1. Serogroup B Meningococcal Disease Outbreak and Carriage Evaluation at a College — Rhode Island, 2015
Hello everyone, thanks for coming this afternoon.
Heidi M. Soeters, PhD MPH
64th EIS Conference
April 23, 2015
National Center for Immunization & Respiratory Diseases
Division of Bacterial Diseases / Meningitis and Vaccine Preventable Diseases Branch

2. Rhode Island Department of Health notified
Cases of Serogroup B Meningococcal Disease at College A, Rhode Island, 2015
Case 1: 19-year-old undergraduate
Case 2: 20-year-old undergraduate
Rare sequence type: ST9069
Rhode Island Department of Health notified
A case of meningococcal disease occurred in a 19-year-old student at College A on January 31st, 2015.
**The Rhode Island Department of Health was notified about this case on February 2nd.
**A second case occurred in a 20-year-old student on February 5th. Rhode Island Department of Health was notified the same day.
The 2 cases resided in different dormitories and had no known epidemiologic links.
Both were determined to be caused by serogroup B Neisseria meningitidis, and to have a **rare sequence type, 9069, never before seen in the U.S.
January
Case of serogroup B meningococcal disease 2

3. Meningococcal Disease
Neisseria meningitidis
10-15% case-fatality ratio
Serogroups A B C W Y and X
Conjugate vaccine protects against A C W and Y
Neisseria meningitidis
10-15% case-fatality ratio
Serogroups A B C W Y and X
Conjugate vaccine protects against A C W and Y
Meningococcal disease, caused by the bacterium Neisseria meningitidis, is a serious illness with a 10-15% case-fatality ratio.
There are multiple serogroups, **with B, C, and Y being the most common in the U.S.
The current meningococcal conjugate vaccine protects against A, C, W, and Y.
Photo by D. Scott Smith, MD, taken at Stanford University Hospital ( 3

4. Meningococcal Transmission
Nasopharyngeal carriage
Asymptomatic
Invasive disease rarely occurs
Spread through close contact
Respiratory or oral secretions
Patients or asymptomatic carriers
Risk factors for disease and carriage among adolescents:
Age1,2
Social mixing3
Smoking1
Meningococcal bacteria are carried in the nasopharynx, and most carriers remain completely asymptomatic.
Only rarely does invasive disease occur.
The bacteria are spread through close contact, specifically via respiratory or oral secretions from patients or asymptomatic carriers.
Important risk factors for both disease and carriage among adolescents include age, social mixing, and smoking.
Sources:
Harrison et al. JID (US)
Jeppesen et al. J Infect (UK)
Mandel et al. JID (US) 4

5. Serogroup B Meningococcal Disease
Meningococcal conjugate vaccine does not protect against serogroup B
Serogroup B capsule antigen is poorly immunogenic
Most common cause of meningococcal disease in persons aged 16 to 21 years
Serogroup B outbreaks:
Serogroup B caused 4 university outbreaks during last 2 years
Outbreak definition*:
≥2 unrelated cases in organization with <5000 persons
≥3 unrelated cases in organization with ≥5000 persons
The meningococcal conjugate vaccine routinely administered to all adolescents does not protect against serogroup B, as the B capsular polysaccharide is similar to human antigens and therefore poorly immunogenic.
This leaves serogroup B as the most common cause of meningococcal disease in persons aged 16 to 21 years, AND the cause of FOUR university outbreaks during the last 2 years, with an outbreak defined as at least 2 or 3 cases depending on organizational size.
*Interim Guidance for Control of Serogroup B Meningococcal Disease in Organizational Settings. 5

6. When Serogroup B strikes on a college campus, it triggers an immediate and massive response, and causes a communications nightmare, triggering many striking headlines such as these.
In the case of College A, all of the above occurred, but this time… one thing was different… 6

7. Serogroup B Meningococcal (MenB) Vaccines
2 vaccines recently licensed in U.S. for persons aged years
Oct 2014 – Trumenba, 3 doses (Wyeth Pharmaceuticals, Inc., a subsidiary of Pfizer Inc.)
Jan 2015 – Bexsero, 2 doses (Novartis Vaccines and Diagnostics)
Licensed on immunogenicity data
Understanding of impact on nasopharyngeal carriage is limited
…This was the first college outbreak to occur since two serogroup B, or MenB, vaccines were licensed for use in the U.S. Trumenba was licensed in October 2014, and Bexsero in January 2015.
Both vaccines were licensed based upon immunogenicity data, BUT…
… our understanding of their impact on nasopharyngeal carriage, and therefore indirect effect on herd immunity, is limited.
Image: Pfizer 7

