The Cuban experience with routine The Cuban experience with routine use of serogroup B OMV vaccineuse of serogroup B OMV vaccine

First Regional Meningococcal SymposiumSabin Institute/PAHO M h 19 20 B Ai A ti

Dr Franklin Sotolongo

Sabin Institute/PAHO March 19-20, Buenos Aires, Argentina

Dr. Franklin Sotolongo

OUTLINEOUTLINE

Outer Membrane Vesicles for Meningococcus BOUTLINE

REVIEW of MENIGOCOCCAL DISEASE in

g(OMV)…

REVIEW of MENIGOCOCCAL DISEASE inCuba

EXPERIENCE f OMV i d l d EXPERIENCE of an OMV vaccine developed in Cuba

OVERVIEW regarding Va-Mengoc-BC CLINICAL DATA

EPIDEMIOLOGICAL IMPACT after vaccine application

POST-LICENSING SURVEILLANCE

Meningococcal Disease in Cuba

Before 1975Some sporadic cases with low

incidence rate record (0 4 105 i h bit t )

(IR x 10(IR x 105 5 inhabitantsinhabitants))

14,3(0,4 x 105 inhabitants)

After 1976An increase of frequency of cases 5,65,6q y

was observed with a higher incidence rate record 1,50,80,8

Meningococcal Disease National gIncidence Rate (1983):

14,3 x 105 population

Children < 1 year old (120 x 105

h b )hab.)

Predominance of serogroup BB:4:P1.19,15

Meningitis epidemic situation was considered a National health problem and a

Ministry of Health top priority

Experience of an OMV meningococcal B vaccine

Proteins identified by Proteomic approachesg

developed in Cuba

VA-MENGOC-BC is a bivalent vaccine of OMV of

OMV from meningococcalstrain B:4:P1.19,15

VA-MENGOC-BC is a bivalent vaccine of OMV of serogroup B meningococcus that includes PorA, Por B, Opa, Opc, Tbp, NspA, high molecular weight proteins, and

th t i d l l h id f N i iother proteins and capsular polysaccharide of Neisseria meningitidis serogroup C.

Overview regarding Overview regarding VaVa‐‐MengocMengoc‐‐BCBC CLINICAL DATACLINICAL DATA

PRE-LICENSING EFFICACY STUDIES: Phase III Clinical Trial

Study Number of bj t Number of EffiStudy

(year) subjects(Age)

Number of doses Efficacy

Randomized Randomized double blinddouble blind

PlaceboPlacebo--controlcontrol(1987)(1987)

106 251106 251(10(10--16 y)16 y) 2 x 50 2 x 50 gg 83%83%

(1987)(1987)

Sierra, GVG. Campa C, Valcarcel NM, Izquierdo Pl, Sotolongo F, C GV R d í CR T MH NIPH ANNALS V l 14Casanueva GV, Rodríguez CR, Terry MH. NIPH ANNALS. Vol. 14 No.2, 1991

Immunogenicity of VA-MENGOC-BC among young adults in Icelandadults in Iceland

Tite

rog

2 SB

A Lo

Perkins B, Jonsdottir H, Briem H, Griffiths E, Plikaytis B, Hoiby A, Rosenqvist E, Holst J, , Sotolongo F, Sierra G, Campa C, Carlone G, Tikhomirov E, Wenger J, Broome C. g , , p , , , g ,Immnunogenicity of two efficacious outer membrane protein-based vaccines among young adults in Iceland. J. Infect. Dis. 177,1998,683-91

Vaccine application strategy in the Cuban populationp p

1st STAGE:

Massive campaign

From: 1989 to 1990

2nd STAGE:

National From: 1989 to 1990

Age groups:

3 th 19

National Immunization

Program3 month - 19 years

2 692 446 peopleFrom: 1991

Age group: InfantsCoverage: 75%

Age group: Infants

•1st dose 3 months

2nd dose 5 months•2nd dose 5 months

Epidemiological impact of Meningococcal B-OMV vaccine in Havana City

Mass vaccination campaign

VA-MENGOC-BC®

Mass vaccination campaign VA-MENGOC-BC®

APRIL 1989Mass vaccination campaign

VA MENGOC BC®APRIL 1989

VA-MENGOC-BC®

APRIL 1989

20112011

Meningococcal disease. Density of Incidence rate in Cuba 1984-1994.

