Pooled immunoglobulins

Protective levels of antibody to a range of diseases are present in pooled normal human serum. Human normal immunoglobulin (HNIG) is available for the short-term prophylaxis of hepatitis A in contacts or travellers who intend to visit countries where hepatitis A is common. However, active immunization is a much better alternative against hepatitis A for frequent travellers to endemic areas. HNIG also protects those with agammaglobulinaemia and has been used in cases of Gram-negative sepsis and C. difficile infection.

Specific immunoglobulins

Preparations of specific immunoglobulins are available for passive immunization against the following:

Types of vaccine

Immune response

Antibodies against the agents of some bacterial and viral infections may be present in the mother’s blood and be passively acquired by the baby (see Part 2 of this book). This gives some protection to the infant at a time when it is poorly equipped to produce specific antibodies, but it may interfere to a varying extent with the infant’s capacity to respond to the stimulus of injected or ingested vaccines in the very early months of life. Although the capacity of the infant to produce specific antibody to injected antigens is poorly developed in the first few months of life, this problem can often be resolved by the use of adjuvants. Thus, effective responses are produced to powerful antigens such as alum-adsorbed toxoids. Pertussis whole-cell vaccines have an adjuvant effect of their own, so the combination of adsorbed toxoids and whole-cell pertussis vaccine (the triple diphtheria, tetanus and pertussis vaccine; DTP) is an effective immunizing complex that used to be given in the UK at 2, 3 and 4 months of age to cover the period when the lethal potential of pertussis is greatest (see below and Ch. 32). The tissues of the newborn respond effectively to BCG vaccine because the protection here is cell-mediated. The use of a high-potency measles vaccine at 6–9 months of age is likely to be exploited in countries where measles kills or severely injures the very young.

When a good specific antibody response is being sought to a toxoid or a killed antigen, the usual procedure is to give three doses of the antigen at spaced intervals. The first or ‘priming’ dose evokes a low level of antibody after a latent period of about 2 weeks, but the second dose elicits a much greater (secondary) antibody response, and this is further boosted by the third dose. The efficacy of injected antigen preparations can be enhanced by slow-release agents such as mineral carriers which have adjuvant effects. With most antigens, the response is better if the first two doses are separated by an interval of a month or two. A third dose is generally recommended at some time thereafter, and further booster doses may be given to maintain immunity.

Duration of immunity

After an effective course of active immunization, a protective amount of antibody may persist in the blood for some years and a subsequent booster injection may maintain protection for a further decade. Much depends upon circumstances that will vary for different vaccines and different groups of people. The duration of active protection cannot be absolutely equated with the presence of demonstrable antibody because factors such as the sensitivity of the test and the actual protective role of the antibody detected have to be taken into consideration.

Age of commencement of active immunization

This must take account of the immaturity of the antibody-forming system in the very early months (see above) and the infectious challenges that a person may encounter early in life and in later years. The start of any immunization programme must be adjusted to the known epidemiology of the diseases that are prevalent in the country in which it is to be instituted, and it must also be related to any serious infective challenges that may be imported from time to time. Poliomyelitis is a good example of a disease that has been largely eradicated from many communities; however, the disease is quick to strike back if the immunization shield is lowered.

Hazards of immunization

Possible adverse reactions to immunization are:

During the first few years of life when many vaccines are given, children tend to have various health problems that include occasional febrile convulsions and may, sadly, include an unexplained cot death or other tragedy. It is inevitable that some of these events will coincide with the period shortly after a vaccine was given to a child and the possibility of a causal relationship will be entertained. The probability of such a link certainly deserves to be considered, but it is most important to bear in mind that the issue is emotive and that ill-balanced or ill-informed adverse publicity can do irreparable harm to an immunization programme. For example, annual notifications of whooping cough in England and Wales dropped from more than 100 000 in the early 1950s to some tens of thousands in the late 1950s as the vaccine gained ground. By the early 1970s (and after modification of the vaccine to take account of a possible deficiency in its protective cover), whooping cough was largely controlled in the UK, with about 75% of children immunized. In the late 1970s, after some ill-informed adverse publicity, acceptance rates for the vaccine fell steeply to 30% or lower, and the uptake of other vaccines was also affected. Epidemics of whooping cough followed in the UK in 1978 and 1982, with tens of thousands of children affected and a number of deaths. As a result of efforts to restore confidence in pertussis vaccine, uptake figures increased in the 1980s and the disease again began to be brought under control. Preliminary results of tests with new (acellular) pertussis vaccines indicate that these are safe and probably more effective.

Over the past few years there has been considerable publicity about claims that autism and inflammatory bowel disease were associated with MMR vaccine. Although several well-conducted studies have failed to confirm the original study, which first drew attention to this hazard, the media in the UK have supported the hypothesis and cover of the vaccine fell to the point that cases and deaths from measles reemerged. Mathematical models of the dynamics of measles in a population show that if the number of susceptibles in the population exceeds 5% there is a possibility of transmission.

