Vaccines apply immunological principles to human health

Vaccination is the best known and most successful application of immunological principles to human health. It exploits the property of immunological memory to provide long lasting protection against infectious disease.

The first vaccine was named after Vaccinia, the cowpox virus. Jenner pioneered its use 200 years ago. It was the first deliberate scientific attempt to prevent an infectious disease and was based on the notion that infection with a mild disease (cowpox) might protect against infection with a similar but much more serious one (smallpox), although it was done in complete ignorance of viruses (or indeed any kind of microbe) and immunology.

It was not until the work of Pasteur 100 years later that the general principle governing vaccination emerged – altered preparations of microbes could be used to generate enhanced immunity against the fully virulent organism. Thus Pasteur’s dried rabies-infected rabbit spinal cords and heated anthrax bacilli were the true forerunners of today’s vaccines, whereas, until very recently, Jenner’s animal-derived (i.e. ‘heterologous’) vaccinia virus had no real successors.

Even Pasteur did not have a proper understanding of immunological memory or the functions of the lymphocyte, which had to wait another half century.

Finally, with Burnet’s clonal selection theory (1957) and the discovery of T and B lymphocytes (1965), the key mechanism became clear.

In any immune response, the antigen(s) induces clonal expansion in specific T and/or B cells, leaving behind a population of memory cells. These enable the next encounter with the same antigen(s) to induce a secondary response, which is more rapid and effective than the normal primary response.

While for many infections the primary response may be too slow to prevent serious disease, if the individual has been exposed to antigens from the organism in a vaccine before encountering the pathogenic organism, the expanded population of memory cells and raised levels of specific antibody are able to protect against disease. The principles of vaccination can be summarized as:

Vaccines can protect populations as well as individuals

Vaccines protect individuals against disease, and if there are sufficient immune individuals in a population, transmission of the infection is prevented. This is known as herd immunity.

The proportion of the population that needs to be immune to prevent epidemics occurring depends on the nature of the infection:

Effective vaccines must be safe to administer, induce the correct type of immunity, and be affordable by the population at which they are aimed. Over the middle of the 20th century for many of the world’s major infectious diseases, this was achieved with brilliant success, culminating in the official eradication of smallpox in 1980. Beyond this era progress was much slower and fears over vaccine safety made development more lengthy and costly. However, the advent of recombinant DNA technology has led to a number of significant advances in the first decade of the 21st century and a number of new, safe and effective vaccines have come onto the market during this period. Despite these successes for many diseases development of an effective vaccine has remained elusive, in particular, parasitic diseases and HIV.

Nevertheless, with the availability of new technologies and a greater understanding of the immunological principles that underlie effective vaccines, the future for new vaccine development looks brighter than it has for some years.

Live vaccines can be natural or attenuated organisms

The new rotavirus vaccines should prevent many infants from dying in developing countries

Infantile diarrhea caused by rotavirus (a double stranded RNA virus of the Reoviridae family) infection accounts for approximately 600 000 deaths per annum worldwide, with the majority of these occurring in developing countries. An effective vaccine would therefore be of great value and save many lives.

In 1998 a vaccine based on live rotavirus was tested on large numbers of infants in the USA. Although the vaccine was found to be effective, approximately 1 in 2500 vaccinated infants developed intussusception (a potentially fatal bowel condition) and it was withdrawn by the manufacturer.

Greater knowledge of the viral molecular biology and techniques manipulating the virus in vitro, have now led to the development of two new and highly effective vaccines against rotavirus infection. These vaccines are marketed under the names Rotarix™ and RotaTeq™. The former is a live attenuated virus produced by repeated passage in animal cell lines in the laboratory (see below). The latter is a complex of 5 different hybrid viruses providing immunity to the 5 most prevalent viral strains. These viruses are based on the bovine rotavirus which is naturally attenuated in human hosts. Into this backbone have been incorporated the human rotavirus viral capsid proteins VP4 or VP7, which are known to be the targets of natural immunity in human rotavirus infection (Fig. 18.w1).

Fig. 18.w1 Reassortment to generate an oral live rotavirus vaccine

Rotavirus reassortant to generate oral live virus vaccine. The human chromosome in the reassorted virus which codes for the capsid protein is colored green. The bovine chromosome coding for the spike protein is brown. RotaTeq is a polyvalent vaccine consisting of five human-bovine reassortants: four G serotypes (G1, G2, G3, G4) representing 80% of the G strains circulating worldwide and one P serotype representing >75% of the P strains circulating worldwide.

(Reprinted by permission from Macmillan Publishers Ltd: Nature Medicine (Buckland BC: The process development challenge for a new vaccine. Nature Medicine 2005;11:S16–S19.).

The vaccine has proven to be safe and well tolerated in testing in Europe and the USA and provides high levels of protection against rotavirus gastroenteritis. It is hoped that future experience will prove it to be equally effective in developing countries.

Attenuated live vaccines have been highly successful

Historically, the preferred strategy for vaccine development has been to attenuate a human pathogen, with the aim of diminishing its virulence while retaining the desired antigens.

This was first done successfully by Calmette and Guérin with a bovine strain (Mycobacterium bovis) of Mycobacterium tuberculosis, which during 13 years (1908–1921) of culture in vitro changed to the much less virulent form now known as BCG (bacille Calmette–Guérin), which has at least some protective effect against tuberculosis.

The real successes were with viruses, starting with the 17D strain of yellow fever virus obtained by passage in mice and chicken embryos (1937), and followed by a roughly similar approach with polio, measles, mumps, and rubella (Fig. 18.2)

Fig. 18.2 Live attenuated vaccines

Attenuated vaccines are available for many, but not all, infections. In general it has proved easier to attenuate viruses than bacteria.

