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# (p. 189) Immunization

Immunization
Chapter:
Immunization
DOI:
10.1093/med/9780198745471.003.0019
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## Overview

After reading this chapter the reader will be familiar with:

• the importance of continuing immunization in the context of declining vaccine preventable diseases incidence,

• the types of vaccine that are currently in use,

• the common components of vaccines and why they are needed,

• the UK immunization programme and its objectives, and

• vaccine side-effects, adverse events, and contraindications.

## 19.1 Introduction to immunization

Vaccines have had a huge impact on human health and may, justifiably, be regarded as the medical intervention that is second only to safe drinking water in reducing deaths and disease. Vaccines utilize the body’s natural defence systems to protect against a number of specific pathogens that have the potential to cause serious disease. Using either attenuated or non-disease-causing components of microbes, they activate the immune system to provide protection before natural exposure to the pathogens can occur.

Vaccines have been used in various forms since around the tenth century ad, when Chinese and Indian physicians provided protection against smallpox using either dried crushed smallpox scabs, which people inhaled, or blister fluid inoculated intradermally (scarification, also known as variolation). Although not without risk (5–20% of recipients developed smallpox; 2–3% died), the benefits of such approaches were evident during smallpox epidemics when death rates were as high as 50% in the unprotected. In the late eighteenth century Edward Jenner introduced a safer approach to smallpox control by using a similar virus from cows (‘cowpox’), with comparable protection but fewer side-effects.

Strictly speaking, the process of generating an immune response to any disease is termed immunization, whereas vaccination refers to the same process for protection against smallpox using cowpox vaccine (vacca means cow in Latin). However, the terms vaccination and immunization continue to be used interchangeably.

## 19.2 Why immunize?

It is important to consider the reasons for continuing with immunization programmes as the diseases and infections caused by vaccine-preventable diseases continue to decline.

Below is an outline of the main reasons for continuing with vaccination and immunization programmes in the face of declining rates of vaccine-preventable diseases/infections.

### 19.2.1 Vaccines work

Vaccines are very effective. They may be used to eradicate disease, as happened with smallpox in 1980 and may soon happen with polio. Alternatively, they may reduce disease occurrence as seen after the introduction of diphtheria vaccine. A similar situation is seen with invasive Haemophilus influenza b (Hib) disease, the commonest cause of bacterial meningitis prior to the introduction of Hib vaccine in 1992, with annually reported cases in the UK having dropped from 850 prior to the introduction of vaccine to 19 in 2013, the majority (17) of which were in those aged >15 years (Table 19.1).

Table 19.1 Vaccination impact on disease incidence in England & Wales (E&W) and the United States (US)

Disease

Cases per year before vaccination (pre-vaccine era)*

E&W (cases in 2010) USA (cases in 2005)

% Reduction

Diphtheria

E&W = 75,000

E&W = 1

E&W = 99.9%

US = 175,885

US = 0

US = 100%

Measles

E&W = 763,531

E&W = 380

E&W = 99.9%

US = 503,282

US = 66

US >99.9%

Pertussis (whooping cough)

E&W = 170,000

E&W = 1519 (2008 data)

E&W = 99.1%

US = 147,271

US = 25,616

US = 82.6%

Polio (wild)

E&W = 7,760

E&W = 0

E&W = 100%

US = 16,316

US = 0

US = 100%

Rubella

E&W = Not Known

E&W = 12

E&W >99.9%**

US = 47,745

US = 11

US >99.9%

Tetanus

E&W = Not Known

E&W = 4 (2008 data)

E&W >99.7%**

US = 1,314

US = 27

US = 97.9%

Invasive Hib disease

E&W = 850

E&W = 37 (2009 data)

E&W = 95.6%

US = 20,000

US = 9

US >99.9

* Maximum cases reported or estimated annually in pre-vaccine era.