Children who are most vulnerable are likely to be least protected. Pertussis, polio and measles spread most effectively when living conditions are overcrowded and unhygienic. To some extent, these diseases depend upon population density for their spread. Some underprivileged groups in a community are in very real danger when the average rate of vaccine uptake falls, because they often have the lowest cover.

In view of the stringency of the regulations that control the quality and efficacy of vaccines, the probability of error lies more with the vaccinator than with the producer. There is a special obligation to ensure that vaccines are properly stored, reconstituted (if relevant) and correctly administered (Box 70.2). Many preparations rapidly lose their potency if frozen and thawed or exposed to temperature variation. This means it is vital to maintain the ‘cold chain’ in which the vaccines are held between 2–8°C. The appropriate instructions and local protocols should be followed in detail. An injectable vaccine must be given with a sterile syringe and needle, a separate sterile syringe and needle must be used for each injection, and the equipment must be disposed of properly. The dangers of contamination with blood-borne viruses such as HIV and hepatitis B and C have led to the search for alternative methods of delivery by air jets or via mucosal surfaces.

Site of injection

This will vary with the vaccine to be given. Specific instructions should be followed. In general, and with the exception of BCG, injectable vaccines are given by intramuscular or deep subcutaneous injection. The anterolateral aspect of the thigh or upper arm is the preferred site for infants. Some doctors and nurses use the upper outer quadrant of the buttock, but fat in this area may interfere with the efficacy of the vaccine, especially hepatitis A and B. In future, the technological advances in delivery methods mentioned above will revolutionize the immunization clinics feared by countless school children.

Adsorbed tetanus toxoid

The preparation in routine use in the UK is adsorbed onto an aluminium salt; it is more effective and less reactive than simple toxoid. A course of three injections given at intervals of about 4 weeks and boosters prior to, and on leaving, school, i.e. a total of five doses, should protect for life, although studies show that the elderly have low levels of protective antibody. Prevention of tetanus should be considered in relation to the management of wounds (see Ch. 22, p. 251).

Diphtheria toxoid

The adsorbed preparation used in the UK and incorporated into the triple DTP vaccine contains aluminium phosphate and affords good protection which is boosted at school entry age. This preparation is not used for adults; a dilute adsorbed diphtheria vaccine preparation is used for people who are more than 10 years old and is now incorporated with tetanus toxoid for school leavers as Td. Active immunization of adults against diphtheria is not practised in the UK as a routine, unless there is a potentially high occupational risk of encountering the organism in laboratory or clinical work, or unless a person has been in contact with a case of diphtheria or is travelling to an endemic area and protection is deemed necessary. A course of erythromycin gives further protection to a close contact, and this has replaced the use of diphtheria antitoxin in contacts. The falling level of immunity to diphtheria among adults in communities that regard themselves as having good preventive medical services gives some cause for concern and calls for continuing vigilance.

Pertussis vaccine

The vaccines in general use are either whole-cell preparations of killed Bordetella pertussis or acellular vaccines containing antigenic components of the organism. The protection afforded by the whole-cell vaccines is generally acknowledged to be considerable, but the acellular vaccine seems to be more effective and appears to have fewer adverse reactions so it is now included in the UK schedule. Adverse reactions that may be associated with pertussis vaccine include soreness at the site of injection, irritability and pyrexia. Reactions such as persistent screaming, shock, vomiting and convulsions have been reported, but the association with pertussis vaccine is not invariably clear.

Haemophilus influenzae type b (Hib) vaccine

Invasive encapsulated strains of H. influenzae, almost always of serotype b, are associated with meningitis, bacteraemia, epiglottitis and other serious infections particularly affecting young children. The risks of severe morbidity and mortality are highest in children in the age range 3–18 months. Hib conjugate vaccines containing the capsular polysaccharide linked to a protein are immunogenic and reduce pharyngeal carriage of the organism. The Hib vaccines used in the UK are given combined as part of the primary immunization. Children in the age range 1–4 years who have not received Hib vaccine can be protected by a single dose of Hib vaccine. Routine immunization of older children or adults with Hib vaccine is not generally recommended unless they are immunocompromised.

Meningococcal group C (MenC) vaccine

In 1999, following an increase in fatal cases of invasive meningococcal disease especially due to group C, the UK government was the first in the world to introduce MenC vaccine to the routine programme. Although it is now given as part of primary immunization at 3, 4 and 13 months, when the campaign started it was necessary to protect the whole population up to 18 years of age. The design of the antigen is similar to Hib in that the relatively poorly immunogenic polysaccharide is covalently linked to a protein carrier which produces a prolonged immune response in naïve infants. As with Hib there are few adverse reactions and the introduction universally to children has led to a great reduction in cases of meningitis and carriage in the nasopharynx of group C meningococci.

