Chapter 10: Vaccination and Immunization Introduction People rarely suffer from the same infectious disease twice.

. o Reinfections normally occur, when: infectious agent exhibit antigenic plasticity ex. Common cold and influenza patient is immunocompromised ex. Immunosuppressive therapy or immunological disorders significant amount of time has passed after the first infection patient may failed to eliminate primary infection ex. Herpes simplex, herpes zoster, chicken pox and HIV/AIDS Early development o attempted control of smallpox (variola major) through: introduction under the skin of healthy individuals of material taken from active smallpox lesions The process became known as variolation attenuated the disease through changing the route of infection of the causal organism from respiratory transmission to cutaneous. occasional cases of smallpox resulted from such treatment Cowpox o a disease of cattle o can be transmitted to man o Symptoms are similar but less severe than those of smallpox Vaccination o used to describe prophylactic measures that use living microorganisms or their products to induce immunity o More general term is immunization describes procedures that induce immunity in the recipient but which do not necessarily involve the use of microorganisms. Vaccination and immunization procedures o used not only to protect the individual against infection but also to protect communities against epidemic disease

Common source infections the reservoir of infection might be animate o e.g. insect vectors of malaria and yellow fever they might also be inanimate o infected drinking water, cooling towers, contaminated food supply In the simplest of cases the source of the infection is transient o i.e. food sourced to a single retail outlet, or to an isolated event such as a wedding reception the onset of new cases is rapid o phased over 11.5 incubation periods o decline in new cases closely follows the elimination of the source leads to an acute outbreak of infection limited socially and geographically to those linked with the source. Example: o Escherichia coli O157 infections in Lanarkshire in the winter of 1996 that was linked to a single retail outlet. o CreutzfeldtJakob disease (vCJD) first recognized in the mid-1990s relate to human exposure to bovine spongiform encephalopathy (BSE)infected beef in the early 1980s Infectious diseases that are transmitted to humans via insect vectors are: o then onset and decline phases of epidemics are rarely observed other than as reflections of the seasonal variation in the prevalence of the insect o endemic within the population group o has a steady incidence of new cases o Diseases such as these are generally controlled by public health measures and environmental control of the vector with vaccination and immunization e.g. yellow fever vaccination

Propagated source infections relate to the direct transmission of an infective agent from a diseased individual to a healthy, susceptible one includes: o inhalation of infective aerosols measles, mumps, diphtheria o direct physical contact syphilis, herpes virus o Poor sanitation introduction of infected faecal material into drinking water (cholera, typhoid) or onto food (Salmonella, Campylobacter). The ease of transmission, and the rate of onset of an epidemic relates not only to the susceptibility status and general state of health of the individuals concerned but also: o to the virulence properties of the organism o the route of transmission o the duration of the infective period associated with the disease o behavioural patterns o age of the population group

Spread of infection Infectious diseases o may either be spread from: a common reservoir of the infectious agent that is distinct from the diseased individuals (common source) a direct transfer from a diseased individual to a healthy one (propagated source).

o the population density (i.e. urban versus rural). Infective period o During this period each infective individual will be capable of transmitting the disease to the susceptible individuals that they encounter The number of persons to which a single infective rate of occurrence of the infection within the population, will depend upon: o the population density with respect to susceptible and infective individuals o the degree and nature of their social interaction, o the duration and timing of the infective period. Rate of transmission o will decrease as the epidemic progresses o recovered individuals will become immune to further infection o reduce the population density of susceptible individuals, and thereby the likelihood of onward transmission o Epidemics therefore often cease before all members of the community have been infected Threshold level o a function of the infectivity of the agent and the population density Effective vaccination programme o one that can maintain the proportion of individuals who are immune to a given infectious disease above the critical threshold level o will not prevent isolated cases of infection but will prevent these from becoming epidemic

As the worldwide elimination of poliomyelitis approaches, there is much debate as to the value of the live (Sabin) vaccine outside of an endemic area. IPV (Inactivated Polio Vaccine) o Vaccine of choice in the UK for prophylaxis against paralytic polio Public perception Public confidence in the safety of vaccines and immunization procedures is essential links have been claimed between the incidence of autism in children and the change in the UK from single measles and German measles vaccines to the combined MMR vaccine Cheap effective vaccines are an essential component of the global battle against infectious disease The newer vaccines, particularly those that have been genetically engineered, are considerably more expensive, putting the costs beyond the budgets of many developing countries.

