Immunization

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Immunization The most important investment that
any country can make in the health of its
children
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OBJECTIVES

• 1 Outline the important contribution that
  vaccination can make to World Health.
• 2 Briefly describe the principles and basis of
  immunization.
• 3 Discuss the different types of vaccine, their
  advantages and disadvantages
• 4 Explain common vaccine strategies for children
  and adults including examples of important
  vaccines.

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Rationale of Immunization

• Objective to produce, without harm to the
  recipient, a degree of resistance sufficient to
  prevent a clinical attack of the natural
  infection and to prevent the spread of infection
  to susceptibles in the community.
• Personal gain and public health benefit
• Degree of resistance may not protect against an
  overwhelming challenge, but exposure may help to
  boost immunity

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Definitions

• Adjuvant
• Adverse reaction
• Antitoxin
• Immunization
• Active
• Passive

• Immunoglobulin e.g.,
• Human Normal Immunoglobulin HNIG
• Human Specific Immunoglobulin / Hyperimmune
  globulin
• Toxoid
• modified bacterial toxin

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Definitions

• Vaccine
• a suspension of live attenuated or inactivated
  microorganisms or fractions thereof administered
  to induce immunity and thereby prevent infectious
  disease
• Vaccination
• the term used to refer to the administration of
  any vaccine or toxin

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Principles of Immunization

• Immunization denotes the process of inducing or
  providing immunity artificially
• Protection from infectious disease
• Usually indicated by the presence of antibody
• Very specific to a single antigen

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Principles of Immunization

• Antigen
• A live or inactivated substance (e.g., protein,
  polysaccharide) capable of producing an immune
  response
• Antibody
• Protein molecules (immunoglobulin) produced by B
  lymphocytes to help eliminate an antigen

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Principles of Immunization

• Active
• Protection produced by the person's own immune
  system, usually permanent
• Immunity and immunologic memory produced, similar
  to the natural infection but without the risk of
  disease
• Passive
• Protection transferred from another person or
  animal as antibody
• This will afford temporary protection
• In infancy, transplacental transfer is the most
  important source

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Sources of Passive Immunity

• Almost all blood or blood products
• Homologous pooled human antibody (immune
  globulin)
• Homologous human hyperimmune globulin
• Heterologous hyperimmune serum (antitoxin)

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Example Antibody for Prevention of Respiratory
Syncytial Virus infection

• RSV-IGIV
• Human hyperimmune globulin
• Contains other antibodies
• Palivizumab (Synagis)
• Mouse monoclonal
• Contains only RSV antibody

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Classification of Vaccinesviral or bacterial

• Live attenuated
• single dose e.g., BCG (related org, shared
  antigens)
• two doses if immunity likely to wane over time,
  e.g., rubella, measles
• three doses for a different reason oral polio in
  primary schedule because there are 3 serotypes of
  poliovirus
• Inactivated
• multiple doses a course typically consists of 3
  doses, /- a subsequent booster
• primary response, secondary response

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Live vaccine

• Attenuated agent (unstable)
• Amplification of response - gradual rise to peak
  response then decline
• Variable but long duration of immunity -the
  immune response produced is similar to that
  produced by the natural infection
• There will be a booster effect with subsequent
  exposure
• There is a possibility of generalised /severe
  infection in an immunocompromised individual
• There may be interference from circulating
  antibody with the take of the vaccine

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Inactivated Vaccines
Whole

• virus
• bacteria
• protein-based
• subunit
• toxoid
• polysaccharide-based
• pure
• conjugate

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Inactivated Vaccines

• Cannot replicate
• There will be minimal interference from
  circulating antibody
• In general they are not as effective as live
  vaccines
• Generally require 3-5 doses
• The immune response produced is mostly humoral
• Antibody titer falls over time

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Examples of live and inactivated vaccines
Live Inactivated

• Viral measles, mumps, rubella, vaccinia,
  varicella, yellow
• fever, oral polio, rotavirus,
• (influenza Flumist, not
  available outside USA at present)
• Bacterial
• BCG (oral typhoid)

• Viral polio, hepatitis A,
• rabies, influenza
• Bacterial (whole cell) pertussis, typhoid,
• (cholera), (plague)

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Inactivated Vaccines
Fractional vaccines

• Subunit hepatitis B, influenza,
• acellular pertussis,
• (typhoid Vi), (Lyme)
• Toxoid diphtheria, tetanus

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Polysaccharide VaccinesDerived from bacterial
capsule

• pneumococcal
• meningococcal
• Haemophilus influenzae type b
• (New) Conjugate polysaccharide vaccines
• Haemophilus influenzae type b
• meningococcal
• pneumococcal

