Immunization
“The most important investment that any
country can make in the health of its’ children”
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.
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
Definitions
• Adjuvant
• Adverse reaction
• Antitoxin
• Immunization
– Active
– Passive
• Immunoglobulin e.g.,
– Human Normal
Immunoglobulin [HNIG]
– Human Specific
Immunoglobulin /
Hyperimmune globulin
• Toxoid
– modified bacterial toxin
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
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
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
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
Sources of Passive Immunity
• Almost all blood or blood products
• Homologous pooled human antibody (immune
globulin)
• Homologous human hyperimmune globulin
• Heterologous hyperimmune serum (antitoxin)
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
Classification of Vaccines
viral 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
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
Inactivated Vaccines
Whole
• virus
• bacteria
• protein-based
– subunit
– toxoid
• polysaccharide-based
– pure
– conjugate
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
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)
Inactivated Vaccines
Fractional vaccines
• Subunit
hepatitis B, influenza,
acellular pertussis,
(typhoid Vi), (Lyme)
• Toxoid
diphtheria, tetanus
Polysaccharide Vaccines:
Derived from bacterial capsule
• pneumococcal
• meningococcal
• Haemophilus influenzae type b
(“New”) Conjugate polysaccharide vaccines
• Haemophilus influenzae type b
• meningococcal
• pneumococcal
Pure Polysaccharide Vaccines
• Not consistently immunogenic in children <2
years of age
• No booster response
• Produce antibody with less functional activity
than that produced by the infection
• Immunogenicity is greatly improved by
conjugation
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% <2 years; 76% < 5 years
• Reduced penicillin susceptibility in 15% - all were vaccine
serotypes
• Based on serotype data, in paediatric patients PCV7
would prevent <90% of cases of sepsis, <82.5% meningitis,
<59% 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 2008;177:225-31
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, O’Hare F, Cotter S, O’Flanagan D,
Johnson H, Barry M
Value Health 2008;May 16 [Epub ahead of print]
The need for a vaccine is determined
by the morbidity and mortality from the
natural infection
e.g., Contrast measles, rubella & hepatitis B
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
• Deaths
2,161,542
365
• Mortality Rate per 100,000
notified cases
16.9
England & Wales, 1970 to 1988
Rubella: Morbidity & Mortality
Morbidity “benign illness”
• children
– thrombotic thrombocytopenic
purpura
1 in 500
• Adults:
– acute polyarticular
arthropathy women > 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
[2050% of patients with these]
Principal morbidity:
Congenital Rubella
Syndrome
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
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
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 >90% (measles 95%)
• Not tetanus!
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
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)
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
Adult immunizations 1
Normal 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)
Adult Immunizations 2
Health 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
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 child’s age
The following reactions to a vaccine are
contraindications to a further dose
• anaphylaxis
• fever > 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 > 4 hr
– convulsions or encephalophathy
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
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 Crohn’s Disease]
Specific examples of immunisation
strategies
measles
rubella
Hepatitis B
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
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
Invasive meningococcal disease
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)
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
Rotavirus vaccines
• Who needs them most?
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?
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
Cancer of the cervix (mortality/100,000)
<3.9
<7.9
<14.0
<23.8
• Mortality falling developed world
• Mortality rising in developing world
<55.6
Who should be screened and how
often?
• 25
• 25-49
• 49-60 (65)
Dr.Papanicolaou – “the Pap smear”
First invitation
Three Yearly
Five Yearly
Which Human Papillomaviruses have
been included in the vaccines
Low Risk
6, 11, 40, 42, 43, 44, 54, 61
Anogenital warts
c. 90% of
6,11,
Genital Warts - US, Europe
High risk
16, 18 45, 31, 33, 52, 58, 35, 16,18,
59, 56, 39, 51, 73, 68, 66
Anogenital neoplasia
c. 70% of Cervical
Cancers - US, Europe
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
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
Influenza A Viral
Structure
•11 genes on 8 pieces
of RNA
• 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
•11 proteins:
viral clumping, facilitates release
haemagglutinin (HA),
of virus from infected cells, is a
neuraminidase (NA),
target for antiviral drugs & acts as
nucleoprotein (NP), M1,
an antigen
M2, NS1,NS2(NEP), PA,
PB1, PB1-F2 and PB2.
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 humanto-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
NVRL: National Virus Reference
Laboratory
CUH - Cork University Hospital
UCHG: University College Hospital
Galway
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
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 >13 years
• 2 doses for the
immunocompromised & those
<13 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
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 >22 million
doses of vaccine worldwide without any safety
concerns (WHO technical report) – not used
previously in an influenza vaccine
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
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)
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
Thank you