Cost

Longevity of the immunity The ideal vaccine provides lifelong protection of the individual against disease Immunological memory o depends on the survival of cloned populations of small B and T lymphocytes (memory cells). o have a lifespan in the body of c. 1520 years Yellow fever vaccination o highly effective, o Must be repeated at 10-year intervals Typhoid vaccines o only effective for 13 years.

Objectives of a vaccine/immunization Programme develop a protective vaccine/immunization programme for each and every infectious disease it should related to the severity and economic impact of the disease upon the community as well as the effects upon the individual

Classes of immunity Immunity to infection o passively acquired: through a preformed and protective antibodies o actively acquired through an immune response following deliberate or accidental exposure to microorganisms or their component parts Active acquired immunity o might involve either or both of the humoral and cell mediated responses.

Severity of the disease Vaccines to be included within a national immunization and vaccination programme are chosen to reflect the infection risks within that country Additional immunization, appropriate for persons travelling abroad, o intended not only to protect the at-risk individual, but also to prevent importing the disease into an unprotected home community.

Passive acquired immunity Effectiveness of the vaccine/immunogen Vaccination and immunization programmes seldom confer 100% protection against the target disease More commonly the degree of protection is c . 6095% Anti-diphtheria and anti-tetanus prophylaxis, o the most efficient immunization programmes, Performance of BCG o highly variable, cholera vaccine (killed) o gives little personal protection o virtually useless in combating epidemics IgG (Immunoglobulin G) o Humoral antibodies o able to cross the placenta from mother to fetus. o provides passive protection of the newborn against those diseases which involve humoral immunity and to which the mother is immune. Secreted antibodies o are also passed to the gut of newborn together with the first deliveries of breast milk (colostrum) o provide some passive protection against infections of the gastrointestinal tract Maternally acquired antibodies o will react not only with antigen associated with a threatening infection but also with antigens introduced to the body as part of an immunization programme

Safety No medical or therapeutic procedure comes without some risk to the patient. All possible steps are taken to ensure safety, quality and efficacy of vaccines and immunological products

Premature immunization o reduce the potency of an administered vaccine. Administration of preformed antibodies o taken from: animals pooled human serum may be administered prophylactically, within a slow release vehicle, for those persons entering parts of the world where diseases such as hepatitis A are endemic Such administrations confer no long-term immunity and will interfere with concurrent vaccination procedures. human cell lines often used to treat an existing infection (e.g. tetanus, diphtheria) or condition (venomous snake bite). Active acquired immunity relates to exposure of the immune system to antigenic materials. Which includes: o a naturally occurring or vaccine-associated infection o it might be associated with the direct introduction of non viable antigenic material into the body o insect or animal bites and stings, inhalation, ingestion or deliberate injection. Injection of antigen o will lead primarily to humoral (IgG, IgM) production Exposure of epithelial tissues (gut, respiratory tract) o will lead not only to the production of secretory antibodies (lgA, lgE) but also, through the common immune response, to a stimulation of humoral antibody. Magnitude and specificity of an immune response o depends not only upon the duration of the exposure to antigen but also upon its timeconcentration profile. During a naturally occurring infection o the levels of antigen in the host are very small at onset and localized to the portal of entry to the host. o Antigens react only with a small, highly defined subgroup of small lymphocytes. These will undergo transformation to produce various antibody classes specific to the antigen undergo a clonal expansion of their number. o microorganisms will release greater amounts of antigenic materials that will, in turn, react with an increasing number of cloned lymphocytes, to produce yet more antibody Antibody levels o will decline with the net result of this encounter being the clonal expansion of particular small lymphocytes relating to a highly specific immunological memory of the encounter o This situation should be contrasted with the injection of a non-replicating immunogen. Non-immune animal o the antigens will react not only with those lymphocytes that are capable of producing antibody of high specificity but also with those of a lower specificity.

