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Immunization
PREVENTION AND CONTROL OF INFECTION
Immunization
What’s new?
Matthijs Backx C
Andrew Freedman
C
Abstract The two most effective interventions to prevent disease, disability and death caused by infectious diseases are sanitation and immunization. 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. The introduction of these vaccines has resulted in the global eradication of smallpox, the elimination of poliomyelitis in large parts of the world and a dramatic reduction in the rates of other diseases. Such has been the success of vaccination programmes that successive generations have been virtually spared diseases such as mumps, measles, rubella and whooping cough. The resurgence of some of the aforementioned illnesses through vaccination failure has reinforced the need to avoid compliancy. New vaccines are continually being developed in the face of newly emergent infectious diseases and the changing epidemiology of existing ones. In addition, new techniques are being exploited to produce vaccines with enhanced efficacy and reduced toxicity.
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Keywords immunization; infectious diseases; vaccine
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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 microorganism. This provides more enduring immunity.
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Types of vaccine Several different types of vaccines are used to induce active immunity (Table 1). Live attenuated vaccines (e.g. Bacillus Calmette–Guerin (BCG) vaccine, 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, wild-type 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 microorganisms 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. Toxoids (e.g. diphtheria, tetanus vaccine) are bacterial toxins that have been rendered non-toxic, but retain the ability to stimulate production of antitoxin.
Active immunization 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. However, inoculation against smallpox was a Middle Eastern technique that had already been publicized in Western Europe by Lady Mary Wortley Montagu. The successful global eradication of smallpox in the late 1970s is testament to the effectiveness of immunization in controlling the spread of infectious diseases.
Matthijs Backx BMBS MRCP(UK) PhD is a Specialist Registrar in Infectious Diseases and Medical Microbiology at the University Hospital of Wales, Cardiff, UK. Competing interests: none declared. Andrew Freedman MA MBBCh MD FRCP(Lond. & Ed) is a Reader and Honorary Consultant Physician in Infectious Diseases at Cardiff University School of Medicine/University Hospital of Wales, Cardiff, UK. Competing interests: none declared.
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A temporary pertussis vaccination programme was introduced in September 2012 for women between 28 and 38 weeks of pregnancy to protect their newborn babies after a sharp increase in the incidence of the disease A new 13-valent pneumococcal conjugate vaccine replaced the 7-valent PCV in 2010 A live attenuated rotavirus vaccine was introduced into the routine childhood vaccination programme in July 2013 In June 2013 the second dose of the meningitis C vaccine was removed from the routine schedule for infants and replaced by an adolescent booster dose at around 14 years. In addition there will be a catch-up programme from mid-August 2014, of limited duration, to offer the vaccine to first time university entrants under the age of 25 years A large outbreak of measles occurred in 2013 centred on the Swansea area, Wales, probably as a consequence of reduced vaccine uptake in the late 1990s and early 2000s when concern around the discredited link between autism and the vaccine was widespread In September 2012 the routine human papillomavirus vaccination programme switched from using Cervarix(r) to the Gardasil(r) HPV vaccine to offer protection against the development of both genital warts and cervical cancer The existing influenza immunization programme will be extended over a number of years to include all children aged two to 16 inclusive. In autumn 2013, immunization with a live attenuated nasal vaccine will be offered to all children aged two years and a limited age range of preschool-aged children through a number of pilots From September 2013 a live attenuated shingles vaccine is to be introduced for people aged 70 years (routine cohort) and 79 years (catch-up cohort) to protect against herpes zoster
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PREVENTION AND CONTROL OF INFECTION
Vaccine types
Contraindications and special considerations for vaccine administration
Vaccines
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Inactivated whole-cell C Polio C Influenza C Hepatitis A C Cholera C Rabies C Japanese encephalitis C Tick-borne encephalitis
Live attenuated C Measles C Mumps C Rubella C Polio C Tuberculosis (BCG) C Varicellaezoster C Yellow fever C Typhoid C Smallpox C Influenza C Rotavirus
C
C
Toxoid C Diphtheria C Tetanus Subunit C Pertussis C Haemophilus influenzae type b C Pneumococcus C Meningococcus C Hepatitis B C Typhoid C Anthrax C Human papillomavirus
C
Table 1 C
Subunit vaccines (e.g. hepatitis B vaccine, pneumococcal capsular polysaccharide vaccine) comprise purified fractions of microorganisms that can stimulate protective immunity.
