Nicole E. Basta, PhD MPhil | Assistant ProfessorDivision of Epidemiology and Community Health

Visiting Research CollaboratorDepartment of Ecology and Evolutionary Biology

Impact of 4CMenB Vaccine (Bexsero®)during an Outbreak at a US University:

Collaborators

Nicole E. Basta1-2, Adel Mahmoud2, Julian Wolfson1, Alexander Ploss2, Brigitte Heller2, Sarah Hanna2, Peter Johnsen2, Robin Izzo2, Bryan Grenfell2, Jamie Findlow3, Xilian Bai3, Ray Borrow3

 1 School of Public Health, University of Minnesota, Minneapolis, MN, USA2 Princeton University, Princeton, NJ, USA3 Vaccine Evaluation Unit, Public Health England, Manchester Royal Infirmary, Manchester, UK

Outline1. Epidemiology of MenB DiseaseIncidence in the US Outbreak Timeline

2. 4CMenB IntroductionVaccination Campaigns

3. Seroprevalence SurveyStudy DesignResults

4. Immunogenicity StudyStudy DesignResults

Outline1. Epidemiology of MenB DiseaseIncidence in the US Outbreak Timeline

2. 4CMenB IntroductionVaccination Campaigns

3. Seroprevalence SurveyStudy DesignResults

4. Immunogenicity StudyStudy DesignResults

US Meningococcal Disease Epidemiology

Cohn et al. 2013 MMWR; MacNeil June 2015 ACIP; CDC

1970-2011

Rat

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r 100

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US Advisory Committee on Immunization Practices (ACIP)

Meningococcal ACWY conjugate vaccine Routine vaccination for all 11-12 year olds

Booster dose at 16 years of age (since 2005)

37/50 states mandate that university students be vaccinated prior to enrollment

www.cdc.gov/vaccines/vpd-vac/mening/who-vaccinate.htm; www.immunize.org/laws/menin.asp

1993-2012

Addressing the challenges of Serogroup B meningococcal disease outbreaks on campuses: A report by the National Foundation for Infectious Diseases

Incidence by Serogroup and Adolescent Vaccine Uptake

Increased Risk of MenB among Infants, Teens, and Young Adults

Sridhar et al. 2015, LID; Cohn et al. 2013 MMWR; MacNeil June 2015 ACIP; CDC

Inci

denc

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r 100

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Serogroup BSerogroup CSerogroup Y

2005-12

US University MenB Outbreaks 2009-2015

MacNeil J. Considerations for use of Seropgroup B Meningococcal Vaccines in Adolescents in US. ACIP. 2015

Location Time Frame Total CasesUniversity 1 Feb – Mar 2009 4

University 2 Nov 2011 2

University 3 Jan 2008 – Nov 2010 13

University 4 Mar 2013 – Mar 2014 9

University 5 Nov 2013 5

University 6 Jan – Feb 2015 2

University 7 Jan – May 2015 7

US University MenB Outbreaks 2009-2015

MacNeil J. Considerations for use of Seropgroup B Meningococcal Vaccines in Adolescents in US. ACIP. 2015

Location Time Frame Total CasesUniversity 1 Feb – Mar 2009 4

University 2 Nov 2011 2

University 3 Jan 2008 – Nov 2010 13

Princeton University Mar 2013 – Mar 2014 9

University 5 Nov 2013 5

University 6 Jan – Feb 2015 2

University 7 Jan – May 2015 7

Princeton University 4-year university located in suburban New Jersey Academic year: Sept - May 5,250 undergraduate students 98% undergrads live on campus 2,650 graduate students

www.princeton.edu

Outbreak Timeline I

Mar Apr May Jun Jul Aug Sep Oct Nov Dec Jan Feb Mar2 0 1 3 2 0 1 4

Case reports courtesy of Pete Johnsen, MD

• Returning from spring break• Went to hospital from airport

1

• Prospective student• Visited for 3 days 1 week prior

2

• Student presents to clinic after hours• Identical genetic fingerprint• Outbreak declared