•From 1984-1994 total decreased from 14,1 (1401 cases) to 0,8 (88 Cases) per 100 000 persons/ year

NPrevaccinal Period

(1984-1988)Vaccinal Period

(1989-1994)14,1 x !05

(1401 cases)8,8 x 105

(922 cases)6,5 x 105

(683 cases)0,8 x 105

(88 cases)

37% reduction 87,7 % reductionSignificant break point observed in

the reduction of morbidity occur in the 1 year age group1 year age group

Pérez Rodríguez A, Dickinson F, Baly A, Martínez R.The Epidemiological Impact of Antimeningococcal B Vaccination in Cuba Mem Inst Oswaldo Cruz Río de Janeir Vol 94:000Antimeningococcal B Vaccination in Cuba. Mem. Inst. Oswaldo Cruz, Río de Janeir, Vol. 94:000-0000, 1999.

Meningococcal disease. Density of Incidence Rate in Children of 1 year oldChildren of 1 year old by Municipalities.

Cuba 1984-1988.

N

Densidad de Incidencia x 100000 Pers.-Año.1 año, 1984-1988 (No. de municipios)

124.35 a 243.50 (11)92.39 a 124.34 (18)47.97 a 92.38 (44)23.56 a 47.96 (40)

0 01 a 23 55 (10)0.01 a 23.55 (10)0 (46)

Pérez Rodríguez A, Dickinson F, Baly A, Martínez R.The Epidemiological Impact of Antimeningococcal B Vaccination in Cuba. Mem. Inst. Oswaldo Cruz, Río de Janeir, Vol. 94:000-0000, 1999.B Vaccination in Cuba. Mem. Inst. Oswaldo Cruz, Río de Janeir, Vol. 94:000 0000, 1999.

Meningococcal disease. Density of Incidence Rate in Children of 1 year oldChildren of 1 year old by Municipalities.

Cuba 1989-1994.

N

Densidad de Incidencia x 100000 Pers.-Año.1 año, 1989 -1994 (No. de municipios)

124.35 a 243.50 (0)92.39 a 124.34 (2)47.97 a 92.38 (6)23.56 a 47.96 (32)

0 01 a 23 55 (45)0.01 a 23.55 (45)0 (84)

Pérez Rodríguez A, Dickinson F, Baly A, Martínez R.The Epidemiological Impact of Antimeningococcal B Vaccination in Cuba. Mem. Inst. Oswaldo Cruz, Río de Janeir, Vol. 94:000-0000, 1999.Vaccination in Cuba. Mem. Inst. Oswaldo Cruz, Río de Janeir, Vol. 94:000 0000, 1999.

Epidemiological impact of Meningococcal B OMV vaccine in the Cuban population

1983-2011l d d f

National Immunization Schedule*Stage 2

Massive campaign *Stage 1

IR 0,1 x 105

Total decreased from

14,3 (1411 cases) to 0,1

(13 Cases) per 105

Stage 2

persons/year2011

Prevaccinal Period(1983-1987)

Vaccinal Period(1988-2011)

14,3 x 105

(1411 cases)8,5 x 105

(875 cases)7,6 x 105

(795 cases)0,1 x 105

(13 cases)

38% reduction morbidity 97 % Reduction morbidity

24% Reduction mortality 98% Reduction mortality

INCIDENCIA DE ENFERMEDAD MENINGOCÓCICA EN LA INCIDENCIA DE ENFERMEDAD MENINGOCÓCICA EN LA POBLACIÓN INFANTIL. CUBA 1990POBLACIÓN INFANTIL. CUBA 1990--20102010