Table 2
Route of immunization Most vaccines are given by intramuscular or by deep subcutaneous injection. BCG must be administered by intradermal injection and rabies vaccine can also be given by this route. The Sabin live polio vaccine, the Ty 21a (a live attenuated typhoid vaccine) and the live rotavirus vaccine are administered orally, whereas one of the influenza vaccines is administered nasally. The oral and nasal vaccines mimic the natural route of infection in order to induce a higher level of local mucosal immunity.
is prepared from cell-free, formalin-inactivated Corynebacterium diphtheriae toxin, which is adsorbed onto an adjuvant to enhance its immunogenicity. A low-dose vaccine is available for adults and for children over 10 years of age, to avoid reactions that can occur in those who have been immunized previously. A booster dose is recommended for travellers living or working in endemic or epidemic areas. Tetanus toxoid is given only as a component of a combination vaccine. It is prepared by formaldehyde treatment of cellfree tetanus toxin, which is adsorbed onto an adjuvant to enhance its immunogenicity. In addition to the primary, threedose course of tetanus immunization, children should be given booster doses before school entry (age 3 years and 4 months to 5 years) and before leaving school (age 13e18 years). Tetanus toxoid vaccine should be administered to individuals who suffer a tetanus-prone wound and who have not been given adequate primary immunization or boosting. If required it is given as a combination vaccine with low-dose diphtheria and inactivated polio. Pertussis vaccine is an acellular vaccine made from highly purified, selected components of the Bordetella pertussis
Vaccine administration The precautions and contraindications that apply to vaccine administration are outlined in Table 2. Specific considerations for individual vaccines are discussed below. Childhood immunizations The childhood immunization schedule currently recommended by the UK Department of Health is shown in Table 3. If a child is not given a vaccine at the recommended time, the vaccine should be given later rather than being omitted. Diphtheria vaccine is given as a component of a combination vaccine and is no longer available as a single antigen. The vaccine
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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 Live vaccines should be delayed until after pregnancy, unless the need of the mother outweighs the possible risk to the fetus Live vaccines should not be given to the following groups of immunosuppressed individuals: Patients with evidence of severe primary immunodeficiency Patients currently being treated for malignant disease with immunosuppressive chemotherapy or radiotherapy, or who have terminated such treatment within at least the last 6 months Patients who have received a solid organ transplant and are currently having immunosuppressive treatment Patients who have received a bone marrow transplant, until at least 12 months after finishing all immunosuppressive treatment, or longer where the patient has developed graft-versus-host disease Patients taking systemic high-dose corticosteroids, until at least 3 months after treatment has stopped Patients taking other types of immunosuppressive drugs (e.g. methotrexate) alone or in combination with lower doses of corticosteroids, until at least 6 months after terminating such treatment Patients with human immunodeficiency virus (HIV) infection may be given some live vaccines depending on the degree of their immunosuppression Immunization may be postponed in acutely unwell individuals and should be deferred in those with evolving neurological conditions until they have recovered or stabilized
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PREVENTION AND CONTROL OF INFECTION
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; Sabin) had to be balanced against the risks of developing vaccine-associated paralytic polio from OPV and the efficacy of inactivated polio vaccine (IPV; Salk). 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 are given 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 be given 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. The pneumococcal conjugate vaccine (PCV) contains polysaccharide from 13 common capsular types and is conjugated to a protein for increased immunogenicity. The addition of a 7valent PCV to the routine vaccination programme in 2006 led to a large reduction in the incidence of both invasive and non-invasive disease due to vaccine serotypes, in both vaccinated and (to a smaller degree) older unvaccinated populations. During the same period, an increase in invasive disease due to non-vaccine serotypes was observed, termed ‘serotype replacement’. Replacement disease has primarily been caused by the extra six serotypes covered by the new 13-valent PCV that replaced the 7valent PCV in 2010. HPA data, since the introduction of the 13valent PCV, shows a demonstrable reduction in the number of invasive infections caused by the serotypes included in this vaccine across all age groups. The rotavirus vaccine is a freeze-dried preparation of a live attenuated strain of rotavirus and is given as an oral preparation. It was introduced to the routine childhood vaccination programme in July 2013. Rotavirus is a common cause of diarrhoea and vomiting amongst babies and young children; the vaccine is expected to reduce the incidence by 80% and resultant hospital admissions due to the disease by 70%. The rotavirus vaccine is given to babies at two months of age and again at three months alongside their other routine childhood vaccinations.
Recommended schedule for childhood immunizations in the UKa 2 months
C C C
3 months
C C C
4 months
C C C
12e13 months
C C C
3 years and 4 monthse5 years
C C
12e13 years 13e18 years
C C
5-in-1 PCV Rotavirus MenC 5-in-1 (second dose) Rotavirus (second dose) 5-in-1 (third dose) PCV (second dose) MenC (second dose) MMR Hib/MenC PCV (third dose) MMR 4-in-1 HPV 3-in-1
5-in-1 e diphtheria, tetanus, acellular pertussis, inactivated polio vaccine, Haemophilus influenzae type b. PCV e pneumococcal conjugate vaccine. MenC e meningococcal C. MMR e measles, mumps, rubella. Hib e Haemophilus influenzae type b. 4-in-1 e diphtheria, tetanus, acellular pertussis, inactivated polio vaccine. HPV e human papillomavirus. 3-in-1 e diphtheria, tetanus, inactivated polio vaccine. PPV e pneumococcal polysaccharide vaccine. a Department of Health.