** Based on US data.

Source: data from Centers for Diseases Control and Prevention (CDC). Summary of Notifiable Diseases—United States, 2005. Morbidity and Mortality Weekly Report (MMWR), Volume 54, Issue, 53: pp. 2–92, Copyright © 2007 CDC, http://www.cdc.gov/mmwr/preview/mmwrhtml/mm5453a1.htm; Yeh S and Lieberman J, Update on adolescent immunization: Pertussis, meningococcus, HPV, and the future. Cleveland Clinic Journal of Medicine, Volume 74, Issue 10, pp. 715, Copyright © 2007 Cleveland Clinic; Public Health England. Notification of Infectious Diseases (NOIDS): Notifiable diseases: annual totals from 1982 to 2014, © 2012 Crown Copyright, https://www.gov.uk/government/publications/notifiable-diseases-historic-annual-totals; Public Health England. Notifiable diseases: annual totals from 1912 to 1981, © 2012 Crown Copyright, https://www.gov.uk/government/publications/notifiable-diseases-historic-annual-totals

### 19.2.2 Improvements in sanitation don’t eliminate infection risk

The major public health successes of the eighteenth to twentieth centuries (clean drinking water, efficient sewage disposal, nutritional improvement, and reduced overcrowding) were the foundation of the improvement in health in the more affluent nations. However, these measures do not necessarily reduce either the frequency or impact of those infectious diseases where human behaviour, or a zoonotic/environmental reservoir, are key risk factors. Respiratory viruses like influenza are almost impossible to control by sanitation alone; sexually transmitted diseases, including human papilloma virus (HPV), are spread by human behaviour; and tetanus spores are widely distributed in the natural environment. Influenza, HPV, and Tetanus Toxoid vaccination can control but not eliminate these different infections.

### 19.2.3 The body’s defences do not always protect against disease

A baby’s defences against infection can remain immature for weeks or months after birth. Vaccination is a key protective measure during this potentially dangerous period. The immune system of a baby exposed to a pathogen may not protect it, but maternally derived antibodies, passively transferred before birth, i.e. specific antibodies, will provide enough protection until its immune system has matured sufficiently to protect it.

A similar situation, although due to different mechanisms, is found in older people who have an increased risk of infection and although they may not mount a particularly effective immunological response when vaccinated, nevertheless even suboptimal protection is useful.

Hepatitis B is an example of an infection against which the immune system at birth is less able to provide protection. As many as 90% of babies born to a mother who is a carrier of the virus will themselves become carriers because of exposure to infected maternal blood at or around the time of birth (PHE 2013a). However, hepatitis B vaccine and hepatitis B immunoglobulin are highly effective at preventing an exposed baby from becoming infected.

Polio is an example of a viral illness against which most peoples’ immune systems are generally highly effective at providing protection. When large outbreaks of polio occurred in England and Wales from the 1940s to the early 1960s, most people who had polio virus infection either recovered without developing any obvious clinical signs and symptoms or had a influenza-like illness with fever and diarrhoea, which got better on its own. However, a few developed viral meningitis, and a small number (perhaps 1 in a 1000) developed paralytic disease, many of whom died (Christie 1948).

If newborns were exposed to polio, their immune system would be unlikely to protect them (as with hepatitis B) but maternally derived passively transferred antibodies would generally protect them until the immune system had matured sufficiently to provide protection.

### 19.2.4 Changing lifestyles increase our infection risk

International travel has increased, including travel to exotic areas with exposure to unfamiliar bacteria and viruses. Yellow fever, rabies, tick-borne encephalitis, and Typhoid are several examples of travel-associated vaccine-preventable infections. Hepatitis A might also be included, because more recent improvements in sanitation in high-income countries in the past 50 years have substantially reduced the numbers of childhood infections, resulting in fewer immune adults and so a greater infection risk to travelling adults.

Furthermore, for some vaccine-preventable diseases, the destination country may require proof of certain vaccinations before allowing entry. Travel to a yellow fever area will require prior vaccination if the individual has previously been in an endemic area. Travel by pilgrims to the Hajj and Umra requires meningococcal ACWY vaccination before the Kingdom of Saudi Arabia will issue an entry visa.

### 19.2.5 Pathogen mutation

Bacterial and viral mutations continue to challenge and reduce the effectiveness of available drugs and vaccines. For example, influenza viruses evade immune responses by changing the antigenic structure of two key surface molecules: Haemagglutinin, which attaches to cell surfaces and initiates infection, and Neuraminidase, which enables newly formed viral particles to exit an infected cell and spread infection. Consequently, some components of the Influenza vaccine are changed annually, resulting in the need to administer the vaccine each year. The development of penicillin resistance by up to 7% of Streptococcus pneumoniae species of the reported invasive isolates in England and Wales (George and Melegaro 2001, 2003) provides further justification for the routine use of conjugate pneumococcal vaccine in infancy.

