vaccination, theoretical basis, - semmelweis...

Vaccination, theoretical basis,

vaccines, compliance and „anti-vax”

tendencies

Zsófia Mészner med habil PhD

Heim Pál National Institute of Paediatrics

Szent László” Municipal Hospital for Infectious Diseases

4th Year, Faculty of Medicine 2018/2019 Academic Year

‘One of the most important medicaldevelopments in the 20th century has beenthe control of once common childhoodinfectious diseases by the administration ofhighly effective vaccines.

With the exception of safe water, noother modality, not even antibiotics, has had such a major effect on mortality reduction and the population growth’Peter G. - NEJM, 1992

Main topics

1. The goals and basic principles of

immunizations

2. Herd immunity vs herd protection

3. National Immunization Programs/NIP

4. Public trust vs. misbeliefs

The goals of immunizations:to „mimic”, what the IS does without

the risks of the disease

artificial

immune

system

innate

natural

passive

(maternal)

adaptive

active

(infections)

passive

(antibodies)

active

(immunization)

My daughter is 2 ys old, the paediatrician

recommends a vaccine against chickenpox.

Is it not better to have chickenpox - the

natural course of this childhood infection -

than immunization?

• Two doses of a chickenpox vaccine give equal protection

without the possible complications of the natural course.

• Better to have the disease, as chickenpox is a mild

childhood infection and will lead to longterm protecion.

If you have not had chickenpox, you should rather try to get vaccinated!!!

Chickenpox may have life-threateningcomplications!

Staphylococcus aureus superinfection

Chickenpox may have life-threatening complications!

Streptococcus pyogenes superinfection

Photo:Andrea Kulcsár MD

Varicella pneumonitis, varicella progressiva

Acut pneumonitis Calcificatio 3 ys later

Varicella encephalitis

Varicella cerebellitis, bilateral striatal necrosis, facialis

paresis, zoster neuralgia, etc…

Congenital varicella syndrome*

l. trimester

– foetal risk

- rare, nearly always fatal

II-III.trimester

– maternal risk

*Hajdi G, Mészner Z, Büky B.: Kongenitális varicella szindróma. Orv Hetil. 1982 Jan 10;123(2):99-101

Neonatal varicella is potentially life-

threatening!

My daughter is 2 ys, the paediatrician

recommends a vaccine against chickenpox.

Is it not better to have chickenpox - the

natural course of this childhood infection -

than immunization?

• Two doses of a chickenpox vaccine give equal protection

without the possible complications of the natural course.

• Better to have the disease, as chickenpox is a mild childhood

infection and will lead to longterm protecion.

Ways to immunize

• Passive immunization

- antibodies

e.g. iv., im.,sc.

• Active immunization (vaccination)

- we „force” the immune system to produce Abs

vaccine

antibodies

antigen

Antigens

trigger AB

response

Definition: Immunization is a process to initiate or augment

resistance to an infectious disease. The goal of immunization is

to prevent, and in some cases eradicate, potentially serious,

life-threatening diseases.

https://www.scripps.org/articles/3066-vaccines-immunizations-overview

Passive immunizationVaccine: immunglobulin preparations from human sera

Effect: Prompt, though short lasting protecion (dose dependent)

Average protecion: max. 1 month (standard dose)

Use:

• Immunodeficiency states– Regular iv. supplementations (IVIG, SCIG)

• Postexposure prophylaxis („hyper” immunoglobulins)– hepatitis B (newborns to HBsAg + mothers, needle prick injuries),

– tetanus

– lyssa

– hepatitis A

– CMV (organ transplants)

– perinatal varicella

2

5

80%.

En example:

Active immunization = antigen presentation

• Vaccine types

– live, but apathogen, attenuated vaccines

• BCG, MMR, VZV, rota, yellow fever)

– killed (inactivated) vaccines

• toxoid – e.g. tetanus, diphteria, pertussis

• viral antigen – e.g. tick borne encephalitis/TBE virus, HAV, HBV, HCV, HPV

• whole virion, split, subunit, e.g. flu,

• polysaccharide, e.g. PS23, typhus, meningococcus

• polysaccharide+protein (PS-conjugates)

– HIB, pneumococcus (10-PCV, 13-PCV)

– meningococcus (menC, men4C, )

The immune response is specific

• The immune response is based on the recognition of the antigen

• Antigen specific (not pathogen spec., e.g. influenza)