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Pure Polysaccharide Vaccines

• Not consistently immunogenic in children lt2 years
  of age
• No booster response
• Produce antibody with less functional activity
  than that produced by the infection
• Immunogenicity is greatly improved by conjugation

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Addition of 7-valent pneumococcal vaccine to
routine schedule of immunisations

• Children who attended hopitals in the greater
  Dublin area, 2002-2004
• Incidence of invasive pneumococcal disease
  10.6/100,000 - 2 deaths
• 61.4 lt2 years 76 lt 5 years
• Reduced penicillin susceptibility in 15 - all
  were vaccine serotypes
• Based on serotype data, in paediatric patients
  PCV7 would prevent lt90 of cases of sepsis,
  lt82.5 meningitis, lt59 pneumonia
• A safe and effective vaccine to be added to the
  infant schedule

Fitzsimons JJ, Chong AL, Cafferkey MT, Butler K.
Ir J Med Sci 2008177225-31
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PCV7 would be cost effective

• Implementing a PCV7 vaccine programme with a
  birth cohort of 61,000, would be expected to
  prevent 7703 cases of pneumococcal infection over
  5 years costs avoided 2.05mi rising to 4.6mi
  allowing for the effect of herd immunity
• Economic evaluation of a universal childhood
  pneumococcal conjugate vaccination strategy in
  Ireland
• Tilson L, Usher C, Butler K, Fitzsimons J, OHare
  F, Cotter S, OFlanagan D, Johnson H, Barry M
• Value Health 2008May 16 Epub ahead of print

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The need for a vaccine is determined by the
morbidity and mortality from the natural infection

• e.g., Contrast measles, rubella hepatitis B

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Measles Morbidity Mortality

• Morbidity in 10
• Otitis Media 5
• RTI 4
• Convulsions 0.5
• Other neurological 0.1
• Hospital Admission 1.4
• Very small risk of SSPE
• 1 in 300,000 cases

• Mortality
• Notifications 2,161,542
• Deaths 365
• Mortality Rate per 100,000 notified cases 16.9
• England Wales, 1970 to 1988

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Rubella Morbidity Mortality

• Morbidity benign illness
• children
• thrombotic thrombocytopenic purpura 1 in 500
• Adults
• acute polyarticular arthropathy women gt men
• chronic arthritis may occasionally develop
• Neurological
• postinfectious encephalopathy and encephalitis 1
  in 4,700 to 1 in 6,000

• Mortality
• due to the neurologic manifestations 20-50 of
  patients with these

Principal morbidity Congenital Rubella Syndrome
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Hepatitis B Morbidity Mortality

• Morbidity
• Up to 90 of vertically infected infants may
  become chronic carriers
• Between 2-20 of infected adults become chronic
  carriers
• Carriers may develop chronic hepatitis, cirrhosis
  or hepatocellular carcinoma

• Mortality
• approximately 1 of those hospitalised with acute
  HBV infection die
• superinfection with delta agent hepatitis D may
  lead to fulminant liver failure
• HBV infection is a major economic burden worldwide

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Immunization Protection of

• infants against the important infectious diseases
  of childhood (early)
• adults and children against the infectious
  hazards of travel (timely)
• susceptible or at risk adults and children
• adults against certain infections that may be
  acquired at work

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HERD IMMUNITY

• When most people in community are immune to a
  particular infection that is spread from person
  to person, the natural transmission of the
  infection is effectively inhibited
• Vaccine uptake rates gt90 (measles 95)
• Not tetanus!

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Routine immunisation schedule from 1st September
2008
Age Immunisations Comment
birth BCG 1 injection
2 months DTaP/Hib/IPV/HepB PCV 2 injections
4 months DTaP/Hib/IPV/HepB MenC 2 injections
6 months DTaP/Hib/IPV/HepB PCV MenC 3 injections
12 months MMR PCV 2 injections
13 months MenC Hib 2 injections
4 to 5 years DTaP/IPV MMR 2 injections
11 to 14 years Td (Tdap) (BCG) ?girls HPV (0, 1, 6months) 2 injections ?3
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Recommended changes to routine immunisation
schedule, 2008

• Pneumococcal conjugate vaccine into primary
  schedule (2 1)
• Hepatitis B vaccine into primary schedule (3)
• Hib and MenC boosters in 2nd year of life
• Hib to remain at 3 1
• MenC to be 2 1
• Td booster for 11-14 years change to Tdap
• ?10- 12yrs girls HPV (0, 1, 6 months)

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Geographical variation

• diphtheria booster for adults
• travellers to an endemic area
• d not D
• IPV versus OPV
• inclusion of Hepatitis B in the routine childhood
  immunization schedule
• Varicella-zoster in routine infant schedule in
  some countries