### 19.2.6 Reducing occupational risk

Particular occupations can increase the risk of infection. For healthcare workers that risk involves bloodborne viruses like hepatitis B, and the potential to both acquire the infection from and spread it to patients.

As the workforce ages, more people are being employed who have an impaired immune system, resulting in the challenge of how to protect them and enable them to continue working. Although vaccines do not necessarily work particularly well in all individuals with an impaired immune response, nevertheless they provide good protection for a significant proportion (including the older population) from vaccine-preventable disease such as influenza and pneumococcal pneumonia.

Many people will become carers at some point. Vaccination may help carers remain well. A good example of this would be the UK recommendation that registered carers receive an influenza vaccine annually (Public Health England 2013b).

## 19.3 Different types of vaccine

In the UK, there are four types of commercially available vaccines classified by their immunogen as:

• toxoid,

• killed/inactivated,

• subunit, and

• live attenuated.

### 19.3.1 Toxoid vaccines

Tetanus and diphtheria are bacterial infections in which disease is caused by a bacterial-secreted toxin that either impairs cell function (tetanus) or kills cells (diphtheria). Some infections, for example, whooping cough, appear to be partly toxin-mediated.

Tetanus Toxoid (TT) vaccine is manufactured by growing a Clostridium tetani (C. tetani) strain that produces large amounts of toxin. The toxin is separated off and treated with formaldehyde to convert it into a toxoid, which is structurally similar to the wild toxin, but can induce cross-reacting antibodies. The changes produced by formaldehyde render it non-toxic. The rationale for tetanus vaccination is based on generating antibodies against the toxoid, which binds the wild toxin and prevents disease development in the event of exposure to C. tetani.

Because the incubation period for tetanus can be as short as 24hrs, it is important that tetanus antibodies constantly circulate throughout the bloodstream: hence the need to ensure completion of the five-dose programme for life-long immunity. Diphtheria toxoid vaccine works in the same way, by inducing cross-reacting antibodies that act to neutralize the wild Corynebacterium diphtheriae toxin, as in the case of tetanus vaccine.

Pure toxoid vaccines are weakly immunogenic, i.e. the immune response to them is limited. This has the obvious advantage that they rarely cause any serious side-effects or adverse events following vaccination, but it also means that the levels of antibody generated are low. In order to achieve an effective and long-lasting immune response, an adjuvant (see section 19.4.2) is added, which results in high and protective antibody levels.

There are two principal advantages of toxoid vaccines:

• As the vaccine antigens are not actively multiplying they cannot cause the disease they prevent and they cannot spread to unimmunised individuals.

• When stored, they are usually stable, long-lasting, and less susceptible to changes in temperature, humidity, and light.

### 19.3.2 Killed/inactivated vaccines

The term ‘killed’ generally refers to bacterial vaccines, whereas ‘inactivated’ is used to describe non-replicating viral vaccines. Typhoid was one of the first killed vaccines to be produced and was used in the British army at the end of the nineteenth century. Polio and hepatitis A are currently the most commonly used inactivated vaccines in the UK. In many countries whole cell whooping cough vaccine, used in the UK until 2004, continues to be the most widely used killed bacterial vaccine.

Killed/inactivated vaccines share the same advantages as toxoid vaccines and, in addition, as they contain the whole virus/bacteria, all the antigens associated with infection are present and will result in antibodies being produced against each of them. Killed/inactivated vaccines usually require several doses, as one dose does not give a strong signal to the immune system because the microbes are unable to multiply in the host.

A local inflammatory reaction at the vaccine site and a fever are quite common side-effects.

### 19.3.3 Subunit vaccines

Subunit vaccines are a more recent development of the killed vaccine approach. However, instead of generating antibodies against all the components of the pathogen, a particular component (or combination) is used and the antibody produced neutralizes or kills the micro-organism to prevent infection. The key requirement is to identify that particular immunogen (see section 19.4.1), or combination of immunogens, which generate antibodies to prevent infection.

Haemophilus influenza b (Hib) is an example of a bacterial subunit vaccine that uses only one immunogen (the polysaccharide capsule). The hepatitis B vaccine also uses only one protein from the viral surface produced using recombinant DNA technology. Influenza vaccine has two immunogens (both viral surface proteins).

Subunit vaccines are very safe, with the most common side-effects being a local reaction at the vaccine site and a fever, and by and large most subunit vaccines produce long-term protection.