INCIDENCIA DE ENFERMEDAD MENINGOCÓCICA SEGÚN INCIDENCIA DE ENFERMEDAD MENINGOCÓCICA SEGÚN GRUPOS DE EDAD. CUBA 1990GRUPOS DE EDAD. CUBA 1990--20102010

INCIDENCIA DE ENFERMEDAD MENINGOCÓCICA SEGÚN INCIDENCIA DE ENFERMEDAD MENINGOCÓCICA SEGÚN GRUPOS DE EDAD. CUBA 1990GRUPOS DE EDAD. CUBA 1990--20102010

2 doses schedule have been applied 2 doses schedule have been applied without boosterwithout boosterwithout boosterwithout booster

Va-Mengoc-BC vaccine for InfantsVa Mengoc BC vaccine for InfantsAge group:

1st dose - 3 months2nd dose - 5 months

What has been observed What has been observed after the vaccination with after the vaccination with after the vaccination with after the vaccination with VAVA--MENGOCMENGOC--BCBC®® vaccine vaccine

in Cuba regarding in Cuba regarding meningococcus strain meningococcus strain meningococcus strain meningococcus strain

isolation?isolation?

Results of our experience in Cuba on Results of our experience in Cuba on strain phenotyping and Men B vaccinestrain phenotyping and Men B vaccinestrain phenotyping and Men B vaccinestrain phenotyping and Men B vaccine

Cases-Epidemic

Carriers-Epidemic

Cases-Epidemic

Serogroups of Serogroups of N.meningitidisN.meningitidis

l d dl d dstrains isolated during strains isolated during epidemic and epidemic and postpost epidemic stagesepidemic stagespostpost‐‐epidemic stages epidemic stages Cuba 1982Cuba 1982--20022002 CasesCases

PostPost--epidemicepidemicCarriersCarriersPostPost--epidemicepidemic

SEROGROUPS of N. meningitidis isolated fromCARRIERS in the Epidemic and Post Epidemic stagesCARRIERS in the Epidemic and Post-Epidemic stages

Cuba 1982-2002

Serogroup Epidemic stage % (n=105)

Postepidemic stage % (n=226)

B 67.62 17.26

NA 32.38 79.65

W135 0.0 2.21

Y 0.0 0.44

Z 0.0 0.44

Martínez I, Sierra G, Núñez N, Izquierdo L, Climent Y, Mirabal M. Caracterización de cepas de Neisseria meningitidis aisladas de portadores en Cuba durante 20 años. Revista Cubana Med Trop 2006;58(2):

SEROTYPESSEROTYPES of of Neisseria meningitidisNeisseria meningitidis isolated from isolated from CARRIERSCARRIERS in the Epidemic and Postin the Epidemic and Post--epidemic stage. epidemic stage.

C b 1982C b 1982 20022002Serotype Epidemic stage %

(n=105)Postepidemic stage

% (n=226)

Cuba 1982Cuba 1982--20022002

(n=105) % (n=226)NT 22.86 70.80

1 0 95 0 441 0.95 0.44

4 70.48 12.39

2b 0.95 0.0

14 0.0 3.10

15 4.76 13.27

Martínez I, Sierra G, Núñez N, Izquierdo L, Climent Y, Mirabal M. Caracterización de cepas de Neisseria meningitidis aisladas de portadores en Cuba durante 20 años. Revista Cubana Med Trop 2006;58(2):

SUBTYPESSUBTYPES of of Neisseria meningitidisNeisseria meningitidis isolated from isolated from CARRIERSCARRIERS in the Epidemic and Postin the Epidemic and Post--epidemic stage. epidemic stage.