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Adult immunizations 1Normal Adults

• Women seronegative for rubella
• rubella
• Previously non-immunised individuals
• tetanus
• Individuals in specific high risk groups
• HBV, HAV, influenza, pneumococcal
• Those travelling abroad
• hepatitis A, typhoid, (polio)

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Adult Immunizations 2Health Care Workers

• Hepatitis B
• Hepatitis A
• Tuberculosis
• Influenza
• immunise those involved in the long term care of
  the elderly

• Check in some clinical circumstances
• varicella immunity
• rubella antibody
• measles antibody
• polio booster to some
• e.g., laboratory staff performing faecal cultures

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Immunization

• Interrupted immunization course
• resume as soon as possible it is not necessary
  to repeat the course
• Late primary immunization
• immunise as soon as possible
• DTaP/IPV/Hib, menC and MMR may be given
  simultaneously
• the number of Hib doses depends on the childs age

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The following reactions to a vaccine are
contraindications to a further dose

• anaphylaxis
• fever gt 40.5oC
• within 48 hours of vaccine administration for
  which no other cause is found
• Any of the following occurring within 72 hours of
  vaccine administration
• prolonged unresponsiveness
• prolonged inconsolable or high-pitched screaming
  for gt 4 hr
• convulsions or encephalophathy

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Vaccines pregnancy

• Live vaccines should generally not be
  administered in pregnancy because of the
  theoretical possibility of harm to the foetus
• However when there is a significant risk of
  exposure to poliomyelitis (e.g., travel to an
  endemic area) the need for immunization
  outweighs any possible risk to the foetus
• Some inactivated vaccines are/may be administered
  in pregnancy e.g., tetanus toxoid

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Complications and side-effects

• Virulent infectious material in the vaccine
• allergic reactions
• toxicity ?harmful effects on the foetus
• harmful effects on immunodeficient hosts
• Other effects
• Suggested effects without substantiation
• MMR - link with autism with Crohns Disease

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Specific examples of immunisation strategies
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measles
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rubella
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Hepatitis B
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Hepatitis B

• Chronic HBV infection with persistence of HBsAg
  occurs in
• up to 90 of infants infected vertically,
• 30 of children 1 to 5 years old infected after
  birth
• in 5 to 10 of older children, adolescents and
  adults with hepatitis B infection

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HBV Perinatal Transmission

• Babies of carrier mothers should receive HB
  vaccine /- hepatitis B hyperimmune globulin
  (HBIG)
• Many countries now include routine neonatal HBV
  immunization in the routine schedule

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Invasive meningococcal disease
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Invasive meningococcal disease

• Polysaccharide vaccine in defined populations
• (PS vaccines generally poorly immunogenic in
  infancy)
• Conjugate PS vaccine in some national
  immunisation schedules
• (enhanced immunogenicity in infancy and
  immunologic memory induced)

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Saudia Arabia pilgrims - Haj

• Very large outbreaks of meningococcal disease in
  pilgrims in 1980s and again in 1990s
• Certification of vaccination is required by the
  authorities since 1988
• Saudi Arabia Ministry of Health issued specific
  requirements in 2000
• Current general recommendation quadrivalent
  ACW135Y

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Rotavirus vaccines

• Who needs them most?

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Anticipated developments

• Individuals in specific high risk groups
• varicella zoster vaccine
• children at high risk
• non-immune health care workers
• Q routine schedule or non-immune adolescents
• At risk infants
• specific RSV immunoglobulin
• How do we define who should be protected?

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• Human papillomaviruses

Two HPV vaccines are now available these
vaccines have been introduced routinely in some
countries a decision was announced then revoked
in Ireland
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Cancer of the cervix (mortality/100,000)
lt3.9
lt7.9
lt14.0
lt23.8
lt55.6

• Mortality falling developed world
• Mortality rising in developing world

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Who should be screened and how often?

• 25 First invitation
• 25-49 Three Yearly
• 49-60 (65) Five Yearly

Dr.Papanicolaou the Pap smear
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Which Human Papillomaviruses have been included
in the vaccines
6,11,

• Low Risk 6, 11, 40, 42, 43, 44, 54, 61
• Anogenital warts

c. 90 of Genital Warts - US, Europe
16,18,

• High risk 16, 18 45, 31, 33, 52, 58, 35, 59,
  56, 39, 51, 73, 68, 66
• Anogenital neoplasia

c. 70 of Cervical Cancers - US, Europe
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HPV Vaccine US Recommendations