Immune response o will cease after this initial (primary) challenge o On a subsequent (secondary) challenge the antigen will react with residual preformed antibody relating to the first challenge together with a more specific subgroup of the original cloned lymphocytes. o As the number of challenges is increased then the proportion of stimulated lymphocytes that are specific to the antigen becomes increased o After a sufficient number of consecutive challenges the magnitude and specificity of the immune response matches that which would occur during a natural infection with an organism bearing the antigen This pattern of exposure brings with it certain problems: Firstly, as the introduced immunogen will react preferentially with preformed antibody rather than lymphocytes then sufficient time must elapse between exposures so as to allow the natural loss of antibody to occur Secondly, immunity to infection will only be complete after the final challenge with immunogen. Thirdly, low specificity antibody produced during the early exposures to antigen might be capable of cross-reaction with host tissues to produce an adverse response to the vaccine. Classes of vaccine Vaccines may be considered as: o live microorganisms o killed microorganisms or purified bacterial o viral components (component vaccines). Recent innovations have included the introduction of DNA vaccines that encode for the transcription of antigen when introduced directly into host tissues or that might be delivered by virus vectors (i.e. adenovirus)

Live vaccines Vaccines may be live, infective microorganisms, attenuated with respect to their pathogenicity but retaining their ability to infect They might be genetically engineered such that one mildly infective organism has been modified so that it causes the expression of antigens from an unrelated pathogen. Major advantages: o the immunization mimics the course of a natural infection such that only a single exposure is required to render an individual immune. o the exposure may be mediated through the natural route of infection (e.g. oral) thereby stimulating an immune response that is appropriate to a particular disease (e.g. secretory antibody as a primary defence against poliomyelitis virus in the gut). Disadvantages o Live attenuated vaccines, administered through the natural route of infection, will be replicated in the patient and could be transmitted to others.

o o

If attenuation is lost during this replicative process then infections might result course of their action and possible side-effects might be affected by the infection and immunological status of the patient.

Killed and component vaccines unable to evoke a natural infection profile with respect to the release of antigen Immunity is not complete until the course of immunization is complete o with the exception of toxin-dominated diseases (diphtheria, tetanus) where the immunogen is a toxoid, it will never match the performance of live vaccine delivery Specificity of the immune response generated in the patient is initially low. This increases the possibility of adverse reactions in the patient. Release profiles of these immunogens can be improved through their formulation with adjuvants immunogenicity of certain purified bacterial components such as polysaccharides can be improved by their conjugation to a carrier

DNA vaccines use of DNA encoding specific virulence factors of defined pathogens to evoke an immune response The DNA is introduced directly into tissue cells by means of a transdermal gene-gun and is transcribed by the recipient cells success in veterinary medicine but has not yet been employed for humans.

Routine immunization against infectious disease Poliomyelitis vaccination it is a picornavirus is the only disease for which both live and killed vaccines compete has three immunologically distinct types (I, II and III) o First phase of poliomyelitis infection acute infection of lymphoid tissues associated with the gastrointestinal tract (Peyers patches) during this time the virus can be found in the throat and in faeces o Second phase characterized by an invasion of the bloodstream, o Third phase the virus migrates from the bloodstream into the meninges Infections range in severity from clinically inapparent (>90%) to paralytic o Paralytic poliomyelitis major illness, but only occurs in 0.12% of infected individuals characterized by the destruction of large nerve cells in the anterior horn of the brain resulting in varying degrees of paralysis Unvaccinated adults are at greater risk from paralytic infection than children The infection is transmitted by the faecaloral route