• Evolves after the first exposure to the antigen

• Takes time – 1-2 weeks

• Adaptive: long lasting or repeated exposure gives stronger effect

• Immune memory: repeated exposure leads to prompt, specific protection

Immune memory

• Memory cells live long

• They need antigen specific T cell interaction

• polysaccharide antigens(pneumococcus, haemophilus, meningococcal capsular antigens) do not elicit T-cell response – there is no memory response (protecion lasts 3-5 ys, <2ys old no response)

• protein conjugates T cell response memory response

– Immunogen since infancy

• Repeated exposure(reinfection, revaccination) results in stronger, longer lasting memory

Live, attenuated vaccines

• They multiply in the body, they „mimic” the natural infection, elicit both humoral and cellular immune response - Bacterial vaccines – e.g.: BCG- Viral vaccines: morbilli, rubella, mumps (MMR), varicella,

yellow fever, - Viral vector vaccines (apathogen virus carries the pathogen

genom) e.g.: rotavirus vaccines

• Benefits of live vaccines:– Long lasting, sustained immune response

• Disadvantage:– Not suitable for immunodeficient states, pregnancy

Killed, inactivated vaccines

• Effect is dependent on dose, route of administration and adjuvant

• Multiple doses are needed – priming and boosters.

• Killed bacteria (e.g. whole cell pertussis) – Out of use generally, because of adverse events

• Inactivated viruses(inactivated polio, hepatitis A, influenza, TBE, rabies, …)– No chance of provoking the infection…..

Vaccines containing purified antigens

• toxoids (diphtheria and tetanus anatoxin), • purified capsular polysaccharides: pneumococcus (23

serotypes), meningococcus (AC, ACWY), typhus (Vi antigen)• polysaccharide protein conjugates: Hib, meningococcus C,

meningococcus ACWY, pneumococcus (10 or 13 serotypes)• acellular pertussis vaccine (aP)• hepatitis-B vaccine (contains HBsAg)• „split” and „subunit” flu vaccines• human papilloma virus (HPV) vaccines (HPV-2, -4, -9)

Advantage: better tolerated, less AEs Diasadvantage: less immunogenicity, but could be improved by

adjuvants

http://www.slideshare.net/MMASSY/immunity-principles-of-vaccination

Main topics

1. The goals and basic principles of immunizations




Herd effect (herd immunity)

Immunised individuals provide indirect protection to susceptible (unvaccinated, partially vaccinated) individuals:

– fewer people infected

– lower shedding by vaccinees

T Jacob John & Reuben Samuel. Eur J Epid 2000;16:601-6

Herd effect – herd protecion

• Most mass vaccinations provide herd protecion

• Protection occurs even when vaccination

coverage is not 100%

• The greater the infectivity (reproductive rate) of a

disease, the higher the immunisation rate

needed to achieve herd „immunity”.

Basic reproductive rate

R0 = The average number of

individuals directly infected by

an infectious case during the

infectious period, while in a

totally susceptible population.

Immunisation and herd immunity

• In a “homogeneously mixed” population, eradication can

be achieved if, through immunisation, R0 is brought

down to <1.

• Relationship between

Pc (proportion successfully immunised) and

R0 (average number of secondary cases from one

primary case in wholly susceptible population) is

Pc = 1- 1/R0

Thus high R0s will necessitate very high coverage rates

Adapted from Anderson & May, Immunisation and herd immunity Lancet 1990;335:641-645

Minimum vaccination coverage required

to stop infection transmission

Infection Mean age of infection

Inter-epidemic

period

Infectious-ness index

Minimum vaccination

coverage (%)

Measles 4-5 2 15-17 92-95

Pertussis 4-5 3-4 15-17 92-95

Mumps 6-7 3 10-12 90-92

Rubella 9-10 3-5 7-8 85-87

Diphtheria 11-14 4-6 5-6 80-85

Polio 12-15 3-5 5-6 80-85

Adapted from Anderson & May, Immunisation and herd immunity Lancet 1990;335:641-645

33,632

24,6

17,6

11,99

0

5

10

15

20

25

30

35

40

1998/99 2000 2001 2002 2003 2004

Ca

se

s p

er

10

0,0

00

Herd Effect in Adults

73% reduction

Lexau C et al JAMA 294:2043-51, 2005 and CDC unpublished data, presented by Dr Cynthia Whitney, IDSA 2005

Mass vaccination

recommended for infants

Invasive Pneumococcal Disease in Adults, Aged 65 + USA 1998-2004

Main topics



3. National Immunization Programs/NIPs

– Successes and challenges


*KERPEL-FRONIUS S: eláadás08/vakcináció08 35

The beginning of immunization in Hungary*

• In the 1760s, smallpox claimed several victims in the royal family.

• Maria Theresa was infected and received last rites in 1767, although she recovered.