8. College A Outbreak Response
Ciprofloxin chemoprophylaxis for 71 close contacts
Mass MenB vaccination campaign
Trumenba
Feb 8 and 11
96% of 3,800 eligible students vaccinated with first dose
Case of serogroup B meningococcal disease
Rhode Island Department of Health notified
January
Vaccination clinics
In response to the outbreak, College A and Rhode Island Department of Health provided chemoprophylaxis to 71 close contacts AND mounted an immediate and highly successful MenB vaccination campaign.
They provided Trumenba to over 3,000 students during one 9-hour clinic on February 8th, along with a catch-up clinic on February 11th.
In total, over 96% of eligible students received the first of 3 doses. 8

9. CDC Meningococcal Carriage Evaluation
Objectives:
Determine baseline prevalence of nasopharyngeal carriage of N. meningitidis
Assess impact of MenB vaccination on carriage
Methods:
Questionnaire & oropharyngeal swab
Specimen evaluation via bacterial culture, real-time PCR, and molecular testing
Case of serogroup B meningococcal disease
Rhode Island Department of Health notified
January
Vaccination clinics
Carriage evaluation
Additionally, CDC was invited to conduct our very first carriage evaluation on a U.S. college campus, with 2 objectives:
To determine the baseline prevalence of nasopharyngeal carriage of Neisseria meningitidis, and
To assess the impact of MenB vaccination on carriage.
The evaluation consisted of a short questionnaire assessing risk factors for meningococcal carriage and disease and an oropharyngeal swab. Specimens were tested using bacterial culture, real-time PCR, and molecular testing. The first of 3 planned carriage evaluations was conducted February 16th through 20th. All undergraduate students at College A and graduate students who lived on campus were eligible to participate. 9

10. N. meningitidis carriage, N (%)
Meningococcal Carriage Evaluation Results, College A, Rhode Island, February 2015
Characteristic
Total N
N. meningitidis carriage, N (%)
Prevalence Ratio
p-value
All students
717
176 (25)
---
Male
247
78 (32)
1.5 ( )
0.001
Female
470
98 (21)
1.0
School Year
Freshman
191
38 (20)
Sophomore
283
86 (30)
1.5 ( )
0.013
Junior
118
30 (25)
1.3 ( )
0.253
Senior
122
21 (17)
0.9 ( )
0.556
Graduate student 3
1 (33)
1.7 ( )
0.534
Overall, 717 students participated.
**176, or 25%, of participating students were carriers of Neisseria meningitidis.
[PAUSE]
**Males were 1.5 times more likely to be carriers,
**and sophomores had the highest carriage prevalence. 10

11. N. meningitidis carriage, N (%)
Meningococcal Carriage Evaluation Results, College A, Rhode Island, February 2015
Characteristic
Total N
N. meningitidis carriage, N (%)
Prevalence Ratio
p-value
Recent antibiotic use1
106
12 (11)
0.4 ( )
0.002
Smoke1
154
51 (33)
1.5 ( )
0.004
Live on campus
655
160 (24)
0.9 ( )
0.808
Recent upper respiratory infection symptoms2
397
105 (26)
1.2 ( )
0.190
Second-hand smoke1
260
74 (28)
1.3 ( )
0.064
Received first dose MenB vaccine
701
170 (24)
0.6 ( )
0.186
Received ACWY vaccine
682
166 (24)
0.9 ( )
0.561
**Recent antibiotic use was associated with decreased carriage,
**smokers had increased carriage,
**and living on campus, recent upper respiratory infection symptoms, second-hand smoke, and meningococcal vaccination were not associated with carriage.
1In the past 30 days
2In the past 2 weeks 11

12. None with outbreak strain (ST9069)
Meningococcal Carriage Evaluation Results, College A, Rhode Island, February 2015
None with outbreak strain (ST9069)
Serogrouping revealed that 31 students, or 4%, specifically had serogroup B carriage, and of those 31…
**none were found to be carrying the outbreak strain.
Note: percentages refer to the proportion of the 717 participants with serogroup-specific nasopharyngeal carriage 12

