1 randomised trial to test the non-specific effects of standard measles vaccine at 4½ and 9 months...
Post on 28-Dec-2015
213 Views
Preview:
TRANSCRIPT
1
Randomised trial to test the non-specific effects of standard measles vaccine at 4½ and 9 months of age: General reduction in childhood mortality
Peter Aaby, Cesario Martins, Christine S Benn, Henrik Ravn. Bandim Health Project, National Institute of Health, Guinea-Bissau
2
Introduction of measles vaccination in African communities:
Annual mortality before and after
0%
2%
4%
6%
8%
10%
12%
14%
Bissau 6-35 mo Senegal 9-60 mo Senegal 9-23 mo Zaire 7-21 mo
BeforeAfter
Measles not more than 10-20% of deaths. Reduction in mortality not due to prevention of acute and long-term effects of measles infection
Measles vaccine (MV) - beneficial non-specific effects (NSE)
3
Introduction of DTP: Rural areas of Guinea-Bissau 1984-87
Follow-up (months)
Sur
viva
l pro
babi
lity
0 1 2 3 4 5 6
0.90
0.92
0.94
0.96
0.98
1.00
DTP –
DTP +
DTP+ / DTP- 1.98 (1.03-3.8)
(N=868)
(N=967)
Children aged 2-8 moFollowed 6 mo
Unvaccinated: travelling; sick; days without vaccines
Diphtheria-Tetanus-Pertussis has negative effects for girls
4
Age (months)
Sur
viva
l pro
babi
lity
4 6 12 18 24 30 36 42 48 54
EZ M
EZ F
Control M
Control F
0
0.6
0.7
0.8
0.9
1.0
High-titre measles vaccine: 2-fold higher female mortality
Lessons from high-titre measles vaccine (HTMV) trials:• EZ HTMV was fully protective against measles => negative non-specific effect• Sex-differential effect• Public health effects: 35% excess mortality from 4 to 60 months => at least ½ mill
annual deaths in AfricaWHO introduced HTMV 1989 and withdrew it in 1992 => Interpretation: Too much of a good thing => Major donors: Money for new vaccines!
=> We looked for important NSEs of other vaccines
Age (months)
Su
rviv
al p
rob
ab
ility
6 12 18 24 30 36 42 48 54 60
EZ M
EZ F
Con M
Con F
0
0.80
0.85
0.90
0.95
1.00
SENEGAL 1987-92, EZ-HTBISSAU 1986-90, EZ-HT
5
020
4060
8010
0M
orta
lity
rate
(pe
r 10
00 y
ears
)
0 3 6 9 12 15 18 21 24 27 30 33 36Age (months)
Male Female
Bandwidth: 4 months
Guinea-Bissau 1992-94
020
4060
80M
orta
lity
rate
(pe
r 10
00 y
ears
)
0 3 6 9 12 15 18 21 24 27 30 33 36Age (months)
Male Female
Bandwidth 4 months
Gambia 1998-2002
Increased female mortality in the age groups of DTP => Change the immunological profile with a live vaccine =>
RCT: Early Measles Vaccine at 4½ m
What can be done to reduce the negative effect of DTP?
