Vaccination schedules in Denmark

Vaccination schedules in Denmark Tyra Grove Krause MD, PhD Senior consultant Department of Infectious Disease Epidemiology Statens Serum Institut e-mail: tgv@ssi.dk

Agenda History of vaccination and vaccination schedules in Denmark Basics on vaccinology Vaccine efficacy and vaccine effectiveness Calculation exercise How to decide to implement a vaccinationprogramme Discussion exercise

Introduction The two public health interventions with the greatest impact are clean water vaccination Vaccination is the most effective medical intervention in the world

Dr. Edward Jenner invents smallpox vaccination in 1796

Immune response to vaccination

Active immunisation 1949 Childhood vaccination programme (Diphteria and Tetanus)

1955 Poliovaccine (IPV) Active immunisation

The Danish Childhood Vaccination Programme Vaccine against Introduction Diphteria (Di/di) 1949 Tetatanus (Te) 1950 Polio (Pol) 1955 Pertussis (Ki) 1961 Measles (M) 1987 Mumps (F) 1987 Rubella (R) 1987 Haemophilus Influenza B (HiB) 1993 Pneumococcus (PCV7) 2007 HPV (HPV) 2008/9

The Danish Childhood Vaccination Programme 2013 3 m DiTeKiPol-Hib + PCV13 5 m DiTeKiPol-Hib + PCV13 12 m DiTeKiPol-Hib + PCV13 15 m MFR 1 4 y MFR 2 (cohort 2004 ->) 5 y ditekipol booster 12 y MFR 2 (cohort 1996 -> 2003) 12-15 y HPV x 3 (cohort 1993 -> 1995)

Vaccines Vaccine component Live attenuated MFR Yellow fever Varicella Inactivated Influenza Polio Subunit Hepatitis B HPV HIB Toxoid Tetanus Difteri Adjuvant Aluminium Cationic Adjuvant Formulations (CAF) Others Preservatives Thiomersal Formaldehyd Antibiotics

Administration Intramuscularly, subcutaneously, intradermally Oral Intranasal Future

Prevention by vaccination To individuals with an increased risk og infection or severe outcomes of infection (health status, occupation, travel etc.) Routinely to a certain population (eg. the childhood vaccination programme, the influenza vaccination programme)

Herd immunity R 0 is the average number of secondary cases in a susceptible population R is the number of secondary cases if the proportion, p, is immune R = R 0 (p R 0 ) If the number of secondary cases should be below 1, then R 0 (p R 0 ) < 1 p > (R 0 1)/ R 0 = 1 1/ R 0 If R 0 =15, what should the proportion, p, of immune be to avoid epidemics? p > 1-1/15 = 0.94 The higher R 0, the higher the proportion of immune needed to! prevent transmission

Basic reproductive number Ro Critical vaccination coverage for eradication Measles 16-18 96% Whooping cough 16-18 90-96% Chicken pox 10-12 85-90% Mumps 11-14 85-90% Rubella 6-7 82-87% Poliomyelitis 6-7 82-87% Smallpox 4-7 70-80% SARS 2-3? Influenza 2-3?

Herd Immunity Vaccination of a certain proportion of the population reduces the transmission of infection even if the microorganism is still there The proportion of the population who is immune protects the susceptible in the population eg. those who do not respond to vaccination in whom the vaccination is contraindicated who do not want vaccination

Herd immunity PCV7 was introduced in september 2006 in UK

Herd- Immunity A decrease of conduloma treatments in both men and women after introduction of HPV vaccination to girls in 2009 (catch-up to cohort 1993)

Clinical trials Licensure

Vaccine Efficacy vs Effectiveness Efficacy is the direct protection to a vaccinated individual as estimated in a regular randomized placebo-controlled trial Selection bias are eliminated, the only difference between the two groups are the vaccine status Effectiveness is an estimate of direct protection in the field study post licensure Selection bias is often a concern Other differences?

Study design (VE) Experimental (phase 3) Randomized Control Trial Observational (phase 4) Cohort study Case-control Traditional case-non case control Test negative case control Screening

Cohort design Compare risk of disease in vaccinated and unvaccinated groups The population at risk needs to be defined Certain age groups, individuals with or without specific diseases, children belonging to certain school districts etc. No previous history of disease (susceptible) and equally exposed to infection

VE in a cohort study No. of person-days No. of 100 person-years No. of cases Incidence / 100 person years Vaccinated 2,354,321 64.5 37 0.57 Un-vaccinated 758,646 20.8 74 3.56 VE = 1-RR = 1-0.57/3.56 = 84%

Test negative case-control Controls are individuals testing negative for the disease FLU + FLU- Vaccinated 17 (a) 159 (b) Unvaccinated 263 (c ) 713 (d) OR = [a/c] / [b/d] = [17/263] / [159/713] = 0.29 VE = 1-OR = 1-0.29 = 0.71 = 71%