Since the introduction of the killed virus (Salk) in 1956 and the live attenuated virus (Sabin) in 1962 there has been a remarkable decline in the incidence of poliomyelitis The inactivated polio vaccine (IPV) o contains formalin-killed poliovirus of all three serotypes On injection, the vaccine stimulates the production of antibodies of the IgM and IgG class that neutralize the virus in the second stage of infection three injections at monthly intervals produces long-lasting immunity to all three poliovirus types. The live, oral polio vaccine (OPV) o widely used in many countries, including the UK and USA. o Main advantages over the IPV vaccine: lower cost and easier administration o OPV contains attenuated poliovirus of each of the three types o Administered as a liquid onto the tongue o The vaccine strains infect the gastrointestinal mucosa and oropharynx o promotes the common immune response and involves both humoral and secretory antibodies. o IgA o secreted within the gut epithelium, provides local resistance to the first stages of poliomyelitis infection. o provides protection at an earlier stage of the infection than does IPV o Infection of epithelial cells with one strain of enterovirus, however, often inhibits simultaneous infection by related strain o At least three administrations of OPV are required o with each dosing conferring immunity to one of the vaccine serotypes o These doses must be separated by a period of at least 1 month in order to allow the previous infection to lapse Booster vaccinations o also provided to cover the eventuality that some other enterovirus infection, present at the time of vaccination, had reduced the response to the vaccine strains Faecal excretion of vaccine virus will occur and may last for up to 6 weeks post-treatment Vaccine-associated poliomyelitis may occur through reversion of the attenuated strains to the virulent wild-type, particularly with types II and III and is estimated to occur once per 4 million doses. o As the wild-type virus can be isolated in faeces, infection may occur in unimmunized contacts as well as vaccine recipients. Measles, mumps and rubella vaccination (MMR) Measles, mumps and rubella (German measles) respiratory routes of transmission and infection caused by members of the paramyxovirus group Each virus is immunologically distinct and has only one serotype Whilst the primary multiplication sites of these viruses are within the respiratory tract the diseases are associated with viral multiplication elsewhere in the host.

Measles Measles is a severe, highly contagious, acute infection that frequently occurs in epidemic form. After multiplication within the respiratory tract the virus is transported throughout the body particularly to the skin where a characteristic maculopapular rash develops. Complications of the disease: o common in malnourished children o the most serious is measles encephalitis can cause permanent neurological injury and death. A single injection produces high-level immunity in over 95% of recipients vaccine induces immunity more rapidly than the natural infection o may be used to control the impact of measles outbreaks. The measles virus cannot survive outside of an infected host

For maximum effect MMR vaccine is recommended for children of both sexes aged 1215 months but can also be given to non-immune adults From October 1996 a second dose of MMR was recommended for children aged 4 years in order to prevent the re-accumulation of sufficient susceptible children to sustain future epidemics Single antigen rubella vaccine continues to be given to girls aged 1014 years, if they have not previously received MMR vaccine. In recent years several research papers have attributed an increase in autism to the introduction of the triple vaccine.

Tuberculosis major cause of death and morbidity worldwide, particularly where poverty, malnutrition and poor housing prevail Human infection is acquired by inhalation of Mycobacterium tuberculosis and M. Bovis primarily a disease of the lungs it causes chronic infection of the lower respiratory tract, but may spread to other sites or proceed to a generalized infection (miliary tuberculosis) Active disease can result either from a primary infection or from a subsequent reactivation of a quiescent infection. the mycobacteria are taken up by alveolar macrophages where they survive and multiply If high numbers of mycobacteria are present then the cellular responses can result in tissue necrosis Reactivation of the healed primary lesions is thought to account for over two-thirds of all newly reported cases of the disease Those most at risk include: o pubescent children o health service staff o individuals intending to stay for more than 1 month in countries where TB is endemic. Live vaccine o required to elicit protection against TB, as both antibody and cell-mediated immunity are required for protective immunity. o Vaccination with BCG (bacille Calmette-Gurin), derived from an attenuated M. bovis strain, commonly used in countries where TB is endemic o The vaccine was introduced in the UK in 1953 and was administered intradermally to children aged 1314 years and to unprotected adults. o a sensitivity test must be carried out before immunization with BCG. o Mantoux skin test assesses an individuals sensitivity to a purified protein derivative (PPD) prepared from heat-treated antigens (tuberculin) extracted from M. tuberculosis. A positive test implies past infection or past, successful immunization. Those with strongly positive tests may have active disease and should be referred to a chest clinic. However, many people with active TB, especially disseminated TB, seroconvert from a positive to a negative skin test. Results of the skin test must therefore be interpreted with care. has little prophylactic effect against postprimary TB in those already infected. TB kills c. 3 million people annually and that drugr esistant strains have emerged

Mumps

infects the parotid glands to cause swelling and a general viraemia Complications: o Pancreatitis o Meningitis o orchitis, o occasionally leads to male sterility can also cause permanent unilateral deafness at any age In the absence of vaccination, infection occurs in >90% of individuals by age 15 years.

