansion of the immune system that begins in infancy primarily reflects this increase in the number of lymphocytes. Phagocytes, on the other hand, increase during the course of a particular infection. An infant’s immune system is strengthened for the first few months by the IgG antibodies that cross the placenta. These immunoglobulins provide less protection, as they break down at a rate of approximately 50% every third week. Breast milk contains large quantities of IgA2 antibodies that already block pathogens in the mucous membranes. A number of breast milk components use various mechanisms to protect the child without causing inflammation and the associated risks to health and development. Other factors in breast milk can also promote development of the immune system (5, 6). Although a child is generally exposed to thousands of antigens every day from food, as well as from bacteria and viruses in the environment, a normal immune system has a great capacity to develop protection against them. The vaccines that children receive these days are much purer than their predecessors. They contain approximately 100 components, as opposed to several thousand previously (7). Children have the ability to develop an effective immune system in response to various antigens, including vaccines, at an early stage. Even preterm infants who weigh less than 1 000 grams at birth have protective antibody levels against these pathogens 7 years after receiving customary combination vaccines (8). Vaccines sometimes cause adverse effects that are similar to the disease. For instance, MMR vaccine can produce symptoms that resemble a mild case of measles. What criteria should a vaccine meet? Above all, a vaccine should fully protect the child against infection for a long time (9). The vaccine should contain the purified pathogenic components that are required to activate the adaptive immune system. Thus, how the immune response to the pathogen has developed should first be determined after infection has occurred. That has already been established for a number of pathogens. To be protected against tetanus, the body needs only to produce antibodies that bind and neutralize tetanus toxin in order to render it harmless. Similarly, when researchers develop vaccines against a pathogen, they must identify the various virulence factors – the pathogenic components that lead to infection. In the best case scenario, immunization against one virulence factor is sufficient. A virulence factor such as the diphtheria toxin must be deactivated to a toxoid, but in a way that it still induces the production of antibodies that effectively neutralize it. The antibodies do not need to specifically target the toxic part as long as the toxic effect is blocked. Neutralizing antibodies can provide effective protection against multiple viral infections in a similar manner. The antibodies do not need to target the pathogenic structures of the virus as long as the virus is neutralized or blocked such that it cannot bind to, permeate and infect target cells in the body. In other cases, more complex protection is needed and the vaccine must also stimulate production of protective T cells. Repeated doses at carefully tested intervals must be administered in many cases in order to ensure immunological memory and thereby the best possible long-term protection. The long-lived memory cells remain after vaccination, usually for many years, and immediately induce a specific immune response when re-exposed to the pathogen. To ensure sufficient protection, including both T cells and antibodies, some vaccines must contain live viruses, but attenuated such that they do not cause disease or more adverse effects than absolutely necessary. Some vaccines need an additive (adjuvant) to induce a sufficient immune response. Researchers must also determine the age at which induction of the most effective, long-term protection is possible. Children should ideally be vaccinated at an early age in order to prevent the maximum number of infections. But that concern must be weighed against the possibility that the immune system may be relatively undeveloped during the first year of life. The immunity that is built up during and after infection is often long-lasting, sometimes for life. Vaccines can have a similar effect, but some may require multiple doses, live viruses or stimulating adjuvants. Vaccination practice has evolved quickly in line with immune system research. Better and better vaccines have been discovered, but much remains to be done (10). Measuring vaccine response Vaccine response must measured how well the person is protected against infection. Establishing how long protection lasts and the possible effect of additional doses is also important. Good yardsticks are often available, for instance the level of serum antibodies against diphtheria and tetanus. Such data enable an assessment of whether additional doses are needed to ensure optimal protection. Neutralizing serum antibodies against some viruses, such as polio, provide information about how well the body may be protected against the particular disease. In some cases, such as when protection may also depend on secretory IgA antibodies that protect the mucous membranes, the number of antibodies may be less informative. For some vaccines, the level of antibodies is not the only measure of protection. The avidity, or functional binding strength, of the antibodies is also revealing. The type of antibodies that have been induced also provides informative data – IgG antibodies dominate when protection is long-lasting (Fig. 1.1.2b). IgG normally