03 overview of_aefi_profile_of_vaccines

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  • Outline Principles of immunization Types of Vaccines and vaccine ingredients Safety concerns and adverse reactions with different types of vaccine.
  • The Goal of immunization The goal of vaccination is to prime the recipient’s immune response in order to generate memory cells, so a heightened immune response (both cell mediated and humoral) will be elicited upon exposure to the specific pathogen. The vaccine itself should produce limited undesirable effects and be relatively inexpensive and mass producible for population vaccinations. These factors are as important as efficacy when regulatory bodies and pharmaceutical companies consider possible vaccines.
  • Attributes of a good vaccine: A good vaccine should elicit an appropriate immune response. Ideally the effect should be durable, offering long- term protection. The vaccine should have minimal and non-serious side effects. The product should be stable at extremes of temperature, over a prolonged period of time and under various exposures to light.
  • Response to immunization: Immunogenicity is determined not only by the chemical and physical states of the antigen, but also by the genetic characteristics of the responding individual, the physiologic condition of the individual (i.e. age, nutrition, gender, pregnancy status, stress, infection) and the manner in which the antigen is presented. Viability of the antigen: Live vaccines multiply in the body. Live vaccines are believed to confer lifelong protection form the disease to those who respond (e.g. MMR). Killed vaccines, however require booster doses or repeat doses to confer permanent immunity. (e.g. diphtheria, tetanus, rabies, typhoid) Exceptions to this rule are Hep B which lasts approximately 10 years and IPV, where duration of immunity is unknown. Total dose: The total dose of killed vaccine is quite important especially since they do not proliferate in the body.There is usually a dose-response curve relationship between the antigen dose and the peak response Route of administration affects rapidity and nature of the immune response. Vaccines administered locally e.g. (nasal or GI) produces IgA at local site whereas IM injection results in IgG production. If the improper route of administration is used, the immune response may be affected. E.g, if Hep B vaccine is administered in adipose tissue in buttock, the sero-conversion rates are reduced substantially compared to IM injection into the deltoid muscle. Age: extremes of age - e.g. very young and very old may be affected. In the first few months of life immunity to some killed vaccines (IPV, pertussis) and many live vaccines may be impaired by maternal antibodies. In the elderly, the antibody response may be depleted. Patients condition and immune state: Genetic Factors: The MHC is essentially the name tag on every cell in the body which identifies itself to the immune system as “self” or “me”. There is therefore extensive polymorphism of the MHC in human populations. Therefore to effectively vaccinate a population, a vaccine must contain epitopes that can be processed and bind to the product of at least one allele in every individual. (ref: Plotkin and Di Priro’s)
  • Types of Antigens The various types of antigens used in the preparation of vaccines are: 1. Live Attenuated (oral polio, BCG, VZV) 2. Killed vaccine (influenza, IPV, hepatitis A, pertussis) 3. Toxoid (tetanus, diphtheria) 4. P urified (sub-unit) antigen (meningococcal vaccine, haemophilus influenzae vaccine) 5. R ecombinant antigen (hepatitis B) 6. DNA vaccines (in investigational phase) 7. Synthetic peptides (in investigational phase) The characteristics of these various vaccine antigens will be discussed during this session.
  • Live Attenuated Vaccines Developed in the 1950’s and 60’s Attributes: Positive – immune response: almost as good a response as having real infection; memory cell production; capable of replicating within host cells cost: cheap because there is no need to administer large amounts of innoculant Negative : – safety and stability Safety issues insufficient attenuation could result in pathogenicity reversion to wild type possible and has been reported with some vaccines e.g. polio and VAPP, yellow fever may be pathogenic on administration to immunodeficient patients – e.g. HIV patients persistent infection eg varicella contamination by other viruses (e.g. retroviruses with measles vaccine) Potential for foetal damage-eg. Rubella vaccine and theoretical risk of congenital anomalies
  • Killed/Inactivated vaccines Killed vaccines are derived from live virus culture which have been inactivated by heat or by chemical means. The final concentrate is tested for sterility, virus inactivation, potency, endotoxin, pH and concentration of residuals etc. Characteristics of Killed/Inactivated vaccines are: They are Grown in bulk They are Inactivated by heat or chemical means Examples include – Salk polio, rabies, hepatitis A, pertussis, influenza vaccines adjuvants may be added to improve the immune response Attributes : Positive no potential for pathogenicity due to the removal of the toxic component Often more stable than live vaccines Negative May need to give repeated doses to generate a protective immune response Cost- often more expensive
  • Purified (Subunit) Antigen Purified subunits are produced such that o nly parts of pathogen necessary to elicit the immune response are used. The potential toxins are avoided. They often tend to require conjugation with proteins to enhance immunogenicity and evoke an adequate immune response. Examples include meningococcal and h.influenzae vaccine. Attributes : Negative cost – often expensive
  • Polysaccharide Conjugate Vaccines During conjugation, the Polysaccharide/oligosaccharide of the antigen is linked (conjugated) to a protein carrier. This Increases antibody response and increases production of memory cells allowing for immunization and an adequate immune response at an earlier age in infants. Subsequent exposure to the antigen serves as a booster effect (via infection /immunization exposure) e.g. Haemophilus influenzae type B vaccines.
  • Recombinant antigen vaccines This technique involves the use of an antigenic subunit of the pathogen which is manufactured in a specific way: Non-pathogenic bacteria or yeasts are altered, using recombinant techniques, to produce an antigen for bulk harvesting. Dangers of viral infection eliminated Example – hepatitis B vaccine Attributes: Positive – safety and cost Additional Notes Recombinant vaccines use a piece of DNA derived from an organism that codes for a protective protein. The DNA is derived either directly from the genome of the organism or by transcription of mRNA or viral RNA into complementary DNA through reverse transcription. This DNA is inserted into an expression vehicle (e.g. E.coli, baculovirus or pox virus, Chinese Hamster ovary cells).This vehicle produces the protective protein which is used as the vaccine. Alternatively, the antigenic protein delivered by means of a bacterial plasmid. This plasmid is injected into the muscle. When an expression vehicle is used, it is important for the protein to be purified after it has been harvested from the cells.