34Summer Break

Princeton Student

Non-Affiliate

Case reports courtesy of Pete Johnsen, MD

Outbreak Timeline II

1 2 3 4

• Studying abroad w/15 students• Left campus 3 weeks prior

5

• Meningococcemia • Low-grade fever, high WBC• No meningeal signs

6 8

• Fever• Positive rapid strep test• Delayed rash onset

7

Mar Apr May Jun Jul Aug Sep Oct Nov Dec Jan Feb Mar2 0 1 3 2 0 1 4

Summer Break

• No sign outbreak was abating

Princeton University MenB Outbreak

1 2 3 4 5 7 86

Mar Apr May Jun Jul Aug Sep Oct Nov Dec Jan Feb Mar2 0 1 3 2 0 1 4

Summer Break

Princeton Student

Source: Princeton University, CDC Non-Affiliate

Sustained transmission over 2 academic years despite extensive public health prevention campaign

At the time, no MenB vaccine was licensed in the US

In the fall of 2013, University officials and the CDC obtained FDA approval to offer 4CMenB to students

Outline1. Epidemiology of MenB DiseaseIncidence in the US Outbreak Timeline

2. 4CMenB IntroductionVaccination Campaigns

3. Seroprevalence SurveyStudy DesignResults

4. Immunogenicity StudyStudy DesignResults

4CMenB Vaccine: Bexsero®

Developed by Novartis (GSK) using reverse vaccinology

NadA (subvariant 3.1) fHbp-GNA2091 fusion protein (fHbp subvariant 1.1) NHBA-GNA1030 fusion protein (NHBA subvariant 1.2) OMVs from strain NZ 98/254 (B:4:P1.7-2,4: ST-42 (cc41/44)

The 2013 outbreak was the first ever use of the vaccine in the US

Photo: Novartis

Outbreak Isolate Characterization Outbreak Isolate: ST-409 (CC41/44/lineage3); PorA P1.5-1,2-2;

fHBP 1.276; NHBA p0002; NadA-

Killed by pooled sera from Chilean clinical trial vaccinees Similar to 2 of the 4 vaccine components (MATS)

96% of amino acids identical to fHBP & 100% to NHBA

McNamara et al. Pediatrics 2015

Rino Rappuoli

fHBP

NHBA

Rossi et al. CVI. 2015

Introduction of MenB-4C Vaccine

1 2 3 4 5 7 86

Mar Apr May Jun Jul Aug Sept Oct Nov Dec Jan Feb Mar

2 0 1 3 2 0 1 4

Summer Break

Recommended1st Dose

Recommended2nd Dose

Key Questions

What impact did 4CMenB have on the outbreak?

How high was vaccine uptake?

How immunogenic is 4CMenB against the outbreak strain?

Outline1. Epidemiology of MenB DiseaseIncidence in the US Outbreak Timeline

2. 4CMenB IntroductionVaccination Campaigns

3. Seroprevalence SurveyStudy DesignResults

4. Immunogenicity StudyStudy DesignResults

Cross-Sectional Seroprevalence Survey – Design

Launched in April 2014

• 9 weeks post-vaccination• 607 students enrolled

Blood sample collection

Questionnaire

Checkout

Consenting

Eligibility & Enrollment

Cross-Sectional Seroprevalence Survey – Design

4CMenB Vaccinees2 Doses 1 Dose Unvaccinated

Age (mean years) 20.5 20.7 22.6Sex: Female 57% 38% 60%Ethnicity: Hispanic/Latino 7% 10% 10%Race: Caucasian 54% 48% 40% Asian/Asian-American 31% 38% 45% African/African-American 9% 5% 15% More than one race 4% 10% 0%Class Year: 1st Year 32% 29% 5% 2nd Year 25% 24% 25% 3rd Year 21% 29% 5% 4th Year 22% 10% 25% Graduate Student 0% 10% 40%

