“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 history
Wealthy 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
DTP 3 coverage
Number of “unimmunised”
children (millions)
But look what happened ! - “EPI” 1974
one of the triumphs of public health
Basic EPI schedule (from 1970s)
Purposefully simple
Birth
(or “first
contact”)
6 weeks
10 weeks
14 weeks
DTP
√
√
√
Polio (OPV)
√
√
√
BCG
9 months
√
Measles
√
4-week spacing, to
optimise boosting
To avoid
maternal
antibody
But circumstances evolved 1975 - 2005
•
Epidemiology changed
–
•
Development of PHC – EPI infrastructure
–
•
“Global Alliance on Vaccines and Immunization”
“Lobbies” ....
–
•
“Strategic Advisory Group of Experts”
GAVI (from 2000)
–
•
Hib, HepB, JapB, Pneumo, Rotavirus, Mening....
WHO “SAGE” (from 1999)
–
•
From very little anywhere to basics virtually everywhere
New vaccines
–
•
of EPI vaccine target diseases ...
single vaccine interests
So …. some countries started to change schedules ….
But circumstances evolved 1975 - 2005
•
Epidemiology changed
–
•
Development of PHC – EPI infrastructure
–
•
“Global Alliance on Vaccines and Immunization”
“Lobbies” ....
–
•
“Strategic Advisory Group of Experts”
GAVI (from 2000)
–
•
Hib, HepB, JapB, Pneumo, Rotavirus, Mening....
WHO “SAGE” (from 1999)
–
•
From very little anywhere to basics virtually everywhere
New vaccines
–
•
of EPI vaccine target diseases ...
single vaccine interests
So …. some countries started to change schedules ….
But circumstances evolved 1975 - 2005
•
Epidemiology changed
–
•
Development of PHC – EPI infrastructure
–
•
“Global Alliance on Vaccines and Immunization”
“Lobbies” ....
–
•
“Strategic Advisory Group of Experts”
GAVI (from 2000)
–
•
Hib, HepB, JapB, Pneumo, Rotavirus, YF, Mening....
WHO “SAGE” (from 1999)
–
•
From very little anywhere to basics virtually everywhere
New vaccines
–
•
of EPI vaccine target diseases ...
single vaccine interests
So …. some countries started to change schedules ….
But circumstances evolved 1975 - 2005
•
Epidemiology changed
–
•
Development of PHC – EPI infrastructure
–
•
“Global Alliance on Vaccines and Immunization”
“Lobbies” ....
–
•
“Strategic Advisory Group of Experts”
GAVI (from 2000)
–
•
Hib, HepB, JapB, Pneumo, Rotavirus, YF, Mening....
WHO “SAGE” (from 1999)
–
•
From very little anywhere to basics virtually everywhere
New vaccines
–
•
of EPI vaccine target diseases ...
single vaccine interests
So …. some countries started to change schedules ….
Conclusions and recommendations – SAGE 2005
“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
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 !
“Optimizing Immunization Schedules”
WHAT does this mean ?
It is NOT about a new schedule
process for decision-making at country or regional level;
•
The goal is a
•
this will be
•
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
continuous, as new vaccines appear and circumstances evolve;
all vaccines, not only one, and to consider other
factors relevant to well baby care
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” –
“Level 2” “Level 3” –
“Level 4” –
1-3 pages concise summary
10 – 20 pages detailed summary
full systematic reviews of
epidemiology, effectiveness
and safety (>> 300 pages)
primary publications
Goal - for each vaccine:
“Level 1” –
“Level 2” “Level 3” –
“Level 4” –
1-3 pages concise summary
10 – 20 pages detailed summary
full systematic reviews of
epidemiology, effectiveness
and safety (>> 300 pages)
primary publications
All 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, by
vaccine, number of studies, follow-up duration and WHO
mortality strata
RV1-1y
RV1-2y
RV5-1y
RV5-2y
Hi mortality
(Rich)
Lo mortality
(Poor)
Hospital admissions due to
rotavirus gastro-enteritis (eg in Malawi)
% of all cases aged < 60 months occurring each week
Hospital admisions due to Rotavirus
Gastro-Enteritis in Malawi
3.0%
% of all cases per week
fitted distribution
2.5%
2.0%
% of all cases
<5 years of age 1.5%
per week of age
1.0%
0.5%
0.0%
0
26
Source: Zaman et al
52
78
104
Age in weeks
130
156
age in weeks
Colin Sanderson and Andy Clark, LSHTM
Age-specific vaccine coverage and delay
data from DHSS surveys for many countries
6
15
DTP 1
32
DTP 2
DTP 3
Colin Sanderson and Andy Clark, LSHTM
Rotavirus gastroenteritis, by age, and
implied number of doses of vaccine they
“could have received” (eg Vellore India)
Colin Sanderson and Andy Clark, LSHTM
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 restrictions
RVGE 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 restrictions
RVGE 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-time
RVGE 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