• Maria Theresa became a strong supporter of inoculation (a predecessor immunisation) setting a strong example by requiring all of her children to be inoculated

• Advocated a broad inoculation program in the Habsburg empire

Maria Theresa 1740-1780

NIP – Hungary 2019*

*http://vaccine-schedule.ecdc.europa.eu/Pages/Scheduler.aspx

NIPS in Europe

• WHO recommendations for each country NIP

– No financial support

• EPI (extended program for immunization) 1979.

– Di-per-te, polio, morbilli, HBV)

• www.who.int

– WHO position papers

• On the prevention of various infections

• Weekly epidemiological report

– English, French

• www.ecdc-eu, www.who.int

– Nips in each country

http://www.who.int/

http://www.cdc-eu/

http://www.who.int/

Childhood immunization programmes

• All EU Member and not yet member States have (a) childhood vaccination schedule(s)

• Other components of a childhood immunisation programme are implemented to various degrees or even absent in the different States

• VENICE survey of immunisation programmes in Europe (2010, 2014):– National vaccination committees in most countries

– Electronic immunisation registries in a bit more than half of the countries, but not all are capable of measuring vaccination coverage

– Compensation schemes for adverse events following immunisation available in less, than half of the countries

The successes

• Smallpox:– eradicated (World Health Assembly Resolution 33.3 (1980))

• Polio:– eliminated in Europe (15th meeting of the European Regional

Certification Commission, Copenhagen, 19 –21 June 2002).

– 0 cases in EU in 2008*. However, we get regular reminders of the risk of importation:

• Netherlands (1992-93): imported case from India; 79 persons were infected, 59 had paralysis and 2 died.

• Bulgaria (2001): imported case from India; 3 babiesbelonging to Roma ethnic community were infected

• Tajikistan (2010): 712 AFP cases of which 458 were laboratory confirmed for wild poliovirus type 1, including 29 deaths.

* ECDC Annual epidemiological report (2015)

Diphteria

• In 2014, 38 cases of diphtheria were reported to TESS

y, 35 of which were laboratory confirmed as due to

C. diphtheriae or C. ulcerans.

• Adults and elderly were the most affected.

• The majority of the cases were not vaccinated or the

vaccination status was reported as unknown.

• Latvia was the only country in the EU to report indigeno

us cases.

• High vaccination coverage must be sustained to prevent

diphtheria cases.



Diphteria in ECDC-EU

Case report

• 6 y boy,

uunvaccinated, died

of diphteria

• No case for the last

28 ys in Spain!

• He was given Di-

antitoxin from

Russia, but died on

that day

• The parebts

claimed, that the

antivax people

misled them…..

Case report

• EWRS (Early warning and Response System)

reported toxic diphteria case from Belgium, 17 March 2016.

• 3 y girl, born in Belgium, no immunization

• Myocarditis, AV Block

• Died – no Di-antitoxin

• She was attending day care!!

• AB prohylaxis, kontact immunization followed..

The successes

• Tetanus:– under control in children (2 cases in EU in 2008*); remaining

cases mainly in unvaccinated older individuals (123 cases in EU in 2012*).

• Diphtheria:– under control (27 cases in EU in 2012*). However, indigenous

transmission of the disease continues in Latvia and suggests that epidemic diphtheria could return to any country in the EU.

• Hib:– included in the national immunisation schedule of all Member

and in neraly all non-member States; continues to have a great impact on the reduction of incidence of Hib. (2542 cases of invasive Haemophilus influenzae disease (all serotypes) in EU in 2012*)

* ECDC Annual epidemiological report (2014.)

… achievements of and challenges…

• Yet this progress faces several threats:

– high levels of population movement,

– the existence of unimmunized groups because of

limited access to health care services and

– a continuing decline in vaccine acceptance among

populations.

• Today, the Region must deal with

– recent and continuing measles outbreaks, and

– the re-emergence of polio last year.

Disease specific challenges

• Measles:

– remains problematic (11326 cases in EU in 2012*).

– ~28000 cases in 2010, due to large outbreak in Roma – Bulgaria

• tipically „difficult to reach” (wandering) population

– UK, Germany, Italy, France, etc. • the problem of the „anthroposophics” (PIDJ, 2011, March)

– WHO Euro 2010 elimination goal not reached

* ECDC Annual epidemiological report (2014.)

A kanyaró szisztémás fertőzés!

ECDC-EU: measles is not a childhood

disease anymore!