  • Methods used to Enhance Immunity Conjugation: Many bacterial pathogens are protected by a polysaccharide capsule. This polysaccharide capsule, however, is not very immunogenic.. If the polysaccharide is bound to a carrier protein , the immune response improves dramatically as does the memory response. The success of the Hib vaccine is proof of how well this technique works. Adjuvants: are substances that are incorporated into, or injected simultaneously with an antigen and that potentiates the immune response. This allows lesser quantities of antigen to be used, fewer doses needed to elicit a long term immune response. Adjuvants are most often used in killed/inactivated vaccines. The most commonly used adjuvants are Aluminium adjuvants, which slow the escape of the antigen from the site of injection thereby lengthening the duration of contact between the antigen and the immune system (i.e. macrophages and other antigen-receptive cells. Although generally recognised as safe, aluminium salts do cause sterile abscesses and nodules at the site of injection. The formation of a small granuloma is inevitable with alum-precipitated vaccines, by virtue of its very action, however, it is important that it is administered IM and not SC since SC administration can result in necrotic breakdown and cyst and abscess formation. DTP is an example of a vaccine containing an adjuvant. Other adjuvants are: Emulsified water-in-oil adjuvants Combination vaccine: A combination vaccine consists of 2 or more antigens which are in the same preparation. This approach is used in many of our vaccines including - MMR, DTP etc. It is very important, however, that these combination vaccines are carefully tested and tried out before introduced. For instance -adjuvants in a combination could reduce the activity of one vaccine and excessively increase the reactivity of the other vaccine. Also, there could be interactions with the buffers, stabilizers etc. E.g, Thiomersal in DTP and Hib vaccines can inactivate the IPV. Live vaccines can interfere with each other as well. The immune response to one vaccine can inhibit the replication of another virus.
  • Inactive Ingredients Suspending agents: Such as water/saline. Incorrect admin or use of suspending agent could be a cause of AEFI.. Antibiotics: Used during the manufacturing phase to suppress the growth of any extraneous contaminants that may be introduced during various processing steps. Antibiotics such as kanamycin and neomycin are commonly recommended by FDA for plasmid DNA vaccines. Preservatives: Added to vaccines when there is a risk of contamination (e.g. multidose vials.) Combination vaccines - preservative/stablilser of 1 vaccine may affect potency of other. Thiomerosal adversely affected potency of IPV combination with DTP vaccine. Whether or not preservative is used, manufacturer still needs to evaluate vaccine potency and reversion to toxicity. Stablilizers - Stability is essential especially where we cannot guarantee cold chain. Instability can cause loss of antigenicity and decreased infectivity of live vaccine. Factors affecting stability - temperature and pH. Bacterial vaccines can become unstable due to hydrolysis and aggregation of protein and carbohydrate molecules. Stabilizers include: MgCl2 (OPV) , MgSO4 (for RSV, measles), lactose-sorbitol and sorbitol-gelatin. Because of concern about BSE - use non-animal products where possible. Residuals in Growth Medium: Speculation about the connection between HIV virus and polio vaccination- this postulated connection has been disproven
  • Combination vaccine: A combination vaccine consists of 2 or more antigens which are in the same preparation. This approach is used in many of our vaccines including - MMR, DTP etc. It is very important, however, that these combination vaccines are carefully tested and tried out before introduced. For instance -adjuvants in a combination could reduce the activity of one vaccine and excessively increase the reactivity of the other vaccine. Also, there could be interactions with the buffers, stabilizers etc. E.g, Thiomersal in DTP and Hib vaccines can inactivate the IPV. Live vaccines can interfere with each other as well. The immune response to one vaccine can inhibit the replication of another virus.
  • Route of Administration The ideal route of administration should elicit an immune response with minimal risk of adverse effects during injection. Deep IM injection preferable for vaccines containing adjuvants (this provides a depot effect and granuloma formation is less likely) The SC/ intradermal route is preferable for live vaccines to lessen risk of neurovascular injury but still immunogenic (e.g. BCG)
  • What is an adverse event following immunization (AEFI)? Although the vaccines in general use in national immunization programmes are extremely safe and effective, adverse events can occur following vaccine administration and no vaccine is perfectly safe. In addition to the vaccines themselves, the process of immunization is a potential source of adverse events. An adverse event following immunization (AEFI) is any adverse event that follows immunization that is believed to be caused by the immunization. Using this terminology allows description and analysis of the event without pre-judging causality. Immunization will naturally be blamed for any event that happens after immunization. Reported adverse events can either be true adverse events, i.e. really a result of the vaccine or immunization process, or coincidental events that are not due to the vaccine or immunization process but are temporally associated with immunization. For the purpose of these guidelines AEFIs are classified into five categories. Immunization can cause adverse events from the inherent properties of the vaccine ( vaccine reaction ), or some error in the immunization process ( programme error ). The event may be unrelated to the immunization, but have a temporal association ( coincidental event ). Anxiety-related reactions can arise from the pain of the injection rather than the vaccine. In some cases the cause of the AEFI remains unknown .
  • Vaccine reactions Vaccine reactions result from the intrinsic properties of the vaccine. The purpose of a vaccine is to induce immunity by causing the recipient's immune system to react to the vaccine. Local reaction, fever and systemic symptoms can result as part of the immune response. In addition, some of the vaccine’s components (eg, aluminum adjuvant, stabilisers or preservatives) can lead to reactions. A successful vaccine reduces these reactions to a minimum while producing the best possible immunity. Parents should be advised about the common, minor reactions and how to manage them. Local reactions : Cold cloth at injection site; Paracetamol Fever : Give extra fluids; Wear cool clothing; Tepid sponge or bath; Paracetamol Irritability, malaise, & systemic systems : Give extra fluids; Paracetamol Paracetamol dose : up to 15mg/kg; maximum of 4 doses in 24 hours (more can damage liver)
  • Common, minor reactions These occur within a day or two of immunization (except for measles/MMR - 6 to 12 days after immunization) and they only last one to a few days. Local reactions include pain, swelling and/or redness at the injection site and can be expected in about 10% of vaccinees, except for those injected with DTP, or tetanus boosters, where up to half can be affected. BCG causes a specific local reaction that starts as a papule (lump) two or more weeks after immunization that then becomes ulcerated and heals after several months, leaving a scar. Individuals with dormant tuberculosis infection often have an accelerated response to BCG. Keloid (thickened scar tissue) from the BCG lesion is more common among Asian and African populations. Systemic reactions include fever and occur in about 10% or less of vaccinees, except for DTP where it is again about half. Other common systemic reactions (e.g., irritability, malaise, ‘off-colour’, anorexia) can also occur after DTP. For measles/MMR and OPV the systemic reactions arise from vaccine virus infection. Measles’ vaccine causes fever, rash and/or conjunctivitis, and affects 5-15% of vaccinees. It is very mild compared to ‘wild’ measles, but for severely immunocompromised individuals, it can be severe, even fatal. Vaccine reactions for mumps (swollen parotid gland) and rubella (arthralgia and swollen lymph nodes) affect less than 1% of children. Rubella vaccine causes symptoms more often in adults, with 15% suffering from arthralgia. Systemic reactions from OPV affect less than 1% of vaccinees with diarrhoea, headache, and/or muscle pain.