Rubella Rubella is a mild, often subclinical infection that is common among children aged between 4 and 9 years Infection during the first trimester of pregnancy brings with it a major risk of abortion or congenital deformity in the fetus (congenital rubella syndrome, CRS). Rubella immunization o introduced to the UK in 1970 for prepubertal girls and non-immune women intending to start families o The vaccine utilizes a live, cold-adapted Wistar RA2713 vaccine strain of the virus. o Major disadvantage: the fetus can be infected possible risk makes it imperative that women do not become pregnant within 1 month of vaccination Prepubertal girls were immunized to extend the period of immunity through the child-bearing years Rubella vaccine is now given to both sexes at the age of 1215 months as part of the MMR programme MMR vaccine introduced to the UK in 1988 for young children of both sexes, replacing single antigen measles vaccine It consists of a single dose of a lyophilized preparation of live attenuated strains ofL o Measles o mumps o rubella viruses. Immunization results in sero-conversion to all three viruses in >95% of recipients

Immunization at 24 weeks of age will ensure that immunization precedes infection, and also negates the requirement for a skin test Passive acquired maternal antibody to TB is unlikely to interfere with the effectiveness of the immunization as immunity relates to a cell-mediated response Alternative strategies involve improvement of the vaccine possibly through the introduction, into the BCG strain, of genes that encode protective antigens of M. tuberculosis.

the primary course of tetanus prophylaxis consists of three doses starting at 2 months of age and is separated by an interval of at least 1month.

Pertussis (whooping cough) Caused by the non-invasive respiratory pathogen Bordetella pertussis Complications: o Bronchopneumonia o repeated post-tussis vomiting leading to weight loss o cerebral hypoxia associated with a risk of brain damage Until the mid-1970s the mortality from whooping cough was about one per 1000 notified cases with a higher rate for infants under 1 year of age. A full course of vaccine o consists of a suspension of killed Bord. pertussis organisms gives complete protection in > 80% of recipients The primary course of pertussis prophylaxis consists of: o three doses starting at 2 months of age and separated by an interval of at least 1 month.

Diphtheria, tetanus and pertussis (DTP) Immunization Immunization against these unrelated diseases is considered together because the vaccines are nonliving often co-administered as a triple vaccine as part of the juvenile vaccination programme

Diphtheria an acute, non-invasive infectious disease associated with the upper respiratory tract The incubation period is from 2 to 5 days the disease remains communicable for up to 4 weeks A low molecular weight toxin is produced which affects myocardium, nervous and adrenal tissues Death results in 35% of infected children Diphtheria immunization o protects by stimulating the production of an antitoxin o This antitoxin will protect against the disease but not against infection of the respiratory tract. Immunogen o is a toxoid o prepared by formaldehyde treatment of the purified toxin o administered while adsorbed to an adjuvant, usually aluminium phosphate or aluminium hydroxide. o The primary course of diphtheria prophylaxis consists of three doses starting at 2 months of age and separated by an interval of at least 1 month. o The immune status of adults may be determined by administration of Schick test toxin essentially a diluted form of the vaccine.

DTP vaccine combinations and administration The primary course of DTP protection consists of: o three doses of a combined vaccine each dose separated by at least 1 month and commencing not earlier than 2 months of age. pertussis component of the vaccine o acts as an additional adjuvant for the toxoid elements o Monovalent pertussis and tetanus vaccines, and combined vaccines lacking the pertussis component (DT) are available The primary course of pertussis vaccination o considered sufficient to confer lifelong protection, especially as the mortality associated with disease declines markedly after infancy. The risks associated with tetanus and diphtheria infection persist throughout life DT vaccination is therefore repeated before school entry, at 45 years of age, and once again at puberty.