### 19.3.4 Live attenuated vaccines

The vaccines described above only generate antibodies. However, antibodies do not usually cross cell membranes and so provide little or no protection against those micro-organisms that live and replicate inside cells, including all viruses. A complementary approach to immunization is required in this situation and this is provided by the use of live attenuated vaccines, which generate special cells (T lymphocytes) that are able to kill virus infected cells.

Variolation against smallpox, described earlier, worked because the micro-organism used was naturally weakened, a process termed ‘attenuation’.

Measles, mumps, and rubella, as MMR, are live attenuated viral vaccines used in the UK children’s immunization programme. BCG is a live attenuated bacterial vaccine, providing some immunity against disease progression and the extra-pulmonary forms of tuberculosis.

The administration of live attenuated measles vaccine imitates the natural infective process with both antibody and cytotoxic T-cells being generated. Serious illness very rarely results, because attenuation has made the measles virus multiply so slowly that these protective mechanisms eliminate the virus before it can cause typical disease. Features of clinical illness may develop but they are usually very mild and require no treatment.

An individual adequately immunized against measles will have both specific antibodies and cytotoxic T-cells in their body so that when wild measles virus is inhaled, cells infected by virus at the site of infection are killed by cytotoxic T-cells: measles viruses that evade these and spread through the bloodstream are then eliminated because antibodies bind to the virus particles and neutralize them.

One disadvantage of live attenuated vaccines is the possibility that they may cause serious features of the illness they are designed to prevent, either because they revert to a more virulent form, or because, for some individuals (e.g. the immunosuppressed), they are insufficiently attenuated. This is, however, an extremely rare occurrence (Mäkelaä et al. 2002; Demicheli et al. 2012).

Until recently it was advised that live attenuated vaccines should normally be given on the same day or four weeks apart, because of concerns that interferon (a cytokine produced in response to exposure from a wild or vaccine virus), may prevent the replication of the second vaccine virus (PHE 2013c). However due to the different immune mechanisms of the various live vaccines used currently this is no longer generalizable. Current advice is that intervals between vaccines should be based on specific evidence for any interference of those vaccines (PHE 2015a). All vaccines with the exception of MMR, yellow fever and chickenpox vaccines, can be given at any time before or after each other—however, yellow fever and MMR vaccines must not be administered on the same day, and chickenpox and MMR vaccines should be given on the same day or if administered separately, a gap of four weeks between them should be observed. When live vaccines are given simultaneously, an appropriate immune response will be mounted to each vaccine immunogen.

In addition, live vaccine should not normally be given in pregnancy or to the immunocompromised, due to the potential but rare risk of vaccine-induced infection. As a precaution, non-live vaccines (excluding influenza, diphtheria, tetanus, whooping cough and inactivated polio) should also be avoided in pregnancy. However, if the risk of infection is considered high further expert advice about their suitability should be sought.

A summary table of some currently available vaccines in the UK, by type of vaccines, is presented in Table 19.2.

Table 19.2 Summary of vaccine types with examples of currently available vaccines in the UK

Vaccine type

Immunogen

Vaccine name example

Toxoid

Diphtheria

Pediacel; Repevax; Infanrix-IPV; Revaxis

Tetanus

Pediacel; Repevax; Infanrix-IPV; Revaxis

Cholera

Dukoral

Killed/Inactivated

Poliomyelitis

Pediacel; Repevax; Infanrix-IPV; Revaxis

Hepatitis A

Avaxim; Epaxal; Havrix monodose; Havrix monodose; Vaqta Paediatrics; Vaqta Adult

Rabies

Rabies Vaccine BP; Rabipur

Japanese encephalitis

Ixiaro

Tick-borne encephalitis

TicoVac

Typhoid

Vivotif

Subunit

Hepatitis B

Engerix B; Fendrix; HBvaxPRO; HBvaxPRO Paediatrics; HBvaxPRO 40; Twinrix Adult (HepA&B); Twinrix Paediatrics (HepA&B)

