This document summarizes key information about understanding vaccine reactions, including: 1. It describes common minor reactions like fever and local reactions as well as rare but more serious reactions like anaphylaxis and seizures. 2. It provides details on adverse events associated with specific vaccines such as disseminated BCG infection, brachial neuritis with the tetanus vaccine, and post-vaccination encephalitis with yellow fever. 3. It discusses immunization of special populations including recommendations for vaccinating HIV-infected individuals and contraindications.

1. UNDERSTANDING VACCINE REACTIONS

2. OVERVIEW Principles of immunization Types of vaccines and vaccine ingredients Safety concerns and adverse reactions with different types of vaccine Adverse events following immunization common, minor reactions rare, major reactions Vaccination of high-risk groups Contraindications to vaccination Adverse events associated with particular vaccines Pathogenesis of serious adverse reactions

3. THE GOAL OF IMMUNIZATION To prime recipient’s immune response To generate B and T memory cells To heighten immune response to pathogens To minimize adverse effects To prevent/reduce severity of infectious diseases To have vaccines of assured quality available for general use (Ref. Vaccine Overview)

4. ATTRIBUTES OF A GOOD VACCINE Appropriate immune response Long-term protection Safe Stable Affordable

5. RESPONSE TO IMMUNIZATION Depends on Viability of antigen Total dose especially killed vaccine Route and site of administration Age of recipient Patient’s condition and immune state Genetic factors

6. TYPES OF ANTIGENS 1. Live attenuated (oral polio, BCG, VZV) 2. Killed vaccine (influenza, IPV, hepatitis A, pertussis) 3. Toxoid (tetanus, diphtheria) 4. P urified (subunit) antigen (meningococcal vaccine, Haemophilus influenzae vaccine) 5. R ecombinant antigen (hepatitis B) 6. DNA vaccines (in investigational phase) 7. Synthetic peptides (in investigational phase)

7. LIVE ATTENUATED VACCINES Live organisms reproduce natural infection, without conferring disease Virulence much reduced In vitro culture Select strains that replicate poorly in target organ - minimize damage

8. LIVE ATTENUATED VACCINES Undergoes potency testing, neuro-virulence testing, test for wild-type strains and other infectious agent E.g. measles, mumps, rubella, VZV, OPV (sabin) , BCG

9. KILLED/INACTIVATED VACCINES Live microorganisms inactivated by heat or chemical means (e.g. formalin) Final concentrate tested for sterility, microorganism inactivation, potency, endotoxin, residuals concentration, pH, etc. E.g. Salk polio vaccine, rabies vaccine, hepatitis A vaccine, pertussis vaccine

10. PURIFIED (SUBUNIT) ANTIGEN Only parts of pathogen necessary to elicit the immune response are used Potential toxins are avoided Need to be conjugated to evoke an adequate T-cell response

11. POLYSACCHARIDE CONJUGATE VACCINES Polysaccharide/oligosaccharide of antigen is linked (conjugated) to a protein carrier increases antibody response and increases of production of memory cells immunologic response at earlier age booster effect on subsequent exposure to antigen (via infection /immunization exposure) E.g. meningococcal vaccine, Haemophilus influenzae type B (Hib) vaccine

12. RECOMBINANT ANTIGEN VACCINES Bulk production of antigenic protein using recombinant technique Recombinant technique - insert DNA from pathogen into expression vehicle (i.e. E. coli, Chinese Hamster ovary cells, yeast, etc) Antigenic protein produced, harvested and purified before use Example – recombinant hepatitis B vaccine

13. METHODS USED TO ENHANCE IMMUNITY Conjugation e.g. Hib vaccine Adjuvants - aluminium salts Why are adjuvants used? What adverse reactions are associated with their use?

