“Vaccines: when to give… and how to mix ….”

or“Optimising immunization schedules” (the story of a

complex initiative)

TEG Symposium March 29-30 2012

Paul Fine LSHTM

Routine immunization – early historyWealthy countries 19th century - widespread smallpox vaccination

post WWII - routine childhood vaccination began eg UK diphtheria – 1941

tetanus – 1950 BCG - 1953

polio (IPV) - 1955 pertussis (nat’l) - 1957 measles – 1968

Poorer countries just smallpox ..... eradication programme from 1967

Globally – in 1974 – only 15 % of children routinely vaccinated

But look what happened ! - “EPI” 1974

one of the triumphs of public health

DTP

3 co

vera

ge

Num

ber o

f “un

imm

unise

d”

child

ren

(mill

ions

)

Basic EPI schedule (from 1970s)Purposefully simple

Birth (or “first contact”

)

6 weeks 10 weeks 14 weeks 9 months

BCG √DTP √ √ √Polio (OPV)

√ √ √

Measles √

To avoid maternal antibody

4-week spacing, to optimise boosting

But circumstances evolved - 1975 - 2005

• Epidemiology changed – of EPI vaccine target diseases ...

• Development of PHC – EPI infrastructure – From very little anywhere to basics virtually everywhere

• New vaccines– Hib, HepB, JapB, Pneumo, Rotavirus, Mening....

• WHO “SAGE” (from 1999)– “Strategic Advisory Group of Experts”

• GAVI (from 2000)– “Global Alliance on Vaccines and Immunization”

• “Lobbies” ....– single vaccine interests

• So …. some countries started to change schedules ….

But circumstances evolved - 1975 - 2005

• Epidemiology changed – of EPI vaccine target diseases ...

• Development of PHC – EPI infrastructure – From very little anywhere to basics virtually everywhere

• New vaccines– Hib, HepB, JapB, Pneumo, Rotavirus, Mening....

• WHO “SAGE” (from 1999)– “Strategic Advisory Group of Experts”

• GAVI (from 2000)– “Global Alliance on Vaccines and Immunization”

• “Lobbies” ....– single vaccine interests

• So …. some countries started to change schedules ….

Increasing

discussion on

need to change the

basic EPI schedule

But circumstances evolved - 1975 - 2005

• Epidemiology changed – of EPI vaccine target diseases ...

• Development of PHC – EPI infrastructure – From very little anywhere to basics virtually everywhere

• New vaccines– Hib, HepB, JapB, Pneumo, Rotavirus, YF, Mening....

• WHO “SAGE” (from 1999)– “Strategic Advisory Group of Experts”

• GAVI (from 2000)– “Global Alliance on Vaccines and Immunization”

• “Lobbies” ....– single vaccine interests

• So …. some countries started to change schedules ….

Increasing

discussion on

need to change the

basic EPI schedule

But, reluctance....

“it’s not that

broke...”

But circumstances evolved - 1975 - 2005

• Epidemiology changed – of EPI vaccine target diseases ...

• Development of PHC – EPI infrastructure – From very little anywhere to basics virtually everywhere

• New vaccines– Hib, HepB, JapB, Pneumo, Rotavirus, YF, Mening....

• WHO “SAGE” (from 1999)– “Strategic Advisory Group of Experts”

• GAVI (from 2000)– “Global Alliance on Vaccines and Immunization”

• “Lobbies” ....– single vaccine interests

• So …. some countries started to change schedules ….

Increasing

discussion on

need to change the

basic EPI schedule

But, reluctance....

“it’s not that

broke...”

Until,

finally....

“Optimizing immunization schedules:

SAGE recognized the importance and timeliness of reviewing the scientific and operational basis for the choice of the optimal schedule for childhood immunization. More than 20 years have passed since the “EPI schedule” of 6, 10 and 14 weeks for DTP-OPV and 9 months for measles vaccine was introduced, and more information has accrued, together with the development of improved techniques for assessing immune responses. There was recognition that immunization schedules in use today vary greatly around the world, and it is unlikely that a single, uniform immunization schedule would suit all countries. WHO should aim to provide countries with advice on the parameters to be considered when they select a schedule. There was unanimous support for a new review of the evidence base, and agreement that changes in schedule are not appropriate without strong evidence to demonstrate benefit.”

Weekly Epidemiological Record, 06/01/06

Conclusions and recommendations – SAGE 2005

Which led to .... • Discussions of how to proceed...– Meeting at LSHTM October 2008– Development of vision and strategy

• “Optimising immunisation schedules” – Initiative under WHO IVR and WHO/SAGE

• Application to Gates– funding started late 2011 !

• The goal is a process for decision-making at country or regional level; • this will be continuous, as new vaccines appear and circumstances

evolve;

• different schedules will be appropriate for different epidemiological areas of the world;

• incremental gains of a new schedule need to be substantial to deserve introduction and justify disruption, and;

• need to look at all vaccines, not only one, and to consider

other factors relevant to well baby care

“Optimizing Immunization Schedules” WHAT does this mean ?

It is NOT about a new schedule

Strategy• Start vaccine by vaccine, one at a time …

– Pneumococcus, Rotavirus, Hib, Hep B, DTP.....– Systematic reviews of vaccine effectiveness and safety– Reviews of epidemiology – Appropriate open presentation of data - 4 “levels”

• Development of and interaction with “NITAGS”– National Immunization Technical Advisory Groups– Gates funded “PROVAC” and “SIVAC” initiatives

And, on the agenda ... but not yet tackled....