Table 3
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%. 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. In 2012 there was a sharp increase in incidence of pertussis with over 9500 cases reported. In response to this the Department of Health introduced a temporary vaccination programme in September 2012 for women between 28 and 38 weeks of pregnancy to protect their newborn babies, who are at the highest risk of severe complications and death and who do not usually start their vaccinations against whooping cough until they are 2 months of age. Poliomyelitis e previously, live oral (Sabin) and enhancedpotency inactivated (Salk) vaccines were available. Both contain 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
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Meningitis e 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. All individuals between one year and 25 years of age, as well as individuals at risk (e.g. contacts of a confirmed group C infection), regardless of age, should be given MenC if they have not been immunized previously. In June 2013 the second dose, given age 4 months, was removed from the routine schedule for infants and replaced by an adolescent booster dose at around 14 years. In addition there will be a catchup programme from mid-August 2014, of limited duration, to
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PREVENTION AND CONTROL OF INFECTION
Notifications of measles in Wales by week. CoSurv Notifications, Public Health Wales.
Vaccines recommended for adults and at-risk individualsa
Chart of number of notifications by week: Week 44 2012 (week commencing 29/10/2012) TO week 18 2013* (week commencing 29/04/2013).
Individuals aged 65 and over C Pneumococcal polysaccharide vaccine C Influenza C Zoster vaccine Individuals in high-risk groups C Hepatitis B C Hepatitis A C Influenza C Bacillus Calmette–Guerin C Pneumococcal polysaccharide vaccine C Chickenpox vaccine Asplenic individuals C Pneumococcal polysaccharide vaccine C Haemophilus influenzae type b C Influenza C Meningitis ACWY conjugate vaccine Elective splenectomy patients should be vaccinated at least 2 weeks before the operation.
180
Number of measles notifications
160 140 120 100 80 60 40 20 0 29/04/2013
15/04/2013
01/04/2013
18/03/2013
04/03/2013
18/02/2013
04/02/2013
21/01/2013
07/01/2013
24/12/2012
10/12/2012
26/11/2012
12/11/2012
29/10/2012
a
Department of Health.
Table 4
Week commencing
mumps, measles or rubella infection. It should also be offered to women of child-bearing age who are seronegative for rubella, and to 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.1,2 Neither the UK Committee on Safety of Medicines nor the Medical Research Council has found any evidence to support any association with autism or bowel disease. Patients 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’. Increased measles cases and mathematical modelling prompted the Chief Medical Officer to introduce an urgent MMR catch-up campaign in 2008. Despite this campaign there were over 2000 confirmed cases of measles in England and Wales reported to the Health Protection Agency (HPA) in 2012, which is the highest annual total since 1994. This figure is likely to be surpassed in 2013 following a major outbreak of measles in Wales centred on the Swansea area with over 1000 cases reported in the period January to March (Figure 1). Experts believe the rise in measles cases can be attributed chiefly to the proportion of unprotected 10e16 year-olds who missed out on vaccination in the late 1990s and early 2000s when concern around the discredited link between autism and the vaccine was widespread. Further catch-up campaigns have been initiated to address this vaccine deficit. The human papillomavirus (HPV) vaccines are subunit vaccines manufactured from the major proteins of the viral capsid of HPV. Virus-like particles are prepared from either recombinant yeast or baculovirus-infected cells. There are currently two
* Data until end of week 18 2013 (29/04/13 to 05/05/13). Data for week 18 is provisional and may increase due to late notifications being received.
Figure 1
offer the vaccine to first time university entrants under the age of 25 years. These changes will make the meningitis C vaccination schedule more effective and offer greater overall public health protection. 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 N. meningitidis. It protects against group A, C, W135 and Y strains only and is administered preferably in a conjugate form. It is indicated for the family and other close contacts of patients with group A, W135 or Y meningococcal infection as well as asplenic patients. The vaccine is also recommended for travellers to certain high-risk areas (e.g. SubSaharan Africa) and is required for Hajj and Umra pilgrims to Saudi Arabia. A vaccine for group B meningococcal disease has recently been approved by the European Union and is undergoing evaluation for inclusion in the routine vaccination programme. Measles, mumps and rubella e 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 schoolleaving age, the MMR vaccine should be offered to children who have not been immunized previously, regardless of previous
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PREVENTION AND CONTROL OF INFECTION
vaccines available, targeting HPV most commonly associated with both cervical cancer and genital warts (GardasilÒ) or cervical cancer alone (CervarixÒ). HPV vaccination using CervarixÒ was implemented in September 2008 for all girls aged 12e13 with a catch-up campaign for girls aged 14 to under 18 years introduced in September 2009. In September 2012 the routine vaccination programme switched to using the GardasilÒ vaccine.