Pneumococcal conjugate

Prevenar13, Synflorix

Pneumococcal polyvalent polysaccharide

Pneumovax Polysaccharide Vaccine

Meningococcal Group C conjugate

NeisVac-C; Menjugate Kit; Menitorix

Meningococcal Group B

Bexsero

Meningococcal ACWY polysaccharide

ACWY Vax

Meningococcal ACWY conjugate

Menveo, Nimenrix

Human Papilloma Virus

Gardasil; Cervarix

Haemophilus influenza type B

Pediacel

Pertussis

Pediacel

Influenza

Influvac

Typhoid

Typhim Vi (polysaccharide vaccine);

Hepatyrix (HepA&Typhoid)

ViATIM (HepA&Typhoid)

Typherix (Typhoid)

Live Attenuated

Rotavirus

Rotarix

Tuberculosis

BCG

Measles; Mumps; and Rubella

MMRvaxPro; Priorix

Influenza

Fluenz Tetra

Varicella (Chickenpox)

Varilrix; Varivax;

Shingles

Zostavax

Typhoid

Vivotif

Yellow Fever

Stamaril

## 19.4 Vaccine components

Vaccines may contain up to three separate groups of components:

• the immunogen,

• active components/ingredients, and

• residuals from the manufacturing process.

### 19.4.1 Immunogen

An immunogen is the vaccine ingredient that gives rise to the adaptive immune response. It is so called because it GENerates an adaptive IMMUNe system response, which has both antibody- and T-cell components. It is sometimes called an antigen, which is slightly different. An antigen GENerates an ANTIbody response only. Strictly speaking, in the context of live attenuated vaccines, immunogen is the more appropriate term.

Immunogens are derived from the appropriate disease-causing bacteria or viruses.

### 19.4.2 Active components

These are ingredients that have a defined use(s) within the vaccine and comprise:

• carrier proteins,

• stabilizers,

• preservatives,

• buffers, and

• solvents (or diluents).

In order to ensure that they are safe and cannot cause serious adverse effects, most vaccine antigens/immunogens are weakened and do not give rise to strong protective immune responses. Therefore, vaccine manufacturers may add an adjuvant: an ingredient that helps the immunogen generate an adequate and protective response. The most commonly used adjuvants are aluminium hydroxide or aluminium phosphate, and these have been used in vaccines for more than 70 years (Centers for Disease Prevention and Control 2015).

#### 19.4.2.2 Carrier proteins

A number of ‘pure’ bacterial or viral components are composed of carbohydrate molecules which are not recognized by T-cells and are thus in some ways immunologically inert. However, they can be modified by linking or conjugating them to a large-molecular-weight carrier protein, which makes them very effective vaccine immunogens because they can now activate T-cells. Typical carrier proteins are Tetanus Toxoid or the mutant diphtheria toxin, CRM197. Vaccines with carrier proteins are known as conjugate vaccines (e.g. Hib, Men C, and Pneumococcal Conjugate Vaccine (PCV)).

#### 19.4.2.3 Stabilizers

These enable the vaccine to remain unchanged in the presence of factors (e.g., heat, light, humidity, acidity) that could cause deterioration in the vaccine’s efficacy. Lactose is a common stabilizer.

#### 19.4.2.4 Preservatives

These are compounds that kill or prevent the growth of micro-organisms, particularly bacteria and fungi. They are used in vaccines to prevent microbial growth in case the vaccine is accidentally contaminated. A common preservative is 2-phenoxyethanol. Thiomersal, which contains small amounts of mercury, can be used; however, there have been theoretical concerns regarding toxicity related to the use of Thiomersal. Following a comprehensive review of the evidence. the WHO has published a statement confirming the safety of Thiomersal in vaccines (WHO 2006). Currently, no vaccines in the UK childhood programme contain Thiomersal.

#### 19.4.2.5 Buffers

These are added to resist changes in pH, adjust tonicity, and maintain osmolarity that might affect the effectiveness of vaccines when they are injected into subcutaneous or muscle tissue (intramuscular). A common buffer used in vaccines is sodium chloride.

#### 19.4.2.6 Solvents

These are needed to ensure that all the vaccine ingredients are at the correct concentration in the final product. The commonly used solvents are saline or sterile water.

### (p. 197) 19.4.3 Residuals from the manufacturing process

Residuals include antibiotics, emulsifiers, and vaccine production media in extremely low concentrations, usually parts per million or billion.

• Antibiotics are added to cell cultures to prevent extraneous bacteria damaging the vaccine during its manufacture. Common ones are neomycin, polymyxin, and streptomycin.