6
Testing non-specific effects of MV
Birth
BCG DTP/OPV 1 2 3 MV
36 mo9 mo6 10 14 weeks
Follow-upOPV
• Recruitment 2003-2007 – Follow-up to 2009• 6,600 randomised to A) Edmonston-Zagreb (EZ) at 4½+9 mo, or B+C)
no vaccine at 4½ mo and EZ MV or Schwarz MV at 9 mo• DTP3 four weeks before enrolment – to prevent the
problem of DTP after MV• Study designed to test a 25% difference in mortalityComparisons• MV versus DTP3 between 4 and 8 months• MV at 4+9 mo versus MV at 9 mo between 9-36 mo
4½ mo
MV vs No vac
77
Procedures
• Newborns were identified in database of Bandim HDSS
• Before inclusion, mothers reminded to complete the OPV/DTP vaccination schedule at 6,10, and 14 wks
• The formal inclusion in the study was carried out at 4½ months of age
8
Measles epidemic in Bissau, 2003/2004
Vaccine efficacy of early MVDefinite measles 94%(77-99)Hospitalisation 100%(46-100)Measles death 100%(-42-100)
9
MV at 4½+9mo vs No vac(DTP3)+MV at 9moFollow to 3 yrs for all children (2003-2009)
0
0.5
1
1.5
2
2.5
3
3.5
4-8 mo 9-36 mo 4-36 mo
MV 4+9 moDTP3+MV 9 mo
0.67(0.4-1.2)
0.71(0.5-1.0)
0.69(0.5-0.9)
Mortalityrate
Two MVs at 4 and 9 mo: 31% (6-49%) (F: 41 %(9-62); M: 18%)Measles inf censored 26% (0-46%)
(NB not against unvaccinated)
10
MV at 4+9mo vs No vac(DTP3)+MV at 9mo by Vitamin A-at-birth status
00.20.40.60.8
11.21.41.61.8
2
Vitamin A Placebo
MV 4+9 moDTP3+MV 9 mo
0.98(0.6-1.5)
0.34(0.2-0.7)
Mortalityrate
P=0.012
Vitamin A may have a fundamental impact on the NSEs
=> Only those who did not receive VAS-at-birth
11
MV at 4+9mo vs No vac(DTP3)+MV at 9mo (3402 infants with no Vitamin A at birth)
0
0.5
1
1.5
2
2.5
3
3.5
4
4-8 mo 9-36 mo 4-36 mo
MV 4+9 moDTP3+MV 9 mo
0.36(0.1-0.9)
0.57(0.3-0.9)
0.51(0.3-0.8)
Mortalityrate
Reduction in overall mortality: Two MV at 4½ and 9 mo: 49% (22-68) (F: 53%(14-74); M: 44%)Measles inf censored 45% (14-65)
12
MRR=0.48 (0.26-0.87)
P-value=0.02
01
23
45
67
accu
mul
ated
mor
talit
y (%
)
750 660 594One-dose405 377 334Two-dose
Number at risk
0 1 2 3Age in Years
Two-dose MV
One-dose MV
Children born before June 2004
MRR=0.53 (0.28-1.00)
P-value=0.050
12
34
56
7ac
cum
ulat
ed m
orta
lity
(%)
1184 1062 940One-dose599 541 485Two-dose
Number at risk
0 1 2 3Age in Years
Two-dose MV
One-dose MV
Children born after June 2004
13
Testing non-specific effects of early measles vaccination: Conclusions
Birth
BCG DTP/OPV 1 2 3 MV
36 mo9 mo6 10 14 weeks
Follow-upOPV
Key features • Low maternal antibody levels • Edmonston Zagreb (EZ) measles vaccine • All had DTP3 before measles vaccine
Conclusions• EZ at 4½ mo is protective against measles infection• MV affects non-measles morbidity - 49% (15-69) reduction in
hospitalisations for girls – 16% for boys• MV vs DTP3 between 4-8 mo: 64% (8-86) reduction in mortality• MV at 4½+9 mo vs MV at 9 mo between 9-36 mo: 43% (7-66)
4½ mo
MV vs No vac
14
Non-specific effects (NSE) of standard MV at 4½ and 9 months of age: General reduction in childhood mortality
• Vaccines stimulate the immune system affecting susceptibility• The NSE are often more important than specific effects• Vaccination programmes should take the NSE into consideration: age at vaccination, number of vaccinations, sequence of vaccinations• Reconsider assumptions –
•Focus: specific diseases or immune deviations•Effects may differ for boys and girls•Interventions interact
• INDEPTH in a unique position to pursue these problems • => EU is (hopefully) going to fund a multicentre trial of early MV
15
HTMV and DTP?
0
10
20
30
40
50
60
SenegalHT
Senegalroutine
Bissau Gambia Sudan Congo
Num
ber
of d
eath
s
0
5
10
15
20
25
30
35
40
SenegalHT
SenegalRoutine
Bissau Gambia Sudan
Nu
mb
er o
f d
eath
s
Girls
Boys
No DTP after HTMV
DTP/IPV after HTMV
F/M ratio: 0.96 (0.7-1.3) F/M ratio: 1.93(1.3-2.8)
HTMV withdrawn for the wrong reason
Not RCT – but this ”proves” a causal biological process
top related