• Procedures for integrating multiple vaccines– “Optimise - Compromise” methods (models ?)

• Data and procedures for integrating operational factors and other (non-vaccine) paediatric interventions

Progress: review and provision of data -

• PCV pilot, Rota almost done..... Hib next . . . – Rota to be presented to SAGE April 2012

• Commissioning reviews– Proposals requested - trying to involve developing countries

• Meetings between reviewers and vaccine experts – very valuable

• Note – potential value to all countries– Current duplication by rich countries

Goal - for each vaccine:“Level 1” – 1-3 pages concise

summary“Level 2” - 10 – 20 pages detailed

summary“Level 3” – full systematic reviews of

epidemiology, effectiveness and safety (>> 300 pages)

“Level 4” – primary publications

Goal - for each vaccine:“Level 1” – 1-3 pages concise

summary“Level 2” - 10 – 20 pages detailed

summary“Level 3” – full systematic reviews of

epidemiology, effectiveness and safety (>> 300 pages)

“Level 4” – primary publicationsAll on website ... with each issue traceable

through hyperlinks ....

Examples of presentations for rotavirus vaccines ….

Should they be introduced ?

If so, by what schedule ?

NB SAGE (2009) recommended

1st dose < 15 weeks last dose < 32 weeks

(intussusception worry)

Example drawn from systematic review of rotavirus vaccine effectiveness .....

Karla Soares-Weiser, “Enhance Reviews”

Summary from systematic reviews of rotavirus vaccines: effectiveness versus severe rotavirus

diarrhoea, byvaccine, number of studies, follow-up duration and

WHO mortality strata

Hi mortality(Rich)

Lo mortality(Poor)

RV1-1y

RV1-2y

RV5-1y

RV5-2y

0.0%

0.5%

1.0%

1.5%

2.0%

2.5%

3.0%

0 26 52 78 104 130 156

% o

f al

l cas

es a

ged

< 60

mon

ths

occu

rrin

g e

ach

wee

k

age in weeksSource: Zaman et al

Hospital admisions due to Rotavirus Gastro-Enteritis in Malawi

% of all cases per weekfitted distribution

Colin Sanderson and Andy Clark, LSHTM

Hospital admissions due to rotavirus gastro-enteritis (eg in Malawi)

Age in weeks

% of all cases <5 years of age per week of age

Age-specific vaccine coverage and delay data from DHSS surveys for many

countries

Colin Sanderson and Andy Clark, LSHTM

DTP 1 DTP 2

DTP 3

6 15 32

Colin Sanderson and Andy Clark, LSHTM

Rotavirus gastroenteritis, by age, and implied number of doses of vaccine they “could have received” (eg Vellore

India)

Age-specific RVGE – by doses received and implied proportion preventable (eg

India)

Assuming higher VE

Assuming lower VE

Colin Sanderson and Andy Clark, LSHTM

D&E Africa, 15+32wk age restrictionsRVGE deaths not prevented by vaccination

RVGE deaths prevented (recipients of 1, 2 and 3 doses)

Drop in effectiveness at 52wks due to lower efficacy assumptions 52wks+ Colin Sanderson and Andy Clark, LSHTM

D&E Africa, no age restrictionsRVGE deaths not prevented by vaccination

RVGE deaths prevented (recipients of 1, 2 and 3 doses)

Drop in effectiveness at 52wks due to lower efficacy assumptions 52wks+ Colin Sanderson and Andy Clark, LSHTM

D&E Africa, 6-10-14wks on-timeRVGE deaths not prevented by vaccination

RVGE deaths prevented (recipients of 1, 2 and 3 doses)

Drop in effectiveness at 52wks due to lower efficacy assumptions 52wks+ Colin Sanderson and Andy Clark, LSHTM

Example - Relationship between estimated number of rotavirus deaths prevented, and

intussusceptions attributable to rotavirus vaccine

Colin Sanderson and Andy Clark, LSHTM; Umesh Parashar and Manish Patel, CDC/Atlanta

We are aware of several problems

eg - that vaccines are not randomly distributed – but often

“preferentially” to those at lowest risk

eg - no “herd immunity”

thus the need for explicit qualifications on all impact estimates

Yet to tackle -

Combining / compromising

multiple vaccines

and other well baby interventions

Operational implications

(suggestions welcome !)

Acknowledgements• WHO-IVR

– Ana Maria Henao-Restrepo, Thomas Cherian, Rudi Eggers, Joachim Hombach, Okwo Bele

• Bill and Melinda Gates Foundation *****– Walt Orenstein, Matt Hansen

• Many experts esp – – SAGE - Jon Abramson, Art Reingold, Oyewale Tomori – Pneumococcal vaccines – Keith Klugman, Orin Levine, Kim Mulholland,

Anthony Scott, Ron Dagan, Cynthia Whitney, Kate O’Brien, ….– Rotavirus vaccines – Umesh Parashar, Manish Patel, Duncan Steele,

Mathuram Santosham, Shabir Madhi ….– Reviews – Colin Sanderson, Andy Clark, Nicola Low, Pippa Scott, Karla

Soares-Weiser, Fiona Russell,…. – SIVAC / PROVAC – Kamel Senouci – Presentation – Xavier Bosch– Wise people – Peter Smith, Linda Wharton, Andy Hall, Robin Biellik etc ..

N.I.C.E….. Dept of Health … etc