• Emulsifiers are needed for vaccines with an oil-in-water adjuvant because the oil will not mix with the water in its absence. Polysorbate 80 (Tween), which is made from sorbitol and oleic acid, is commonly used.

• Vaccine production media: vaccine immunogens are made in a variety of production media, and residuals of the growth media may be present. Polio can be grown in cultures of kidney cells, some proteins which may be present in the vaccine following production.

## 19.5 Side-effects, adverse events, and unrelated events post immunization

Side-effects are known and expected outcomes that occur after vaccine administration. In contrast an adverse event is a response that is both harmful and unintended and which occurs at the normal dose. Unrelated events comprise any outcomes, which are not a direct or indirect effect of the vaccine.

• Side-effects: these are commonly seen after vaccination and result from a direct effect of the vaccine immunogen or any of the vaccine components. For example, local redness and swelling at the injection site, or fever, due to an acute but expected inflammatory response.

• Adverse events: these are rare and unusual occurrences after vaccination, resulting from an immune mediated hypersensitivity reaction (e.g. anaphylaxis).

• Unrelated events: these events would have occurred whether the person would have been vaccinated or not – they are not caused by the administered vaccine.

Detailed information on individual vaccine side-effects and adverse events are documented in the Summary of Product Characteristics supplied with the vaccine or on the Electronic Medicines Compendium website (http://www.medicines.org.uk/emc/).

## 19.6 Vaccine contraindications

The (very few) contraindications to any vaccination are:

• previous anaphylactic reaction to the vaccine antigen or any other vaccine component,

• acute and systemic illness (acute febrile illness) on the intended day of vaccination, postpone until they have recovered, or

• an evolving neurological disorder or current neurological deterioration, including poorly controlled epilepsy, immunization should be deferred until the condition stabilizes—seek advice.

For live attenuated vaccines, extra contraindications are:

• immunosuppression or pregnancy (individual risk assessment is needed).

## 19.7 Vaccination programme objectives

The objectives of a vaccination programme are disease eradication, elimination, local control, or protection of special groups.

• Eradication describes the permanent removal of the causal organism from the world. This happened with smallpox in the 1970s and should happen with polio in the next few years. Disease eradication requires a human-only pathogen, a vaccine with a high protective efficacy, global vaccine uptake rates resulting in both high individual coverage and herd protection (vaccination of a significant portion of a population providing protection for non-immune individuals), and a readily recognizable early disease state so that affected individuals can be isolated to prevent further disease transmission.

• Elimination refers to complete disease removal at a country level. The requirements are the same as for eradication with the exception that once a disease has been eliminated vaccination is still required at levels that prevent disease spread because of the potential for reintroduction from endemic countries. The UK was declared polio free by the WHO in 2002 (WHO 2002).

• Local control describes the reduction of disease frequency to acceptable lower levels. Tetanus is an example because the organism is ubiquitous in the environment, so cannot be eradicated.

• Protection of special groups is similar to local control and is the objective of the influenza vaccination programme. Influenza virus constantly mutates, there is an animal source of infection, and the available amounts of vaccine considerably limit the numbers of people who can be immunized.

## 19.8 The developing UK immunization programme

The introduction of new vaccines in the UK has usually been in response to an identified epidemiological need, such as epidemics causing extensive morbidity and mortality. It is also influenced by the technological expertise in developing vaccines. An understanding that a toxin caused diphtheria led to the development of the toxoid vaccine in the early twentieth century. The ability to predict and subsequently identify bacterial proteins involved in disease pathogenesis led to the development of the new meningococcal B vaccine licensed in 2014.

Adults vaccinated as babies between the 1960s and 1980s generally received diphtheria, tetanus, whooping cough, and polio vaccines: protection was against eight diseases (including three whooping cough and three polio types) but used about 3,600 immunogens, because of whole cell whooping cough and polio vaccines, which contained all their pathogens’ components. A baby born in 2011 will have received diphtheria, tetanus, whooping cough, polio, meningitis type C, Hib, and pneumococcal vaccines: protection was against 23 infections (including 13 pneumococcal types) but fewer than 100 immunogens, and better protection was associated with significantly fewer vaccine components, due to the development of subunit vaccines. The immune system can theoretically deal with tens of thousands of immunogens, but this complex discussion is rarely needed if it is understood that it is the immunogen content rather than the number of vaccines that matters in generating an immune response. This addresses the misconception around ‘overloading the immune system with multiple vaccines’.

From the mid twentieth century, the UK national immunization programme (https://www.gov.uk/government/collections/immunisation) was initially focused on infants and young children with the aim of eliminating diseases like diphtheria, tetanus, whooping cough, polio, and tuberculosis. As these became better controlled, programmes to eliminate measles, rubella, certain forms of meningitis, pneumonia, and influenza were introduced, with considerable expansion of the programme into adolescence, young adulthood, and the elderly. More recently, targeted programmes to address occupational, travel, and patients at risk because of underlying diseases have been introduced, and vaccination is now considered to be a life-long activity. Table 19.4 shows the current England and Wales adolescent and adult immunization programme.

Table 19.4 UK adolescent and adult vaccination programme, from September 2015

UK adolescent and adult vaccination programme 2015

Programme and vaccine

Age

16–24

25–64

65–69

70–79

≥80

Universal

TdIPV

5 doses for lifetime protection

MMR

2 doses for lifetime protection

Not likely to be required for those born before 1970, as they are less likely to be susceptible

Shingles

Not recommended

70-, 78-, and 79- year-olds on September 1st

1 dose Zostavax for 70 (routine) and 78/79 (catchup) year olds from September 2014

Targeted

Men B

Give one dose to splenectomized individuals

Currently is Bexsero

Men C

1 dose if not previously given. If a dose is received <10 years of age, booster dose between 13–18 years or before starting higher education.

Not recommended

Meningococcal C was replaced by quadrivalent conjugate ACWY vaccine from August, 2015, i.e. due to increases in MenW cases in the UK

Pneumococcal

For at-risk groups 1 dose or 5 yearly*

Universal 1 dose

*5 yearly if in a group whose antibodies would be expected to drop more quickly

Influenza

1 dose annually for at risk groups

Universal annually

Children aged 6 months to < 9 years who are in clinical risk groups and not received influenza vaccine previously should be offered a second dose

HPV

3 doses*

Not recommended

*Females up to 18 years

BCG

1 dose*—up to 35 years (DH), or 65 years (NICE)

*If in at risk group

Varicella

adolescents (≥13 years) and adults 2 doses*

*If in at risk group—no data on use in elderly

Pertussis

1 dose*

Not recommended

*All pregnant women ≥ 20 weeks

Occupational/travel

Hepatitis A

2 doses for long-term protection

The second between six and twelve months after the first dose

Hepatitis B

3 doses with post serology if Chronic Renal Failure (CRF)

Post serology if CRF or occupational

In 2015, a baby born in the UK, by 13 months of age, will have been offered a number of highly effective and very safe vaccines that provide protection against 31 different bacteria and viruses, including MenB and rotavirus, again using only about 100 immunogens (Table 19.3).

Table 19.3 Baby/child/adolescent vaccine schedule, UK (from September 2015)

Age

Vaccine

Birth

• Hepatitis B (HBV)

• Tuberculosis (BCG)

• Intramascular (IM)

Risk groups only

2 months

• Diphtheria, tetanus, acellular pertussis (whooping cough), Haemophilus influenza type b, inactivated poliomyelitis (polio) (DTaP-Hib-IPV)

IM

IM vaccine administered antero-lateral aspect of thigh

• Pneumococcal conjugate (PCV)

IM

IM vaccine administered antero-lateral aspect of thigh

• Meningococcal B (Men B)

IM

Introduced in 2015

• Rotavirus (Rotarix)

Oral

3 months

• Diphtheria, tetanus, acellular pertussis (whooping cough), Haemophilus influenza type b, inactivated poliomyelitis (polio) (DTaP-Hib-IPV)

IM

IM vaccine administered antero-lateral aspect of thigh

• Meningococcal C (Menjugate Kit or NeisVac)—to be removed in 2016

IM

IM vaccine administered antero-lateral aspect of thigh

• Rotavirus (Rotarix)

Oral

4 months

• Diphtheria, tetanus, acellular pertussis (whooping cough), Haemophilus influenza type b, inactivated poliomyelitis (polio) (DTaP-Hib-IPV)

IM

IM vaccines administered antero-lateral aspect of thigh.

