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“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
covera
ge
Num
ber
of
“unim
mun
ised
” ch
ildre
n (
mill
ion
s)
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 th
e
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 th
e
basic EPI schedule
But, reluctance....
“it’s not th
at
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 th
e
basic EPI schedule
But, reluctance....
“it’s not th
at
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 a
ll c
ase
s a
ge
d <
60
mo
nth
s o
ccu
rrin
g e
ach
w
ee
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