  • Rare, more serious reactions Most of the rare and more serious vaccine reactions (e.g., seizures, thrombocytopaenia, hypotonic-hyporesponsive episodes, persistent inconsolable screaming) do not lead to long term problems. Anaphylaxis, while potentially fatal, is treatable without leaving any long term effects. Although encephalopathy is included as a rare reaction to measles or DTP vaccine, it is not certain that this is in fact caused by these vaccines. Seizures are mostly febrile and risk depends on age, with much lower risk in infants under the age of 4 months or over the age of six years. Reactions to measles/MMR (except allergic and anaphylaxis) do not occur if already immune (~90% of those receiving a second dose).
  • Rare, more serious reactions Most of the rare and more serious vaccine reactions (e.g., seizures, thrombocytopaenia, hypotonic-hyporesponsive episodes, persistent inconsolable screaming) do not lead to long term problems. Anaphylaxis, while potentially fatal, is treatable without leaving any long term effects. Although encephalopathy is included as a rare reaction to measles or DTP vaccine, it is not certain that this is in fact caused by these vaccines. Seizures are mostly febrile and risk depends on age, with much lower risk in infants under the age of 4 months or over the age of six years. Reactions to measles/MMR (except allergic and anaphylaxis) do not occur if already immune (~90% of those receiving a second dose ).
  • Rare, more serious reactions Most of the rare and more serious vaccine reactions (e.g., seizures, thrombocytopaenia, hypotonic-hyporesponsive episodes, persistent inconsolable screaming) do not lead to long term problems. Anaphylaxis, while potentially fatal, is treatable without leaving any long term effects. Although encephalopathy is included as a rare reaction to measles or DTP vaccine, it is not certain that this is in fact caused by these vaccines. Seizures are mostly febrile and risk depends on age, with much lower risk in infants under the age of 4 months or over the age of six years. Reactions to measles/MMR (except allergic and anaphylaxis) do not occur if already immune (~90% of those receiving a second dose).
  • Rare, more serious reactions Most of the rare and more serious vaccine reactions (e.g., seizures, thrombocytopaenia, hypotonic-hyporesponsive episodes, persistent inconsolable screaming) do not lead to long term problems. Anaphylaxis, while potentially fatal, is treatable without leaving any long term effects. Although encephalopathy is included as a rare reaction to measles or DTP vaccine, it is not certain that this is in fact caused by these vaccines. Seizures are mostly febrile and risk depends on age, with much lower risk in infants under the age of 4 months or over the age of six years. Reactions to measles/MMR (except allergic and anaphylaxis) do not occur if already immune (~90% of those receiving a second dose).
  • Immunization of Special Populations Pregnant women: Major safety concerns during pregnancy are the potential for teratogenicity and induction of abortion. Vaccination should only be carried in pregnancy if it is indicated. Live viral vaccines are usually not recommended due to these concerns Birth defects unrelated to the vaccine may be falsely attributed to the vaccine . Newer vaccines/regimens may have unknown effects and should therefore be used with caution Women (esp. adolescents) may not be aware of or disclose pregnancy- The question arises as to whether we should we screen for pregnancy during vaccination campaigns?
  • Immunization of Special Populations Immunocompromised Patients Concerns have been raised about the safety of live vaccines in immunocompromised patients. The potential risks need to be weighed against the benefits in these patient groups who may be particularly vulnerable to the vaccine-preventable disease. Concerns are that they may not respond adequately to vaccination or may develop a disseminated infection from live attenuated vaccines.
  • Immunization of Special Populations Live vaccines should be used with caution in patients with symptomatic HIV infection, because they are potentially pathogenic. BCG vaccine is contraindicated in symptomatic patients because of the possibility of disseminated infection. Injected polio vaccine should be used rather than live attenuated vaccine if available. Measles vaccine should be given to all HIV positive children, because the risk of measles infection in an HIV positive child outweighs the potential risk of the vaccine. Yellow fever vaccine is not recommended in symptomatic patients because of insufficient data.
  • Contraindications Certain contraindications apply to all vaccines. An anaphylactic reaction to a vaccine contraindicates further doses of that vaccine. If an individual has had an anaphylactic reaction to a vaccine constituent, any vaccine containing that constituent is contraindicated. Moderate or severe illness with or without fever is a contraindication to vaccination. However, mild intercurrent illnesss with low grade pyrexia is not a contraindication to vaccination. Nor are previous mild to moderate local reactions, or fever after previous doses. Concurrent antimicrobial therapy and recent exposure to infectious disease are not contraindications. A history of penicillin or other allergies either in the recipient or their family is also not a contraindication to vaccination. OPV and MMR vaccine are contraindicated in immunocompromised patients. In HIV infected individuals their use is advocated despite the risk of pathogenicity in symptomatic patients, because of the benefits in protection against the vaccine-preventable disease.
  • Contraindications See previous page
  • Seizures Seizures have been particularly associated with measles and the pertussis component of DTP vaccination Febrile seizures: a seizure occuring in association with pyrexia (temperature>38 degrees celsius) Afebrile seizures: a seizure occuring in an apyrexial patient. Febrile seizures more common with Pertussis vaccination than with other vaccines. Any vaccine which provokes febrile response may potentially precipitate febrile seizures in a child. Such seizure are not associated with long term sequelae and do not predispose children to the development of epilepsy in later life.
