Meningococcal vaccines the journey continues
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Meningococcal Vaccines The Journey Continues. Canadian Public Health Association Conference June 19, 2011. Bryna Warshawsky, Associate Medical Officer of Health 519-663-5317 ext. 2427; [email protected] Outline. Background Epidemiology Journey Polysaccharide vaccines

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Meningococcal vaccines the journey continues

Meningococcal VaccinesThe Journey Continues

Canadian Public Health

Association Conference

June 19, 2011

Bryna Warshawsky, Associate Medical Officer of Health

519-663-5317 ext. 2427; [email protected]


Outline

Outline

  • Background

  • Epidemiology

  • Journey

    • Polysaccharide vaccines

    • Conjugate C vaccines

    • Conjugate quadrivalent vaccines

    • Meningococcal A vaccine

    • Meningococcal B vaccines


Background

Background


Meningococcal disease

Meningococcal Disease

  • Neisseria meningitidis

  • Gram negative diplococci

  • Thirteen different serogroups, classified by their polysaccharide (sugar) capsule

  • Most common A, B, C, Y, W135 and X


Meningococcal disease1

Meningococcal Disease

  • Causes:

    • meningitis - inflammation of the lining brain

    • meningococcemia - in the blood

    • Disseminated intravascular coagulation (DIC)

  • Presents as fever, headache, vomiting, stiff neck, photophobia and petechial rash

  • Fatal in approximately 10%

  • Long term sequelae 10 - 20% such as hearing loss, amputation or neurologic


Immunogenicity

Immunogenicity

  • Vaccines authorized based on immunogenicity, not efficacy

  • Correlate of protection

  • Serum bactericidal antibody (SBA) titre

    • Dilution of serum able to kill meningococcal bacteria in vitro; requires the addition of complement

    • Using human complement correlate is ≥1:4

    • Measure:

      • Percent achieving titre

      • Geometric mean titre


Protection

Protection

  • Circulating antibody titre

  • Immune memory

    • May be too slow for post-exposure protection

  • Herd immunity


Epidemiology

Epidemiology


Meningococcal by year and serogroup source naci statement august 2009

Meningococcal by Year and SerogroupSource: NACI Statement, August 2009


Meningococcal epidemiology

Meningococcal Epidemiology

  • 2006:

    • 210 cases in Canada

    • Serogroup C 43 cases0.13/100,000

    • Serogroup B 113 cases0.34/100,000

    • Serogroup Y27 cases0.08/100,000

    • Serogroup W135 6 cases 0.02/100,000

    • Serogroup A2 cases0.01/100,000

    • Other 19 cases

NACI Statement, CCDR, Volume 35 • ACS-3 April 2009


The journey

The Journey


Meningococcal vaccines the journey continues

Meningococcal A

Quadrivalent conjugate

A, C, Y and W135

Meningococcal B

Conjugate C

Polysaccharide

A, C

A, C, Y, W135

2001

1960 - 1980

2006

2010


Polysaccharide vaccines

Polysaccharide Vaccines


Naci recommendation polysaccharide vaccine

NACI Recommendation – Polysaccharide Vaccine

  • asplenic patients, sickle cell disease

  • complement deficient, properdin or factor D deficiency

  • travellers e.g. Hajj, Mecca, Saudi Arabia

  • laboratory workers who handle meningococcal specimens

  • military

  • close contacts of serogroups A, C, Y, W135

  • outbreaks of serogroups A, C, Y, W135


Conjugate c vaccines

Conjugate C Vaccines


Conjugate vaccines

Conjugate Vaccines

  • Sugar linked to a protein

    • diphtheria toxoid

    • diphtheria toxoid mutant – CRM 197

    • tetanus toxoid

  • T cell dependent

  • Works in young children

  • Decreases carriage leading to herd immunity

  • Boostable response


Naci recommendations meningococcal c conjugate

NACI RecommendationsMeningococcal C conjugate

  • Routine program:

    • 2 months to 4 year olds

    • adolescents

    • young adults

    • consider for 5-10 year olds

  • Post exposure for serogroup C

  • Outbreaks serogroup C

NACI; CCDR, 2001; 27:2-36


Meningococcal vaccines the journey continues

Richmond P et al. The Journal of Infectious Disease; 2001; 183:160-3


Meningococcal vaccines the journey continues

Richmond P et al. The Journal of Infectious Disease; 2001; 183:160-3


Quadrivalent conjugate a c y w135

Quadrivalent ConjugateA, C, Y, W135


Conjugate a c y w135

Conjugate A, C, Y, W135

  • MenactraTM (sanofi pasteur) – diphtheria toxoid

    • Authorized for use May 2006

    • Authorized for ages 2 – 55 years

    • Not very immunogenic in infants

  • MenveoTM (Novartis ) - mutant diphtheria toxoid CRM197

    • Authorized for use May 2010

    • Mix lyophilized A with liquid C, Y, W135

    • Authorized for ages 11-55 years

    • Has been shown to be immunogenic in infants


Naci recommendation

NACI Recommendation

  • asplenic patients, sickle cell disease

  • complement deficient, properdin or factor D deficiency

  • travellers e.g. Hajj, Mecca, Saudi Arabia

  • laboratory workers who handle meningococcal specimens

  • military

  • close contacts of serogroups A, Y, W135

  • outbreaks of serogroups A, Y, W135

  • primary antibody deficiencies

  • HIV positive - consider


Naci recommendation adolescent vaccination

NACI RecommendationAdolescent Vaccination

  • Meningococcal C conjugate or quadrivalent conjugate vaccines can be used depending on epidemiology and other considerations

  • Give an adolescent doses even if vaccinated at young age

NACI, CCDR, May 2007;33(ACS-3):1-23 NACI, CCDR, April 2009;36(ACS-3):1-40.