14. COMPONENTS OF THE VACCINE FORMULATION Suspending agents e.g. water, saline Preservatives e.g. thiomerosal Stabilisers e.g. sorbitol and hydrolyzed gelatin - MMR Adjuvants e.g. aluminium Salts Other substances which may be present Residuals in the growth medium Antibiotics, e.g. neomycin, streptomycin - IPV, varicella vaccine

15. COMBINATION VACCINES Diphtheria-tetanus-pertussis (DPT) pertussis component has adjuvant effect for diphtheria and tetanus toxoids Different viruses in one vaccination e.g. OPV-type 1, 2, 3 polioviruses

16. ROUTE OF ADMINISTRATION Should elicit immune response with minimal risk Deep IM preferable for vaccines with adjuvants (depot effect and less granuloma formation) SC/intradermal - better for live vaccines to lessen risk of neurovascular injury but still immunogenic (e.g. BCG)

17. WHAT IS AN ADVERSE EVENT FOLLOWING IMMUNIZATION (AEFI)? A medical incident that takes place after an immunization, causes concern, and is believed to be caused by immunization Vaccine reaction - caused by vaccine’s inherent properties Programme error - caused by error in vaccine preparation, handling, or administration Coincidental - happens after immunization but not caused by it ( a chance association) Injection reaction - anxiety or pain of injection not vaccine Unknown - cause cannot be determined

18. VACCINE REACTIONS Common, minor reactions vaccine stimulates immune system settle on their own warn parents and advise how to manage Rare, more serious reactions anaphylaxis (serious allergic reaction) vaccine specific reactions

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. MANAGEMENT OF COMMON, MINOR REACTIONS Local reaction cold cloth at injection site paracetamol Fever >38 ° C give extra fluids tepid sponging paracetamol Irritability malaise and systemic symptoms give extra fluids paracetamol

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. 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. 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. RARE, MORE SERIOUS REACTIONS BCG Hib HepB Measles/ MMR/MR Suppurative lymphadenitis BCG osteitis Disseminated BCG infection 1 in 1000 to 1 in 10 000 1 in 3000 to 1 in 100 million ~1 in 1 million None known Anaphylaxis 1 in 6-900 000 Febrile seizures Thrombocytopaenia (low platelets) Severe allergic reaction Anaphylaxis Encephalopathy 1 in 3000 1 in 30 000 ~1 in 100 000 ~1 in 1 million <1 in 1 million Reaction Incidence

25. RARE, MORE SERIOUS REACTIONS (2) Tetanus Pertussis ( DPT- whole cell) Reaction Incidence Polio (OPV) Vaccine associated paralytic poliomyelitis Risk is higher for first dose, adults, and immunocompromised 1 in 2.4-3.3 million doses 1 in 750 000 first dose compared to 1 in 5.1 million for subsequent doses Brachial neuritis Anaphylaxis 0.5-1 in 100 000 1 in 100 000 to 1 in 2 500 000 Persistent inconsolable screaming Seizures Hypotonic, hyporesponsive episode (HHE) Anaphylaxis Encephalopathy (Note: Risk may be zero) 1 in 15 to 1 in 1000 1 in 1750 to 1 in 12 500 1 in 1000 to 1 in 33 000 1-6 in million 0-1 in 1 million

26. IMMUNIZATION OF SPECIAL POPULATIONS PREGNANT WOMEN Safety concerns: potential teratogenicity and induction of abortion Vaccinate only if indicated Live viral vaccines usually not recommended Birth defect unrelated to the vaccine may be falsely attributed to the vaccine Newer vaccines/regimens may have unknown effects - use with caution Women (especially adolescents) may not be aware of or disclose pregnancy should we screen for pregnancy?

27. IMMUNIZATION OF SPECIAL POPULATIONS IMMUNOCOMPROMISED PATIENTS Patients may be immunocompromised due to HIV congenital immunological dysfunction immunosuppression, e.g. steroids, chemotherapy, etc. May not respond adequately to vaccination Risk of disseminated infection from live attenuated vaccines

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. CONTRAINDICATIONS True contraindications are rare Current serious febrile illness delay vaccine administration History of severe AEFI after previous dose Evolving neurological disease avoid whole cell pertussis vaccine (e.g. uncontrolled epilepsy) Type 1 hypersensitivity to egg - avoid yellow fever & influenza but can use vaccines made in chick fibroblasts Symptomatic HIV avoid BCG WHO Immunization Policy 1996

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. 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. ADVERSE EVENTS ASSOCIATED WITH SPECIFIC VACCINES WHO case definitions are used here Lack of standardized case definitions in the literature e.g. fever The Brighton collaboration developing case definitions for AEFI promoting global implementation of these definitions [email_address] http://brightoncollaboration.org

33. ANAPHYLAXIS Type 1 hypersensitivity reaction Circulatory failure Bronchospasm +/- laryngospasm/laryngeal oedema respiratory distress May include pruritis, flushing, angioedema, seizures, vomiting, abdominal cramps & incontinence Occurs in previously sensitized individuals

34. ANAPHYLAXIS Reported less from developing countries Less sensitization? Less reporting? Anaphylaxis is rare (1/1 000 000 vaccinations) Fainting is common Untrained staff may misdiagnose fainting/dizziness for anaphylaxis or vice versa Administration of adrenaline in a faint may be dangerous PROMPT MANAGEMENT IS VITAL!

