vaccination schedules past, present and future

Vaccination Schedules Past, Present and Future Is there some rationale?

Edwin J. Asturias, MD Associate Professor of Pediatric Infectious Diseases

and Epidemiology, Center for Global Health

RIVM RVP Research Day [January 2019]

Presenter

Presentation Notes

These are the 3 things I want you to get from this lecture: why do we have the schedules we have, why we should reflect on them, and ensure we protect our gains Let me offer you this…

Definition of immunization schedule

“An immunization schedule is a schematic of the ideal timing of administration of one or more vaccines, based on the best opportunity to provide protection and minimize risk in the prevention of vaccine preventable diseases.”

Edwin J. Asturias

Presenter

Presentation Notes

During this presentation I will try to provide a historic perspective on how vaccine schedules came to be, what parameters are used to design them, what evidence we have to turn them into policy, the new challenges driven by new vaccines, and try to test my hypothesis that we are ready for a new spring in vaccine schedules.

Why are schedules important?

• Programmatic: framework for delivery of vaccines to target population

• Evaluation of coverage

• Research and development: Parameters for vaccine studies (harmonization with existing vaccine schedules…)

• Public guidance and confidence

Presenter

Presentation Notes

Now, why do we care about schedules? First they provide a framework for delivering vaccines, they also give us a way to evaluate the performance of programs, they guide the research and development, and finally they provide the means of informing the consumers when and how vaccines should be given.

Immunization Schedules in the United States and Great Britain -1967-68

Karzon, DT. Postgrad Med J 45; 147: 1969

Presenter

Presentation Notes

The history of immunization schedules dates back to the availability of the first effective vaccines. As an example, in David Karzon from Buffalo, New York, published a paper comparing the immunization schedules of the US vs. Great Britain. As you can see, both schedules were more relaxed that they are now providing for windows of vaccination at each dose. A difference in the administration of BCG and boosters can also be noted.

Childhood (0-18 months) Immunization schedules in the USA and UK 2018

United States 2018 United Kingdom 2018

(2m)

(3m)

(4m)

(12m)

Presenter

Presentation Notes

Of course that contrast with the complexity of the immunization schedules today in both countries, as we try to deliver couple dozen antigens before the age of infection in young children

Immunization schedule in the Netherlands

Expanded Program of Immunization

Founded by WHA27.57

• DTP3 @ 5% • No schedule • Program and

personnel support

1974 1980 1984

• DTP3 @ 20% • Primary health

care based

• DTP3 @ 41% • >20 schedules • Revision of

evidence needed

Presenter

Presentation Notes

In 1974, the Expanded Immunization Program was created by the resolution of the World Health Assembly. At that time, the coverage of DTP was only 5%, the resolution did not provide any guidance on schedules, but began to provide support for program and personnel. Six years later, the coverage of DTP had increased only to 20% and a decade later to 41%, mainly in countries in the Americas and Asia. It was clear that a review of the evidence to provide countries with better guidance was needed.

Global vaccine coverage estimates 1980-2016

DPT-1 and DPT-3 by completion

Rapid EPI Schedule rationale • Identify earliest starting age • Define shortest effective intervals

between doses • Complete primary series as early

as possible to increase coverage

Halsey NA, Galazka A. The efficacy of DPT and oral poliomyelitis immunization schedules initiated

from birth to 12 weeks of age. Bull WHO; 63:1151-69, 1985

EPI program success globally by 2015 Vaccine Preventable Disease

Global cases at peak 1980-1990

Global cases (2015)

Global Vaccine Coverage (2015)

% Reduction from reported

peak

Diphtheria 97,511 4,530 84% 95% Neo Tetanus 31,886 3,569 83% 88% Pertussis 1,968,363 142,512 84% 92% Polio 223$ <1000 >95% >99% Hib meningitis 500,000 8,371 64% 83% Measles 3,852,242 195,760 85% 95% Rubella 114,251 22,427 46% 80%

http://www.who.int/immunization_monitoring/diseases/en/

Prepared by E. Asturias

Presenter

Presentation Notes

The impact of the widespread use of these important vaccines has had a substantial impact in most in the targeted diseases around the world. From Polio to diphtheria, and measles, more than 90% reduction in the number of cases has been achieved since the reported peak of the global incidence. However, most of this achievement can not only be attributed to the effect of the routine EPI immunization schedule. In fact, the overall coverage in most districts is still lagging below 80%, except for those diseases that our now being targeted by elimination strategies like polio and measles.