Meningococcal vaccines the journey continues

Jackson LA et al. Clinical Infectious Diseases 2009;49:e1-10

C non-inferior; others Menveo superior


Meningococcal vaccines the journey continues

All Menveo superior

Jackson LA et al. Clinical Infectious Diseases 2009;49:e1-10


Effectiveness data from us menactra tm

Effectiveness Data from US MenactraTM

  • 14 vaccine failures in the US

    • 8 serogroup C; 6 serogroup Y

    • Median age at vaccination 18 years (12-20 years)

    • Mean time from vaccination to disease 395 days (43-1021 day)

    • 3 underlying conditions

    • 3 fatal (21% case fatality)

  • Vaccine effectiveness estimated at 80-85% within 2 – 3 years after vaccination

MacNeil et al. Pediatric Infectious Disease Journal, June 2011;30(6):451-455


Effectiveness data from us menactra tm1

Effectiveness Data from US MenactraTM

  • Case control study – 108 cases; 158 controls

  • 78% effectiveness over 5 years of vaccination

    (95% CI: 29-93%)

    • Vaccinated < 1 year ago 95% (95% CI:10-100%)

    • Vaccinated 1 year ago 91% (95% CI:10-101% ??)

    • Vaccinated 2-5 years ago 58% (95% CI: -72% - 89%)

  • Waning protection over time

ACIP; MMWR; January 8, 2011;60(3):72-76.


Us vaccination recommendation

US Vaccination Recommendation

  • Adolescents

    • 11-12 year of age and booster at 16 years

  • High risk conditions

    • 2-dose primary schedule – 2 months apart

    • Booster every five year

  • Exposure risk(microbiologist, travelers to endemic countries)

    • 1-dose primary schedule

    • Booster 3 years later (2-6 years of age)

    • Booster 5 years later (7 years of age or older)

ACIP; MMWR; January 8, 2011;60(3):72-76.


Guillain barr syndrome gbs

Guillain Barré Syndrome (GBS)

  • Passive surveillance suggested a possible association between GBS and MenactraTM

  • Two large studies in US using managed care organization data have not found any association

  • Past GBS no longer needs to be considered a precaution for MenactraTM

Presentations by Velentgas and Weintraub to ACIP; June 2010.


Provincial schedules

Provincial Schedules


Provincial schedules1

Provincial Schedules

Canadian Nursing Coalition on Immunization (CNCI) as of April 19, 2011

http://www.phac-aspc.gc.ca/im/ptimprog-progimpt/table-1-eng.php


Meningococcal a

Meningococcal A


Menafrivac tm

MenAfriVacTM

  • Conjugate meningococcal A vaccine for Sub-Saharan Africa meningitis belt

  • Meningitis Vaccine Project

  • Introduced into Burkina Faso, Mali and Niger in December 2010 with dramatic effects

  • Plans for Cameroon, Chad and Nigeria, then other countries

  • Given to 1-29 year olds

  • Cost less than 50 cents per dose

  • Estimated to prevent 1 million cases and save $300 million over the next decade

http://www.meningvax.org/


Meningococcal b

Meningococcal B


Difficulties with development

Difficulties with Development

  • Capsule structurally identical to fetal brain cell adhesion molecules

    • Induce a weak immune response

    • Could involve production of autoantibodies

  • Outer-membrane-vesicle vaccine

    • Strain specific PorA, highly variable across strains

    • Each outbreak needs its own vaccine

    • Vaccines incorporate multiple PorAs


Reverse vaccinology

Reverse Vaccinology

  • Take the genetic composition of the bacteria

  • Look for genes that may represent surface exposed proteins

  • Put into Escherichia coli expression system to make proteins

  • Mice immunized and antibodies assessed by serum bactericidal antibody (SBA) assay

  • Best candidate antigens made into vaccine


Novartis vaccine bexsero

Novartis Vaccine – Bexsero

  • Factor H binding protein (fHbp) – fusion protein

  • Neisserial heparin-binding antigen (NHBA) - fusion protein

  • Neisserial adhesin A (NadA)

  • Outer-membrane-vesicle New Zealand (OMVnz)

  • Aluminum adjuvant


Immunogenicity1

Immunogenicity

  • Needs to be assessed using serum bactericidal antibody (SBA) assays against various strains that express the target antigens

  • Evidence showing it is immunogenic at various ages and has an acceptable safety profile

Bai et al. Expert Opin Biol Ther 2011


Coverage of strains

Coverage of Strains

  • Because of the antigenic variation and different levels of expression of the proteins, need to assess how well the vaccine will protect against circulating strains

  • Meningococcal antigen typing assay (MATS)

  • ELISA measures cross-reactivity and quantity of the antigen

  • Correlates with serum bactericidal antibody (SBA) assay

Donnelly J et al. PNAS Early Edition


Coverage of strains1

Coverage of Strains

  • Strains exceeded the threshold value for any of the three antigens had a ≥ 80% chance of being killed by SBA

  • MATS will allow for assessing expected strain coverage in various countries


Pfizer vaccine

Pfizer Vaccine

  • Contains two factor H binding proteins, to cover various strains

  • In Phase II trials


The journey continues

The Journey Continues

?? Questions ??

Thank You


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