The existing influenza immunization programme will be extended over a number of years to include all children aged 2e16 inclusive. In autumn 2013, immunization with a live attenuated vaccine will be offered to all children aged 2 years and a limited age range of preschool-aged children through a number of pilots. Varicellaezoster virus (VZV) e a live attenuated VZV vaccine is licensed for the protection of seronegative, healthy adults and adolescents. The vaccine contains a live-attenuated VZV obtained from human diploid cells. Hypersensitivity to any of the vaccine components, immunosuppression and active untreated tuberculosis (TB) are contraindications to the use of this vaccine. 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. From September 2013 VZV vaccine is to be introduced for people aged 70 years (routine cohort) and 79 years (catch-up cohort) to protect against herpes zoster. Hepatitis B vaccine contains recombinant viral surface antigen adsorbed onto an adjuvant. 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 high-risk groups, including: parenteral drug abusers those who change sexual partners frequently individuals with haemophilia and others requiring regular administration of blood or blood products, 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 those in 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. A proportion of individuals may not respond to vaccination and will require protection with hepatitis B immunoglobulin if exposed to the virus. A pentavalent vaccine for hepatitis B, H. influenzae type b, diphtheria, pertussis and tetanus is now available for routine infant vaccination in developing countries.
Other vaccines Vaccines recommended for adults and at-risk individuals are listed in Table 4. Pneumococcal polysaccharide vaccine (PPV) comprises 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: cerebrospinal fluid leaks (e.g. following trauma or surgery) asplenia or severe splenic dysfunction (including celiac and sickle cell disease) chronic renal, heart, liver or lung disease immunosuppression, including HIV infection diabetes mellitus cochlear implants all adults over 65 years of age. Antibody titres are likely to decline rapidly in individuals with no spleen, splenic dysfunction or chronic renal disease and reimmunization with 23-valent PPV is recommended every 5 years in these groups. 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 vaccines 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 with trivalent vaccine, containing two subtypes of influenza A and one type B virus, will not control an epidemic and is therefore recommended for individuals at high risk, including pregnant women at any stage of their pregnancy and those with: chronic respiratory disease, including asthma chronic heart, liver or renal disease diabetes mellitus immunosuppression from disease or treatment, including splenic dysfunction chronic neurological conditions, including stroke, transient ischaemic attack (TIA) and conditions in which respiratory function may be compromised due to neurological disease. Influenza vaccine is also recommended for all those aged over 65 years, for residents of nursing homes and other long-stay 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.
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PREVENTION AND CONTROL OF INFECTION
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 tetanus-prone wounds, particularly if they have not received previous 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. Varicellaezoster immunoglobulin is recommended for postexposure prophylaxis in immunocompromised patients and in at-risk 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.
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: men who have sex with men 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 disease in the primary case. Tuberculosis e BCG vaccine contains a live attenuated strain derived from Mycobacterium bovis and is administered as a single intradermal dose. It is recommended for the following groups, some of whom may require preliminary tuberculin skin testing: contacts of individuals with active respiratory TB immigrants from countries with a high incidence of TB (>40/100,000) 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 longer than 3 months in countries with a high incidence of TB. 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.
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 varicellaezoster. Preparations for intramuscular administration can be used for short-term protection, particularly against hepatitis A, though its use for this purpose has declined since the introduction of the active vaccine. HNIg is also indicated following exposure to measles in non-immune pregnant women, infants under 12 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 fetal damage. Specific immunoglobulins are prepared by pooling plasma from individuals who have recently recovered from, or been
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REFERENCES 1 Taylor B, Miller E, Farrington CP, et al. Autism and measles, mumps, and rubella vaccine: no epidemiological evidence for a causal association. Lancet 1999; 353: 2026e9. 2 Bellaby P. Communication and miscommunication of risk: understanding UK parents’ attitudes to combined MMR vaccination. Br Med J 2003; 327: 725e8.
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PREVENTION AND CONTROL OF INFECTION
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 (updated March 2013). (A comprehensive handbook covering UK immunization schedules and details of individual vaccines.). Orenstein WA, Pickering LK, Mawle A, Hinman AR, Wharton M. Immunization. In: Mandell GL, Bennett JE, Dolin R, eds. Principles and practice of infectious diseases. 7th edn. Philadelphia: Elsevier, 2004; 3917e50 [A review of the principles of vaccine immunology and development.].
