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)

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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)

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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)

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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

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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

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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