13. Conclusions Next Steps
Mass MenB vaccination campaign quickly achieved high vaccine coverage
No further serogroup B meningococcal disease cases associated with College A have been identified
Despite high carriage prevalence, no outbreak strain identified
Next Steps
In conclusion, the mass MenB vaccination campaign quickly achieved high vaccination coverage and no further serogroup B meningococcal disease cases associated with College A have been identified. Despite a high baseline meningococcal carriage prevalence of 25%, no students were found to be carrying the outbreak strain.
Regarding next steps, a second carriage evaluation was conducted last week in conjunction with the 2nd dose vaccination clinic. Nearly 900 students participated and results are forthcoming.
To complete the assessment of the impact of MenB vaccination on carriage among students at College A, a third carriage evaluation is planned for September 2015 in conjunction with final dose of MenB, so stay tuned.
Second carriage evaluation conducted April 2015
Third carriage evaluation planned for September 2015 13

14. Rhode Island Meningococcal Carriage Evaluation Team
CDC
Manisha Patel* Lucy McNamara* Melissa Whaley* Xin Wang* Jessica MacNeil* Stacey Martin* Nathan Raines* Jeni Vuong* Conrad Quinn Leonard Mayer Tami Skoff Amanda Faulkner Amy Blain Christine Miner Adria Lee Anna Acosta Sarah Meyer How-Yi Chang Mollie Harrison
Rhode Island Department of Health
Nicole Alexander-Scott*
Utpala Bandy*
Akshar Patel
Cindy Vanner*
John Fulton
James Rajotte
I’d like to acknowledge the following individuals and agencies for quickly mobilizing, putting in long hours, and doing fantastic work.
Koren Kanadanian*
Kenneth Sicard*
Kris Monahan
Steve Sears*
Kathy Kelleher
Michael Kraten
College A
*Co-authors 14

15. Thank you.
The findings and conclusions in this report are those of the authors and do not necessarily represent the official position of the Centers for Disease Control and Prevention.
National Center for Immunization & Respiratory Diseases
Division of Bacterial Diseases / Meningitis and Vaccine Preventable Diseases Branch 15

16. Extra Slides 16

17. Incidence of Meningococcal Disease in the US — 1993–2012
Incidence per 100,000
2013:
~530 cases
3 serogroups of N. meningitidis – B, C, and Y – are the primary causes of human disease in the US. Incidence of all serogroups of meningococcal disease has declined in the US since 1993, with a historic low of only about 530 cases reported in 2013.
Year
Source: ABCs cases 1993–2012 estimated to the US population with 18% correction for underreporting. 17

18. Incidence of Meningococcal Disease in the US by Age — 2005–2012
Persons years of age are at increased risk for meningococcal disease, particularly from Serogroup B. 18

19. Trumenba (Bivalent rLP2086)
3 dose series
0, 2, and 6 months
Licensed for ages years
Serogroup B capsule antigen poorly immunogenic
Trumenba instead based on 2 lipidated factor H binding proteins (fHbp)
Outer membrane proteins
Meningococcal virulence factors which aid evasion of innate immunity
Outer membrane
Whereas serogroup A-C-W-Y vaccines are based on the capsular polysaccharide of the bacteria that is specific to each serogroup, the serogroup B capsule antigen is poorly immunogenic due to its similarity to human antigens. As a result, rMenB is instead based on 2 other meningococcal antigens: the outer membrane proteins known as factor H binding proteins. However, due to variability in these antigens, not all strains of serogroup B are expected to be covered by the vaccine.
Capsule (serogroup)
Image from: Rosenstein et al N Engl J Med 344: 19

20. Advisory Committee on Immunization Practices (ACIP) vote: February 2015
A serogroup B meningococcal (MenB) vaccine series should be administered to persons aged ≥10 years at increased risk for meningococcal disease. (Category A) This includes:
Persons with persistent complement component deficiencies1
Persons with anatomic or functional asplenia2
Microbiologists routinely exposed to isolates of Neisseria meningitidis
Persons identified to be at increased risk because of a serogroup B meningococcal disease outbreak
MMWR Policy Note coming soon
June 2015: May consider expanded recommendation for MenB
1Including inherited or chronic deficiencies in C3, C5-9, properdin, factor D, factor H, or taking eculizumab (Soliris®)
2Including sickle cell disease 20