Poliomyelitis vaccines

The control of poliomyelitis is one of the great success stories of active immunization, and the worldwide eradication of poliomyelitis is a goal of the WHO which has nearly been achieved. The Salk vaccine came first; this is a killed mixture of the three types of poliovirus (1, 2 and 3). A course of three injections is given at appropriate intervals and in the UK it is combined with the other infant vaccines.

The oral polio vaccine (OPV) was favoured in the UK and many other countries. It is the live-attenuated form developed by Sabin. This is a mixture of the three types, and it is given orally on three occasions, usually at the same time as the infant vaccinations in the early months. As it is a live preparation, the vaccine must be stored and held according to the manufacturer’s instructions. OPV colonizes the gut and gives rise to local and humoral antibodies. The faeces contain live virus for some time, and poliomyelitis caused by a vaccine strain is a rare, but recognized, hazard which is why at the end stage of eradication of the disease it is recommended for countries to swap to the injectable form.

Pneumococcal vaccines

The 23 valent polysaccharide vaccine has been available for over three decades but its place in universal protection of vulnerable patients has not been established. Splenectomized and immunocompromised people should be routinely immunized preferably before surgery or therapy. A conjugate vaccine, produced initially against 7 types of pneumococci is commercially available in many countries and with the inclusion of other common serotypes, has been used either for universal vaccination or to protect infants at highest risk. There is evidence from North America that the universal infant programme has produced a significant decrease in pneumococcal disease in the elderly. There is hope that these vaccines will become more widely available in resource-poor countries where the need is greatest.

Measles, mumps and rubella (MMR) vaccine

This is a mixture of live-attenuated strains of these three viruses in freeze-dried form; it has to be stored at 2–8°C (not frozen), reconstituted according to the manufacturer’s instructions and used promptly. One injection of the mixture is given between 12 and 15 months in the UK schedule, and the second dose in the fifth year, before entry to school.

The measles component may give rise to fever or malaise and sometimes a rash about a week after inoculation. The mumps component may cause some parotid swelling, seen about 3 weeks after inoculation. Very occasional cases of mumps vaccine-associated meningo-encephalitis occur; these generally occur at 3 weeks after use of the Urabe strain. It is usually benign, but there may be confusion with other more serious syndromes in this age group. The rubella component is not usually associated with reactions in this age group, though temporary malaise, mild fever and arthralgia occurring about the ninth day after vaccination have been noted in some older recipients of rubella vaccine.

It is hoped that high vaccine coverage with two doses of MMR vaccine in the UK schedule will eradicate measles, mumps and rubella in this country as it nearly has done in North America. Much depends upon public faith in the immunization programme, which has been undermined by media-led campaigns about the safety of MMR.

All seronegative women of childbearing age and seronegative professional attendants who might come into contact with pregnant women should be offered rubella vaccine after a test for immunity. Although it is not thought to be teratogenic, any woman of childbearing age who is given the vaccine should avoid pregnancy for a month.

BCG

The attenuated strain of bovine tubercle bacillus known as bacille Calmette–Guérin (BCG) produces cross-immunity to human tuberculosis and has significantly contributed to the control of that disease and to the other important mycobacterial disease, leprosy, in many countries. An intradermal injection of the live-attenuated vaccine is given on the lateral aspect of the arm at the level of the deltoid insertion, but not higher, or on the upper lateral surface of the thigh. Instruction on the reconstitution of the freeze-dried vaccine, the dosage and the detailed technique of giving a truly intradermal injection, should be most carefully observed. With the exception of newborn children, any recipient of BCG vaccination should have been tested for hypersensitivity to tuberculin and found to be negative. Tuberculin tests include the Mantoux test, in which diluted tuberculin is injected intradermally, and the Heaf test, which is done with a multiple puncture apparatus (see Ch. 18).

Hepatitis B vaccine

For the protection of groups of people considered to be at special risk of acquiring hepatitis B, a bioengineered vaccine is now in common use. A course of three intramuscular injections is given (not into the buttock) at intervals of 1 and 5 months; thus, it takes 6 months to complete the course, and this is of practical importance. Following needlestick injuries or known contact with the virus it is possible to give an accelerated course although efficacy may not be as good. Protective antibody responses are generally achieved in about 90% of those given the vaccine, with a range of responses from weak to strong, but there is a worrying minority of nonresponders (10–15% in those over 40 years of age). Antibody responses should be checked at least 6 weeks after completion of a course, and it may be prudent to give poor responders or nonresponders a booster dose or a repeat course. Nonresponse rates are particularly worrying among patients on maintenance haemodialysis, for whom a higher dose preparation is available. In the general population, the protection afforded to responders is thought to last for about 5 years, when a booster dose of vaccine may be given. Established policy must await further experience with hepatitis vaccines, which in many countries are being given universally as part of the routine schedule. Great success has been claimed in Asia in reducing prevalence and preventing cancer.

Other vaccines

Various vaccines are available for the protection of special groups of people or for individuals in special circumstances (Box 70.3). The reader is referred to the appropriate chapters for more detailed consideration of such topics as: