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Immunization
DEFENCE AGAINST INFECTION
Immunization
What’s new?
Matthijs Backx C
Andrew Freedman C C
Pneumoccoccal conjugate vaccine introduced into childhood immunization schedule Human papillomavirus vaccine introduced for girls aged 12e13 Routine BCG vaccination for children aged 10e14 discontinued
Abstract Immunization against infectious agents to induce a specific, protective immune response can be achieved actively or passively. Passive immunization is the administration of preformed protective antibodies; this immunity is short lived. Active immunization involves the administration of antigens to induce humoral and/or cell-mediated immune responses to a specific micro-organism; this provides more enduring immunity. The first description of active immunization is attributed to Edward Jenner, who, in 1796, induced protective immunity to smallpox by inoculating cowpox (vaccinia) vesicle fluid into the skin of susceptible individuals, though inoculation against smallpox was a Middle Eastern technique that had already been publicized in Western Europe by Lady Mary Wortley Montagu (1689e1762). The successful global eradication of smallpox in the late 1970s is testament to the efficacy of immunization in controlling the spread of infectious diseases. There are now many vaccines in routine use, to prevent the major infectious diseases of childhood and to protect against infections encountered through travel or occupational exposure. Other vaccines are under-developed, and new techniques are being exploited to produce vaccines with enhanced efficacy and reduced toxicity.
Toxoids (e.g. diphtheria, tetanus vaccine) are bacterial toxins that have been rendered non-toxic, but retain the ability to stimulate production of antitoxin. Subunit vaccines (e.g. hepatitis B vaccine containing viral surface antigen, pneumococcal capsular polysaccharide vaccine) comprise purified fractions of micro-organisms that can stimulate protective immunity. Route of immunization Most vaccines are given by intramuscular or deep subcutaneous injection. BCG must be administered by intradermal injection, however, and rabies vaccine can also be given by this route. The Sabin live polio vaccine and Ty 21a, a live attenuated typhoid vaccine, are administered orally to mimic the natural route of infection and to induce a higher level of local mucosal immunity. Vaccine administration The precautions and contraindications that apply to vaccine administration are outlined in Table 2. Specific considerations for individual vaccines are discussed below.
Keywords immunization; infectious diseases; vaccine
Active immunization
Childhood immunizations The childhood immunization schedule currently recommended by the UK Department of Health is shown in Table 3. If a child fails to receive a vaccine at the recommended time, the vaccine should be given later rather than being omitted, because it is important that every child is fully immunized. Diphtheria vaccine is given as a component of a combination vaccine and is no longer available as a single antigen. The vaccine is prepared from cell-free formalin-inactivated Corynebacterium diphtheriae toxin, which is adsorbed onto an adjuvant (aluminium phosphate or hydroxide) to enhance its immunogenicity. A low-dose vaccine is available for adults and for children over 10 years of age, to avoid the serious reactions that can occur in those who have been immunized previously. A booster dose is recommended for travellers living or working in areas that have experienced a recent resurgence of this infection (e.g. countries of the former USSR). Tetanus toxoid is given only as a component of a combination vaccine. It is prepared by formaldehyde treatment of cell-free tetanus toxin, which is adsorbed onto an adjuvant. In addition to the primary, three-dose course of tetanus immunization, children should receive booster doses before school entry (age 3e5 years) and before leaving school (age 13e18 years). Booster doses are not recommended in adults unless they suffer a tetanus-prone wound and have not received a reinforcing dose of toxoid within the last 10 years. If required, it is given as a combination vaccine with low-dose diphtheria and inactivated polio. The vaccine
Types of vaccine Several different types of vaccine are used to induce active immunity (Table 1). Live attenuated vaccines (e.g. BCG for tuberculosis (TB), measles/mumps/rubella (MMR) vaccine) comprise bacteria or viruses that are able to infect and replicate within the host but whose virulence is reduced so that they do not cause disease. These vaccines produce long-term immunity after a single dose. However, they carry a small risk of reversion to a virulent, wildtype strain, as has been documented with Sabin polio vaccine, and are contraindicated in most immunosuppressed individuals. Inactivated whole-cell vaccines (e.g. pertussis, hepatitis A, Salk polio vaccine) contain micro-organisms that have been inactivated by physical or chemical means and retain their immunogenicity but not their infectivity. These vaccines are less effective than live vaccines at producing long-term immunity, and multiple doses are usually required. Matthijs Backx BMBS MRCP(UK) is a Clinical Research Fellow at Nottingham University, UK. Competing interests: none declared. Andrew Freedman MA MB BChir MD FRCP (Lond & Edin) is Senior Lecturer and Honorary Consultant Physician in Infectious Diseases at Cardiff University School of Medicine/University Hospital of Wales, UK. Competing interests: none declared.
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DEFENCE AGAINST INFECTION
polio viruses of types I, II and III, and three doses of either are required for primary immunization. Recipients of the oral vaccine may excrete attenuated polio virus for up to 6 weeks after a dose. This provides community benefit as contacts of recently immunized children could be protected through acquisition of vaccine virus. However, vaccine-associated poliomyelitis has occurred occasionally in recipients and their contacts when the vaccine strain has reverted to a virulent form. The risk of wild-type polio virus being imported and the benefits of oral polio vaccine (OPV) need to be balanced against the risks of developing vaccine-associated paralytic polio from OPV and the efficacy of inactivated polio vaccine (IPV). Therefore the OPV was withdrawn in 2004 and only the IPV is currently used in a combination vaccine. Haemophilus influenzae type b (Hib) vaccine comprises protein-conjugated capsular polysaccharide and is given as a combination vaccine to infants in three doses. Children aged 12 months receive a single dose of Hib vaccine in combination with the meningitis C vaccine (MenC). The vaccine is not required for those over 4 years old, because the risk of infection declines sharply above this age. Children and adults with splenic dysfunction should also receive a single dose of Hib/MenC vaccine. Introduction of the Hib vaccine caused a dramatic decrease in the incidence of invasive H. influenzae type b disease. However, doctors must remain aware that fully vaccinated infants can still develop serious H. influenzae diseases such as epiglottitis and meningitis. MMR combined vaccine is a freeze-dried preparation containing live attenuated strains of each virus. A single dose results in protective antibody responses to all three viruses in more than 90% of recipients. MMR vaccine is recommended for all children aged around 13 months, regardless of any history of previous infection with one or more of these viruses. A booster dose is given at 3e5 years. At school-leaving age, the MMR vaccine should be offered to boys and girls who have not been immunized previously, regardless of previous mumps, measles or rubella infection. It should also be offered to women of child-bearing age who are seronegative for rubella or any susceptible adult depending on their past vaccination status and future risk of exposure and disease. In 1998, a highly-publicized paper in the Lancet suggested a possible link between the MMR vaccine, bowel disease and autism. This resulted in considerable controversy and a dangerous decline in vaccine uptake in the UK. Increased measles cases and mathematical modelling prompted the Chief
Live and inactivated vaccines Inactivated whole-cell C C C C C C C C
Pertussis (whole-cell) Polio (Salk) Influenza Hepatitis A Cholera Rabies Japanese encephalitis Tick-borne encephalitis
Subunit C
Pertussis (acellular)
Haemophilus influenzae type b C Pneumococcus C Meningococcus (groups A, C, Y, W135) C Hepatitis B C Typhoid (capsular polysaccharide) C Anthrax C Human papillomavirus C
Live attenuated Measles Mumps C Rubella C Polio (Sabin) C BCG C Varicella-zoster C Yellow fever C Typhoid e oral (Ty 21a) C Smallpox Toxoid C C
C C
Diphtheria Tetanus
Table 1
should not be given to adults at intervals of less than 10 years, because severe local reactions may occur. Pertussis vaccine is an acellular vaccine made from highly purified selected components of the Bordetella pertussis organism and is given only as part of a combination vaccine. Anxieties regarding the potential neurological complications of pertussis vaccination and confusion about the contraindications led to poor uptake of the vaccine in the late 1970s and early 1980s, resulting in epidemics of the disease. The uptake is now more than 90%, however, and the incidence of infection has declined sharply. The only absolute contraindication to the vaccine is a severe generalized reaction to a previous dose. Stable neurological conditions (e.g. cerebral palsy) are not a contraindication. Immunization should be deferred in those with an evolving neurological problem until the condition stabilizes. Poliomyelitis: previously, live oral (Sabin) and enhancedpotency inactivated (Salk) vaccines were available. Both contain
Precautions and contraindications C C C C
C
C
Avoid giving any vaccine during acute febrile illness Live vaccines should not be given during pregnancy, unless the need outweighs the possible risk to the foetus Immunization should not be given to individuals with a history of serious local or general reaction to a previous dose or a component of the vaccine If more than one live vaccine is required, they should be administered at least 3 weeks apart or, if this is not possible, they should be given simultaneously at different sites Live vaccines should not be given to patients taking high-dose corticosteroids or other immunosuppressive drugs, who are receiving generalized irradiation, or who have leukaemia, lymphoma or congenital immunodeficiency Patients with HIV infection can be given measles/mumps/rubella and polio live vaccines, but should not receive BCG or yellow fever vaccines
Table 2
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Ó 2009 Elsevier Ltd. All rights reserved.
DEFENCE AGAINST INFECTION
asking about the vaccination should be given the Chief Medical Officer’s advice that: ‘MMR is the safest and best way to protect children against measles, mumps and rubella’. The pneumococcal conjugate vaccine (PCV) contains polysaccharide from seven common capsular types and is conjugated to a protein for increased immunogenicity. It was added to the routine vaccination programme in 2006 and is administered in three doses to infants 2, 4 and 13 months of age. The introduction of PCV has led to a dramatic reduction in vaccine strain invasive pneumococcal disease (Figure 1).2 Pneumococcal polysaccharide vaccine (PPV) comprises of purified capsular polysaccharide from each of 23 types of Streptococcus pneumoniae that account for 90% of the strains causing serious infection in the UK. It should be considered for individuals in whom the risk of contracting pneumococcal pneumonia is increased or the infection is particularly dangerous, including the following: individuals with cerebrospinal fluid leaks, e.g. following trauma or surgery asplenia or severe splenic dysfunction (including coeliac and sickle cell disease) chronic renal, heart, liver or lung disease immunosuppression, including HIV infection diabetes mellitus cochlear implants all adults >65 years of age Antibodies are likely to decline rapidly in asplenic patients, patients with splenic dysfunction and in patients with renal failure and therefore re-immunization is recommended every 5 years in this specific risk group.
Recommended schedule for childhood immunizations in the UKa Age
Vaccine
C
2 months old
C
3 months old
C
4 months old
C
12 months old Around 13 months old
C
C
3e5 years
C
13e18 years old
DTaP/IPV/Hib PCV DTaP/IPV/Hib MenC DTaP/IPV/Hib MenC PCV Hib/MenC MMR PCV DTaP or dTaP MMR Td/IPV
DTaP, diphtheria/tetanus/acellular pertussis; IPV, inactivated polio vaccine; Hib, Haemophilus influenzae type b; MMR, measles/mumps/rubella; PCV, pneumococcal conjugate vaccine; MenC, meningococcal C; Td, tetanus and low-dose diptheria. a
Department of Health
Table 3
Medical Officer to introduce an urgent MMR catch-up campaign in 2008. Reviews of the evidence by a number of institutions including the Cochrane Library have found no evidence to support any association with autism or bowel disease.1 Patients
Cumulative weekly number of reports of invasive pneumococcal disease due to any of the seven serotypes in PrevenarTM: children aged ‹ 2 years in England and Wales by epidemiological year, July–June (2003–to date) 350
03–04
04–05
05–06
06–07
07–08
08–09
Number of reports
300
250
200
Introduction of PrevanarTM Green line: Week 36 2006
150
100
50
0 26
28
30
32
34
36
38
40
42
44
46
48
50
52
1
3
5
7
9
11
13
15
17
19
21
23
25
Week Graph is based on week of isolation, therefore numbers for most recent weeks may not be complete. Numbers of reports of serotyped cases shown in the graph are not adjusted to account for any change that may have occurred over time and between age groups in the proportion of all invasive pneumococcal disease cases that are serotyped. The 7-valent conjugate vaccine was introduced into the childhood immunization schedule on the 4 September 2006, which corresponds with week 36 above. Reproduced with kind permission of the Health Protection Agency, Centre for Infections
Figure 1
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DEFENCE AGAINST INFECTION
The human papillomavirus (HPV) vaccines are subunit vaccines manufactured from the major proteins of the viral capsid of HPV. Virus-like particles (VLPs) are prepared from either recombinant yeast or baculovirus-infected cells derived from a type of moth. There are currently two vaccines available targeting HPV most commonly associated with cervical cancer and genital warts (GardasilÒ) or cervical cancer alone (CervarixÒ). In clinical trials both vaccines are over 99% effective at preventing pre-cancerous lesions associated with HPV type 16 or 18 in young uninfected women.3,4 HPV vaccination using CervarixÒ was implemented in September 2008 for all girls aged 12e13. A catch-up campaign for girls aged 14e18 years commenced September 2009. The MenC conjugate vaccine is made from capsular polysaccharide that has been extracted from cultures of group C Neisseria meningitidis and is administered in three doses to infants aged 3, 4 and 12 months old. All individuals between one year and 25 years of age as well as individuals at risk (e.g. splenic dysfunction, contacts of a confirmed group C infection), regardless of age, should receive MenC if they have not been previously immunized. MenC vaccine offers no protection against other types of meningococcal disease. Meningococcal polysaccharide A, C, W135, Y vaccine is a purified lyophilized extract of the polysaccharide outer capsule of the aforementioned groups of Neisseria meningitidis. It protects against group A, C, W135 and Y strains only e there is currently no effective vaccine for group B meningococcus. It is indicated for the family and other close contacts of patients with group A, W135 or Y meningococcal infection. The vaccine is also recommended for travellers to certain high-risk areas (e.g. sub-Saharan Africa) and is required for Hajj and Umra pilgrims to Saudi Arabia. Patients scheduled to have a splenectomy should start their immunization programme 3 months before their spleen is removed. This maximizes the antibody response to the vaccine and allows adequate dosing at correct intervals. In the case of an emergency splenectomy all relevant immunizations should be given at least two weeks post-surgery or when the patient is sufficiently well.
Vaccines recommended for adults1 Women of child-bearing age seronegative for rubella C MMR Previously unimmunized individuals C Polio C Tetanus C Diphtheria (low-dose adsorbed) Individuals in high-risk groups C Hepatitis B C Hepatitis A C Influenza C BCG C Pneumococcal polysaccharide vaccine Asplenic individuals C Pneumococcal polysaccharide vaccine C Haemophilus influenzae type b C Influenza C Meningitis C Table 4
The universal vaccination of children aged 10e14 was discontinued in 2005 because of the continued decline in TB rates in the indigenous UK population. BCG vaccine should not be given to HIV-infected or other immunocompromised individuals. Influenza vaccines are prepared each year using viral strains resembling those likely to be prevalent during the winter. The viruses are grown in the allantoic cavity of chick embryos and are therefore contraindicated in individuals with egg allergy. Three types of vaccine are available e those prepared by disrupting whole viruses using organic solvents, those containing purified haemagglutinin (HA) and neuraminidase (NA) surface antigens, and those containing highly purified HA and NA antigens reconstituted into virosomes. Immunization will not control an epidemic and is therefore recommended only for individuals at high risk, including those with: chronic respiratory disease, including asthma chronic heart, liver or renal disease diabetes mellitus immunosuppression from disease or treatment, including splenic dysfunction. Influenza vaccine is also recommended for all those aged over 65 years, for residents of nursing homes and other longstay facilities, and for the main carers of the elderly or disabled. Employers should offer annual vaccination to all healthcare workers who are directly involved in patient care. Hepatitis B vaccine contains recombinant viral surface antigen adsorbed onto aluminium hydroxide. The initial course comprises three injections given at 0, 1 and 6 months. Full protective immunity may take up to 6 months to develop, and a booster dose may be required 3e5 years later. Vaccination should be used for post-exposure prophylaxis and given to highrisk groups, including: parenteral drug abusers those who change sexual partners frequently
Other vaccines Vaccines recommended for adults are listed in Table 4. BCG vaccine contains a live attenuated strain derived from Mycobacterium bovis. A single intradermal dose is given. It is recommended for the following groups, if BCG vaccination has not been performed previously. Some may require tuberculin skin testing prior to vaccination: contacts of individuals with active respiratory TB immigrants from countries with a high incidence of TB all children up to the age of 16 with a parent or grandparent who was born in a country with a high incidence of TB all infants born into UK communities with a high incidence of TB healthcare workers or laboratory workers who might have contact with TB veterinary staff working with susceptible animals (e.g. cows, badgers) staff working in prisons, residential homes or hostels for the homeless travellers under the age of 35 staying >3 months in countries with a high incidence of TB
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individuals with haemophilia and others receiving blood or blood products regularly, and any carers who are responsible for administration of the blood products close family contacts of patients with hepatitis B infection infants born to infected mothers patients with chronic renal failure and any carers who are responsible for dialysis healthcare workers and other high-risk occupations (e.g. morticians, embalmers) inmates of custodial institutions individuals and staff in residential accommodation for those with learning difficulties patients with chronic liver disease families adopting children from countries with a high prevalence of hepatitis those travelling to countries with a high or intermediate prevalence of hepatitis B who are at high risk or who plan to remain for a long period of time. Approximately 10e15% of people do not respond adequately to the vaccine. Poor responses are mainly related to obesity, age over 40 years and smoking. Knowledge of response to immunization is important for the handling of subsequent exposure to hepatitis B. A pentavalent vaccine for hepatitis B, H. influenzae type b, diphtheria, pertussis and tetanus is now available for routine infant vaccination in developing countries. Varicella-zoster virus (VZV): a live attenuated VZV vaccine is licensed for the protection of seronegative, healthy adults and adolescents. The UK Department of Health recommends the vaccine for seronegative healthcare workers who come into contact with patients. It is also recommended for laboratory staff who may be exposed and for healthy susceptible contacts of immunocompromised patients. Those with a clear history of chickenpox or shingles can be considered immune and do not require antibody testing. Hepatitis A vaccine containing inactivated whole virus may be administered as a monovalent vaccine or in a combination vaccine containing hepatitis B or typhoid. Immunization is recommended for the following groups: those who change sexual partners frequently individuals at occupational risk, e.g. laboratory workers, sewage workers patients with haemophilia treated with plasma-derived clotting factors, or who have severe liver disease or have been infected with hepatitis B or C travellers to high- or intermediate-risk areas. parenteral drug abusers. Post-exposure prophylaxis should be used for close contacts of confirmed cases of hepatitis A, if within 7 days of onset of jaundice in the primary case.
of the active vaccine. HNIg is also indicated following exposure to measles in non-immune pregnant women, infants under 9 months of age and immunocompromised children and adults. The value of HNIg in non-immune pregnant women who have been exposed to rubella is uncertain, but it may reduce the risk of foetal damage. Specific immunoglobulins are prepared by pooling plasma from individuals who have recently recovered from, or been immunized against, a particular infection. The high specific antibody content means that these immunoglobulins can provide immediate protection following possible exposure. The following preparations are available: Hepatitis B immunoglobulin is normally used in conjunction with active vaccine to protect individuals who may have been exposed through needle-stick or other puncture wounds, and babies born to mothers who were infected during pregnancy or who are high-risk carriers. Tetanus immunoglobulin is indicated for individuals who have heavily contaminated wounds, particularly if they have not received prior immunization or their immune status is uncertain. Active immunization (a booster dose or a full course) should also be given as appropriate. Rabies immunoglobulin is given, with vaccine, to unvaccinated individuals who have been bitten by an animal that may have rabies. Varicella-zoster immunoglobulin is recommended for postexposure prophylaxis in immunocompromised patients and in atrisk pregnant women and newborn infants. Botulism antitoxin is recommended for post-exposure prophylaxis of botulism and for treatment of those thought to be suffering from botulism. This trivalent antitoxin neutralizes toxin produced by Clostridium botulinum types A, B and E. The antitoxin is produced in horses and hypersensitivity reactions are therefore common.
Adverse reactions Vaccines are extensively safety tested before licensing. However, careful post-marketing surveillance is essential. In the UK, all serious suspected reactions should be reported using the Yellow Card scheme. With new vaccine formulations (indicated by a black triangle), all suspected reactions should be reported.
Novel approaches to vaccine development Novel approaches to vaccine development include: mutation or deletion of specific viral genes to produce attenuated strains insertion of genes encoding antigens that induce protective immunity into vaccine vectors (e.g. vaccinia, BCG) use of synthetic peptides as immunogens ‘naked’ DNA vaccines new adjuvants and delivery systems (e.g. lipid micelles) use of cytokines (e.g. interleukin-12) to enhance the immune response. It is hoped that these approaches will lead to the development of effective vaccines against important pathogens such as HIV, malaria, hepatitis C and TB. A
Passive immunization Human normal immunoglobulin (HNIg) is prepared from the pooled plasma of blood donors and contains antibodies to several common viruses, including hepatitis A, measles, rubella and varicella-zoster. Preparations for intramuscular administration can be used for short-term protection, particularly against hepatitis A in travellers, though its use has declined since the introduction
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DEFENCE AGAINST INFECTION
REFERENCES 1 Demicheli V, Jefferson T, Rivetti A, Price D. Vaccines for measles, mumps and rubella in children. Cochrane Database Syst Rev; 2005. CD004407. DOI: 10.1002/14651858.CD004407.pub2. 2 http://www.hpa.org.uk/web/HPAwebFile/HPAweb_C/1245581527892. 3 Harper DM, Franco EL, Wheeler CM, et al. Sustained efficacy up to 4.5 years of a bivalent L1 virus-like particle vaccine against human papillomavirus types 16 and 18. Lancet 2006; 367: 1247e55. 4 Ault KA, FUTURE II Study Group. Effect of prophylactic human papillomavirus L1 virus-like particle vaccine on risk of cervical intraepithelial neoplasia grade 2, grade 3 and adenocarcinoma in situ: a combined analysis of four randomized controlled trials. Lancet 2007; 369: 1861e8.
(A comprehensive handbook covering UK immunization schedules and details of individual vaccines.) Orenstein WA, Wharton M, Bart KJ, et al. Immunization. In: Mandell GL, Bennett JE, Dolin R, eds. Principles and practice of infectious diseases. 6th edn. Philadelphia: Elsevier; 2004: 3557e89. (A review of the principles of vaccine immunology and development.)
Practice points C
C
C
FURTHER READING Department of Health, Welsh Office, Scottish Office Home and Health Department, Department of Health and Social Security (Northern Ireland). Immunization against infectious diseases. London: HMSO, 2006.
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Vaccination is the safest, most effective way to avoid serious infectious diseases If a child does not receive a vaccine at the recommended time, it should be given later rather than omitted Live vaccines should not normally be given to immunocompromised individuals Media scares concerning vaccines may result in reduced vaccine uptake, with potentially serious consequences
Ó 2009 Elsevier Ltd. All rights reserved.
Immunization
What’s new?
Matthijs Backx C
Andrew Freedman C C
Pneumoccoccal conjugate vaccine introduced into childhood immunization schedule Human papillomavirus vaccine introduced for girls aged 12e13 Routine BCG vaccination for children aged 10e14 discontinued
Abstract Immunization against infectious agents to induce a specific, protective immune response can be achieved actively or passively. Passive immunization is the administration of preformed protective antibodies; this immunity is short lived. Active immunization involves the administration of antigens to induce humoral and/or cell-mediated immune responses to a specific micro-organism; this provides more enduring immunity. The first description of active immunization is attributed to Edward Jenner, who, in 1796, induced protective immunity to smallpox by inoculating cowpox (vaccinia) vesicle fluid into the skin of susceptible individuals, though inoculation against smallpox was a Middle Eastern technique that had already been publicized in Western Europe by Lady Mary Wortley Montagu (1689e1762). The successful global eradication of smallpox in the late 1970s is testament to the efficacy of immunization in controlling the spread of infectious diseases. There are now many vaccines in routine use, to prevent the major infectious diseases of childhood and to protect against infections encountered through travel or occupational exposure. Other vaccines are under-developed, and new techniques are being exploited to produce vaccines with enhanced efficacy and reduced toxicity.
Toxoids (e.g. diphtheria, tetanus vaccine) are bacterial toxins that have been rendered non-toxic, but retain the ability to stimulate production of antitoxin. Subunit vaccines (e.g. hepatitis B vaccine containing viral surface antigen, pneumococcal capsular polysaccharide vaccine) comprise purified fractions of micro-organisms that can stimulate protective immunity. Route of immunization Most vaccines are given by intramuscular or deep subcutaneous injection. BCG must be administered by intradermal injection, however, and rabies vaccine can also be given by this route. The Sabin live polio vaccine and Ty 21a, a live attenuated typhoid vaccine, are administered orally to mimic the natural route of infection and to induce a higher level of local mucosal immunity. Vaccine administration The precautions and contraindications that apply to vaccine administration are outlined in Table 2. Specific considerations for individual vaccines are discussed below.
Keywords immunization; infectious diseases; vaccine
Active immunization
Childhood immunizations The childhood immunization schedule currently recommended by the UK Department of Health is shown in Table 3. If a child fails to receive a vaccine at the recommended time, the vaccine should be given later rather than being omitted, because it is important that every child is fully immunized. Diphtheria vaccine is given as a component of a combination vaccine and is no longer available as a single antigen. The vaccine is prepared from cell-free formalin-inactivated Corynebacterium diphtheriae toxin, which is adsorbed onto an adjuvant (aluminium phosphate or hydroxide) to enhance its immunogenicity. A low-dose vaccine is available for adults and for children over 10 years of age, to avoid the serious reactions that can occur in those who have been immunized previously. A booster dose is recommended for travellers living or working in areas that have experienced a recent resurgence of this infection (e.g. countries of the former USSR). Tetanus toxoid is given only as a component of a combination vaccine. It is prepared by formaldehyde treatment of cell-free tetanus toxin, which is adsorbed onto an adjuvant. In addition to the primary, three-dose course of tetanus immunization, children should receive booster doses before school entry (age 3e5 years) and before leaving school (age 13e18 years). Booster doses are not recommended in adults unless they suffer a tetanus-prone wound and have not received a reinforcing dose of toxoid within the last 10 years. If required, it is given as a combination vaccine with low-dose diphtheria and inactivated polio. The vaccine
Types of vaccine Several different types of vaccine are used to induce active immunity (Table 1). Live attenuated vaccines (e.g. BCG for tuberculosis (TB), measles/mumps/rubella (MMR) vaccine) comprise bacteria or viruses that are able to infect and replicate within the host but whose virulence is reduced so that they do not cause disease. These vaccines produce long-term immunity after a single dose. However, they carry a small risk of reversion to a virulent, wildtype strain, as has been documented with Sabin polio vaccine, and are contraindicated in most immunosuppressed individuals. Inactivated whole-cell vaccines (e.g. pertussis, hepatitis A, Salk polio vaccine) contain micro-organisms that have been inactivated by physical or chemical means and retain their immunogenicity but not their infectivity. These vaccines are less effective than live vaccines at producing long-term immunity, and multiple doses are usually required. Matthijs Backx BMBS MRCP(UK) is a Clinical Research Fellow at Nottingham University, UK. Competing interests: none declared. Andrew Freedman MA MB BChir MD FRCP (Lond & Edin) is Senior Lecturer and Honorary Consultant Physician in Infectious Diseases at Cardiff University School of Medicine/University Hospital of Wales, UK. Competing interests: none declared.
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Ó 2009 Elsevier Ltd. All rights reserved.
DEFENCE AGAINST INFECTION
polio viruses of types I, II and III, and three doses of either are required for primary immunization. Recipients of the oral vaccine may excrete attenuated polio virus for up to 6 weeks after a dose. This provides community benefit as contacts of recently immunized children could be protected through acquisition of vaccine virus. However, vaccine-associated poliomyelitis has occurred occasionally in recipients and their contacts when the vaccine strain has reverted to a virulent form. The risk of wild-type polio virus being imported and the benefits of oral polio vaccine (OPV) need to be balanced against the risks of developing vaccine-associated paralytic polio from OPV and the efficacy of inactivated polio vaccine (IPV). Therefore the OPV was withdrawn in 2004 and only the IPV is currently used in a combination vaccine. Haemophilus influenzae type b (Hib) vaccine comprises protein-conjugated capsular polysaccharide and is given as a combination vaccine to infants in three doses. Children aged 12 months receive a single dose of Hib vaccine in combination with the meningitis C vaccine (MenC). The vaccine is not required for those over 4 years old, because the risk of infection declines sharply above this age. Children and adults with splenic dysfunction should also receive a single dose of Hib/MenC vaccine. Introduction of the Hib vaccine caused a dramatic decrease in the incidence of invasive H. influenzae type b disease. However, doctors must remain aware that fully vaccinated infants can still develop serious H. influenzae diseases such as epiglottitis and meningitis. MMR combined vaccine is a freeze-dried preparation containing live attenuated strains of each virus. A single dose results in protective antibody responses to all three viruses in more than 90% of recipients. MMR vaccine is recommended for all children aged around 13 months, regardless of any history of previous infection with one or more of these viruses. A booster dose is given at 3e5 years. At school-leaving age, the MMR vaccine should be offered to boys and girls who have not been immunized previously, regardless of previous mumps, measles or rubella infection. It should also be offered to women of child-bearing age who are seronegative for rubella or any susceptible adult depending on their past vaccination status and future risk of exposure and disease. In 1998, a highly-publicized paper in the Lancet suggested a possible link between the MMR vaccine, bowel disease and autism. This resulted in considerable controversy and a dangerous decline in vaccine uptake in the UK. Increased measles cases and mathematical modelling prompted the Chief
Live and inactivated vaccines Inactivated whole-cell C C C C C C C C
Pertussis (whole-cell) Polio (Salk) Influenza Hepatitis A Cholera Rabies Japanese encephalitis Tick-borne encephalitis
Subunit C
Pertussis (acellular)
Haemophilus influenzae type b C Pneumococcus C Meningococcus (groups A, C, Y, W135) C Hepatitis B C Typhoid (capsular polysaccharide) C Anthrax C Human papillomavirus C
Live attenuated Measles Mumps C Rubella C Polio (Sabin) C BCG C Varicella-zoster C Yellow fever C Typhoid e oral (Ty 21a) C Smallpox Toxoid C C
C C
Diphtheria Tetanus
Table 1
should not be given to adults at intervals of less than 10 years, because severe local reactions may occur. Pertussis vaccine is an acellular vaccine made from highly purified selected components of the Bordetella pertussis organism and is given only as part of a combination vaccine. Anxieties regarding the potential neurological complications of pertussis vaccination and confusion about the contraindications led to poor uptake of the vaccine in the late 1970s and early 1980s, resulting in epidemics of the disease. The uptake is now more than 90%, however, and the incidence of infection has declined sharply. The only absolute contraindication to the vaccine is a severe generalized reaction to a previous dose. Stable neurological conditions (e.g. cerebral palsy) are not a contraindication. Immunization should be deferred in those with an evolving neurological problem until the condition stabilizes. Poliomyelitis: previously, live oral (Sabin) and enhancedpotency inactivated (Salk) vaccines were available. Both contain
Precautions and contraindications C C C C
C
C
Avoid giving any vaccine during acute febrile illness Live vaccines should not be given during pregnancy, unless the need outweighs the possible risk to the foetus Immunization should not be given to individuals with a history of serious local or general reaction to a previous dose or a component of the vaccine If more than one live vaccine is required, they should be administered at least 3 weeks apart or, if this is not possible, they should be given simultaneously at different sites Live vaccines should not be given to patients taking high-dose corticosteroids or other immunosuppressive drugs, who are receiving generalized irradiation, or who have leukaemia, lymphoma or congenital immunodeficiency Patients with HIV infection can be given measles/mumps/rubella and polio live vaccines, but should not receive BCG or yellow fever vaccines
Table 2
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asking about the vaccination should be given the Chief Medical Officer’s advice that: ‘MMR is the safest and best way to protect children against measles, mumps and rubella’. The pneumococcal conjugate vaccine (PCV) contains polysaccharide from seven common capsular types and is conjugated to a protein for increased immunogenicity. It was added to the routine vaccination programme in 2006 and is administered in three doses to infants 2, 4 and 13 months of age. The introduction of PCV has led to a dramatic reduction in vaccine strain invasive pneumococcal disease (Figure 1).2 Pneumococcal polysaccharide vaccine (PPV) comprises of purified capsular polysaccharide from each of 23 types of Streptococcus pneumoniae that account for 90% of the strains causing serious infection in the UK. It should be considered for individuals in whom the risk of contracting pneumococcal pneumonia is increased or the infection is particularly dangerous, including the following: individuals with cerebrospinal fluid leaks, e.g. following trauma or surgery asplenia or severe splenic dysfunction (including coeliac and sickle cell disease) chronic renal, heart, liver or lung disease immunosuppression, including HIV infection diabetes mellitus cochlear implants all adults >65 years of age Antibodies are likely to decline rapidly in asplenic patients, patients with splenic dysfunction and in patients with renal failure and therefore re-immunization is recommended every 5 years in this specific risk group.
Recommended schedule for childhood immunizations in the UKa Age
Vaccine
C
2 months old
C
3 months old
C
4 months old
C
12 months old Around 13 months old
C
C
3e5 years
C
13e18 years old
DTaP/IPV/Hib PCV DTaP/IPV/Hib MenC DTaP/IPV/Hib MenC PCV Hib/MenC MMR PCV DTaP or dTaP MMR Td/IPV
DTaP, diphtheria/tetanus/acellular pertussis; IPV, inactivated polio vaccine; Hib, Haemophilus influenzae type b; MMR, measles/mumps/rubella; PCV, pneumococcal conjugate vaccine; MenC, meningococcal C; Td, tetanus and low-dose diptheria. a
Department of Health
Table 3
Medical Officer to introduce an urgent MMR catch-up campaign in 2008. Reviews of the evidence by a number of institutions including the Cochrane Library have found no evidence to support any association with autism or bowel disease.1 Patients
Cumulative weekly number of reports of invasive pneumococcal disease due to any of the seven serotypes in PrevenarTM: children aged ‹ 2 years in England and Wales by epidemiological year, July–June (2003–to date) 350
03–04
04–05
05–06
06–07
07–08
08–09
Number of reports
300
250
200
Introduction of PrevanarTM Green line: Week 36 2006
150
100
50
0 26
28
30
32
34
36
38
40
42
44
46
48
50
52
1
3
5
7
9
11
13
15
17
19
21
23
25
Week Graph is based on week of isolation, therefore numbers for most recent weeks may not be complete. Numbers of reports of serotyped cases shown in the graph are not adjusted to account for any change that may have occurred over time and between age groups in the proportion of all invasive pneumococcal disease cases that are serotyped. The 7-valent conjugate vaccine was introduced into the childhood immunization schedule on the 4 September 2006, which corresponds with week 36 above. Reproduced with kind permission of the Health Protection Agency, Centre for Infections
Figure 1
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The human papillomavirus (HPV) vaccines are subunit vaccines manufactured from the major proteins of the viral capsid of HPV. Virus-like particles (VLPs) are prepared from either recombinant yeast or baculovirus-infected cells derived from a type of moth. There are currently two vaccines available targeting HPV most commonly associated with cervical cancer and genital warts (GardasilÒ) or cervical cancer alone (CervarixÒ). In clinical trials both vaccines are over 99% effective at preventing pre-cancerous lesions associated with HPV type 16 or 18 in young uninfected women.3,4 HPV vaccination using CervarixÒ was implemented in September 2008 for all girls aged 12e13. A catch-up campaign for girls aged 14e18 years commenced September 2009. The MenC conjugate vaccine is made from capsular polysaccharide that has been extracted from cultures of group C Neisseria meningitidis and is administered in three doses to infants aged 3, 4 and 12 months old. All individuals between one year and 25 years of age as well as individuals at risk (e.g. splenic dysfunction, contacts of a confirmed group C infection), regardless of age, should receive MenC if they have not been previously immunized. MenC vaccine offers no protection against other types of meningococcal disease. Meningococcal polysaccharide A, C, W135, Y vaccine is a purified lyophilized extract of the polysaccharide outer capsule of the aforementioned groups of Neisseria meningitidis. It protects against group A, C, W135 and Y strains only e there is currently no effective vaccine for group B meningococcus. It is indicated for the family and other close contacts of patients with group A, W135 or Y meningococcal infection. The vaccine is also recommended for travellers to certain high-risk areas (e.g. sub-Saharan Africa) and is required for Hajj and Umra pilgrims to Saudi Arabia. Patients scheduled to have a splenectomy should start their immunization programme 3 months before their spleen is removed. This maximizes the antibody response to the vaccine and allows adequate dosing at correct intervals. In the case of an emergency splenectomy all relevant immunizations should be given at least two weeks post-surgery or when the patient is sufficiently well.
Vaccines recommended for adults1 Women of child-bearing age seronegative for rubella C MMR Previously unimmunized individuals C Polio C Tetanus C Diphtheria (low-dose adsorbed) Individuals in high-risk groups C Hepatitis B C Hepatitis A C Influenza C BCG C Pneumococcal polysaccharide vaccine Asplenic individuals C Pneumococcal polysaccharide vaccine C Haemophilus influenzae type b C Influenza C Meningitis C Table 4
The universal vaccination of children aged 10e14 was discontinued in 2005 because of the continued decline in TB rates in the indigenous UK population. BCG vaccine should not be given to HIV-infected or other immunocompromised individuals. Influenza vaccines are prepared each year using viral strains resembling those likely to be prevalent during the winter. The viruses are grown in the allantoic cavity of chick embryos and are therefore contraindicated in individuals with egg allergy. Three types of vaccine are available e those prepared by disrupting whole viruses using organic solvents, those containing purified haemagglutinin (HA) and neuraminidase (NA) surface antigens, and those containing highly purified HA and NA antigens reconstituted into virosomes. Immunization will not control an epidemic and is therefore recommended only for individuals at high risk, including those with: chronic respiratory disease, including asthma chronic heart, liver or renal disease diabetes mellitus immunosuppression from disease or treatment, including splenic dysfunction. Influenza vaccine is also recommended for all those aged over 65 years, for residents of nursing homes and other longstay facilities, and for the main carers of the elderly or disabled. Employers should offer annual vaccination to all healthcare workers who are directly involved in patient care. Hepatitis B vaccine contains recombinant viral surface antigen adsorbed onto aluminium hydroxide. The initial course comprises three injections given at 0, 1 and 6 months. Full protective immunity may take up to 6 months to develop, and a booster dose may be required 3e5 years later. Vaccination should be used for post-exposure prophylaxis and given to highrisk groups, including: parenteral drug abusers those who change sexual partners frequently
Other vaccines Vaccines recommended for adults are listed in Table 4. BCG vaccine contains a live attenuated strain derived from Mycobacterium bovis. A single intradermal dose is given. It is recommended for the following groups, if BCG vaccination has not been performed previously. Some may require tuberculin skin testing prior to vaccination: contacts of individuals with active respiratory TB immigrants from countries with a high incidence of TB all children up to the age of 16 with a parent or grandparent who was born in a country with a high incidence of TB all infants born into UK communities with a high incidence of TB healthcare workers or laboratory workers who might have contact with TB veterinary staff working with susceptible animals (e.g. cows, badgers) staff working in prisons, residential homes or hostels for the homeless travellers under the age of 35 staying >3 months in countries with a high incidence of TB
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individuals with haemophilia and others receiving blood or blood products regularly, and any carers who are responsible for administration of the blood products close family contacts of patients with hepatitis B infection infants born to infected mothers patients with chronic renal failure and any carers who are responsible for dialysis healthcare workers and other high-risk occupations (e.g. morticians, embalmers) inmates of custodial institutions individuals and staff in residential accommodation for those with learning difficulties patients with chronic liver disease families adopting children from countries with a high prevalence of hepatitis those travelling to countries with a high or intermediate prevalence of hepatitis B who are at high risk or who plan to remain for a long period of time. Approximately 10e15% of people do not respond adequately to the vaccine. Poor responses are mainly related to obesity, age over 40 years and smoking. Knowledge of response to immunization is important for the handling of subsequent exposure to hepatitis B. A pentavalent vaccine for hepatitis B, H. influenzae type b, diphtheria, pertussis and tetanus is now available for routine infant vaccination in developing countries. Varicella-zoster virus (VZV): a live attenuated VZV vaccine is licensed for the protection of seronegative, healthy adults and adolescents. The UK Department of Health recommends the vaccine for seronegative healthcare workers who come into contact with patients. It is also recommended for laboratory staff who may be exposed and for healthy susceptible contacts of immunocompromised patients. Those with a clear history of chickenpox or shingles can be considered immune and do not require antibody testing. Hepatitis A vaccine containing inactivated whole virus may be administered as a monovalent vaccine or in a combination vaccine containing hepatitis B or typhoid. Immunization is recommended for the following groups: those who change sexual partners frequently individuals at occupational risk, e.g. laboratory workers, sewage workers patients with haemophilia treated with plasma-derived clotting factors, or who have severe liver disease or have been infected with hepatitis B or C travellers to high- or intermediate-risk areas. parenteral drug abusers. Post-exposure prophylaxis should be used for close contacts of confirmed cases of hepatitis A, if within 7 days of onset of jaundice in the primary case.