Franciaország

Németország

Görögország

Olaszország

Románia

Többi EU/EEA

ECDC-EU and Europe

„not included”:• Switzerland

• Albany

• Serbia

• Bosnia-

Hercegovina

• Montenegro

• Ukraine

• Etc…

Number of Reported Measles Cases by WHO Regions

2019

RegionMember States*

Suspected cases

Measles cases

Clin Epi Lab Jan Feb Mar Apr May Jun Jul Aug Sep Oct Nov DecDate

Received

AFR 35/47 51026 49646 2989 45921 736 38522 11124 0 0 0 0 0 0 0 0 0 0 2019-03

AMR 23/35 1503 270 0 0 270 80 190 0 0 0 0 0 0 0 0 0 0 2019-03

EMR 9/21 923 282 34 2 246 231 51 0 0 0 0 0 0 0 0 0 0 2019-03

EUR 51/53 18822 18169 13290 608 4271 18112 57 0 0 0 0 0 0 0 0 0 0 2019-03

SEAR 10/11 6688 5301 3349 424 1528 4611 690 0 0 0 0 0 0 0 0 0 0 2019-03

WPR 21/27 3575 670 325 5 340 669 1 0 0 0 0 0 0 0 0 0 0 2019-03

Total 149/194 82537 74338 19987 46960 7391 62225 12113 0 0 0 0 0 0 0 0 0 0

2018

RegionMember States*

Suspected cases

Measles cases

Clin Epi Lab Jan Feb Mar Apr May Jun Jul Aug Sep Oct Nov DecDate

Received

AFR 42/47 80902 54740 16345 30871 7524 2953 4257 5057 3824 2845 1707 1632 1220 1781 5062 9942 14460 2019-03

AMR 32/35 28734 16615 0 0 16615 3 16 84 153 291 204 410 138 645 2608 5887 6176 2019-03

EMR 20/21 79726 57054 29535 15555 11964 4002 4862 8067 7974 9648 5650 4484 2765 3030 3045 2234 1293 2019-03

EUR 53/53 96452 83103 50946 4174 27983 5668 6609 7421 7735 8719 7131 5410 3705 2730 5433 9924 12618 2019-03

SEAR 11/11 104040 82384 57299 17936 7149 8983 8975 14268 12199 10891 5025 3461 3841 3305 4089 3513 3834 2019-03

WPR 26/27 75214 30381 18290 1742 10349 1926 2479 3388 3229 3051 2422 2221 1949 1923 2610 3042 2141 2019-03

Total 184/194 465068 324277 172415 70278 81584 23535 27198 38285 35114 35445 22139 17618 13618 13414 22847 34542 40522

Notes: Based on data received 2019-03 - This is surveillance data, hence for the last month, the data may be incomplete. * Member States

Reporting / Total Member States in Region

Measles case distribution (EUR), 2015-2019

20

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Nu

mb

er o

f m

eas

les

case

s

UkraineSerbiaRussian FederationRomaniaOthersKyrgyzstan

KazakhstanItalyGermanyGeorgia

France

Notes: Based on data received 2019-03 - Data Source: IVB Database

Measles cases: Ukraine

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DiscardedClinicalEpi

Lab Month of onset

Nu

mb

er o

f ca

ses

National (6-9 Y)

Cov: 67%

National (1-9 Y)

Cov: 57%

National SIA Sub-national SIA

02000400060008000

100001200014000

<1 year 1-4 years 5-9 years 10-14 years 15-19 years 20-29 years 30+ years

0 doses 1 dose 2+ doses Unknown

Age at onset

Nu

mb

er o

f ca

ses

Ukraine age distribution, vaccination status, and incidence, 2018-02 to 2019-01

01000200030004000500060007000

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den

ce r

ate

per

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00

,00

0

6582

4865.15336.1 4920.2

1548.81007

489.8

YearConfirmed

Cases

2006 945

2007 232

2008 41

2009 24

2010 42

2011 1313

2012 12744

2013 3308

2014 2326

2015 141

2016 90

2017 4782

2018 53218

2019 13760

Romania, 29 March 2019 – ongoing measels epidemic, 62 fatal cases

http://cnscbt.ro/index.php/informari-saptamanale/rujeola-1

http://cnscbt.ro/index.php/analiza-date-supraveghere/evaluarea-acoperirii-vaccinale/397-analiza-rezultate-av-18-luni


• Pertussis:

– the increase in the number of reported cases (observed since 2003), continued in 2012 (42525 cases, confirmed 38840*).

– shift to young children/adolescents/young adults due to waning immunity

– solutions:• some Member States recently introduced additional booster doses

to cover this age group.

• „Coccon” strategy for family plannig couples

• the 10 yearly adult dt booster could be replaced by dapT

*ECDC Annual Epidemiological report 2014.