  • Adverse reaction to BCG vaccination Disseminated BCG: Widespread infection.with Mycobacterium bovis may develop 1-12 months after BCG . This usually occurs in immunocompromised individuals. It may be confirmed microbiologically by isolation of Mycobacterium bovis BCG strain. Patients with disseminated BCG should be treated with an antituberculous regimen including Rifampicin and Isoniazid . Osteitis/Osteomyelitis: Infection of the bone with M bovis BCG strain may occur. Patients developing this complication are managed in the same manner as those with disseminated BCG. Described particularly in Scandinavia and Eastern Europe. Association particularly with the Goteberg strain. Treatment: BCG strain is resistant to PZA - therefore need to consider addition of ethambutol.
  • Suppurative lymphadenitis: This occurs within 2- 6 months of BCG vaccination. Case Definition: 1 lymph node> 1.5 cm in size OR draining sinus over a lymph node Suppurative lymphadenitis usually occurs in the axilla, on the same side as innoculation. Management: The lesion will heal spontaneously over months One only needs to manage actively if the involved nodes stick to skin or form draining sinuses. Management in such cases would involve surgical drainage and local installation of antituberculous drug. Note: Systemic Rx is with antituberculous drugs is ineffective in such cases.
  • Tetanus vaccine Brachial Neuritis This presents with pain in shoulder and upper arm. This is followed by weakness with or without wasting of arm and shoulder muscles. Sensory loss not prominent. Dysfunction is limited to the nerve plexus of the arm, without involvement of other peripheral or central nervous system structures. Brachial neuritis occurs 2-28 days after vaccination. The pathogenesis is not clearly understood. It is possibly a manifestation of immune complex disease. Usually associated with the administration of multiple doses. Management is symptomatic.
  • Encephalopathy and encephalitis The development of encephalopathy and encephalitis are possibly associated with Measles and Pertussis vaccine It is NOT certain that these vaccines are causative. Case definition of encephalopathy: 2 out of 3 of: 1. Seizures 2. Alteration of consciousness lasting for one day or more 3. Distinct change in behaviour for one day or more A temporal relationship with the administration of the vaccine must also exist Within 48hrs with DTP Within 7-12 days after measles or MMR
  • Encephalitis and measles vaccination An analysis of claims for encephalitis following measles vaccine in the USA found clustering of events 8-9 days after vaccination (Wetbel 1998, Duclos 1998) This supports, but does not prove, the possibility that measles vaccine was causative. Risk is less than 1 case per million
  • Hypotonic hypotensive episode (HHE or shock-collapse) Mainly associated with DTP Case definition: An event of sudden onset occurring within 48 (usually less than 12) hours of vaccination and lasting from one minute to several hours. In a child < 10 years of age 3. ALL of the following must be present -Limpness (hypotonic) -Reduced responsiveness -Pallor or cyanosis- or failure to observe/ recall HHE is a transient, self limiting reaction of unknown pathogenesis. It is NOT a contraindication to further vaccination.
  • Yellow Fever Vaccine E ncephalitis: Post-vaccination encephalitis may occur in infants under 6 months of age. Onset is 7-21 days after vaccination. There is no significant risk in older children and adults Insufficient data on safety in symptomatic HIV+ patients, therefore the vaccine should be avoided in such patients Use if the vaccine is contraindicated in pregnancy (unless a significant risk of contracting yellow fever exists.) Reports of deaths associated with
  • Influenza vaccine and GBS: The 1976 swine influenza virus was associated with an increase of Guillain- Barre Syndrome (GBS). The rate, that exceeded the background rate, was slightly less than 10 per million. CDC 1998.The risk from subsequent vaccines, prepared from different virus strains, is less clear. A recent study found an overall elevated risk of GBS of 1.7 in the 6 weeks following vaccination in the 1992-1993 and 193-194 seasons. This represented n excess of 1 or 2 cases per million vaccine recipients (Lasky et al, 1998) MMR and Autism: There is at present no conclusive evidence to suggest an association between MMR and autism. The alleged association is based on studies with methodological problems, and has been refuted. (Duclos and Ward, 1998) Polio and HIV:The postulated link between polio vaccine and the origins of the HIV epidemic have been disproved. Hepatitis B and Multiple Sclerosis: At present available data, though limited, does not demonstrate a causal association. In France where the concern was raised, the background rate of demyelinating disease was 1-3 cases per 100 000. Notification rate of demyelinating disease in temporal association with Hep B vaccination was 0.6 per 100 000. DTP and permanent brain damage: The USA Safety Committee agreed in 1994 that there was insufficient evidence to conclude that pertussis vaccine could cause permanent brain damage. (Edwards et al, 1999) Aluminium and macrophagic myofasciitis- more research needed. Based on available evidence at present, there is no health risk from the administration of alumnium containig vaccines.
