Impact of 4CMenB Vaccine (Bexsero) during an outbreak at a US University

1. Nicole E. Basta, PhD MPhil | Assistant Professor
Division of Epidemiology and Community Health
Visiting Research Collaborator
Department of Ecology and Evolutionary Biology
Impact of 4CMenB Vaccine (Bexsero®)
during an Outbreak at a US University:

2. 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, USA
2 Princeton University, Princeton, NJ, USA
3 Vaccine Evaluation Unit, Public Health England, Manchester Royal
Infirmary, Manchester, UK

3. Outline
1. Epidemiology of MenB Disease
Incidence in the US
Outbreak Timeline
2. 4CMenB Introduction
Vaccination Campaigns
3. Seroprevalence Survey
Study Design
Results
4. Immunogenicity Study
Study Design
Results

4. Outline
1. Epidemiology of MenB Disease
Incidence in the US
Outbreak Timeline
2. 4CMenB Introduction
Vaccination Campaigns
3. Seroprevalence Survey
Study Design
Results
4. Immunogenicity Study
Study Design
Results

5. US Meningococcal Disease Epidemiology
Cohn et al. 2013 MMWR; MacNeil June 2015 ACIP; CDC
1970-2011
Rateper100,0000

6. 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

7. 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

8. 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
Incidenceper100,000
Serogroup B
Serogroup C
Serogroup Y
2005-12

9. 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 Cases
University 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

10. 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 Cases
University 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

11. 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

12. Outbreak Timeline I
Mar Apr May Jun Jul Aug Sep Oct Nov Dec Jan Feb Mar
2 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
3
4
Summer Break
 Princeton Student
 Non-Affiliate

13. 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 Mar
2 0 1 3 2 0 1 4
Summer Break
• No sign outbreak was abating

14. Princeton University MenB Outbreak
 1 2 3 4 5 7 8
6
Mar Apr May Jun Jul Aug Sep Oct Nov Dec Jan Feb Mar
2 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

15. Outline
1. Epidemiology of MenB Disease
Incidence in the US
Outbreak Timeline
2. 4CMenB Introduction
Vaccination Campaigns
3. Seroprevalence Survey
Study Design
Results
4. Immunogenicity Study
Study Design
Results

16. 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

17. 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

18. Introduction of MenB-4C Vaccine
 1 2 3 4 5 7 8
6
Mar Apr May Jun Jul Aug Sept Oct Nov Dec Jan Feb Ma
r
2 0 1 3 2 0 1 4
Summer Break
Recommended
1st Dose
Recommended
2nd Dose

19. Key Questions
 What impact did 4CMenB have on the outbreak?
 How high was vaccine uptake?
 How immunogenic is 4CMenB
against the outbreak strain?

20. Outline
1. Epidemiology of MenB Disease
Incidence in the US
Outbreak Timeline
2. 4CMenB Introduction
Vaccination Campaigns
3. Seroprevalence Survey
Study Design
Results
4. Immunogenicity Study
Study Design
Results

21. Cross-Sectional Seroprevalence Survey – Design
9
Apr
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
Vaccina on
Recommended
 Launched in April 2014
• 9 weeks post-vaccination
• 607 students enrolled