bind most effectively, while IgM (which appear first in the immune response) bind more weakly because of their lower specificity. Their lower specificity at that point enables them to bind, and possibly protect, more broadly. The obvious benefits of vaccination are protection against disease and the spread of infection, while the drawbacks are the risk of adverse effects or complications. Assessing the value of vaccination against a particular disease requires knowledge of both the disease and the vaccine, i.e. the risk of developing the disease and the risks associated with having it, as well as the advantages and disadvantages of the vaccine itself. Most Swedes have grown up with the concept of vaccination and associate it with basic services provided by child health centres and schools. However, far from everyone understands how vaccines work or that they vary just as diseases do. Nor are the methods by which vaccine is tested and controlled, or what is meant by efficacy, widely known. A vaccine contains part of the pathogen that causes a particular disease, or an attenuated form of the entire pathogen. The vaccine is insufficient to induce the disease but sufficient to stimulate the body to develop protective mechanisms against it. Chapter 1.1 describes the immunological processes involved. The word vaccination is derived from the Latin word for ‘cow’ (vacca) because the first vaccination experiments consisted of inoculating humans with material from skin lesions caused by cowpox. The medical use of vaccines is regulated in the same way as other medical products. Vaccines are hence subject to the same phases of research and development as other medical drugs, including that studies and trials must be approved by the ethical research committee and the national medicines regulatory authority. The Swedish Medical Products Agency (MPA) is responsible, in consultation with the European Medicines Agency (EMA), for evaluating which drugs are satisfactorily documented to be approved for sale in Sweden and EU. The agencies are also responsible for monitoring that each product maintains the level of quality for which it was approved. The criteria used for evaluation of medical products are generally used in a stricter way for preventive drugs such as vaccines as compared to those that are used for curative treatment. Vaccines that are part of a general vaccination programme are subject to particularly stringent evaluation, because of the large number of healthy people, usually children, involved. When administering a curative drug you want to know the number of patients who improve or recover from a disease. When administering a vaccine you want to know the numbers of people who do not get the disease, ie the number that remain healthy despite exposure to infection. A control group is needed in both cases to assure proper assessment. The control group in a prospective (going forward in time) clinical study of a new drug or vaccine consists preferably of subjects who are untreated or unvaccinated. But that is not always feasible. If there already is an established treatment that works well, the new drug or vaccine must for ethical reasons be compared with the established option. That is also the case when changing the dosage of a drug treatment, such as the age at which a vaccine is to be administered. Protective efficacy Treatment efficacy is the difference shown between an intervention group that receives the treatment being studied and a control group that does not. Vaccine efficacy measures the extent to which the vaccine protects against disease in a prospective placebo-controlled study. The result is presented as a percentage with its associated confidence interval and is referred to as the ‘point estimate of efficacy. The exact definition is 1 minus RR, where RR (relative risk) is the incidence rate (e.g. disease per 100 000) in vaccinated people divided by the incidence rate in unvaccinated people. Expressed differently, vaccine efficacy is the percentage reduction of disease among vaccinated persons compared to other persons (1). Although the above definition may sound precise, the point estimate of efficacy is affected by a number of study design variables. The most important variables are the sensitivity and specificity of the case definition used for the disease – ie whether the study measures protection against carriership, the disease in general or severe disease and the methods used for case ascertainment, and also the length of time that vaccine efficacy is to be measured.(2) Relative efficacy Relative treatment efficacy, a comparison of the new vaccine (intervention group) with an older vaccine against the same disease (control group), is also best examined in a prospective controlled study. However, the study outcome is not the point estimate of efficacy, which requires a comparison with an unvaccinated population. Instead the result of a comparison between two vaccines is presented as the relative risk, which means the ratio of incidence in the intervention and control group. This ratio depends both on the intervention and on the control group. Relative efficacy estimates of the same new vaccine may therefore vary radically depending on the control vaccine chosen. Whether comparing a new vaccine with placebo or with a previous vaccine, the size of the study is determined by the difference to be confirmed or ruled out, as well as how common the disease is. The reason is that a sufficient number of cases are required in order to confirm or rule out any difference be
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