  • 03 overview of_aefi_profile_of_vaccines

    1. 1. UNDERSTANDING VACCINE REACTIONS
    2. 2. OVERVIEW <ul><li>Principles of immunization </li></ul><ul><li>Types of vaccines and vaccine ingredients </li></ul><ul><li>Safety concerns and adverse reactions with </li></ul><ul><li>different types of vaccine </li></ul><ul><li>Adverse events following immunization </li></ul><ul><ul><li>common, minor reactions </li></ul></ul><ul><ul><li>rare, major reactions </li></ul></ul><ul><li>Vaccination of high-risk groups </li></ul><ul><li>Contraindications to vaccination </li></ul><ul><li>Adverse events associated with particular vaccines </li></ul><ul><li>Pathogenesis of serious adverse reactions </li></ul>
    3. 3. THE GOAL OF IMMUNIZATION <ul><li>To prime recipient’s immune response </li></ul><ul><li>To generate B and T memory cells </li></ul><ul><li>To heighten immune response to pathogens </li></ul><ul><li>To minimize adverse effects </li></ul><ul><li>To prevent/reduce severity of infectious diseases </li></ul><ul><li>To have vaccines of assured quality available for general use </li></ul>(Ref. Vaccine Overview)
    4. 4. ATTRIBUTES OF A GOOD VACCINE <ul><li>Appropriate immune response </li></ul><ul><li>Long-term protection </li></ul><ul><li>Safe </li></ul><ul><li>Stable </li></ul><ul><li>Affordable </li></ul>
    5. 5. RESPONSE TO IMMUNIZATION <ul><li>Depends on </li></ul><ul><ul><li>Viability of antigen </li></ul></ul><ul><ul><li>Total dose </li></ul></ul><ul><ul><ul><li>especially killed vaccine </li></ul></ul></ul><ul><ul><li>Route and site of administration </li></ul></ul><ul><ul><li>Age of recipient </li></ul></ul><ul><ul><li>Patient’s condition and immune state </li></ul></ul><ul><ul><li>Genetic factors </li></ul></ul>
    6. 6. TYPES OF ANTIGENS <ul><ul><li>1. Live attenuated (oral polio, BCG, VZV) </li></ul></ul><ul><ul><li>2. Killed vaccine (influenza, IPV, hepatitis A, pertussis) </li></ul></ul><ul><ul><li>3. Toxoid (tetanus, diphtheria) </li></ul></ul><ul><ul><li>4. P urified (subunit) antigen (meningococcal vaccine, Haemophilus influenzae vaccine) </li></ul></ul><ul><ul><li>5. R ecombinant antigen (hepatitis B) </li></ul></ul><ul><ul><li>6. DNA vaccines (in investigational phase) </li></ul></ul><ul><ul><li>7. Synthetic peptides (in investigational phase) </li></ul></ul>
    7. 7. LIVE ATTENUATED VACCINES <ul><li>Live organisms </li></ul><ul><ul><li>reproduce natural infection, without conferring disease </li></ul></ul><ul><li>Virulence much reduced </li></ul><ul><li>In vitro culture </li></ul><ul><li>Select strains that replicate poorly in target organ - minimize damage </li></ul>
    8. 8. LIVE ATTENUATED VACCINES <ul><li>Undergoes potency testing, neuro-virulence testing, test for wild-type strains and other infectious agent </li></ul><ul><li>E.g. measles, mumps, rubella, VZV, OPV (sabin) , BCG </li></ul>
    9. 9. KILLED/INACTIVATED VACCINES <ul><li>Live microorganisms inactivated by heat or chemical means (e.g. formalin) </li></ul><ul><li>Final concentrate tested for sterility, microorganism inactivation, potency, endotoxin, residuals concentration, pH, etc. </li></ul><ul><li>E.g. Salk polio vaccine, rabies vaccine, hepatitis A vaccine, pertussis vaccine </li></ul>
    10. 10. PURIFIED (SUBUNIT) ANTIGEN <ul><li>Only parts of pathogen necessary to elicit the immune response are used </li></ul><ul><li>Potential toxins are avoided </li></ul><ul><li>Need to be conjugated to evoke an adequate T-cell response </li></ul>
    11. 11. POLYSACCHARIDE CONJUGATE VACCINES <ul><li>Polysaccharide/oligosaccharide of antigen is linked (conjugated) to a protein carrier </li></ul><ul><ul><li>increases antibody response and increases of production of memory cells </li></ul></ul><ul><ul><li>immunologic response at earlier age </li></ul></ul><ul><ul><li>booster effect on subsequent exposure to antigen (via infection /immunization exposure) </li></ul></ul><ul><li>E.g. meningococcal vaccine, Haemophilus influenzae type B (Hib) vaccine </li></ul>
    12. 12. RECOMBINANT ANTIGEN VACCINES <ul><li>Bulk production of antigenic protein using recombinant technique </li></ul><ul><li>Recombinant technique - insert DNA from pathogen into expression vehicle (i.e. E. coli, Chinese Hamster ovary cells, yeast, etc) </li></ul><ul><li>Antigenic protein produced, harvested and purified before use </li></ul><ul><li>Example – recombinant hepatitis B vaccine </li></ul>
    13. 13. METHODS USED TO ENHANCE IMMUNITY <ul><li>Conjugation e.g. Hib vaccine </li></ul><ul><li>Adjuvants - aluminium salts </li></ul><ul><ul><li>Why are adjuvants used? </li></ul></ul><ul><ul><li>What adverse reactions are associated with their use? </li></ul></ul>
    14. 14. COMPONENTS OF THE VACCINE FORMULATION <ul><li>Suspending agents e.g. water, saline </li></ul><ul><li>Preservatives e.g. thiomerosal </li></ul><ul><li>Stabilisers e.g. sorbitol and hydrolyzed gelatin - MMR </li></ul><ul><li>Adjuvants e.g. aluminium Salts </li></ul><ul><li>Other substances which may be present </li></ul><ul><li>Residuals in the growth medium </li></ul><ul><li>Antibiotics, e.g. neomycin, streptomycin - IPV, varicella vaccine </li></ul>
    15. 15. COMBINATION VACCINES <ul><li>Diphtheria-tetanus-pertussis (DPT) </li></ul><ul><ul><li>pertussis component has adjuvant effect for diphtheria and tetanus toxoids </li></ul></ul><ul><li>Different viruses in one vaccination e.g. OPV-type 1, 2, 3 polioviruses </li></ul>
    16. 16. ROUTE OF ADMINISTRATION <ul><li>Should elicit immune response with minimal risk </li></ul><ul><li>Deep IM preferable for vaccines with adjuvants (depot effect and less granuloma formation) </li></ul><ul><li>SC/intradermal - better for live vaccines </li></ul><ul><ul><ul><li>to lessen risk of neurovascular injury but still immunogenic (e.g. BCG) </li></ul></ul></ul>
