prof sir brian greenwood @ mrf's meningitis & septicaemia in children & adults 2015

THE AFRICAN MENINGOCOCCAL

CARRIAGE CONSORTIUM

Brian Greenwood

London School of Hygiene & Tropical Medicine

Meningitis Research Fund MeetingNovember 4th 2015

THE AFRICAN MENINGITIS BELT

(Lapeyssonnie, Bull WHO 1963;28 suppl:3-114)

CHARACTERISTICS OF MENINGOCOCCAL DISEASE IN THE AFRICAN MENINGITIS BELT

High rate of endemic infection

Regular epidemics - geographical limitation - periodicity - marked seasonality - large size - mainly serogroup A (prior to vaccination)

What lies behind this unique epidemiology?

‘’Cases of meningitis can be considered uncertain and irregular indicators of the spread of meningococcal infections in a

population. The real flow is submerged and can be revealed

solely by uncovering subclinical infections.’’

(Phair and Schoenbach Amer J Hyg 1944; 40:525-41)

MENINGOCOCCAL CARRIAGE IN AFRICA Literature Review to 2007

Overall carriage rate varied from 1- 30%

Age pattern very variable

Is the heterogeneity due to methodological problems?

(Trotter and Greenwood, LID 2007;12:797-803)

THE GENESIS OF MENAFRICAR CONSORTIUM

2006 Workshop on meningococcal carriage in Africa, sponsored by the Wellcome Trust.

2007 Project development grant from the Wellcome Trust, Workshop in London.

2008 Award of a grant to the consortium by the Gates Foundation.

2009 Award of a strategic award to the consortium from the Wellcome Trust, First formal meeting of the consortium, Bamako, Mali .

THE MENAFRICAR CONSORTIUM

Armauer Hansen Research Institute, Ethiopia

Centre de Recherche Médicale et Sanitaire, Niger

Centre de Support en Santé Internationale, Chad

Centre pour le Développement des Vaccins, Mali

University of Maiduguri, Nigeria

The Navrongo Health Research Centre, Ghana

Institut de Recherche pour le Développement, Senegal

LSHTM + 13 NORTHERN PARTNERS

OBJECTIVES

Measurement of the prevalence of meningococcal carriage across the African meningitis belt prior to the introduction of MenAfriVac.

Investigation of the pattern of spread of meningococci within households in the African meningitis belt.

Investigation of the background level of immunity to the serogroup A meningococcus across the African meningitis belt.

Determination of the impact of MenAfriVac on serogroup A meningococcal carriage.

METHODS

CROSS-SECTIONAL SURVEYS

Random selection of households (DSS or census).

Age stratification (<1, 1-4, 5-14, 15-29, 30 or > years).

Urban and rural sites.

Target of 2,000 or 5,000 subjects per survey.

Blood samples obtained from a subset of participants.

HOUSEHOLD STUDIES

Cross-sectional study

First household visit

visit 2

visit 3

visit 4

Identification of a carrier

Household follow up

6 months of follow up

Carrier

Missing

Not a carrier

Method 1 Method 2

Nasopharynx

aloneNasopharynx & tonsil

OPTIMUM METHOD OF SWABBING

(No significant difference between the two methods)

(Basta et al, PLoS One 2013)

CAPACITY DEVELOPMENT IN LABORATORY ASSAYS

Serology Lab, Mali Training courses, VEU, PHE, Manchester CVD, Bamako, Mali

MICROBIOLOGY

Culture onselective medium

Swab

Gram stain Oxidase tests

ONPGPositive

Culture blood agar

Molecular characterisation

Biochemicaltests

Seroagglutination

DNA preparation

(MenAfriCar Consortium TMIH 2013;18:968-78)PCR

On-site

Oxford

MOLECULAR BIOLOGY

Speciation – rplF sequencing assay.

Genogrouping – RT PCR assay (A, W ,X ,B ,C ,Y) and capsule null (cnl) assay.

Genetic diversity – porA and fetA sequencing

Whole genome sequencing – MenA isolates

SEROLOGY

Meningococcal polysaccharide IgG ELISA (all centres)

Bactericidal assay (Mali and Niger)

Validation at the Vaccine Evaluation Unit, PHE, Manchester

(MenAfriCar Consortium TMIH 2013;18:968-78)

CROSS-SECTIONAL SURVEYS

CARRIAGE PREVALENCE – CROSS SECTIONAL SURVEYS

1687 carriers from 48,490 participants; 3.5% overall (all meningococci )

Chad Ethiopia Ghana Mali Niger Nigeria Senegal Overall0%

5%

10%

15%

20%

25%

Survey 1 (rainy) Survey 2 (rainy) Survey 3 (dry)ca

rria

ge p

reva

lenc

e

(MenAfriCar consortium. J Infect Dis 2015;212:1298-307)

CARRIAGE PREVALENCE BY AGE AND SEX

(MenAfriCar consortium. J Infect Dis. 2015;212:1298-307)

