34 Protecting the host

vaccination

Vaccines are one of the most effective public health tools. This chapter will review how vaccines work, and the vaccines in current use. However, although vaccination is very cost-effective as a public health measure, saving many lives (immunization saves an estimated 2.5 million deaths each year from diphtheria, tetanus, pertussis and measles), in 2008 an estimated 1.8 million people died from a vaccine-preventable disease, as a result of poor vaccine uptake. Many others die from infectious diseases such as HIV for which there is as yet no effective vaccine, so new vaccines are also needed (Table 34.1).

Table 34.1 Infectious agents that are major killers

Organism	Disease	Estimated annual deaths (millions)
HIV	AIDS	1.8
Mycobacterium tuberculosis	Tuberculosis	1.7
Plasmodium spp.	Malaria	0.8
Total		4.3

We currently lack effective vaccines against these organisms, although bacille Calmette–Guérin (BCG) vaccination can provide protection against disseminated forms of childhood tuberculosis, and pulmonary tuberculosis in some parts of the world. Most of the deaths from HIV are in Africa, and most of the deaths from malaria are in African children. Sources: Figures for 2009 from WHO.

Vaccination exploits the ability of the immune system to develop immunological memory, so that it can rapidly mobilize its forces to fight infection when required. Vaccines can be of different types, including live attenuated organisms, killed organisms, or subunit vaccines. Depending on the vaccine type, more than one dose may be needed to achieve or maintain optimal protection. Adjuvants are often required to increase immunity. A lot has been learnt about how to make a good vaccine, but for some vaccines we lack measurable correlates of protection. It is therefore no surprise that the development of new and more effective vaccines is a major area of research. Successful vaccination also requires an understanding of the epidemiology of disease transmission, for example, to estimate what proportion of a given population needs to be vaccinated to produce herd immunity, as discussed in Chapter 31.

Vaccination – a four hundred year history

‘Never in the history of human progress’, wrote the pathologist Geoffrey Edsall, ‘has a better and cheaper method of preventing illness been developed than immunization at its best’. The greatest success story in medicine, the elimination of smallpox, began before either immunology or microbiology were recognized as disciplines – indeed before the existence of microbes or the immune system was even suspected. As a result of the pioneering work of Jenner with vaccinia (Box 34.1), all forms of specific, actively induced immunity are now referred to as ‘vaccination’.

Box 34.1 Lessons in Microbiology

Edward Jenner (1749–1823)

The English physician Edward Jenner (Fig. 34.1) is regarded as the founder of modern vaccination, but he was by no means the first to try the technique. The ancient practice of ‘variolation’ dates back to tenth-century China, and arrived in Europe in the early eighteenth century via Turkey. The technique involved the inoculation of children with dried material from healed scabs of mild smallpox cases, and was a striking foretaste of the principles of modern attenuated viral vaccines. This practice was, however, both inconsistent and dangerous, and Jenner’s innovation was to show that a much safer and more reliable protection could be obtained by deliberate inoculation with cowpox (vaccinia) virus. Milkmaids exposed to cowpox were traditionally known to be resistant to smallpox and so retained their smooth complexions. In 1796, Jenner tested his theory by inoculating 8-year-old James Phipps with liquid from a cowpox pustule on the hand of Sarah Nelmes. Subsequent inoculation of the boy with smallpox produced no disease. Although greeted with scepticism at first, Jenner’s ideas soon became accepted, and he went on to inoculate thousands of patients in a shed in the garden of his house at Berkeley, Gloucestershire. He ultimately achieved world fame, though his fellowship of the Royal Society was conferred for a quite different piece of work on the nesting habits of the cuckoo!

Figure 34.1 Edward Jenner (1749–1823).

The principle of vaccination is simple: to prime the adaptive immune system to the antigens of a particular microbe so that on first contact with the live organism a rapid and effective secondary immune response will be induced by memory T and B cells. Vaccination therefore depends upon the ability of lymphocytes, both B and T cells, to respond to specific antigens and develop into memory T and B cells, and represents a form of actively enhanced adaptive immunity. The passive administration of preformed elements, such as antibody, is considered in Chapter 35.

Aims of vaccination

The aims of vaccination can vary from preventing symptoms to eradication of disease

The most ambitious aim of vaccination is eradication of the disease. This has been achieved for smallpox, the eradication of polio is being attempted, and there has clearly been a dramatic downward trend in the incidence of most of the diseases against which vaccines are currently in use (Fig. 34.2). However, as long as any focus of infection remains in the community, the main effect of vaccination will be protection of the vaccinated individual against infection.

Figure 34.2 The effect of vaccination on the incidence of various viral diseases in the USA and the UK. Most infections have shown a dramatic downward trend after the introduction of a vaccine (arrows), but the right-hand panels show the resurgence in disease when vaccine uptake is reduced following vaccine ‘scares’.