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Practice points C
C
C
C
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Vaccination is the safest and the most effective way to avoid serious infectious diseases If a child is not given 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 2013 Elsevier Ltd. All rights reserved.
Immunization
What’s new?
Matthijs Backx C
Andrew Freedman
C
Abstract The two most effective interventions to prevent disease, disability and death caused by infectious diseases are sanitation and immunization. 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. The introduction of these vaccines has resulted in the global eradication of smallpox, the elimination of poliomyelitis in large parts of the world and a dramatic reduction in the rates of other diseases. Such has been the success of vaccination programmes that successive generations have been virtually spared diseases such as mumps, measles, rubella and whooping cough. The resurgence of some of the aforementioned illnesses through vaccination failure has reinforced the need to avoid compliancy. New vaccines are continually being developed in the face of newly emergent infectious diseases and the changing epidemiology of existing ones. In addition, new techniques are being exploited to produce vaccines with enhanced efficacy and reduced toxicity.
C
C
C
C
Keywords immunization; infectious diseases; vaccine
C
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 microorganism. This provides more enduring immunity.
C
Types of vaccine Several different types of vaccines are used to induce active immunity (Table 1). Live attenuated vaccines (e.g. Bacillus Calmette–Guerin (BCG) vaccine, 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, wild-type 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 microorganisms 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. Toxoids (e.g. diphtheria, tetanus vaccine) are bacterial toxins that have been rendered non-toxic, but retain the ability to stimulate production of antitoxin.
Active immunization 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. However, inoculation against smallpox was a Middle Eastern technique that had already been publicized in Western Europe by Lady Mary Wortley Montagu. The successful global eradication of smallpox in the late 1970s is testament to the effectiveness of immunization in controlling the spread of infectious diseases.
Matthijs Backx BMBS MRCP(UK) PhD is a Specialist Registrar in Infectious Diseases and Medical Microbiology at the University Hospital of Wales, Cardiff, UK. Competing interests: none declared. Andrew Freedman MA MBBCh MD FRCP(Lond. & Ed) is a Reader and Honorary Consultant Physician in Infectious Diseases at Cardiff University School of Medicine/University Hospital of Wales, Cardiff, UK. Competing interests: none declared.
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A temporary pertussis vaccination programme was introduced in September 2012 for women between 28 and 38 weeks of pregnancy to protect their newborn babies after a sharp increase in the incidence of the disease A new 13-valent pneumococcal conjugate vaccine replaced the 7-valent PCV in 2010 A live attenuated rotavirus vaccine was introduced into the routine childhood vaccination programme in July 2013 In June 2013 the second dose of the meningitis C vaccine was removed from the routine schedule for infants and replaced by an adolescent booster dose at around 14 years. In addition there will be a catch-up programme from mid-August 2014, of limited duration, to offer the vaccine to first time university entrants under the age of 25 years A large outbreak of measles occurred in 2013 centred on the Swansea area, Wales, probably as a consequence of reduced vaccine uptake in the late 1990s and early 2000s when concern around the discredited link between autism and the vaccine was widespread In September 2012 the routine human papillomavirus vaccination programme switched from using Cervarix(r) to the Gardasil(r) HPV vaccine to offer protection against the development of both genital warts and cervical cancer The existing influenza immunization programme will be extended over a number of years to include all children aged two to 16 inclusive. In autumn 2013, immunization with a live attenuated nasal vaccine will be offered to all children aged two years and a limited age range of preschool-aged children through a number of pilots From September 2013 a live attenuated shingles vaccine is to be introduced for people aged 70 years (routine cohort) and 79 years (catch-up cohort) to protect against herpes zoster
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Ó 2013 Elsevier Ltd. All rights reserved.
PREVENTION AND CONTROL OF INFECTION
Vaccine types
Contraindications and special considerations for vaccine administration
Vaccines
C
Inactivated whole-cell C Polio C Influenza C Hepatitis A C Cholera C Rabies C Japanese encephalitis C Tick-borne encephalitis
Live attenuated C Measles C Mumps C Rubella C Polio C Tuberculosis (BCG) C Varicellaezoster C Yellow fever C Typhoid C Smallpox C Influenza C Rotavirus
C
C
Toxoid C Diphtheria C Tetanus Subunit C Pertussis C Haemophilus influenzae type b C Pneumococcus C Meningococcus C Hepatitis B C Typhoid C Anthrax C Human papillomavirus
C
Table 1 C
Subunit vaccines (e.g. hepatitis B vaccine, pneumococcal capsular polysaccharide vaccine) comprise purified fractions of microorganisms that can stimulate protective immunity.