35. SEIZURES Particularly associated with measles and DTP vaccination (pertussis component ) febrile seizures Temp >38 afebrile seizures Temp normal Febrile seizures more common with pertussis An association with non-febrile seizures has not been proven

36. ADVERSE REACTIONS TO BCG Disseminated BCG widespread infection, 1-12 months after BCG usually in immunocompromised individual confirm by isolation of Mycobacterium bovis BCG strain treat with antituberculous regimen including Rifampicin and Isoniazid Osteitis/osteomyelitis infection of the bone with M bovis BCG strain management as above

37. ADVERSE REACTIONS TO BCG Suppurative lymphadenitis occurs within 2-6 months of BCG vaccination case definition 1 lymph node> 1.5 cm in size/draining sinus over a lymph node usually occurs in the axilla, on the same side as innoculation Management heals spontaneously over months only treat if sticking to skin or draining surgical drainage and local installation of antituberculous drug systemic Rx is ineffective

40. TETANUS VACCINE Brachial neuritis Presents with pain in shoulder and upper arm Followed by weakness +/- wasting of arm and shoulder muscles Sensory loss not prominent Occurs 2-28 days after vaccination Possibly a manifestation of immune complex disease Management is symptomatic

41. ENCEPHALOPATHY AND ENCEPHALITIS Possibly associated with measles & pertussis vaccine Case definition of encephalopathy 2 out of 3 of seizures alteration of consciousness lasting for one day or more distinct change in behavior for one day or more Temporal relationship within 48 hrs with DTP within 7-12 days after measles or MMR

42. 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

43. HYPOTONIC HYPOTENSIVE EPISODE (HHE OR SHOCK-COLLAPSE) Mainly associated with DTP Case definition 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 ALL of the following must be present limpness (hypotonic) reduced responsiveness pallor or cyanosis - or failure to observe/recall Transient, self-limiting, NOT a contraindication to further vaccination

44. POLIO VACCINE - ACUTE FLACCID PARALYSIS Vaccine associated paralytic poliomyelitis Occurs within 4-30 days of receipt of OPV or 4-75 days after contact with vaccine recipient 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 .

45. YELLOW FEVER VACCINE Encephalitis Post-vaccination encephalitis in infants < 6 months Onset – 7-21 days from vaccination No significant risk in older children and adults Insufficient data on safety in symptomatic HIV+ patients = do not vaccinate Contraindicated in pregnancy unless significant risk of contracting yellow fever exists

46. YELLOW FEVER VACCINE Multiple organ failure Small number of case reports Clinical presentation: fever, myalgia, headache, and confusion, followed by severe multisystemic illnesses “ 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.” Martin M. et al., Lancet Vol. 358, July 2001

47. JAPANESE ENCEPHALITIS VACCINE Mouse brain derived inactivated vaccine Cell culture derived inactivated vaccine Cell culture-derived live vaccine Hypersensitivity reactions, generalized urticaria, facial angio-oedema and respiratory distress are described incidence 1-64/10 000 mouse brain derived inactivated vaccine recipients possible relation to gelatin (used as a stabilizer) overall, 10-1000 serious allergic reactions per million doses Neurological events 1-2.3 cases per million doses Case reports of acute disseminated encephalomyelitis

48. UNPROVEN ASSOCIATIONS AND PUBLIC CONCERNS Influenza vaccine and Guillaine Barré Syndrome MMR and autism, Crohn’s disease Polio and HIV Hepatitis B and multiple sclerosis DTP and permanent brain damage DTP and increased risk of mortality Aluminium and macrophagic myofasciitis Bovine spongiform encephalopathy (BSE) Thiomerosal Multiple vaccines given simultaneously

49. CONCLUSIONS Important to understand the safety profile of commonly used vaccines Safety profile of vaccines depends on risk factors of person being vaccinated AEFI system must identify priority events which need to be reported Important to understand possible mechanisms, treatment and possible prevention of vaccine reactions