<1 years 1-4 years 5-14 years 15-29 years 30+ years0%

1%

2%

3%

4%

5%

6%

Females Males

Carr

iage

pre

vale

nce

RISK FACTORS FOR CARRIAGE

Country

Age

Crowding: >2 people per room)

Smoking in household

Indoor kitchen

Season: dry season

Recent vaccination with a meningitis vaccine

No associations with respiratory symptoms

or social gatherings

(MenAfriCar consortium. J Infect Dis. 2015 ;212:1298-307)

GENOTYPE OF CARRIERS

A A/X

B C

W X

X/C Y

cnl

Survey 1; 2010 (rainy) 584/17042

Survey 2; 2011 (rainy) 455/15936

Survey 3; 2012 (dry) 648/15512

Capsule null

W

A

Capsule null

Capsule null

(MenAfriCar Consortium. J Infect Dis. 2015 ;212:1298-307)

WW

SEROGROUP A MENINGITIS EPIDEMIC IN CHAD

Districts in epidemic/ alert in 2012Districts vaccinated with “MenAfriVac” in December 2011

N’Djaména

MandeliaDistricts in epidemic/alert in 2012Districts vaccinated with “MenAfriVac” in December 2011

N’Djaména

EPIDEMIC MENINGITIS IN CHAD 2012

13-15 months 2-4 months 4-6 months0

1

2

1

All meningococci

Epidemic strain

VACCINATION

Pre-vaccination Post-vaccination

Percentage carriage

IMPACT OF PsA-TT ON MENINGOCOCCAL CARRIAGE – CHAD 2012

(Daugla et al. Lancet 2014; 383:40-47)

32

[Adjusted OR = 0.019, 95% CI 0.002, 0.14]

CHAD ETHIOPIA

N=14

N=71

N=49

Pre-vaccination Post vaccination

N=120 N=122 N=147

XS1 XS2 XS30

10

20

30

40

50

60

70

80

90

100 no/partial porAP.12-1,2-59P.12-1,13-2P.7-2,30-3P.7-2,30-2P.7,30-6P.7,30-3P.7,30-2P.7,13-18P.7,13-1P.7,13P.5-14,10-86P.5-1,2-2P.5-1,10-1P.5-2,10-2P.5,2P.22-1,14P.22-14P.22-11,15-30P.22-11,15-25P.22-11,15-1P.22-11,9P.19-1,15-1P.19,15P.17-1,23P.17,16-4P.18-1,34P.18,25 P.18,25-21P.18,25-19P.18-11,42P.5-1,10-62P.18-11,42-1

perc

enta

ge o

f N.m

enin

gitid

is (%

)

NO VACCINATION!

IMPACT OF MENAFRIVAC ON STRAIN DISTRIBUTION

0

1

2

3

4

5

6

7

8

9

Vaccinated

Non-vaccinated

2009 2010 2011 2012

Wee

kly

inci

denc

e/10

0,00

0

Vaccination PsA-TT

INITIAL IMPACT OF PsA-TT ON CASES OF MENINGITIS IN CHAD - 2012

Incidence odds ratio 0.096 (0.05,0.19) (Daugla et al. Lancet 2014; 383:40-47)

IMPACT OF PsA-TT ON MENINGITIS CASES IN CHAD, WEEKS 1-26, 2009-13

0

1

2

3

4

5

6

7

8

9

N'Djamena

Rest of Chad

2009 2010 2011 2012

Wee

kly

inci

denc

e/10

0,00

0

2013

Vaccination 2012

Vaccination 2011 2012

(Gamougam et al. Emerg Infect Dis 2015;21:115-8)

MENINGITIS CASES CHAD - UPDATE

WHO Meningitis Weekly Bulletin September 2015

MenAfriVac completed

WHAT NEXT?

Disease outbreak news 23 July 2015

Between 1 January and 28 June 2015, the Ministry of Public Health of Niger notified WHO of 8,500 suspected cases of meningococcal meningitis, including 573 deaths. This was the largest meningitis outbreak caused by Neisseria meningitidis serogroup C in the African meningitis belt.

http://www.who.int/csr/don/23-july-2015-niger/en/

MENINGITIS IN THE AFRICAN MENINGITIS BELT - 2015

CONCLUSIONS

Carriage of Neisseria meningitidis and of non-meningococcal Neisseria species varies markedly by place and time in the African meningitis belt.

Carriage of Neisseria meningitidis is generally at a lower prevalence and of shorter duration in the meningitis belt than in industrialised countries.

In households with a carrier younger children are infected by their older siblings.

There is a high background prevalence of serogroup A anti-meningococcal antibodies across the meningitis belt which are probably not protective.

MenAfriVac protects against serogroup A meningococcal carriage and meningitis.

There is still much that is unknown about the epidemiology of epidemic meningitis in the meningitis belt which could be investigated by further carriage studies.

ACKNOWLEDMENTS