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)

• RSV-IGIV– Human hyperimmune globulin

– Contains other antibodies

• Palivizumab (“Synagis”)– Mouse monoclonal

– Contains only RSV antibody

Example: Antibody for Prevention of Respiratory Syncytial Virus infection

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

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

• virus• bacteria

• protein-based– subunit– toxoid

• polysaccharide-based– pure– conjugate

Whole

• 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

Inactivated Vaccines

Examples of live and inactivated vaccines

• Viral measles, mumps, rubella,vaccinia, varicella, yellow

fever, oral polio, rotavirus,

(influenza “Flumist”, not available outside USA at present)

• BacterialBCG (oral

typhoid)

• Viralpolio, hepatitis A,

rabies, influenza

• Bacterial (whole cell)pertussis,

typhoid,(cholera),

(plague)

Live Inactivated

Inactivated Vaccines

• Subunit hepatitis B, influenza,

acellular pertussis,

(typhoid Vi), (Lyme)

• Toxoid diphtheria, tetanus

Fractional vaccines

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 2,161,542

• Deaths 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 [20-50% 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 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)

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

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

<3.9 <7.9 <14.0 <23.8 <55.6

Cancer of the cervix (mortality/100,000)

• Mortality falling developed world• Mortality rising in developing world

Who should be screened and how often?

• 25 First invitation

• 25-49 Three Yearly

• 49-60 (65) Five Yearly

Dr.Papanicolaou – “the Pap smear”

Which Human Papillomaviruses have been included in the vaccines

Low Risk 6, 11, 40, 42, 43, 44, 54, 61

Anogenital warts

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

Anogenital neoplasia

6,11,

16,18,

c. 90% ofGenital Warts - US, Europe

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

CDC, June 2006

Cervical cancer screening recommendations have NOT changed for females who receive HPV vaccine

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.

Influenza Viral Structure

• 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

There are 15 H and 9 N subtypes known

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” - NovartisDifferent vaccines produced in the USA

Pandemic H1N1 2009 vaccines approved in Ireland

• “Pandemrix”

• Split virion grown in eggs

• 3.75g 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• 7.5g 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