(Data from Mims and White and the Health Protection Agency, UK.)

In certain cases, the aim of vaccination may be more limited: namely, to protect the individual against symptoms or pathology. For example, diphtheria and tetanus vaccines only induce immunity against the toxins produced by the bacteria, as it is the effect of these toxins rather than the simple presence of the microbe itself that is harmful.

The importance of herd immunity

Successful vaccination programmes rely not only on the development and use of vaccines themselves, but also on an understanding of the epidemiologic aspects of disease transmission. If enough individuals in a population are immunized, this will reduce or stop transmission of the infection. This is called herd immunity. By having your own child immunized, you therefore help protect the whole community – but conversely, when too many parents decide that their child will not be immunized, because they think the risk of their child getting the disease is low, this may contribute to the disease becoming more common (Fig. 34.2)

It is therefore important to know how many individuals in a population must be immunized to produce herd immunity, and also whether immunity should be boosted by re-vaccination.

Vaccines can be of different types

Vaccines can be based on whole organisms, either live or inactivated, or components of the infectious agent (Table 34.2).

Table 34.2 Types of vaccine

Types of vaccine	Examples
Live attenuated
Viral	Measles, mumps, rubella, vaccinia, varicella, yellow fever, zoster, oral polio, intranasal influenza, rotavirus
Bacterial	BCG, oral typhoid
Inactivated
Whole virus	Polio, influenza, hepatitis A, rabies
Whole bacteria	Pertussis, cholera, typhoid
Fractions
Toxoids	Diphtheria, tetanus
Protein subunits	Hepatitis B, influenza, acellular pertussis, human papillomavirus
Polysaccharides	Pneumococcal, meningococcal, Salmonella typhi (Vi), Haemophilus influenzae type b
Conjugates	Haemophilus influenzae type b, pneumococcal, meningococcal

Note that not all types of vaccine are available in all countries. Vaccines are also available for bioterrorism agents such as anthrax and plague, and for vaccinia.

Live vaccines are designed to induce immunity in a similar way to the actual infection. Most live vaccines use attenuated organisms that were attenuated using culture in eggs, animals or in tissue culture (Fig. 34.3); these attenuated organisms replicate to a limited extent in the vaccinated individual but do not cause disease in healthy people. However, the immunosuppression associated with HIV infection can produce problems with live vaccines. For example, infants with HIV infection given BCG vaccination can develop disseminated BCGosis. HIV-infected individuals with severe immunosuppression should not be given live vaccines such as measles or varicella, but they can be given inactivated vaccines.

Figure 34.3 Live attenuated vaccines (e.g. polio) were originally produced by allowing viruses to grow in unusual conditions, and selecting the randomly occurring mutants that had lost virulence.

Inactivated vaccines are safe to use in the immunocompromised, although they may not be as immunogenic, and a good adjuvant may be needed. Inactivation can use heat or fixation, for example, with formalin. Types of fixatives and preservatives in use in vaccines are given in Table 34.3. Another difference between live and attenuated vaccines is that inactivated vaccines are not affected by circulating antibody, but live attenuated vaccines may be.

Table 34.3 Fixatives and preservatives used in current vaccines

Fixatives
Formalin	TdaP, HepA, Hib, influenza, polio
Glutaraldehyde	DtaP, DtaP-HepB-IPV
Preservatives
EDTA	Rabies, varicella
Phenol	Pneumococcal, inactivated typhoid
2-phenoxyethanol	DtaP, HepA, HepA-HepB, inactivated poliovirus
β-propiolactone	Rabies
Sodium deoxycholate	Influenza
Thiomersal	DtaP, DtaP-Hib, HepB, influenza, meningococcal vaccine

TdaP, combined tetanus, diphtheria and pertussis; DtaP, combined diphtheria, tetanus and pertussis; HepA, hepatitis A; HepB, hepatitis B; Hib, Hameophilus influenzae type b; IPV, inactivated polio vaccine.

Individual antigens or toxins can also be used as a vaccine, with adjuvant. Purified proteins are used in the acellular pertussis vaccine and recombinant proteins are used in the vaccines for hepatitis B. A number of protein antigens can also be joined together as a fusion protein and given with adjuvant. Polysaccharides form the basis of the pneumococcal vaccine, but as polysaccharide vaccines are not immunogenic in children under 2 years of age, conjugate vaccines that use a polysaccharide linked to a protein have been developed for pneumococcal and meningococcal disease, and for Haemophilus influenzae type b (Hib). For some bacteria, it is the toxin that is pathogenic – so this can be inactivated to make a toxoid, as in the tetanus toxoid vaccine. If individual components of an organism form the basis of a vaccine, an adjuvant will be needed to boost immune responses. Multiple doses of protein or polysaccharide are usually needed, as these vaccines are less immunogenic than vaccines with whole organisms.