Table 2
Route of immunization Most vaccines are given by intramuscular or by deep subcutaneous injection. BCG must be administered by intradermal injection and rabies vaccine can also be given by this route. The Sabin live polio vaccine, the Ty 21a (a live attenuated typhoid vaccine) and the live rotavirus vaccine are administered orally, whereas one of the influenza vaccines is administered nasally. The oral and nasal vaccines mimic the natural route of infection in order to induce a higher level of local mucosal immunity.
is prepared from cell-free, formalin-inactivated Corynebacterium diphtheriae toxin, which is adsorbed onto an adjuvant to enhance its immunogenicity. A low-dose vaccine is available for adults and for children over 10 years of age, to avoid reactions that can occur in those who have been immunized previously. A booster dose is recommended for travellers living or working in endemic or epidemic areas. Tetanus toxoid is given only as a component of a combination vaccine. It is prepared by formaldehyde treatment of cellfree tetanus toxin, which is adsorbed onto an adjuvant to enhance its immunogenicity. In addition to the primary, threedose course of tetanus immunization, children should be given booster doses before school entry (age 3 years and 4 months to 5 years) and before leaving school (age 13e18 years). Tetanus toxoid vaccine should be administered to individuals who suffer a tetanus-prone wound and who have not been given adequate primary immunization or boosting. If required it is given as a combination vaccine with low-dose diphtheria and inactivated polio. Pertussis vaccine is an acellular vaccine made from highly purified, selected components of the Bordetella pertussis
Vaccine administration The precautions and contraindications that apply to vaccine administration are outlined in Table 2. Specific considerations for individual vaccines are discussed below. Childhood immunizations The childhood immunization schedule currently recommended by the UK Department of Health is shown in Table 3. If a child is not given a vaccine at the recommended time, the vaccine should be given later rather than being omitted. Diphtheria vaccine is given as a component of a combination vaccine and is no longer available as a single antigen. The vaccine
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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 Live vaccines should be delayed until after pregnancy, unless the need of the mother outweighs the possible risk to the fetus Live vaccines should not be given to the following groups of immunosuppressed individuals: Patients with evidence of severe primary immunodeficiency Patients currently being treated for malignant disease with immunosuppressive chemotherapy or radiotherapy, or who have terminated such treatment within at least the last 6 months Patients who have received a solid organ transplant and are currently having immunosuppressive treatment Patients who have received a bone marrow transplant, until at least 12 months after finishing all immunosuppressive treatment, or longer where the patient has developed graft-versus-host disease Patients taking systemic high-dose corticosteroids, until at least 3 months after treatment has stopped Patients taking other types of immunosuppressive drugs (e.g. methotrexate) alone or in combination with lower doses of corticosteroids, until at least 6 months after terminating such treatment Patients with human immunodeficiency virus (HIV) infection may be given some live vaccines depending on the degree of their immunosuppression Immunization may be postponed in acutely unwell individuals and should be deferred in those with evolving neurological conditions until they have recovered or stabilized
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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; Sabin) had to be balanced against the risks of developing vaccine-associated paralytic polio from OPV and the efficacy of inactivated polio vaccine (IPV; Salk). 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 are given 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 be given 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. The pneumococcal conjugate vaccine (PCV) contains polysaccharide from 13 common capsular types and is conjugated to a protein for increased immunogenicity. The addition of a 7valent PCV to the routine vaccination programme in 2006 led to a large reduction in the incidence of both invasive and non-invasive disease due to vaccine serotypes, in both vaccinated and (to a smaller degree) older unvaccinated populations. During the same period, an increase in invasive disease due to non-vaccine serotypes was observed, termed ‘serotype replacement’. Replacement disease has primarily been caused by the extra six serotypes covered by the new 13-valent PCV that replaced the 7valent PCV in 2010. HPA data, since the introduction of the 13valent PCV, shows a demonstrable reduction in the number of invasive infections caused by the serotypes included in this vaccine across all age groups. The rotavirus vaccine is a freeze-dried preparation of a live attenuated strain of rotavirus and is given as an oral preparation. It was introduced to the routine childhood vaccination programme in July 2013. Rotavirus is a common cause of diarrhoea and vomiting amongst babies and young children; the vaccine is expected to reduce the incidence by 80% and resultant hospital admissions due to the disease by 70%. The rotavirus vaccine is given to babies at two months of age and again at three months alongside their other routine childhood vaccinations.
Recommended schedule for childhood immunizations in the UKa 2 months
C C C
3 months
C C C
4 months
C C C
12e13 months
C C C
3 years and 4 monthse5 years
C C
12e13 years 13e18 years
C C
5-in-1 PCV Rotavirus MenC 5-in-1 (second dose) Rotavirus (second dose) 5-in-1 (third dose) PCV (second dose) MenC (second dose) MMR Hib/MenC PCV (third dose) MMR 4-in-1 HPV 3-in-1
5-in-1 e diphtheria, tetanus, acellular pertussis, inactivated polio vaccine, Haemophilus influenzae type b. PCV e pneumococcal conjugate vaccine. MenC e meningococcal C. MMR e measles, mumps, rubella. Hib e Haemophilus influenzae type b. 4-in-1 e diphtheria, tetanus, acellular pertussis, inactivated polio vaccine. HPV e human papillomavirus. 3-in-1 e diphtheria, tetanus, inactivated polio vaccine. PPV e pneumococcal polysaccharide vaccine. a Department of Health.