Q. Why would passage of a virus in a non-human species be a rational way of developing a vaccine for use in humans?

A. The selective pressure on the virus to retain genes needed for virulence in humans and for human-to-human transfer is removed. Consequently some variants may lose these genes and are at no disadvantage in the animal, but will retain antigenicity for use as attenuated vaccine strains.

Just how successful the vaccines for polio, measles, mumps, and rubella are is shown by the decline in these four diseases between 1950 and 1980 (Fig. 18.3).

Fig. 18.3 Effect of vaccination on the incidence of viral disease

The effect of vaccination on the incidence of various viral diseases in the USA has been that most infections have shown a dramatic downward trend since the introduction of a vaccine (arrows).

Killed vaccines are intact but non-living organisms

Killed vaccines are the successors of Pasteur’s killed vaccines mentioned above:

Figure 18.4 lists the main killed vaccines in use today. These are gradually being replaced by attenuated or subunit vaccines. However, in the case of polio, some countries are reverting to the use of killed vaccine which is safer than the attenuated vaccine, even though it is less effective. This choice only becomes relevant when the risk of contracting the disease is low in comparison with the risk of developing adverse reactions to the vaccine.

Fig. 18.4 Killed (whole organism) vaccines

The principal vaccines using killed whole organisms.

Inactivated toxins and toxoids are the most successful bacterial vaccines

The most successful of all bacterial vaccines – tetanus and diphtheria – are based on inactivated exotoxins (Fig. 18.5), and in principle the same approach can be used for several other infections. An inactive, mutant form of diphtheria toxin (CRM₁₉₇) has been used as the basis for a number of newly generated conjugate vaccines (see below).

Fig. 18.5 Toxin-based vaccines

The principal toxin-based vaccines. Note that there are no vaccines against the numerous staphylococcal and streptococcal exotoxins, or against bacterial endotoxins such as lipopolysaccharides.

Subunit vaccines and carriers

Aside from the toxin-based vaccines, which are subunits of their respective microorganisms, a number of other vaccines are in use which employ antigens either purified from microorganisms or produced by recombinant DNA technology (Fig. 18.6). For example, a recombinant Hepatitis B surface antigen synthesized in baker’s yeast, has been in use since 1986.

Fig. 18.6 Subunit vaccines

Conjugate vaccines are replacing pure polysaccharides. N. meningitidis type B is non-immunogenic in humans because the capsular polysaccharide cross-reacts with self carbohydrates towards which the host is immunologically tolerant.

Acellular pertussis vaccine consisting of a small number of proteins purified from the bacterium has been available for some years now, and has been shown to be effective, safer and less toxic than the whole killed-organism vaccine. It is usually administered as part of a DTaP (Diphtheria, Tetanus, Pertussis) combination vaccine routinely given to infants.

Conjugate vaccines are effective at inducing antibodies to carbohydrate antigens

Although protein antigens such as hepatitis B surface antigen are immunogenic when given with alum adjuvant (see below), for many types of bacteria, virulence is determined by the bacterial capsular polysaccharide, prime examples being Neisseria meningitidis, Streptococcus pneumoniae, and Haemophilus influenzae B. Such carbohydrate antigens, though they can be isolated and have been used for vaccination, are poorly immunogenic, particularly in infants under 2 years, and often do not induce IgG responses or long-lasting protection. Attempts to boost immunity by repeat administration of these vaccines can actually compromise immunity by depleting the pool of antibody-producing B cells.

Q. Why do polysaccharide antigens not induce IgG responses or lasting immunity?

A. Polysaccharide antigens are not processed for presentation to TH cells, so they do not induce class switching, affinity maturation, or generate memory T cells (see Chapters 8 and 9).

A major advance in the efficacy of subunit vaccines has been obtained by conjugating the purified polysaccharides to carrier proteins such as tetanus or diphtheria toxoid. These protein carriers, which can now be produced in highly purified form by recombinant DNA techniques, are presumed to recruit TH cells and the conjugates induce IgG antibody responses and more effective long lasting protection.

Starting with Haemophilus influenzae (Hib) in the early 1990s, conjugate vaccines for Neisseria meningitis strains A, C, Y and W-135 are also now in widespread usage. In the UK up until 1992 when the vaccine was introduced, Hib was the major cause of infantile meningitis leading to many hundreds of cases per year. The introduction of the vaccine led to a very rapid decline making Hib meningitis now a very rare occurrence (Fig. 18.7).

Fig. 18.7 Introduction of the vaccine led to a rapid decline in Hib meningitis

Incidence of H. influenzae type B in children in England and Wales (1990–2004). Vaccination was initiated in 1992. There was an upsurge in cases after 1999, possibly because the vaccine was less effective when used in combination with other vaccines, but this was controlled with a further campaign, initiated in 2003.

(Based on data from the Health Protection Agency.)

Conjugate meningitis vaccines

The serogroup C meningococcal vaccine was first introduced in the UK in 1999 and has resulted in a reduction of >80% in the incidence of infection. The vaccine has also been used successfully in Australia, Canada, and in Europe. Since 2005 a tetravalent combination conjugate vaccine active against strains A, C, Y, and W-135 has been available across the developed world.

In many parts of Africa meninigitis is endemic. Across the so-called ‘meningitis belt’ of the sub-Saharan region hundreds of thousands of cases per year may occur during epidemics, mainly of serogroup A and latterly W-135 type meningococci. As mentioned in the main text, a version of the combination conjugate vaccine, labelled MenAfriVac™ and produced in India at reasonable cost especially for the developing world, has just been licensed for a phased roll-out across Africa starting in late 2010.

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