22. Sample'Tracking'Form'
!
1"
___________________________________
Impact'of'Meningococcal'B'Vaccination'during'the'
2013'Princeton'University'Outbreak'
___________________________________
I. Blood Sample Collection
(Completed by Phlebotomist)
1."Today’s"date"
04/☐☐/14"(MM/DD/YY)
2."Time"blood"collected"
☐☐: ☐☐(24"hr"clock)
3."Estimated"volume"of"blood"collected"
☐☐. ☐ml (each"tube"is"8.5ml)
4."Phlebotomist"ID"number"
☐☐
5."Comments"
!
!
II. Sample Monitoring Table
(Completed by Sample Monitor)
6."Time"finished"clotting/moved"to"cool"box"
(30$60&mins&from&collection&time&(2&above))& ☐☐: ☐☐(24"hr"clock)
7."Time"sent"to"lab"
☐☐: ☐☐(24"hr"clock)
8."Comments"
9."Name"of"sample"monitor"
"
Participant"ID"
Number"
!
Blood sample
collection
Informed)Consent)Form))
!
This)study)has)been)approved)by)the)Institutional)Review)Board)for)Human)Subjects)
!
All!information!that!you!provide!for!this!study!will!be!kept!strictly!confidential.!All!
results!will!be!reported!in!aggregate!and!will!not!include!information!that!will!make!
it!possible!to!identify!you.!Research!records!will!be!stored!securely!in!a!locked!
cabinet!and!on!passwordZprotected!computers.!The!research!team!will!be!the!only!
party!that!will!have!access!to!your!identifiable!data.!Collaborating!academic,!
governmental,!or!commercial!laboratories!may!have!access!to!your!vaccination!
status,!questionnaire,!and!demographic!information,!but!not!your!name!or!
birthdate.!
!
Compensation:)
You!will!be!given!a!$20!gift!card!after!completion!of!the!study!visit.!!!
)
Who)to)contact)with)questions:)
)
1. PRINCIPAL!INVESTIGATOR:!
! ! ! Nicole!E.!Basta,!PhD,!Associate!Research!Scholar!
Department!of!Ecology!and!Evolutionary!Biology,!Princeton!University!
Phone:!609Z258Z7523,!Email:!nbasta@princeton.edu!
!
2.! If!you!have!questions!regarding!your!rights!as!a!research!subject,!or!if!problems!arise!which!you!do!not!feel!
you!can!discuss!with!the!Investigator,!please!contact!the!Institutional!Review!Board!at:!
!
Office!of!Research!Integrity!and!Assurance!!
Human!Research!Protection!Program,!Princeton!University!
Phone:!(609)!258Z0865,!Email:!irb@princeton.edu!
!
3. I!understand!the!information!that!was!presented!and!that:!
!
! A.! My!participation!is!voluntary,!and!I!may!withdraw!my!consent!and!discontinue!participation!in!the!
research!at!any!time.!!My!refusal!or!withdraw!will!not!result!in!any!penalty.!
!
! B.! By!signing!this!agreement,!I!do!not!waive!any!legal!rights!or!release!Princeton!University!or!its!
agents!for!negligence.!
!
4. Check!all!that!apply:!
☐!I!consent!to!participate!in!this!research!by!completing!a!questionnaire!and!providing!a!blood!sample.!
☐!I!consent!to!have!my!blood!sample!and!questionnaire!data,!both!labeled!only!with!a!code,!stored!for!
future!analyses.!
☐!I!consent!to!being!contacted!in!the!future!and!asked!to!participate!in!a!possible!followZup!study!to!assess!
longerZterm!immune!responses.!
!
!
_____________________|________________________!!
Participant!Name!!!!!!!!!!!!!!!!!!Participant!Signature!
!
_____________________!!
Date!
!!!!!!______________________|________________________!!
!!!!!!!!Study!Staff!Name!!!!!!!!!!!!!!!!!!!Study!Staff!Signature!
!
!!!!!!!______________________!!
!!!!!!!Date!
Page!2!of!2!
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Participant!ID!
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!
Questionnaire
Checkout
Consenting
Enrollment Form
___________________________________
Impact of Meningococcal B Vaccination during the
2013 Princeton University Outbreak
___________________________________
1. Today’s Date: 04/☐☐/14
MM/DD/YY
2. First Name:
___________________________
3. Last Name:
___________________________
4. Date of Birth: ☐☐/☐☐/☐☐
MM/DD/YY
5. Class Year: (circle one) 2014 2015 2016 2017 GRAD
6. PUID Number:
☐☐☐☐☐☐☐☐☐
7. Email:
___________________________@princeton.edu
8. Eligibility:
a) Did you receive an email invitation for this study?
☐ Yes ☐ No
b) Are you currently sick (feverish, etc) or do you have a medical
condition that makes collection of a blood sample inadvisable
(severe anemia or a clotting abnormality, etc)?
☐ Yes ☐ No
9. Vaccination Status:
How many doses of the MenB vaccine have you received?
☐ 2 ☐ 1 ☐ None
Participant ID
Number
Eligibility &
Enrollment
Cross-Sectional Seroprevalence Survey – Design

23. 4CMenB Vaccinees
2 Doses 1 Dose Unvaccinated
Age (mean years) 20.5 20.7 22.6
Sex: 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

24. Vaccination Coverage in First 6 Months
Class
year
n
1st dose
(%)
2nd dose
(%)
2018 1315 97 91
2017 1292 100 96
2016 1349 98 93
2015 1320 99 94
2014 1280 96 91
Grads 835 80 60
All Undergrads
• 98% 1 dose
• 93% 2 doses
Student Health Advisory
Board; University Health
Services; Environmental
Health and Safety

25.  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

26. 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

27. Outline
1. Epidemiology of MenB Disease
Incidence in the US
Outbreak Timeline
2. 4CMenB Introduction
Vaccination Campaigns
3. Seroprevalence Survey
Study Design
Results
4. Immunogenicity Study
Study Design
Results

28. 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
9
Apr
7 86
Sept Oct Nov Dec Jan Feb Mar
2 0 1 3
Summer Break
Mar Apr May Jun Jul Aug Sept Oct Nov
2 0 1 4
Vaccina on
Recommended
for New
Students
Vaccina on
Recommended

29. Fall 2014 MenB Vaccination Campaigns
Class of 2018:
 97% received 1st dose
 91% received 2nd dose



30. 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

31. 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

32. 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

33. US MenB Vaccination Recommendations
Updated 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

34. 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

35. 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

36. Thank you