Table 3
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%. 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. In 2012 there was a sharp increase in incidence of pertussis with over 9500 cases reported. In response to this the Department of Health introduced a temporary vaccination programme in September 2012 for women between 28 and 38 weeks of pregnancy to protect their newborn babies, who are at the highest risk of severe complications and death and who do not usually start their vaccinations against whooping cough until they are 2 months of age. Poliomyelitis e previously, live oral (Sabin) and enhancedpotency inactivated (Salk) vaccines were available. Both contain 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
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Meningitis e 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. All individuals between one year and 25 years of age, as well as individuals at risk (e.g. contacts of a confirmed group C infection), regardless of age, should be given MenC if they have not been immunized previously. In June 2013 the second dose, given age 4 months, was removed from the routine schedule for infants and replaced by an adolescent booster dose at around 14 years. In addition there will be a catchup programme from mid-August 2014, of limited duration, to
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Notifications of measles in Wales by week. CoSurv Notifications, Public Health Wales.
Vaccines recommended for adults and at-risk individualsa
Chart of number of notifications by week: Week 44 2012 (week commencing 29/10/2012) TO week 18 2013* (week commencing 29/04/2013).
Individuals aged 65 and over C Pneumococcal polysaccharide vaccine C Influenza C Zoster vaccine Individuals in high-risk groups C Hepatitis B C Hepatitis A C Influenza C Bacillus Calmette–Guerin C Pneumococcal polysaccharide vaccine C Chickenpox vaccine Asplenic individuals C Pneumococcal polysaccharide vaccine C Haemophilus influenzae type b C Influenza C Meningitis ACWY conjugate vaccine Elective splenectomy patients should be vaccinated at least 2 weeks before the operation.
180
Number of measles notifications
160 140 120 100 80 60 40 20 0 29/04/2013
15/04/2013
01/04/2013
18/03/2013
04/03/2013
18/02/2013
04/02/2013
21/01/2013
07/01/2013
24/12/2012
10/12/2012
26/11/2012
12/11/2012
29/10/2012
a
Department of Health.
Table 4
Week commencing
mumps, measles or rubella infection. It should also be offered to women of child-bearing age who are seronegative for rubella, and to 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.1,2 Neither the UK Committee on Safety of Medicines nor the Medical Research Council has found any evidence to support any association with autism or bowel disease. Patients 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’. Increased measles cases and mathematical modelling prompted the Chief Medical Officer to introduce an urgent MMR catch-up campaign in 2008. Despite this campaign there were over 2000 confirmed cases of measles in England and Wales reported to the Health Protection Agency (HPA) in 2012, which is the highest annual total since 1994. This figure is likely to be surpassed in 2013 following a major outbreak of measles in Wales centred on the Swansea area with over 1000 cases reported in the period January to March (Figure 1). Experts believe the rise in measles cases can be attributed chiefly to the proportion of unprotected 10e16 year-olds who missed out on vaccination in the late 1990s and early 2000s when concern around the discredited link between autism and the vaccine was widespread. Further catch-up campaigns have been initiated to address this vaccine deficit. The human papillomavirus (HPV) vaccines are subunit vaccines manufactured from the major proteins of the viral capsid of HPV. Virus-like particles are prepared from either recombinant yeast or baculovirus-infected cells. There are currently two
* Data until end of week 18 2013 (29/04/13 to 05/05/13). Data for week 18 is provisional and may increase due to late notifications being received.
Figure 1
offer the vaccine to first time university entrants under the age of 25 years. These changes will make the meningitis C vaccination schedule more effective and offer greater overall public health protection. 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 N. meningitidis. It protects against group A, C, W135 and Y strains only and is administered preferably in a conjugate form. It is indicated for the family and other close contacts of patients with group A, W135 or Y meningococcal infection as well as asplenic patients. The vaccine is also recommended for travellers to certain high-risk areas (e.g. SubSaharan Africa) and is required for Hajj and Umra pilgrims to Saudi Arabia. A vaccine for group B meningococcal disease has recently been approved by the European Union and is undergoing evaluation for inclusion in the routine vaccination programme. Measles, mumps and rubella e 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 schoolleaving age, the MMR vaccine should be offered to children who have not been immunized previously, regardless of previous
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vaccines available, targeting HPV most commonly associated with both cervical cancer and genital warts (GardasilÒ) or cervical cancer alone (CervarixÒ). HPV vaccination using CervarixÒ was implemented in September 2008 for all girls aged 12e13 with a catch-up campaign for girls aged 14 to under 18 years introduced in September 2009. In September 2012 the routine vaccination programme switched to using the GardasilÒ vaccine.