    17. 17. WHAT IS AN ADVERSE EVENT FOLLOWING IMMUNIZATION (AEFI)? <ul><li>A medical incident that takes place after an immunization, causes concern, and is believed to be caused by immunization </li></ul><ul><li>Vaccine reaction - caused by vaccine’s inherent properties </li></ul><ul><li>Programme error - caused by error in vaccine preparation, handling, or administration </li></ul><ul><li>Coincidental - happens after immunization but not caused by it ( a chance association) </li></ul><ul><li>Injection reaction - anxiety or pain of injection not vaccine </li></ul><ul><li>Unknown - cause cannot be determined </li></ul>
    18. 18. VACCINE REACTIONS <ul><li>Common, minor reactions </li></ul><ul><ul><li>vaccine stimulates immune system </li></ul></ul><ul><ul><li>settle on their own </li></ul></ul><ul><ul><li>warn parents and advise how to manage </li></ul></ul><ul><li>Rare, more serious reactions </li></ul><ul><ul><li>anaphylaxis (serious allergic reaction) </li></ul></ul><ul><ul><li>vaccine specific reactions </li></ul></ul>
    19. 19. COMMON, MINOR REACTIONS Irritability, malaise & systemic symptoms Fever >38 o C BCG Hib HepB Measles/ MMR Polio (OPV) DTP (pertussis) Tetanus 90-95% 5-15% Adults: 15%; Children: 5% ~10% - Up to 50% ~10%* - 2-10% - 5-15% <1% Up to 50% ~10% - - 1-6% 5% rash <1%** Up to 55% ~25% * Rate of local reactions likely to increase with booster doses, up to 50-85% ** Symptoms include diarrhoea, headache, and/or muscle pains Vaccine Local reaction (pain, swelling, redness)
    20. 20. MANAGEMENT OF COMMON, MINOR REACTIONS <ul><li>Local reaction </li></ul><ul><ul><li>cold cloth at injection site </li></ul></ul><ul><ul><li>paracetamol </li></ul></ul><ul><li>Fever >38 ° C </li></ul><ul><ul><li>give extra fluids </li></ul></ul><ul><ul><li>tepid sponging </li></ul></ul><ul><ul><li>paracetamol </li></ul></ul><ul><li>Irritability malaise and systemic symptoms </li></ul><ul><ul><li>give extra fluids </li></ul></ul><ul><ul><li>paracetamol </li></ul></ul>
    21. 21. RARE, MORE SERIOUS REACTIONS 0.76-1.3 (1 st dose) 0.17 (subsequent doses) 0.15 (contacts) 4-30 days Vaccine-associated paralytic poliomyelitis (VAPP) Risk is higher for first dose, adults, and immunocompromised OPV 333 33 1-50 5-12 days 15-35 days 0-1 hour Febrile seizures Thrombocytopaenia Anaphylaxis Measles /MMR 1-2 5 0-1 hour 1-6 weeks Anaphylaxis Guillain Barré syndrome Hep B Nil known Hib 100-1000 1-700 2 2-6 months 1-12 months 1-12 months Suppurative lymphadenitis BCG osteitis Disseminated BCG BCG Rate per million doses Onset interval Reaction Vaccine
    22. 22. RARE, MORE SERIOUS REACTIONS (2 ) 1000-60 000 570 570 20 0-1 0-24 hours 0-3 days 0-24 hours 0-1 hour 0-3 days Persistent (>3 hrs) inconsolable screaming Seizures Hypotonic, hyporesponsive episode (HHE) Anaphylaxis/shock Encephalopathy DPT Nil extra to tetanus reactions Tetanus-diphtheria 5-10 1-6 6-10 2-28 days 0-1 hour 1-6 weeks Brachial neuritis Anaphylaxis Sterile abscess Tetanus Rate per million doses Onset interval Reaction Vaccine
    23. 23. RARE, MORE SERIOUS REACTIONS (3) 500-4000 in infants<6 months 5-20 7-21 days 0-1 hours Post-vaccination Encephalitis Allergic reaction/anaphylaxis Yellow fever 10-1000 1-2.3 Serious allergic reaction Neurological event Japanese encephalitis Rate per million doses Onset interval Reaction Vaccine
    24. 24. RARE, MORE SERIOUS REACTIONS BCG Hib HepB Measles/ MMR/MR <ul><li>Suppurative lymphadenitis </li></ul><ul><li>BCG osteitis </li></ul><ul><li>Disseminated BCG infection </li></ul><ul><li>1 in 1000 to 1 in 10 000 </li></ul><ul><li>1 in 3000 to 1 in 100 million </li></ul><ul><li>~1 in 1 million </li></ul><ul><li>None known </li></ul><ul><li>Anaphylaxis </li></ul><ul><li>1 in 6-900 000 </li></ul><ul><li>Febrile seizures </li></ul><ul><li>Thrombocytopaenia </li></ul><ul><li>(low platelets) </li></ul><ul><li>Severe allergic reaction </li></ul><ul><li>Anaphylaxis </li></ul><ul><li>Encephalopathy </li></ul><ul><li>1 in 3000 </li></ul><ul><li>1 in 30 000 </li></ul><ul><li>~1 in 100 000 </li></ul><ul><li>~1 in 1 million </li></ul><ul><li><1 in 1 million </li></ul>Reaction Incidence
    25. 25. RARE, MORE SERIOUS REACTIONS (2) Tetanus Pertussis ( DPT- whole cell) Reaction Incidence Polio (OPV) <ul><li>Vaccine associated paralytic poliomyelitis </li></ul><ul><li>Risk is higher for first dose, adults, and immunocompromised </li></ul><ul><ul><li>1 in 2.4-3.3 million doses </li></ul></ul><ul><ul><li>1 in 750 000 first dose compared to 1 in 5.1 million for subsequent doses </li></ul></ul><ul><ul><li>Brachial neuritis </li></ul></ul><ul><ul><li>Anaphylaxis </li></ul></ul><ul><ul><li>0.5-1 in 100 000 </li></ul></ul><ul><ul><li>1 in 100 000 to 1 in 2 500 000 </li></ul></ul><ul><ul><li>Persistent inconsolable screaming </li></ul></ul><ul><ul><li>Seizures </li></ul></ul><ul><ul><li>Hypotonic, hyporesponsive episode (HHE) </li></ul></ul><ul><ul><li>Anaphylaxis </li></ul></ul><ul><ul><li>Encephalopathy (Note: Risk may be zero) </li></ul></ul><ul><ul><li>1 in 15 to 1 in 1000 </li></ul></ul><ul><ul><li>1 in 1750 to 1 in 12 500 </li></ul></ul><ul><ul><li>1 in 1000 to 1 in 33 000 </li></ul></ul><ul><ul><li>1-6 in million </li></ul></ul><ul><ul><li>0-1 in 1 million </li></ul></ul>
