2 Active vaccines and passive immunisation
2.1 From passive to active
Since Jenner's pioneering discovery, many new vaccines have been developed (Table 1). The country in which a vaccine was first introduced is usually the one that developed it; France and the USA are among the most prominent: for example, rabies, plague and BCG vaccines were first used in France, polio vaccines were introduced first in the USA. There has often been a considerable time lag between dates of first use in the country in which a vaccine was pioneered and its adoption elsewhere (e.g. BCG vaccination was delayed in the UK until 1954), and some countries have never adopted particular vaccines. Some were immediately introduced in mass vaccination programmes (e.g. against polio), and others have only been used selectively to control outbreaks. Continuing research means that the ‘first’ vaccines against a particular infectious disease are superseded by more effective preparations. Some vaccines are now so effective that the infections they protect against are termed vaccine-preventable diseases – the WHO has placed the highest priority on achieving mass vaccination against diphtheria, whooping cough (pertussis), tetanus, measles, mumps, rubella, polio and TB.
The incidence of most of the diseases in Table 1 was declining in most countries in the world for some time before the introduction of the relevant vaccine, due to improvements in public health and living standards. However, the annual toll of mortality and morbidity was significantly greater than it is today and sharp declines in the incidence occurred when an effective vaccination programme was introduced, as Figure 3 and the Polio Case Study illustrate.
Table 1 Year of first use anywhere of a vaccine against some major infectious diseases.
|Infectious disease||First use|
|tetanus antitoxin (passive)||1890|
|diphtheria antitoxin (passive)||1893|
|pertussis (whooping cough)||1926|
|hepatitis A (passive)||1945|
|meningitis C (polysaccharide)||1977|
|varicella zoster (chickenpox)||1995|
|meningitis C (conjugate)||1999|
When people use the term vaccination, they nearly always mean active vaccination, i.e. immunising an individual with pathogen-specific antigens in order to induce a protective immune response against subsequent infection with that pathogen. The antigens in the vaccine elicit a primary immune response, which takes 7–14 days to reach its peak before subsiding. ‘Booster’ doses of the vaccine increase the protection against that infection by ensuring that it will be met by an enhanced secondary immune response.
Explain why the antibodies produced during the secondary response are more effective than those of the primary response.
There is a shorter lag time before pathogen-specific antibodies appear (typically 2–3 days); the overall level of antibodies is higher and they persist for longer; less IgM and more IgG is produced (due to class switching), which increases the protection in the blood stream; the affinity of the antibody binding sites for the target antigen is generally higher, so they bind more strongly.
In a small number of infectious diseases, active vaccines can also be given therapeutically to people who are already infected, to stimulate their immune system to eliminate the pathogens, or at least slow the progression of the disease. This approach is being tested extensively in trials of therapeutic vaccines against established HIV infection.
However, there is another type of procedure, termed passive immunisation, which is used therapeutically to treat particular infectious diseases after symptoms have developed, or for post-exposure prophylaxis. In passive immunisation, the recipient is directly injected with antibodies from another immune individual, who had either developed immunity following an infection or after immunisation with an active vaccine. The procedure is described as ‘passive’ because recipients do not manufacture the antibodies for themselves. Indeed, the presence of passively acquired antibodies may reduce the ability of recipients to manufacture their own antibodies (because of negative feedback controls operating in the immune system).
Under what circumstances would it be advantageous to give someone pre-prepared antibodies against an infectious agent?
Passive immunisation is particularly important in certain life-threatening infections where there are no anti-infective drugs or they act too slowly; active vaccination takes too long to stimulate a protective immune response.
The most important infections in which passive immunisation is used are listed in Table 2. The use of passive immunisation often preceded the introduction of an active vaccine against certain infections (see Table 1 earlier)
Table 2 Current examples of passive immunisation.
|Disease||Source of antibodies||Usage|
|tetanus||human or horse serum||after symptoms develop|
|diphtheria||human or horse serum||after symptoms develop|
|gangrene||horse serum||after exposure|
|botulism||horse serum||after exposure|
|hepatitis B||human serum||after exposure|
|rabies||human serum||after exposure (plus active vaccine)|
Explain why pathogen-specific antibodies are given immediately to people with suspected tetanus, diphtheria or botulism. How do they protect the patient?
All three bacterial diseases are caused by a potentially fatal exotoxin, and it is imperative to neutralise it in the blood as quickly as possible. The passively acquired antibodies bind to the toxin, which can no longer bind to host cells or disrupt metabolic processes. The toxin-antibody complexes are usually destroyed by phagocytosis.
Passive immunisation is also used for some serious viral diseases such as rabies, where the antiserum is administered after exposure to the infected bite, together with active vaccination (see Table 2). Passively administered antibodies can also be important for individuals who suffer from certain immunodeficiencies in which they cannot manufacture their own antibodies. Such people are extremely susceptible to many types of infection and administration of pooled human antibodies (which contain a mixture of protective antibodies against many pathogens) can keep them in health. As Table 2 shows, some antisera for passive immunisation may be raised in horses by injecting them with the antigen and later using their serum as a source of specific antibodies.
What problems would you expect to result from infusing human subjects repeatedly with horse antiserum?
Horse serum contains proteins unique to horses, which are recognised as ‘non-self’ by the human recipient's immune system. The increasingly powerful immune response to these proteins gradually destroys the horse antibodies, so passive protection from the antiserum declines. More seriously, the recipient's blood capillaries can become blocked by aggregates of human antibodies bound to horse proteins, triggering local inflammation and even kidney failure.
Although passive immunisation is now used infrequently due to the introduction of more effective chemotherapeutic agents and active vaccines, it was critically important in the past. For example, horse antiserum prevented thousands of deaths from tetanus among allied soldiers in World War I, and it can still be life-saving in some conditions.