• Pneumococcal conjugate (PCV)

IM

IM vaccines administered antero-lateral aspect of thigh

• Meningococcal B (Men B)

IM

Introduced in 2015

One year old

• Haemophilus influenza type b/Meningococcal C (Menitorix)

IM

IM vaccines administered antero-lateral aspect of thigh

• Pneumococcal conjugate (PCV)

IM

IM vaccines administered antero-lateral aspect of thigh

• Meningococcal B (Men B)

IM

IM vaccines administered antero-lateral aspect of thigh

• Measles, Mumps, Rubella (M-M-RVAXPRO)

IM or SC (Subcutaneous)

IM vaccines administered antero-lateral aspect of thigh

2 years

• Influenza vaccine (reassortant, live attenuated) (Fluenz tetra)

Nasal spray

3 years

• Influenza vaccine (reassortant, live attenuated) (Fluenz tetra)

Nasal spray

4 years

• Influenza vaccine (reassortant, live attenuated) (Fluenz tetra)

Nasal spray

3 years 4 months or soon thereafter

• Diphtheria, tetanus, acellular pertussis (whooping cough), inactivated poliomyelitis (polio) (dTaP-IPV)

IM

Vaccine administered in deltoid

• Measles, Mumps, Rubella (M-M-RVAXPRO)

• IM or

• SC (Subcutaneous)

Vaccine administered in deltoid

5 years

• Influenza vaccine (reassortant, live attenuated) (Fluenz tetra)

Nasal spray

School Year 1

6 years

• Influenza vaccine (reassortant, live attenuated) (Fluenz tetra)

Nasal spray

School Year 2

12–13 years

• Human Papilloma Virus Vaccine (Gardasil). A two-dose schedule is recommended in girls under 15 years—second dose at least 6 months after the first dose. If course commenced late, girls aged 15 years and over should receive a three-dose schedule

IM

Female only programme Vaccine administered in deltoid

14 years (around)

• Meningococcal C (replaced by quadrivalent conjugate ACWY vaccine in August, 2015)

IM

Vaccine administered in deltoid

14 years (around)

• Diphtheria, tetanus, inactivated poliomyelitis (polio) (dT-IPV)

IM

Vaccine administered in deltoid

14 years (around)

• Measles, Mumps, Rubella (M-M-RVAXPRO) (Catch-up if not received two doses previously)

IM or SC

Vaccine administered in deltoid

Source: data from Public Health England. The complete routine immunisation schedule from summer 2014 (London: Public Health England, 2014), © 2014 Crown Copyright, https://www.gov.uk/government/publications/the-complete-routine-immunisation-schedule, accessed 2 Jun. 2015.

Diphtheria, tetanus, whooping cough, polio, and measles vaccines are core vaccines offered in all WHO countries. Other vaccines are added to this, partly as determined by the disease’s epidemiology and the status of other preventable disease programmes, partly by the strength of the current immunization programme and health system, including availability, performance, and funding, and partly by vaccine availability. For example, in Nigeria yellow fever vaccine is offered to infants because the disease is endemic; in Japan the Japanese encephalitis vaccine is offered universally beginning at 3 years of age for the same reason (http://apps.who.int/immunization_monitoring/globalsummary).

In addition, the public and private sector have come together internationally in the GAVI alliance with the aim of ‘Saving children’s lives and protecting people’s health by increasing access to immunisation in developing countries’ (GAVI the Vaccine Alliance 2015). They have made great progress with introducing some of the more costly vaccines into poor countries with high disease burden, most recently HPV vaccine (GAVI the Vaccine Alliance 2014).

## 19.9 Vaccine efficacy and effectiveness

One way of quantifying how well a vaccine prevents disease is to calculate its protective efficacy (PE). In a randomized controlled trial, where equal numbers receive vaccine and placebo, all subjects are followed for the same length of time, and none are lost to follow-up, PE (as a %) is calculated as:

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The above formula measures the proportionate reduction in disease incidence following the introduction of a vaccine. Vaccine effectiveness is a similar measure but estimates how good a vaccine is under the real conditions of everyday use.

## 19.10 Conclusions

Immunization is a highly successful public health programme that protects infants, children, adolescents, adults, and the elderly against a range of common, and not so common, infections.

The success is such that health workers in the UK no longer see the infections that caused hundreds of thousands of deaths and sickness among the population in the mid-twentieth century.

With the knowledge acquired from vaccination against infections about how the immune system functions, it is very likely that the role of immunisation will expand in the near future to treat other diseases, including chronic diseases and cancers.

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