Vaccination Status n %

2 Doses 566 93.3

1 Dose 21 3.5

Unvaccinated 20 3.3

Cross-Sectional Survey – Participant Characteristics

Vaccination Coverage in First 6 MonthsClass year n 1st dose

(%)2nd dose

(%)2018 1315 97 912017 1292 100 962016 1349 98 932015 1320 99 942014 1280 96 91Grads 835 80 60

All Undergrads• 98% 1 dose• 93% 2 doses

Student Health Advisory Board; University Health Services; Environmental Health and Safety

Serum Bactericidal Antibody (hSBA) Assay conducted by Ray Borrow’s Lab in the VEU PHE Function antibody assay used to license

meningococcal vaccines

% Seropositive (hSBA titers≥4) against: Outbreak strain 5/99 NadA vaccine strain (mismatched) 44/76-SL fHBP vaccine strain (matched)

Geometric Mean Titers (GMTs)

Lab Analysis of Serological Samples

Immune Response against the Vaccine Reference Strains – Subset of Sera

1) All unvaccinated participants

2) We randomly selected a subset vaccinees who had received two doses and had :

- No outbreak titer: hSBA < 4- Low outbreak titer: hSBA = 4 - 8 - High outbreak titer: hSBA > 8

Outline1. Epidemiology of MenB DiseaseIncidence in the US Outbreak Timeline

2. 4CMenB IntroductionVaccination Campaigns

3. Seroprevalence SurveyStudy DesignResults

4. Immunogenicity StudyStudy DesignResults

Pre/Post-Vaccination Immunogenicity Study - Design Established an observational immunogenicity cohort:

Pre-vaccination (n=140) 4-weeks post-second dose (n=193)

Same protocol for data collection, sample collection, and hSBA analysis

Fall 2014 MenB Vaccination Campaigns

Class of 2018: 97% received 1st dose 91% received 2nd dose

Key Results I 67% of those vaccinated with 2 doses of 4CMenB during an

outbreak were seropositive against the outbreak strain

94-100% of those vaccinated with 2 doses were seropositive against 5/99 NadA (mismatched with outbreak strain) Strong evidence of vaccine response in all students No correlation with outbreak strain response

87-100% of those vaccinated with 2 doses were seropositive against 44/76-SL fHBP (matched with outbreak strain) GMTs varied significantly by strength of outbreak response Modest correlation with outbreak strain response

Key Results II• Same proportion with titers >4 at baseline against the

outbreak strain

• 33% in the cross-sectional study of those vaccinated with 2 doses had no evidence of sufficient hSBA immunity against the outbreak strain

Concern about side effects, lack of concern about MenB, and time constraints cited as reasons for incomplete vaccination Opportunities to further improve public health messaging

Discussion Points

• First evaluation of immune responses following 4CMenB vaccination during an outbreak in US

• Vaccination should be part of a comprehensive prevention and control strategy

• Predicting strain coverage should incorporate individual-level hSBA titers given the variation observed and low response to the outbreak strain

US MenB Vaccination RecommendationsUpdated 2015

Teens and young adults (16 - 23 year olds) may also be vaccinated with a serogroup B meningococcal vaccine, preferably at 16 - 18 yrs Two (Bexsero®) or three doses (Trumenba®) are needed

Preteens, teens, and young adults should be vaccinated with a serogroup B meningococcal vaccine if they are identified as being at increased risk of meningococcal disease.

http://www.cdc.gov/vaccines/vpd-vac/mening/who-vaccinate.htm

Next Steps

Assessment of breadth of immunity

Investigation of long-term immunity

Results have important implications for vaccination policy and efforts to prevent and control outbreaks

Vaccine Evaluation Unit, Public Health England Ray Borrow, Jamie Findlow, Xilian Bai

Princeton University Alex Ploss, Adel Mahmoud, Bryan Grenfell, Peter Johnsen, Robin Izzo, Sarah Hanna ’15, Angelica Chen ’17 Student participants

Acknowledgements

MenB Outbreak Investigation and Vaccine Introduction

Funding

Thank you