21. Immunologic Response to 1 Dose of Trumenba
30-40% of persons exhibited a 4-fold response to the reference strain after 1 dose
Range of response depends on what strain is tested 21

22. Trumenba Vaccine Safety
Currently no post-licensure data for Trumenba
Vaccine safety survey being conducted at College A 22

23. Carriage evaluation participants
College A
Small private college
~4,500 students total
~3,800 undergraduates
Residential college
70% students from New England
78% white
Characteristic
Total student body
Carriage evaluation participants
P-value
Female
57%
66%
<0.001
Live on-campus
79%
91% 23

24. Outbreak details 2 cases in ~4,500 students
Attack rate = 44 cases per 100,000 students
489-fold higher than the national incidence in persons aged years 24

25. College A Mass Vaccination Campaign
Eligible students:
all undergraduate students
graduate students who:
live or work on campus OR
are in an intimate relationship with an undergraduate OR
are asplenic or immunocompromised
Students were directed to report to the vaccination clinic
If declined vaccination, required to sign opt-out form
Vaccine offered at no cost to eligible participants
Dose 1: Feb 2015
Dose 2: April 2015
Dose 3: September 2015 25

26. Number of persons vaccinated with the first dose of MenB, by school year (N = 3,496)
Other = faculty, staff, continuing education students, exchange students 26

27. Questionnaire (1) 1. Sex: □ Male □ Female
2. How old are you? _________ years
3. What type of student are you?
□ Freshman □ Sophomore □ Junior □ Senior □ Graduate student
4. Did you receive the serogroup B meningococcal vaccine (Trumenba®) during the recent vaccine campaign in response to the outbreak?
□ Yes: If so, what date? ____/____/________ □ No □ Don’t Know
5. Did you receive a quadrivalent serogroup ACWY meningococcal vaccine (Menveo® or Menactra®)? This meningitis vaccine is recommended for adolescents at ages 11 and 16, or before heading off to college.
□ Yes □ No □ Don’t Know
If yes, what date? ____/____/________ □ I can’t remember
6. Have you taken any antibiotics for any reason in the past 30 days? Examples of antibiotics include cipro, Z-Pak (azithromycin), penicillin, etc. 27

28. Questionnaire (2)
7. During the last two weeks, did you have any upper respiratory infection symptoms such as cough, runny nose, or sore throat?
□ Yes □ No
8. What are your current living arrangements?
□ Dorm with roommate(s) □ Apartment/house with roommate(s)
□ Dorm alone □ Apartment/house with family □ Apartment/house alone
7. In the past 30 days, did you smoke tobacco (cigarettes, cigars, hookah) or marijuana?
□Yes, every day □Yes, some days □No, not at all
8. In the past 30 days, were you exposed to secondhand smoke?
9. In a typical week, how often do you join activities that have been identified as "risk factors" for meningococcal meningitis, such as visiting bars or nightclubs or attending parties?
□ Less than once a week or never □ 2-3 times a week
□ Once a week □ 4 or more times a week 28

29. Bacterial Culture Methods
Modified Thayer Martin agar plates
Selected for Neisseria species
Plates inspected after 24, 48, and 72 hours 29

30. N. meningitidis carriage, N (%)
Meningococcal Carriage Evaluation Results, College A, Rhode Island, February 2015
Characteristic
Total N
N. meningitidis carriage, N (%)
Prevalence Ratio
p-value
How often visit bars, clubs, parties
<1 time/week
185
20 (11)
1.0
1 time/week
241
57 (24)
2.2 ( )
0.001
2-3 times/week
273
94 (34)
3.2 ( )
<0.001
≥4 times/week 18
5 (28)
2.6 ( )
0.030
Living on-campus versus off-campus, and recent upper respiratory infection symptoms were not associated with carriage, while students with recent antibiotic use were half as likely to be carriers. 30

31. N. meningitidis carriage, N (%)
Meningococcal Carriage Evaluation Results, College A, Rhode Island, February 2015
Characteristic
Total N
Serogroup B
N. meningitidis carriage, N (%)
Prevalence Ratio
p-value
All students
717
31 (4)
---
Male
247
14 (6)
1.6 ( )
0.202
Female
470
17 (3)
1.0
School Year
Freshman
191
3 (2)
Sophomore
283
15 (5)
3.4 ( )
0.052
Junior
118
7 (6)
3.8 ( )
0.051
Senior
122
5 (4)
2.6 ( )
0.184
Graduate student 3
1 (33)
21.2 ( )
0.002
Overall, 717 students participated in the carriage evaluation.
176, or 25%, of participating students were carriers of Neisseria meningitidis.
Males were 1.5 times more likely to be carriers, and sophomores had the highest carriage prevalence. 31