„Cocoon-ing”

• dapT±IPV – Boostrix/GSK,

Adacel/sanofi

• For family

planning couples,

grandparents

• For pregnant

women

– Between the

gest weeks 26-

32 (in UK from

the 16th)


• Hepatitis B:– „risk of the risk based approach‟ (no EU data on

case load in children).– Perinatal infections (targeted screening for HBsAg positive

mothers may not catch all cases)

– Early childhood infections (close contact)

• Invasive pneumococcal disease:– heterogeneity / lack of surveillance systems. (14757

cases in EU in 2008*)– Concerns over serotype replacement

– New generation of pneumococcal vaccines incl more serotypes



• HPV– HPV vaccination does not replace cancer screening

• VENICE2 2010 survey: – 17/27 Member States introduced HPV vaccination in

national immunisation schedule

• Very expensive vaccine: – vast majority of countries with no HPV vaccination

routine are from Eastern Europe, with the cost of the vaccine being a major impediment


Hungary: HPV-2, HPV-9 in school program since 2015.

The systemic challenges

• Difficulties in bridging immunisation schedulesfor

~100,000 children (0-14y) migrating between countries

every year.

• Diversity in terms of:

– target disease

– target populations

– products used

– schedules and vaccine co-administration

– mandatory or voluntary vaccination

• Solution:

– Immunization Card (Hu)

„United in diversity”

Summary of successes and challenges

• vaccines and immunization have contributed to

– dramatic health improvements in the WHO European

Region

– particularly among children

• There is room for improvement for

– surveillance methodology

– well known effective vaccine use – e.g. MMR

– newcomers – HPV, PCV, rota, …

Main topics





Even before the www antivax misbeliefs were present!!

Evolution of vaccination

Incidence

of disease

Pre-vaccine

period

Vaccine

coverage

Adverse events

Time (years)

Outbreak

Loss of

confidenceResumption

of confidence

We have forgotten

the seriousness of

some diseases

Vaccines are victims

of their own success

0 20 40 60 80 100

Use of aborted fetal tissue

Multiple simultáneous vaccines increase risk

"Hot lots" with more AE

Homeopathy is a better alternative

Diseases have declined without vaccines

Violation of civil liberties

Vaccine immunitty is temporary or ineffective

Policy motivated by profit

Vaccines erode immunity

Underreporting of AE

Vaccines cause idiopathic illness

Antivaccination myths

promoted in the Internet

Wolfe RM et al. JAMA 2002;287:3245

Zimmermann RK et al. J Med Internet Res 2006;7:e17Reports (n)

Selfish attitude

“My child doesn’t need a vaccine,

because of herd immunity” – BUT

no protection against imported infections

if infection occurs at greater age – prognosis is

worse

infection abroad

Decline in Haemophilus Influenza

Decline in Polio and Measles

Decline in Rubella

Role ofMedia

Nigeria, KANO state immunization boycott:International impact on polio eradication

August, 2003: OPV immunization halted in Kano state, Northern Nigeria, after rumors circulated by hardline religious clerics stating that:

“OPV vaccine could cause sterility in girls”

Nigeria: Kano state: from local to international impact

Endemic countries

Wild virus type 1

Wild virus type 3

Importations

Polio spread from Kano, to

10 countries:

- Ivory Coast

- Ghana

- Togo

- Benin

- Burkina Faso

- Cameroon

- Central African Republic

- Chad

- Sudan

- Botswana

Polio cases as of June 15, 2004

Soon after boycott started, Kano became epicenter of big and fast growing outbreak of polio, spread to whole country: 83% global cases from Nigeria

then to neighboring countries, including 10 that previously had been free of polio

Importations

Current vaccine scares: Potential

threats to national and international

immunization programs

MMR and autism: Lessons learned

• Most people learn about medicine and science from newspaper, magazine stories, radio, TV programmes and the internet

• Most parents trust health care providers: in Attitudes, Knowledge and Practice survey of physicians in Italy: most important factor in decision of parents to vaccinate

• Health care workers must be trained to be well informed of both benefits of immunization as well as issues of parental concern regarding vaccine safety

• Engage the news media, train health care workers!

Increasing

antivax

activities !

Eligible vaccines instead of compulsory

„To vaccinate=capital sin!”

No registered speciality in HU

Claims to be an internist

Advocates homeopathy

Several published books for

lay people on the harmful

effects of immunization

Private practice in HU and A

GP

Vice-president of

the most colourful

antivax website

Admits to give

„paper shots”

Health literacy survey 2015

Problems with „eligible NIP” …..

vaccination, theoretical basis, - semmelweis...

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