GMC responses to diphtheria and tetanus in children receiving 3 doses of DTwP-IPV by interval

Modified from Brown GC et al AJPH 1964;79 (7):585

3 4 5

4 5 6

5 6 7

3 5 7

7 8 9

5 7 9

3 4 5

4 5 6

5 6 7

3 5 7

7 8 9

5 7 9 Diphtheria Tetanus

Presenter

Presentation Notes

For example, for the revised EPI schedule, even though it was clear that responses were better at older ages and if 2 months rather than o

0 2 4 6 12 2y 5y Age

Edw

in A

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ias

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Elements used to design an optimal schedule for the primary series in infants

Risk of Infection

Dutch national immunization schedule compliance 2017

Scheepers ED. Eur J Pedia 2017; 176:769

Hib invasive disease incidence in UK 1990-2015

2,3,4 m (3+0) + Catch-up toddlers

Spijkerman et al JAMA. 2013;310(9):930-937.

Pneumococcal Serotype-Specific Antibody GMCs Measured at 4 different Time Points (95% CI) in 4 different schedules in Netherlands

Pneumococcal vaccine introduction as of 2015 – 190,000 deaths averted

Knoll M. Presented at SAGE Oct 2017

17

Current Primary Series Immunization Schedules around the world as of 2017

6-10-14 weeks 2-4-6 months 2-3-4(5) months

Infant schedules

3-5-12 months http://apps.who.int/immunization_monitoring/globalsummary/schedules

Age distributions for administration of EPI vaccines in children aged 18–35·9 months

Clark and Sanderson. Lancet 2009; 373: 1543

2.5 4.5 8 m

Immunization coverage with DTPCV4, 2015

The boundaries and names shown and the designations used on this map do not imply the expression of any opinion whatsoever on the part of the World Health Organization concerning the legal status of any country, territory, city or area or of its authorities, or concerning the delimitation of its frontiers or boundaries. Dotted lines on maps represent approximate border lines for which there may not yet be full agreement. © WHO 2017. All rights reserved

<50% (4 countries or 3% )

50-79% (22 countries or 16% )

80-89% (21 countries or 15% )

>=90% (67 countries or 49% )

Not available/ Not in schedule Not applicable

No coverage data reported (22 countries or 16% ) Data source: WHO/IVB Database, as of 16 May 2017 Map production Immunization Vaccines and Biologicals (IVB), World Health Organization

Courtesy of Laure DUMOLARD (WHO)

Should we do away with early starting and short-interval immunization schedules? • Suboptimal for vaccine responses Maternal antibody interference Requires more doses

• Not being implemented and used as such • Leads to substandard vaccine schedule

research • Circular argument for the rational of primary

care visits for infants

21

Countries with recommended for immunization of pregnant women 2018

http://apps.who.int/immunization_monitoring/globalsummary/schedules

TT/Td vaccine coverage 2016

Influenza vaccine recommended 2018

Resurgence of pertussis in the Netherlands

Meta-analysis of Influence of Maternally Derived Antibody and Infant Age at Vaccination on Infant Vaccine Responses

Voysey M. JAMA Pediatr. 2017;171(7):637-646. doi:10.1001/jamapediatrics.2017.0638

Presenter

Presentation Notes

Number of Weeks’ Delay Required to Offset the Effect of Increased Infant Concentrations of Maternal AntibodyA delay in first immunization results in a beneficial effect that is the combination of less maternal antibody due to antibody decay, and older age when first immunized. Solid lines indicate estimates based on maternal antibody half-lives as detailed in eMethods. Dotted lines indicate sensitivity analyses using half-lives of 7 days longer and 7 days shorter. A 5-fold increase in infant levels of maternal pertussis antibodies due to a prenatal immunization program could be offset with a 5.04-week delay in first immunization assuming pertussis antibodies decay with a half-life of 36 days (solid dark blue line). Using a range of half-life estimates of 29 to 43 days gives a range of 4.6- to 5.4-weeks’ delay required (dotted dark blue line). Details of calculations are provided in the eMethods in the Supplement.

Seroprotection rates (±95% CI) according to pre-IPV serostatus and vaccination schedule

Gaensbauer JT, Asturias EJ et al under review CID 2018

Summary of effects of Tdap immunization in pregnant women on infant responses

Study Location Infants (n) Measure Outcome

Munoz FM et al 2014 NCT00707148

USA Tdap= 33 Control= 12

Ab responses after 3rd and 4th DTaP vaccines

↓ anti-FH IgG (p < .01) (40.6 EU/mL vs 78.6 EU/mL)

Maertens K et al 2016 NCT01698346

Vietnam Tdap= 30 Control= 37

Ab responses pre-post 4th Infanrix-Hexa or DTwP

↓ anti-TT IgG (p < .001)

Maertens K et al 2016 NCT01698346

Belgium Tdap= 55 Control= 24

Ab responses pre-post 4th Infanrix-Hexa

↓ anti-Prn IgG (p= 0.003) ↓ and anti-DT IgG (p= 0.023)