• Routine vaccination of females 11 or 12 years of
  age
• The vaccination series can be started as young as
  9 years of age at the clinician's discretion
• Vaccination is recommended for females 13-26
  years of age who have not been previously
  vaccinated (Note not Mandatory)
• Ideally vaccine should be administered before
  onset of sexual activity

CDC, June 2006
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HPV Vaccine and Cervical Cancer Screening

• 30 of cervical cancers are caused by HPV types
  not prevented by the available HPV vaccines
• Vaccinated females could subsequently be infected
  with non-vaccine high-risk HPV types
• Sexually active females could have been infected
  prior to vaccination

Cervical cancer screening recommendations have
NOT changed for females who receive HPV vaccine
CDC, June 2006
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Influenza A Viral Structure

• Haemagglutinin (HA) mediates binding of the virus
  to sialic acid receptors on target cells, and
  entry of the viral genome into the target cell,
  acts as an antigen
• Neuraminidase (NA) prevents viral clumping,
  facilitates release of virus from infected cells,
  is a target for antiviral drugs acts as an
  antigen

• 11 genes on 8 pieces of RNA
• 11 proteins haemagglutinin (HA), neuraminidase
  (NA), nucleoprotein (NP), M1, M2,
  NS1,NS2(NEP), PA, PB1, PB1-F2 and PB2.

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Influenza Viral Structure
There are 15 H and 9 N subtypes known

• HA the human cell and avian cell receptors differ
  biochemically
• It is believed that the HA of avian origin must
  acquire human receptor-binding specificity to
  generate strains capable of human-to-human
  transmission
• Limited passage in humans may be sufficient to
  cause such a change
• Swine nasopharyngeal cells may have receptors for
  both human and avian strain

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NVRL National Virus Reference Laboratory CUH -
Cork University Hospital UCHG University College
Hospital Galway
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Pandemic H1N1 vaccines

• All produced by the mock-up approach vaccines
  produced for avian influenza (H5N1), quality
  safety and immunogenicity studies when pandemic
  H1N1 emerged, H1N1 was substituted for H5N1 in
  these vaccines
• 3 now licensed in Europe
• Pandemrix GlaxoSmithKline
• Celvapan Baxter
• Focetria - Novartis
• Different vaccines produced in the USA

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Pandemic H1N1 2009 vaccines approved in
Ireland

• Pandemrix
• Split virion grown in eggs
• 3.75?g antigen
• Adjuvant (AS03)
• Thiomersal preservative
• 10-dose vial can be used for up to 24 hours
  after opening
• 1 dose sufficient for immunocompetent gt13 years
• 2 doses for the immunocompromised those lt13
  years

• Celvapan
• Whole virus inactivated, grown in vero cells
• 7.5?g antigen
• No adjuvant
• No added thiomersal
• 10-dose vial must be used within 3 hours of
  opening
• 2 doses recommended at present for all recipients

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Pandemic H1N1 vaccines Concerns 1

• Local reactions
• Systemic reactions
• Thiomersal suggested link with autism and other
  neurodegenerative conditions - not confirmed
• Adjuvant (AS03) has been used in gt22 million
  doses of vaccine worldwide without any safety
  concerns (WHO technical report) not used
  previously in an influenza vaccine

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Pandemic H1N1 vaccines Concerns 2

• Guillain-Barre Syndrome (GBS)
• The annual incidence of GBS in developed
  countries is c. 1-2 cases per 100,000 population.
  
• There is evidence of a preceding infection in
  most cases of GBS, most commoly Campylobacter, or
  less commonly, influenza
• In the USA in 1976, use of a swine flu vaccine
  was followed by a statistical association
  suggesting an excess risk of GBS of c.
  9/1,000,000 vaccinees. Studies conducted since
  1976 have not found an excess risk of GBS
  associated with influenza vaccines
• Influenza vaccine contraindicated if history of
  GBS within 6 weeks of previous influenza
  vaccination
• Consider if GBS within past 12 months

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Rabies

• Highest case fatality ratio
• Fatal encephalomyelitis
• WHO 40,000-70,000 RIP annually
• Transmission lick, scratch, bite, aerosol
• Incubation 9d-2yrs
• Pre exposure Vaccine HDCV (0,7,21or28)
• Post exposure HDCV (0,3,7,14,30)HRIG
• (wound toilet, tetanus and
  antibiotics)

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Some Future Vaccines

• HIV
• hepatitis C
• cytomegalovirus
• herpes simplex
• EBV
• RSV
• new tuberculosis vaccine

• malaria
• killed VZ vaccine
• Group B strep
• Additional N. meningitidis Group B vaccines
• E. coli 0157
• new cholera vaccine
• Candida albicans
• Aspergillus species

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Thank you