32. N. meningitidis carriage, N (%)
Meningococcal Carriage Evaluation Results, College A, Rhode Island, February 2015
Characteristic
Total N
Serogroup B
N. meningitidis carriage, N (%)
Prevalence Ratio
p-value
Recent antibiotic use1
106
2 (2)
0.4 ( )
0.202
Smoke1
154
6 (4)
0.9 ( )
0.769
Live on campus
655
28 (4)
0.9 ( )
0.834
Recent upper respiratory infection symptoms2
397
20 (5)
1.5 ( )
0.299
Second-hand smoke1
260
11 (4)
1.0 ( )
0.927
Received first dose MenB vaccine
701
31 (4)
---
Received ACWY vaccine
682
27 (4)
0.3 ( )
0.04
Recent antibiotic use was associated with decreased carriage, smokers had increased carriage, and living on campus, recent upper respiratory infection symptoms, second-hand smoke, and meningococcal vaccination were not associated with carriage.
1In the past 30 days
2In the past 2 weeks 32

33. N. meningitidis carriage, N (%)
Meningococcal Carriage Evaluation Results, College A, Rhode Island, February 2015
Characteristic
Total N
Serogroup B
N. meningitidis carriage, N (%)
Prevalence Ratio
p-value
How often visit bars, clubs, parties
<1 time/week
185
7 (4)
1.0
1 time/week
241
10 (4)
1.1 ( )
0.849
2-3 times/week
273
13 (5)
1.3 ( )
0.617
≥4 times/week 18
1 (6)
1.5 ( )
0.712
Living on-campus versus off-campus, and recent upper respiratory infection symptoms were not associated with carriage, while students with recent antibiotic use were half as likely to be carriers. 33

34. Why are there so many non-groupable N. meningitidis isolates?
Non-groupable = no capsule
Non-groupable isolates common in carriage evaluations
Non-groupable bacteria more likely to develop carriage state
Capsule inhibits binding to cells, so get washed out of nasopharynx and don’t develop carriage state as easily 34

35. Rhode Island Department of Health notified
Why no ST9069?
Maybe ST9069 not conducive to carrier state
More likely to just cause invasive disease
Well-targeted chemoprophylaxis
Only swabbed 717, not whole campus
Maybe didn’t sample carriers of ST9069
Maybe MenB vaccine had quick effect
Case of serogroup B meningococcal disease
Rhode Island Department of Health notified
January
Vaccination clinics
Carriage evaluation 35

36. PCR vs. culture results 715/717 had concordant results
1 specimen Nm by biochemical testing, but PCR negative
1 specimen Nm by PCR, but negative by biochemical testing 36

37. What do we know about meningococcal carriage?
UK: ~30% among university students
US:
3.2% among Georgia and Maryland high school students (2006-7)1
7.5% among social network of a case in Minnesota (included some university students; 2008)2
MenB vaccine impact on carriage
No data for Trumenba (3 doses)
Bexsero (2 doses)
Associated with lower carriage prevalence in children 1-7 years3
Associated with decreased carriage by 3 months after 2nd dose4
Sources:
Harrison et al. JID (US)
Delbos et al. Vaccine (France)
Wu et al. NEJM (US)
Read et al. Lancet (UK) 37

38. Second carriage evaluation at College A
Conducted in conjunction with mass vaccination clinic for second dose of MenB
April 12 & 15, 2015
2,247 students vaccinated
888 students participated in carriage evaluation
322 (36%) also participated in 1st carriage evaluation
Lab results pending 38

39. Why 3 carriage evaluations?
February, April, and September 2015
Can assess:
Baseline carriage prevalence
Impact of MenB vaccination on:
Serogroup B
Other serogroups (MenB vaccine not specific for Serogroup B)
Carriage acquisition 39

40. Limitations Timing of carriage evaluation Sample size
Students swabbed 5-12 days after first MenB dose
Sample size
Not entire student body
Target: 1200
Started in middle of school year
Ideal to look at carriage trends over course of entire school year 40