    26. 26. IMMUNIZATION OF SPECIAL POPULATIONS PREGNANT WOMEN <ul><li>Safety concerns: potential teratogenicity and induction of abortion </li></ul><ul><li>Vaccinate only if indicated </li></ul><ul><li>Live viral vaccines usually not recommended </li></ul><ul><li>Birth defect unrelated to the vaccine may be falsely attributed to the vaccine </li></ul><ul><li>Newer vaccines/regimens may have unknown effects - use with caution </li></ul><ul><li>Women (especially adolescents) may not be aware of or disclose pregnancy </li></ul><ul><ul><li>should we screen for pregnancy? </li></ul></ul>
    27. 27. IMMUNIZATION OF SPECIAL POPULATIONS IMMUNOCOMPROMISED PATIENTS <ul><li>Patients may be immunocompromised due to </li></ul><ul><ul><li>HIV </li></ul></ul><ul><ul><li>congenital immunological dysfunction </li></ul></ul><ul><ul><li>immunosuppression, e.g. steroids, chemotherapy, etc. </li></ul></ul><ul><li>May not respond adequately to vaccination </li></ul><ul><li>Risk of disseminated infection from live attenuated vaccines </li></ul>
    28. 28. IMMUNIZATION OF SPECIAL POPULATIONS WHO/ UNICEF recommendations for vaccination of HIV-infected children and women of childbearing age 5 doses Y Y Tetanus toxoid N (need studies) Y Yellow fever As for uninfected Y Y HepB 6 and 9 months Y (depends) Y Measles 0, 6, 10, 14 weeks Y (IPV if available) Y OPV 6, 10, 14 weeks Y Y DTP Birth N Y BCG Optimal timing Symptomatic Asymptomatic Vaccine
    29. 29. CONTRAINDICATIONS <ul><li>True contraindications are rare </li></ul><ul><li>Current serious febrile illness </li></ul><ul><ul><li>delay vaccine administration </li></ul></ul><ul><li>History of severe AEFI after previous dose </li></ul><ul><li>Evolving neurological disease </li></ul><ul><ul><li>avoid whole cell pertussis vaccine </li></ul></ul><ul><ul><li>(e.g. uncontrolled epilepsy) </li></ul></ul><ul><li>Type 1 hypersensitivity to egg - avoid yellow fever & influenza but can use vaccines made in chick fibroblasts </li></ul><ul><li>Symptomatic HIV </li></ul><ul><ul><li>avoid BCG </li></ul></ul>WHO Immunization Policy 1996
    30. 30. CONTRAINDICATIONS * Risk benefit assessment when administered to HIV positive individuals Adopted from Plotkin pg 66-67 Anaphylactic reaction to neomicin, streptomycin or polymyxin B IPV Immunodeficiency, or immunodeficient household contact* OPV Encephalopathy within 7 days of administration DTP Anaphylactic reaction to vaccine or vaccine constituent Severe febrile illness All vaccines Contraindication Vaccine
    31. 31. CONTRAINDICATIONS * Risk benefit assessment when administered to HIV-positive individuals Adopted from Plotkin pg 66-67 Anaphylactic reaction to common baker’s yeast Hepatitis B Anaphylactic reaction to egg, immunodeficiency Yellow fever None Hib Anaphylaxis, pregnancy, immunodeficiency* MMR Contraindication Vaccine
    32. 32. ADVERSE EVENTS ASSOCIATED WITH SPECIFIC VACCINES <ul><li>WHO case definitions are used here </li></ul><ul><li>Lack of standardized case definitions in the literature </li></ul><ul><ul><li>e.g. fever </li></ul></ul><ul><li>The Brighton collaboration </li></ul><ul><ul><li>developing case definitions for AEFI </li></ul></ul><ul><ul><li>promoting global implementation of these definitions </li></ul></ul>[email_address] http://brightoncollaboration.org
    33. 33. ANAPHYLAXIS <ul><li>Type 1 hypersensitivity reaction </li></ul><ul><li>Circulatory failure </li></ul><ul><li>Bronchospasm +/- laryngospasm/laryngeal oedema </li></ul><ul><ul><li>respiratory distress </li></ul></ul><ul><li>May include pruritis, flushing, angioedema, seizures, vomiting, abdominal cramps & incontinence </li></ul><ul><li>Occurs in previously sensitized individuals </li></ul>
    34. 34. ANAPHYLAXIS <ul><li>Reported less from developing countries </li></ul><ul><ul><li>Less sensitization? </li></ul></ul><ul><ul><li>Less reporting? </li></ul></ul><ul><li>Anaphylaxis is rare (1/1 000 000 vaccinations) </li></ul><ul><li>Fainting is common </li></ul><ul><li>Untrained staff may misdiagnose fainting/dizziness for anaphylaxis or vice versa </li></ul><ul><li>Administration of adrenaline in a faint may be dangerous </li></ul><ul><ul><ul><li>PROMPT MANAGEMENT IS VITAL! </li></ul></ul></ul>
    35. 35. SEIZURES <ul><li>Particularly associated with measles and DTP vaccination (pertussis component ) </li></ul><ul><ul><li>febrile seizures Temp >38 </li></ul></ul><ul><ul><li>afebrile seizures Temp normal </li></ul></ul><ul><li>Febrile seizures more common with pertussis </li></ul><ul><li>An association with non-febrile seizures has not been proven </li></ul>
    36. 36. ADVERSE REACTIONS TO BCG <ul><li>Disseminated BCG </li></ul><ul><ul><li>widespread infection, 1-12 months after BCG </li></ul></ul><ul><ul><li>usually in immunocompromised individual </li></ul></ul><ul><ul><li>confirm by isolation of Mycobacterium bovis BCG strain </li></ul></ul><ul><ul><li>treat with antituberculous regimen including Rifampicin and Isoniazid </li></ul></ul><ul><li>Osteitis/osteomyelitis </li></ul><ul><ul><li>infection of the bone with M bovis BCG strain </li></ul></ul><ul><ul><li>management as above </li></ul></ul>
    37. 37. ADVERSE REACTIONS TO BCG <ul><li>Suppurative lymphadenitis </li></ul><ul><ul><li>occurs within 2-6 months of BCG vaccination </li></ul></ul><ul><ul><ul><li>case definition </li></ul></ul></ul><ul><ul><ul><li>1 lymph node> 1.5 cm in size/draining sinus over a lymph node </li></ul></ul></ul><ul><ul><ul><li>usually occurs in the axilla, on the same side as innoculation </li></ul></ul></ul><ul><ul><li>Management </li></ul></ul><ul><ul><ul><li>heals spontaneously over months </li></ul></ul></ul><ul><ul><ul><li>only treat if sticking to skin or draining </li></ul></ul></ul><ul><ul><ul><li>surgical drainage and local installation of antituberculous drug </li></ul></ul></ul><ul><ul><ul><li>systemic Rx is ineffective </li></ul></ul></ul>