One or more vaccine antigens can also be delivered by a viral vector, such as modified vaccinia virus Ankara (MVA) that was safely used in humans at the end of the smallpox eradication campaign.

Some vaccines are designed to boost immunity using only selected antigens or by using a different delivery route. For example, some new TB vaccines in development would boost the immunity induced by BCG by giving key antigens delivered by a viral vector (Fig. 34.4), or a fusion protein with adjuvant.

Figure 34.4 It is now possible to insert genes coding for antigens of one or more microorganisms into a large virus such as modified vaccinia virus Ankara (MVA), so that they replicate and are released into the host. A new MVA vaccine is currently being developed for TB that expresses a secretory TB protein.

Recipients of haemopoietic stem cell transplants may need to be revaccinated after the infusion of haemopoietic stem cells, as otherwise antibody titres to vaccine-preventable diseases decline.

Adjuvants

Adjuvants increase the immunity induced by a vaccine in a number of ways. Adjuvants can improve the immune response to the vaccine antigens through inducing activation of Toll-like receptors (TLR) on dendritic cells to improve antigen presentation, or by forming an antigen depot which allows antigen to persist and to leak out slowly over time. The earliest adjuvants consisted of water in oil emulsions, and Freund’s complete adjuvant which included dead mycobacteria in a water in oil emulsion is very effective, although not suitable for use in humans. Other adjuvants increase antigen presentation, or enhance particular types of immunity, such as antibodies or Th1 immunity. The dramatic effect of adding an adjuvant to a vaccine is shown in Figure 34.5. Aluminium salts are powerful adjuvants and used in many vaccines (Box 34.2). Experimentally, cytokines such as IL-1, IL-2, IFNγ, IL-12 and IL-18, as well as some chemokines, have been tested as adjuvants. Compounds such as liposomes, lipid containing vesicles, have also been used, but so far only monophosphoryl lipid A has been used in a licensed vaccine (HPV, Cervarix).

Figure 34.5 Effects of adjuvants on antibody responses of mice to egg albumin. Mice were injected subcutaneously with egg albumin in saline or in Freund’s incomplete adjuvant. Antibody titres at intervals over time are shown. The blue symbols represent antigen in saline, and the red symbols antigen in adjuvant.

(Redrawn from: Hunter, R. (2002) Vaccine 20:S7–S12.)

Box 34.2 Adjuvants in Currently Used Vaccines

Aluminium salts*	DTaP, Hib, HepA, HepB, HPV, MMR, rabies, rotavirus, rubella, varicella
Monophosphoryl lipid A (MPL)	HPV (Cervarix)

^* aluminium hydroxide, aluminium hydroxyphosphate sulphate, aluminium phosphate, aluminium potassium sulphate

Vaccine safety

As vaccines are given to healthy individuals, it is important that they are safe. In 1926, live M. tuberculosis was inadvertently given to healthy children instead of BCG, leading to the Lubeck disaster, and in 1942, US military personnel were vaccinated with yellow fever virus contaminated with hepatitis B virus (see Ch. 15). Safety testing is now rigorous, requiring extensive quality controls and animal testing, prior to trials or use in humans. Some of the more important issues are summarised in Box 34.3. It is particularly critical that vaccines derived from live organisms are inactivated to ensure they are safe and that vaccines are preserved appropriately to ensure that vaccine immunogenicity is retained. Examples of fixatives and preservatives used in current vaccines are given in Table 34. 3.

Vaccines in current use

Diphtheria, tetanus and pertussis

The diphtheria vaccine consists of the inactivated toxoid. Toxigenic Corynebacterium diphtheriae is grown in liquid culture and the filtrate inactivated with formaldehyde to produce the toxoid. This is a highly effective vaccine, giving > 90% protection. Three or four doses are required to give good protection, with a booster every 10 years. It is now given in different formulations with other vaccines.

The inactivated toxin from Clostridium tetani, inactivated using formaldehyde, is used to vaccinate against tetanus. Tetanus toxoid was first produced in 1924. Again, this is a very effective vaccine, but boosters are required every 10 years. In some developing countries neonatal tetanus is still a problem; if the mother has been immunized against tetanus this will protect the newborn baby but, in 2009, the World Health Organization estimated that only 83% of newborn babies were protected against neonatal tetanus.

The first vaccine developed against pertussis was a whole cell vaccine, which was available from the mid 1940s and introduced in the UK in 1957 (Fig. 34.6). However, although four doses of vaccine induced 70–90% protection against serious whooping cough, concerns over the safety of the vaccine in the UK in the 1970s led to resurgence of disease. Whether the vaccine did induce brain damage is unclear, but concerns did lead to the development of a safer acellular pertussis vaccine.