C b 1982C b 1982 20022002Subtype Epidemic stage

% (n=105) Postepidemic stage

% (n=226) P1 NST 17 14 34 96

Cuba 1982Cuba 1982--20022002

P1.NST 17.14 34.96

P1.13 3.82 16.81

P1.19,15 61.91 4.87,

P1.6 7.62 12.39

P1.15 2.85 5.31

P1.19 4.76 0.44

P1.4 0.0 5.31

0 0 6 64P1.7 0.0 6.64

P1.12 0.95 4.43

Others 0.95 8.84Others 0.95 8.84

Martínez I, Sierra G, Núñez N, Izquierdo L, Climent Y, Mirabal M. Caracterización de cepas de Neisseria meningitidis aisladas de portadores en Cuba durante 20 años. Revista Cubana Med Trop 2006;58(2):

Molecular diversity among strains of Molecular diversity among strains of N.meningitidisN.meningitidis isolated before and after mass isolated before and after mass

i i i i C bi i i i C b

•The strain type B:P1.19,15:F5-1:ST-33(cc-32) was

immunization in Cubaimmunization in Cuba

yp , ( )the main responsible of the epidemic occurred in Cuba during the 80´s

•Between the period before and after h i i i h i ifithe immunization there was a significant

decrease in the hypervirulent clonal complexes ST-32 and ST-41/44 after the introduction of the OMV serogroup B introduction of the OMV serogroup B vaccine

Yanet Climent a,1,*, Rachel Urwin b,1,2, Daniel Yero a,1, Isabel Martinez a, Alejandro Martín c,Yanet Climent a,1, , Rachel Urwin b,1,2, Daniel Yero a,1, Isabel Martinez a, Alejandro Martín c, Franklin Sotolongo a, Martin C.J. Maiden b, Rolando PajónThe genetic structure of Neisseria meningitidis populations in Cuba before and after the introduction of a serogroup BC vaccine Infection, Genetics and Evolution 10 (2010) 546–554

Molecular diversity among strains of Molecular diversity among strains of N.meningitidisN.meningitidis isolated before and after mass isolated before and after mass

immunization in Cubaimmunization in Cuba

The number of hypervirulent li d d i ifi tl

immunization in Cubaimmunization in Cuba

lineages decreased significantly

Yanet Climent a,1,*, Rachel Urwin b,1,2, Daniel Yero a,1, Isabel Martinez a, Alejandro Martín c, Franklin Sotolongo a, Martin C.J. Maiden b, Rolando PajónThe genetic structure of Neisseria meningitidis populations in Cuba before and after the introduction of a serogroup BC vaccine Infection, Genetics and Evolution 10 (2010) 546–554

Post-marketing surveillance

VAVA--MENGOCMENGOC--BCBC®®.. Phase IV studies.

Adverse events following immunization reports detected by passive notification.

Cuba 2003-2010

AEFI reports

Applied doses

Reports per doses

Rate x 105

doses

38 23

Systemic Adverse Events

Symptoms & signs n Rate x 105 doses

Headache 4 0,20765 2 001 064 1 / 2615.77 38.23

IC95%(36-41)

Headache 4 0,20

Irritability 82 4,10

Local reactions 190 9,49

General malaise 26 1,30

Rash 27 1,35

Nausea 2 0,10

Vomiting 14 0,70

Fever ≥39ºC 589 29,43

The OMV vaccines can beclassified as moderately

reactogenicPersistent crying 22 1,10

reactogenic

Holsts J. et al/Vaccine (2009)

REMARKS

VA-MENGOC-BC® is a vaccine which has been used effectively in Cuba, and it has also been shown to be ffi i i i i h L i A i efficacious in vaccinees in other Latin American

countries

The immune response to VA-MENGOC-BC® is not The immune response to VA MENGOC BC is not completely restricted strain-specific

The carrier strain characteristics have changed after i ti Th bl t bl d vaccination. The non-groupable, non-serotypable and

non-subtypable strains prevailed in the post-epidemic stage and the number of hypervirulent lineages decreased significantly

During more than 23 years of use over 60 million doses have been applied with good tolerability and safety

“ True Medicine… True Medicine is not curing,

but preventing…”José Marti

Cuban National Hero

Thank you…

Gracias…