    38. 40. TETANUS VACCINE <ul><li>Brachial neuritis </li></ul><ul><li>Presents with pain in shoulder and upper arm </li></ul><ul><li>Followed by weakness +/- wasting of arm and shoulder muscles </li></ul><ul><li>Sensory loss not prominent </li></ul><ul><li>Occurs 2-28 days after vaccination </li></ul><ul><li>Possibly a manifestation of immune complex disease </li></ul><ul><li>Management is symptomatic </li></ul>
    39. 41. ENCEPHALOPATHY AND ENCEPHALITIS <ul><li>Possibly associated with measles & pertussis vaccine </li></ul><ul><li>Case definition of encephalopathy </li></ul><ul><ul><li>2 out of 3 of </li></ul></ul><ul><ul><ul><li>seizures </li></ul></ul></ul><ul><ul><ul><li>alteration of consciousness lasting for one day or more </li></ul></ul></ul><ul><ul><ul><li>distinct change in behavior for one day or more </li></ul></ul></ul><ul><li>Temporal relationship </li></ul><ul><ul><li>within 48 hrs with DTP </li></ul></ul><ul><ul><li>within 7-12 days after measles or MMR </li></ul></ul>
    40. 42. ENCEPHALITIS AND MEASLES VACCINATION <ul><li>An analysis of claims for encephalitis following measles vaccine in the USA found clustering of events 8-9 days after vaccination (Wetbel 1998, Duclos 1998) </li></ul><ul><li>This supports, but does not prove, the possibility that measles vaccine was causative </li></ul><ul><li>Risk is less than 1 case per million </li></ul>
    41. 43. HYPOTONIC HYPOTENSIVE EPISODE (HHE OR SHOCK-COLLAPSE) <ul><li>Mainly associated with DTP </li></ul><ul><ul><li>Case definition </li></ul></ul><ul><ul><ul><li>Event of sudden onset occurring within 48 (usually less than 12) hours of vaccination and lasting from one minute to several hours </li></ul></ul></ul><ul><ul><ul><li>In a child < 10 years of age </li></ul></ul></ul><ul><li>ALL of the following must be present </li></ul><ul><ul><li>limpness (hypotonic) </li></ul></ul><ul><ul><li>reduced responsiveness </li></ul></ul><ul><ul><li>pallor or cyanosis - or failure to observe/recall </li></ul></ul><ul><li>Transient, self-limiting, NOT a contraindication to further vaccination </li></ul>
    42. 44. POLIO VACCINE - ACUTE FLACCID PARALYSIS <ul><li>Vaccine associated paralytic poliomyelitis </li></ul><ul><li>Occurs within 4-30 days of receipt of OPV or 4-75 days after contact with vaccine recipient </li></ul>Case Following a national immunization day in 1996, cases of paralysis were reported after receiving OPV. On laboratory analysis, the wild virus was found, showing that the children had been infected with wild poliovirus before immunization. The cases of poliovirus were coincidental, and not caused by the vaccine .
    43. 45. YELLOW FEVER VACCINE <ul><li>Encephalitis </li></ul><ul><li>Post-vaccination encephalitis in infants < 6 months </li></ul><ul><li>Onset – 7-21 days from vaccination </li></ul><ul><li>No significant risk in older children and adults </li></ul><ul><li>Insufficient data on safety in symptomatic HIV+ patients = do not vaccinate </li></ul><ul><li>Contraindicated in pregnancy unless significant risk of contracting yellow fever exists </li></ul>
    44. 46. YELLOW FEVER VACCINE <ul><li>Multiple organ failure </li></ul><ul><li>Small number of case reports </li></ul><ul><li>Clinical presentation: </li></ul><ul><ul><li>fever, myalgia, headache, and confusion, followed by severe multisystemic illnesses </li></ul></ul><ul><ul><li>“ The temporal association …(illness onset 2-5 days after vaccination), serological responses, isolation of variant vaccine virus from serum and cerebrospinal fluid, and demonstration of yellow fever virus antigen in liver tissue collectively suggest a causal association between yellow fever vaccine and the severe multisystemic illness in these patients.” </li></ul></ul>Martin M. et al., Lancet Vol. 358, July 2001
    45. 47. JAPANESE ENCEPHALITIS VACCINE <ul><li>Mouse brain derived inactivated vaccine </li></ul><ul><li>Cell culture derived inactivated vaccine </li></ul><ul><li>Cell culture-derived live vaccine </li></ul><ul><li>Hypersensitivity reactions, generalized urticaria, facial angio-oedema and respiratory distress are described </li></ul><ul><ul><li>incidence 1-64/10 000 mouse brain derived inactivated vaccine recipients </li></ul></ul><ul><ul><li>possible relation to gelatin (used as a stabilizer) </li></ul></ul><ul><ul><li>overall, 10-1000 serious allergic reactions per million doses </li></ul></ul><ul><li>Neurological events 1-2.3 cases per million doses </li></ul><ul><ul><li>Case reports of acute disseminated encephalomyelitis </li></ul></ul>
    46. 48. UNPROVEN ASSOCIATIONS AND PUBLIC CONCERNS <ul><li>Influenza vaccine and Guillaine Barré Syndrome </li></ul><ul><li>MMR and autism, Crohn’s disease </li></ul><ul><li>Polio and HIV </li></ul><ul><li>Hepatitis B and multiple sclerosis </li></ul><ul><li>DTP and permanent brain damage </li></ul><ul><li>DTP and increased risk of mortality </li></ul><ul><li>Aluminium and macrophagic myofasciitis </li></ul><ul><li>Bovine spongiform encephalopathy (BSE) </li></ul><ul><li>Thiomerosal </li></ul><ul><li>Multiple vaccines given simultaneously </li></ul>
    47. 49. CONCLUSIONS <ul><li>Important to understand the safety profile of commonly used vaccines </li></ul><ul><li>Safety profile of vaccines depends on risk factors of person being vaccinated </li></ul><ul><li>AEFI system must identify priority events which need to be reported </li></ul><ul><li>Important to understand possible mechanisms, treatment and possible prevention of vaccine reactions </li></ul>

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