Immunostimulation And Vaccination
In most animals the combination of innate resistance and stimulation of adaptive responses by antigen is adequate to cope with common infections (otherwise the species would not survive!). However, the immune system does have its shortcomings, and some of these can be overcome by artificial means. Indeed, the introduction of vaccines has probably saved more lives than any other medical intervention to date. But there are still no effective vaccines against many of the world’s most common infectious diseases, including HIV, tuberculosis and malaria.
Most effective vaccines need to stimulate both innate and adaptive immunity. Adaptive immune responses suffer from their initial slow- ness, so that high levels of antibody may arrive too late to prevent death or disability (e.g. tetanus, polio) even though surviving patients are resistant to reinfection. Specific immunization overcomes this problem by ensuring there is a high level of immunity before exposure. This may be active (top right), in which antigen is used to safely generate immunological memory, aided in some cases by the boosting power of special non-specific stimulants or adjuvants (top left), or passive, in which preformed antibody is injected, with more rapid but short-lived effect. Immunotherapy, as distinct from vaccination, refers to stimulating immune responses to cure, rather than prevent, disease. In general, conventional vaccines are ineffective when administered after exposure, although there are exceptions (rabies, chickenpox vaccination for prevention of shingles). Finally, when some component of the immune system is deficient (see Fig. 33), efforts can be made to correct this by replacement of hormones, enzymes, cytokines, cells or organs.
Despite 200 years of cumulative success, there is a growing irrational fear of vaccination in the industrialized world and a corresponding rise in cases of dangerous illnesses such as measles and polio. Continued efforts at educating the public are required to ensure society benefits fully from the benefits of universal vaccination.
Adjuvants are materials that increase the response to an antigen given at the same time. One way in which many adjuvants work is by creating a slow-release depot of antigen, thus prolonging the time for which the immune system remains in contact with antigen. In addition, they contain substances that activate macrophages and dendritic cells and via this pathway also increase antigen presentation (see Fig. 18). The most powerful adjuvants (e.g. Freund’s complete, which contains extracts of Mycobacterium tuberculosis) are too tissue-destructive for human use. Most human vaccines use a mixture of insoluble aluminium salts (alum) as adjuvant, but considerable efforts are being made to find more effective alternatives such as saponin.
Replacement therapy In some cases of severe combined immunodeficiency, bone marrow grafting has restored function; where adenosine deaminase (ADA) is deficient, this enzyme may also be restored by blood transfusion or, more recently, by gene therapy.
Cytokines Interferons, interleukins and other cytokines have potential for increasing the activity of their target cells, but their use in the clinic has been limited. IFNα has proved useful in certain viral dis- eases (e.g. hepatitis B and C), while G-CSF is used to boost granulocyte numbers after radiation or chemotherapy. However, the side effects of administering large amounts of cytokines systemically often limit their usefulness. More targeted cytokine release, e.g. by gene therapy, may prove more effective.
Antibody In patients already exposed to disease, passively transferred antibody antiserum may be life-saving; examples are rabies, tetanus, hepatitis B and snake bite. Originally, antisera were raised in horses, but the danger of serum sickness (see Fig. 36) makes ‘humanized’ monoclonal antibodies (see Fig. 15) preferable wherever possible. Monoclonal antibodies against ‘self’ molecules have also proved remarkably effective in controlling some tumours (see Fig. 42). T cells are more difficult to administer, because they need to be obtained from the same individual to prevent rejection. However, T cells against cytomegalovirus, which are isolated from blood, stimulated with virus and cytokines, and then readminstered to the patient, have proved useful in controlling this infection in immunosuppressed individuals (e.g. after transplantation).
The term ‘vaccine’ was introduced by Pasteur to commemorate Jenner’s classic work with cowpox (vaccinia), but was extended by him to all agents used to induce specific immunity and mitigate the effects of subsequent infection. Vaccines are given as early as practical, taking into account the fact that the immune system is not fully developed in the first months of life, and that antibody passively acquired from the mother via the placenta and/or milk will specifically prevent the baby making its own response. In general, this means a first injection at about 6 months, but where antibody is not of major importance (e.g. BCG) vaccines can be given effectively within 2 weeks of birth.
Living heterologous vaccines work by producing a milder but cross-protecting disease; one example is vaccinia, which has effectively allowed the elimination of smallpox. Another is BCG (attenuated bovine tuberculosis), which provides partial protection against tuberculosis especially when given to infants. However, with the rapid rise in tuberculosis worldwide, improved vaccines are urgently needed.
Living attenuated viruses (measles, mumps, yellow fever, rubella) produce subclinical disease and usually excellent protection. However, care is needed in immunodeficient patients. The measles, mumps and rubella vaccines are usually administered together (MMR). Public confidence in this vaccine was severely damaged by flawed research claiming a link between the vaccine and autism.
Toxoids are bacterial toxins (e.g. diphtheria, tetanus) inactivated with formalin but still antigenic. These relatively simple vaccines have provided some of the most effective and reliable vaccines available to this day.
Capsular polysaccharides induce some (primarily IgM) antibody against meningococcal, pneumococcal and Haemophilus spp. infection. However, the level and persistence of protective antibody can be greatly enhanced by coupling the polysaccharide to protein antigens, which stimulate a strong ‘helper’ response. Tetanus or diphtheria toxoid is frequently used for this purpose. These ‘conjugate’ vaccines have proved of particular value in the fight against bacterial meningitis.
Subunit vaccines include the first of the ‘second-generation’ vaccines, in which the purified antigens are produced by recombinant DNA technology. The first examples of subunit vaccines were hepatitis A and B surface antigens and they provide a high (>90%) level of protection. A recombinant surface antigen vaccine against the sexually transmitted human papillomavirus was introduced in 2007 and pre- vents both viral infection and the subsequent development of cancer of the cervix, which is caused by this virus.
DNA, vectors An interesting idea is to insert genes from one microbe into another less virulent one such as vaccinia, attenuated Salmonella or even HIV-based ‘viruses’ which have been altered so as to prevent them replicating. These ‘recombinant’ organisms often stimulate strong immunity to the inserted antigens. If the vector has a large enough genome (e.g. BCG), multiple antigens could be introduced into a single vector, cutting down the need for repeated doses. A recent trial of such a ‘recombinant’ vaccine gave the first suggestion of protection against HIV infection. Some of the properties of the vaccines in common use are summarized in the table opposite (representing 2012 UK guidelines).