Screening method For use with surveillance data population vaccine coverage known Compare coverage in cases with population VE= PPV PCV PPV (1-PCV) PPV: populationvaccine coverage PCV: vaccine coverage in cases Coverage must relate to the same population as cases (so stratify by age etc) Cannot adjust for confounding variable unless population coverage stratified by that variable

Screening method (2) Cases Vaccinated = 5 / 53 (0.094 or 9.4%) Coverage = 0.69 (69%) VE = 1- PCVx(1-PPV) (1-PCV)PPV) = 1-0.094 (1-0.69) (1-0.094) 0.69 = 1-0.094 0.31 = 0.953 = 95.3% 0.906 0.69

Results case 1 Influ A pos Influ negative vaccinated 165 428 unvaccinated 199 616 VE= 1-(165/199)/(428/616)x 100%= -19% Influ B pos Influ negative vaccinated 7 428 unvaccinated 28 616 VE= 1-(7/28)/(428/616)x 100%= 75%

Aims of a Vaccination Programme Eradication disease and causal agent removed worldwide (e.g. Smallpox) Elimination disease disappeared from one WHO region but remains elsewhere (e.g. Polio) Containment the point at which the disease no longer constitutes a significant health problem (e.g. Hib) Prevent colonization Prevent disease Prevent severe disease Prevention of disease in close contact

The Succes Story In 1979 smallpox was declared eradicated by WHO Only humans affected, no animal resevoir No asymptomatic carriers Effective vaccine

Less successful targets WHO had a target of eradicating polio in 2000 Only in 2002 Europe was declared free of polio Asymptomatic cases Live Vaccine Virus (OPV) may cause disease WHO has a target of eliminating measles by 2020 Huge measles outbreaks in Europe Vaccination coverage <95% Hard to reach groups

Vaccination Programmes Has the disease a serious public health impact? How effective is the vaccine? Is it cost-effective to vaccinate? What are the side effects? Can the vaccine be given together with other vaccines? Ethical considerations?

Other considerations Can vaccination have longterm consequences? Replacement Postponing disease to older agegroup Lack of natural boosting Can we monitor the programme?

Surveillance Vaccinationcoverage The illness or the pathogen that you vaccinate against Sero-surveys Side effects

Side Effects As all other pharmaceutical products vaccines may cause side-effects In contrast to most pharmaceutical products vaccines are not used for treatment of ill individuals but given to healthy individuals to prevention disease Vaccines need to be safe!!

Side Effects Among the 0-2 year old children congenital neurological and developmental are defects are often diagnosed Children wil often have infections which may occur after vaccinations Risk of association between vaccination and disease in time which may not be causal!

Introduction of vaccinationprogramme Kilde: R.T. Chen, CDC

Mæslinger: Forekomst i Danmark, 1862-2007

Mæslinger i Danmark, 1960-2008 100000 10000 Antal (log skala) 27612 35651 15656 33242 21188 13187 23490 6295 1000 100 10 1 622 404 180 162 129 115 36 20 119 61 32 28 27 14 1980 1982 1984 1986 1988 1990 1992 1994 1996 1998 2000 2002 2004 2006 2008 År 6 11 2 2 2011:83 11

Measles 2011 Age 4-59 years 33% > 18 years 51% was admitted to hospital Among those > 18 years 71% was admitted

Coverage of MFR1 og 2 10 January 2012

Expected number of complications to disease and serious side effects of vaccination in a birth cohort of 65.000 Complication/Side effect Measles MMR vaccination Otitis media Pneumoni 4550 0 2600 0 Thombocytopeni 19 ~1 every second year Anafylaxis Postinfectious encephalitis SSPE (Subacute Sclerosing Pan Encephalitis) 0 ~1 every 16. year 25 ~1 every third year ~1 every second year Death 6 0 0

Decision making in Denmark Scientific Advice Data Vaccination commite Pediatrician GP Infections Disease Experts SSI Danish Medicines Agency Scientific Advice Recommendation

MTV Also called Health Technology Assessment Technology Perspectives of citizens and patients Organisation Economics

MTV-approach Tecnology (in this case the vaccine) Disease burden VE of vaccine Side Effects Interactions with other vaccines

MTV-approach Perspectives of the citizens and patients What are the attitudes of the parents towards the vaccine Organisation Organisational experience from other countries How, where and when can the vaccine be administered in a Danish setting

Economics What are the costs? Vaccines Administration of vaccines Surveillance What are the gains? Lifes lost YLDs = Years Lived with Disability Parents days of work Herd immunity

SST s criteria for including new vaccines Seriousness of disease (deaths, permanent complications) Efficacy and effectiveness of vaccine Safety vaccine Experiences from use in other populations (gains/risk) Parents accept Fitting in to existing programme Ecological effects (replacement, postponing disease to older age ) Cost effectiveness How many vaccines in programme

Recent MTVs in DK 2003: Hepatitis B not introduced in programme selective screening vaccination of at-risk population 2007: HPV vaccination introduced to 12-year old girls 2012: Not recommended 2014: Not recommended

MTV-rotavirus http://sundhedsstyrelsen.dk/publ/pu bl2012/06juni/mtv- RotavirusMedBilag.pdf