The existing influenza immunization programme will be extended over a number of years to include all children aged 2e16 inclusive. In autumn 2013, immunization with a live attenuated vaccine will be offered to all children aged 2 years and a limited age range of preschool-aged children through a number of pilots. Varicellaezoster virus (VZV) e a live attenuated VZV vaccine is licensed for the protection of seronegative, healthy adults and adolescents. The vaccine contains a live-attenuated VZV obtained from human diploid cells. Hypersensitivity to any of the vaccine components, immunosuppression and active untreated tuberculosis (TB) are contraindications to the use of this vaccine. 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. From September 2013 VZV vaccine is to be introduced for people aged 70 years (routine cohort) and 79 years (catch-up cohort) to protect against herpes zoster. Hepatitis B vaccine contains recombinant viral surface antigen adsorbed onto an adjuvant. 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 high-risk groups, including: parenteral drug abusers those who change sexual partners frequently individuals with haemophilia and others requiring regular administration of blood or blood products, 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 those in 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. A proportion of individuals may not respond to vaccination and will require protection with hepatitis B immunoglobulin if exposed to the virus. A pentavalent vaccine for hepatitis B, H. influenzae type b, diphtheria, pertussis and tetanus is now available for routine infant vaccination in developing countries.
Other vaccines Vaccines recommended for adults and at-risk individuals are listed in Table 4. Pneumococcal polysaccharide vaccine (PPV) comprises 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: cerebrospinal fluid leaks (e.g. following trauma or surgery) asplenia or severe splenic dysfunction (including celiac and sickle cell disease) chronic renal, heart, liver or lung disease immunosuppression, including HIV infection diabetes mellitus cochlear implants all adults over 65 years of age. Antibody titres are likely to decline rapidly in individuals with no spleen, splenic dysfunction or chronic renal disease and reimmunization with 23-valent PPV is recommended every 5 years in these groups. 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 vaccines 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 with trivalent vaccine, containing two subtypes of influenza A and one type B virus, will not control an epidemic and is therefore recommended for individuals at high risk, including pregnant women at any stage of their pregnancy and those with: chronic respiratory disease, including asthma chronic heart, liver or renal disease diabetes mellitus immunosuppression from disease or treatment, including splenic dysfunction chronic neurological conditions, including stroke, transient ischaemic attack (TIA) and conditions in which respiratory function may be compromised due to neurological disease. Influenza vaccine is also recommended for all those aged over 65 years, for residents of nursing homes and other long-stay 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.
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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 tetanus-prone wounds, particularly if they have not received previous 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. Varicellaezoster immunoglobulin is recommended for postexposure prophylaxis in immunocompromised patients and in at-risk 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.
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: men who have sex with men 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 disease in the primary case. Tuberculosis e BCG vaccine contains a live attenuated strain derived from Mycobacterium bovis and is administered as a single intradermal dose. It is recommended for the following groups, some of whom may require preliminary tuberculin skin testing: contacts of individuals with active respiratory TB immigrants from countries with a high incidence of TB (>40/100,000) 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 longer than 3 months in countries with a high incidence of TB. 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.
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 varicellaezoster. Preparations for intramuscular administration can be used for short-term protection, particularly against hepatitis A, though its use for this purpose has declined since the introduction of the active vaccine. HNIg is also indicated following exposure to measles in non-immune pregnant women, infants under 12 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 fetal damage. Specific immunoglobulins are prepared by pooling plasma from individuals who have recently recovered from, or been
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REFERENCES 1 Taylor B, Miller E, Farrington CP, et al. Autism and measles, mumps, and rubella vaccine: no epidemiological evidence for a causal association. Lancet 1999; 353: 2026e9. 2 Bellaby P. Communication and miscommunication of risk: understanding UK parents’ attitudes to combined MMR vaccination. Br Med J 2003; 327: 725e8.
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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 (updated March 2013). (A comprehensive handbook covering UK immunization schedules and details of individual vaccines.). Orenstein WA, Pickering LK, Mawle A, Hinman AR, Wharton M. Immunization. In: Mandell GL, Bennett JE, Dolin R, eds. Principles and practice of infectious diseases. 7th edn. Philadelphia: Elsevier, 2004; 3917e50 [A review of the principles of vaccine immunology and development.].
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Practice points C
C
C
C
634
Vaccination is the safest and the most effective way to avoid serious infectious diseases If a child is not given 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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