of the active vaccine. HNIg is also indicated following exposure to measles in non-immune pregnant women, infants under 9 months of age and immunocompromised children and adults. The value of HNIg in non-immune pregnant women who have been exposed to rubella is uncertain, but it may reduce the risk of foetal damage. Specific immunoglobulins are prepared by pooling plasma from individuals who have recently recovered from, or been immunized against, a particular infection. The high specific antibody content means that these immunoglobulins can provide immediate protection following possible exposure. The following preparations are available: Hepatitis B immunoglobulin is normally used in conjunction with active vaccine to protect individuals who may have been exposed through needle-stick or other puncture wounds, and babies born to mothers who were infected during pregnancy or who are high-risk carriers. Tetanus immunoglobulin is indicated for individuals who have heavily contaminated wounds, particularly if they have not received prior immunization or their immune status is uncertain. Active immunization (a booster dose or a full course) should also be given as appropriate. Rabies immunoglobulin is given, with vaccine, to unvaccinated individuals who have been bitten by an animal that may have rabies. Varicella-zoster immunoglobulin is recommended for postexposure prophylaxis in immunocompromised patients and in atrisk pregnant women and newborn infants. Botulism antitoxin is recommended for post-exposure prophylaxis of botulism and for treatment of those thought to be suffering from botulism. This trivalent antitoxin neutralizes toxin produced by Clostridium botulinum types A, B and E. The antitoxin is produced in horses and hypersensitivity reactions are therefore common.
Adverse reactions Vaccines are extensively safety tested before licensing. However, careful post-marketing surveillance is essential. In the UK, all serious suspected reactions should be reported using the Yellow Card scheme. With new vaccine formulations (indicated by a black triangle), all suspected reactions should be reported.
Novel approaches to vaccine development Novel approaches to vaccine development include: mutation or deletion of specific viral genes to produce attenuated strains insertion of genes encoding antigens that induce protective immunity into vaccine vectors (e.g. vaccinia, BCG) use of synthetic peptides as immunogens ‘naked’ DNA vaccines new adjuvants and delivery systems (e.g. lipid micelles) use of cytokines (e.g. interleukin-12) to enhance the immune response. It is hoped that these approaches will lead to the development of effective vaccines against important pathogens such as HIV, malaria, hepatitis C and TB. A
Passive immunization Human normal immunoglobulin (HNIg) is prepared from the pooled plasma of blood donors and contains antibodies to several common viruses, including hepatitis A, measles, rubella and varicella-zoster. Preparations for intramuscular administration can be used for short-term protection, particularly against hepatitis A in travellers, though its use has declined since the introduction
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REFERENCES 1 Demicheli V, Jefferson T, Rivetti A, Price D. Vaccines for measles, mumps and rubella in children. Cochrane Database Syst Rev; 2005. CD004407. DOI: 10.1002/14651858.CD004407.pub2. 2 http://www.hpa.org.uk/web/HPAwebFile/HPAweb_C/1245581527892. 3 Harper DM, Franco EL, Wheeler CM, et al. Sustained efficacy up to 4.5 years of a bivalent L1 virus-like particle vaccine against human papillomavirus types 16 and 18. Lancet 2006; 367: 1247e55. 4 Ault KA, FUTURE II Study Group. Effect of prophylactic human papillomavirus L1 virus-like particle vaccine on risk of cervical intraepithelial neoplasia grade 2, grade 3 and adenocarcinoma in situ: a combined analysis of four randomized controlled trials. Lancet 2007; 369: 1861e8.
(A comprehensive handbook covering UK immunization schedules and details of individual vaccines.) Orenstein WA, Wharton M, Bart KJ, et al. Immunization. In: Mandell GL, Bennett JE, Dolin R, eds. Principles and practice of infectious diseases. 6th edn. Philadelphia: Elsevier; 2004: 3557e89. (A review of the principles of vaccine immunology and development.)
Practice points C
C
C
FURTHER READING Department of Health, Welsh Office, Scottish Office Home and Health Department, Department of Health and Social Security (Northern Ireland). Immunization against infectious diseases. London: HMSO, 2006.
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Vaccination is the safest, most effective way to avoid serious infectious diseases If a child does not receive a vaccine at the recommended time, it should be given later rather than omitted Live vaccines should not normally be given to immunocompromised individuals Media scares concerning vaccines may result in reduced vaccine uptake, with potentially serious consequences
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