Tetanus Immunization against bacteria associated with meningitis not an infectious disease relates to the production of a toxin by germinating spores and vegetative cells of Clostridium tetani might infect a deep puncture wound grows anaerobically at infected sites The toxin is adsorbed into nerve cells and acts like strychnine on nerve synapses Tetanus immunization o employs a toxoid o protects by stimulating the production of antitoxin. This antitoxin will neutralize the toxin as the organisms release it and before it can be adsorbed into nerves it may be used prophylactically in those non-immunized persons who have recently suffered a candidate injury The toxoid, as with diphtheria toxoid formed by reaction with formaldehyde and is adsorbed onto an inorganic adjuvant. Menigococcal immunization Meningococcus (Neisseria meningitides) o Bacterium that exclusively colonizes and or infects humans o There is no animal reservoir o Present as normal flora of the pharynx o Can cause meningitis and septicaemia o Life-threatening o There are at least 12 subtypes or serogroups of menigococcus but groups B and C account for the majority of the cases in Europe and America o Neisseria meningitides group A does not normally cause disease in UK but an endemic cause in the places called the meningitis belt Senegal (west Africa) to Ethiopa (East) o Group C is most common in the age under 1 year old group in UK.mortality is highest in adolescent No vaccine available for group B but for A and C it is available

The new MenC conjugate vaccine: o Comprises capsular polysaccharide component conjugated to a carrier protein (usually diphtheria and tetanus toxoid) o Vaccine is very effective in the young and is suitable for protecting infants o Normally administered along with DTaP and Hib at 3,4 and 12 months o Single dose is sufficient to immunize individual over 12 months of age o Used to provide prophylaxis for teenagers, adolescents and young adults o Group A vaccine is available in epidemic areas

Immunogenic in children and the childhood vaccination schedule recommends that doses be given at 2 and 4 months of age with a booster at 13 months

Haemophilus influenza type b (Hib) immunization Can cause infection ranging from bronchitis, pneumonia, pericarditis and otitis media to life-threatening, invasive disease (meningitis and bacteriaemia) Most common in young children Normally caused by encapsulated strains of the bacterium Has six typeable capsular serotypes Complication: o Deafness o Intellectual impairment Haemophilus influenza is a normal microbiota of the nasopharynx in health individual Vaccine o Purified preparations of the polysaccharide capsule of the major serotypes of the bacterium associated with disease o Must be conjugated onto a protein carrier (diphtheria or tetanus toxoids) to enhance efficacy o Given in combination with DTaP/IPV/HiB or Hib/MenC conjugate vaccine

Human papillomavirus (HPV) vaccination Human papillomavirus are group of viruses hat infect squamous epithelia including: o Skin o Mucosal surfaces of the upper respiratory and anogenital tracts Approximately 100 types of HPV (40 of these types infect the genital tract) Associated with genital warts and cervical cancer and also with cancers of the mouth and throat Not all types of HPV are carcinogenic Genital HPV infections are transmitted primarily through sexual intercourse Can be transmitted from mother to child Vaccine: o Comprises recombinant subunits expressed in yeast or in cells of insect origin such that vaccine contains non-infectious, virus-like particles o Reduce the incidence of cervical cancer o Administered to females Between the age of 12-12 and a catch up programme for older females (up to age of 18) Immunization of special risk groups Immunization protocols include: o Cholera o Typhoid o Meningitis (group A) o Anthrax o Hepatitis A and B o Japanese encephalitis o Rabies o Tick-borne encephalitis o Yellow fever

Pneumococcal vaccination Streptococcus pneumonia o Encapsulated gram + coccus o Part of the normal microbiota of the nasal cavity and associated tissues but commensal strains are often avirulent o Versatile pathogen which cause sinusitis or otitis media o Can also cause: Deep lung infections Systemic infections: Bacteraemic pneumonia Bacteriaemia Meningitis Infection is highest during winter Transmission by aerosols or direct contact with respiratory secretions Vaccine: o Pneumococcal polysaccharide vaccine (PPV) Contains purified capsular polysaccharide from 23 capsular types of bacterium Effective vaccine in adults Recommended for adults over 65 yrs. old and at-risk group aged 2 yrs. old and above o Pneumococcal conjugate vaccine (PCV) Comprises capsular polysaccharides from 7 common capsular types Conjugated to protein in manner similar to Hib and MenC