Halperin SA et al 2018 NCT00553228

Canada Tdap= 138 Control= 134

↓ anti-PT and FHA at 6, 7 & 12 m ↓ anti-PRN & FIM at 7 m

Should we do away with early starting and short-interval immunization schedules? • Suboptimal for vaccine responses Maternal antibody interference Requires more doses

• Not being implemented as such • Leads to substandard vaccine schedule

research • Maternal programs in the future will likely

cover the early age gap

Integrating Maternal and Infant Schedules

Infant Pregnancy

Trimester 6 8 10 14 16 20 24

EPI

3, 5 months 2, 4, 6 months

Susceptibility period

Weeks

Last updated April 2018

12m + 2nd dose

9 m + 2nd dose

Global coverage and schedules of measles containing vaccines – June 2016

Proportion of infants of vaccinated and naturally immune women still immune as a function of time to loss of immunity

Belgium Canada

E Leuridan et al. BMJ 2010;340:bmj.c1626 H.F Pabst. Vaccine 1999; 17:182

Presenter

Presentation Notes

Proportion of infants of vaccinated women and naturally immune women still immune as a function of time to loss of immunity. Shaded area is 95% confidence interval in Belgium and Canada

Measles age-specific incidence by Region 2011-2016 Age-group

From N.S. Crowcroft SAGE Measles WG 2017

Vaccine schedules and conjugate (Hib) vaccines in special populations (HIV, PTB)

von Gottberg A (GERM-SA) Vaccine. 2012;30(3):565-71 Ladhani S. Clin Microbiol Infect. 2010;16(7):948-54

South Africa Hib<5 years from 0.7 to 1.3/100,000 (2003 to 2009). 51% “vaccine failures” HIV (+) in 34%

Underlying condition UK n=220

Other n=38

Prematurity (<37wk) 6 18

Malignancy 4 4 Congenital 5 5 Other 3 8 Total 16 32

Presenter

Presentation Notes

clinical and immunological features of children with Hib vaccine failure, who were identified through national surveillance between 1996 and 2001 in Europe, Israel and Australia. True vaccine failure was defined as invasive Hib disease occurring ≥2 weeks after one dose, given after the first birthday, or ≥1 week after ≥2 doses, given at <1 year of age.

Kent A. Pediatrics. 2016 Sep;138(3).

Pneumococcal (PCV13) IgG GMCs after primary vaccination for each serotype and group in premature infants in the UK

2, 4 m 2, 3, 4 m 2, 4, 6 m

Presenter

Presentation Notes

A recent study from the UK has shown that in the case of premature infants, a 3 dose schedule with 2 months intervals is optimal to achieve appropriate levels of protection in the primary series against each of the serotypes contained in the PCV13 vaccine

Vaccination schedules to attain the goal of Population Immunity (Community Protection)

• HepA vaccine: 2 vs. 1 dose • PCV: UK 1+1 schedule? • IPV: 1-2 doses – best timing and issues with

silent transmission (more tomorrow)

Trend of Hepatitis A incidence rates and cases of hepatic failure due to HAV in Argentina pre and post 1 dose HAV program

Adapted from Vizzotti C. PIDJ. 2014;33(1):84-8

IOM Assessment of Studies of Health Outcomes Immunization Schedule – 2013

• DHHS should incorporate study of the safety of the overall childhood immunization schedule into its processes for setting priorities for research

• Refrain from RCT of the childhood immunization schedule that compare safety outcomes in fully vaccinated children with those unvaccinated children or using alternative schedules

Human Vaccines & Immune 2014

Rates of consistent users of alternate schedules according to birth month, 2003-2009, Oregon, USA

Robison S G et al. Pediatrics 2012;130:32-38 ©2012 by American Academy of Pediatrics

Variable Consistent shot limiters

Non-limiters

Number shots per visit 1.5 3.2

Number of visits < 9 m 4.2 3.2

Completion HepB @ 9 m 28% 92.1%

Presenter

Presentation Notes

Consistent shot-limiting rates according to birth month, with distinct periods identified by using Joinpoint analysis as (A) mild decline from July of 2003 to October of 2006, (B) steep increase from November of 2006 to September of 2008, and (C) flat from October of 2008 to October of 2009. Results do not include those avoiding all immunizations.

Comparison of challenges for immunization schedules in HIC and LMIC

Issue LMICs Europe USA Alignment with best immunogenicity + +++ ++ Booster doses + +++ +++ Crowding of injections +/++ +++ +++ Vaccine hesitancy/spacers +/- ++ +++ Maternal immunization +/- ++ ++ Programmatic flexibility + ++ +/-

Summary • Immunization schedules are paramount for

vaccine development and deployment • Boosters > 12 months crucial for long term and

indirect protection for most antigens

• Primary series could be modified Ages for best immunological fit and delivery

2 doses in the first year probably sufficient

• Schedules will need to address safety and crowding for upcoming vaccines and confidence

vaccination schedules past, present and future

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