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Neisseria lactamica induces anti-Neisseria
meningitidis B-cell responses
Adam P. Dale*, Anastasia A. Theodosiou, Jay R. Laver, Eleanor F. Roche, Andrew
Gorringe, Marta E. Polak, Robert C. Read
*NIHR Academic Clinical Lecturer
University of Southampton, UK
MBChB, PhD, MRCP, FRCPath
Background:
• There is an inverse relationship between pharyngeal colonisation with Neisseria lactamica (Nlac) and Neisseria meningitidis
(Nmen).
Aims:
• To assess whether Nlac colonisation induces anti-Nmen B cell responses.
• To assess whether B cell response frequencies were associated with Nlac
colonisation density.
• Controlled human infection with Nlac displaces Nmen and prevents new Nmen
colonisation events.
• The mechanism underlying this phenomenon is not yet elucidated. If it was
understood, it could be exploited to develop novel strategies to prevent Nmen
colonisation +/- disease.
• Nlac colonisation does not induce anti-Nmen serum bactericidal activity (SBA).
• We propose that the induction of cross-reactive adaptive cellular or humoral
responses, independent of SBA, may be responsible for observed effect.
Study flow diagram: Nlac/Nmen colonisation:
Participant
number
0
TS TS NW TS NW TS NW
1
2
3
5
6
8
10
11
12 x x
15
17
18
19
21
23
24
26
27
29
30
0
TS TS NW TS NW TS NW
4
7
9
13
14
16
20
22
25
28
31
Intervention (Nlac Y92-1009)
7 14 28
7 14 28
Control (PBS)
Figure 1. Study flow diagram showing allocation to
groups, study completion and participants included in the
immunological analyses. Hb – haemoglobin concentration
in whole blood.
1. To establish if pharyngeal colonisation with Nlac induces Nlac-specific B cell responses that
are cross-reactive with Nmen.
2. To assess whether the magnitude of Nlac-specific B cell responses induced following Nlac
colonisation were associated with Nlac colonisation density.
1. Academic Unit of Clinical and Experimental Sciences, University of Southampton, Southampton, SO16 6YD, UK. 2. Public Health England,
Porton Down, Salisbury, SP4 0JG, UK.*correspondence to: a.p.dale@soton.ac.uk
Colonisation with Neisseria lactamica induces plasma
cells that are cross-reactive with Neisseria meningitidis.
Adam P. Dale1*, Anastasia A. Theodosiou1, Jay R. Laver1, Eleanor F. Roche1, Andrew Gorringe2, Marta E. Polak1,
Andrew T. Vaughan1, Robert C. Read1.
oduction Results
1. Academic Unit of Clinical and Experimental Sciences, University of Southampton, Southampton, SO16 6YD, UK. 2. Public Health England,
Porton Down, Salisbury, SP4 0JG, UK.*correspondence to: a.p.dale@soton.ac.uk
nisation with Neisseria lactamica induces plasma
hat are cross-reactive with Neisseria meningitidis.
Dale1*, Anastasia A. Theodosiou1, Jay R. Laver1, Eleanor F. Roche1, Andrew Gorringe2, Marta E. Polak1,
Andrew T. Vaughan1, Robert C. Read1.
Results
Participant
number
0
TS TS NW TS NW TS NW
1
2
3
5
6
8
10
11
12 x x
15
17
18
19
21
23
24
26
27
29
30
0
TS TS NW TS NW TS NW
4
7
9
13
14
16
20
22
25
28
31
Intervention (Nlac Y92-1009)
7 14 28
7 14 28
Control (PBS)
Screening
Ineligible (n=18)
• N. meningitidis colonised
(n=6)
• N. lactamica colonised
(n=2)
• Hb below cut off (n=8)
• Other reason (n=2)
Analysed (n=17) Analysed (n=10)
Assessed for eligibility
(n=50)
Withdrawn prior to
allocation (n=1)
• New immunocompromised
contact (n=1)
Allocation
Follow-up visits (days 7, 14 & 28 post-inoculation)
Excluded from immunological analysis
(n=3)
• N. meningitidis colonisation at day 0
(n=1)
• Not colonised with N. lactamica following
inoculation (n=2)
Excluded from immunological analysis
(n=1)
• N. meningitidis colonisation at day 0
(n=1)
Allocated to intervention (n=20) Allocated to control (n=11)
Eligible (n=32)
Immunological analysis
A C
7
B
Nlac
on
Number of
challenge
participants
% Male
Age
(years, median
with range)
D
Figure 3. Colonisation with Nlac ind
PBS-inoculated participants and assesse
specific for Nlac Y92-1009-dOMV (A, C
adjusted for non-antigen-specific SFU by
105 PBMCs is shown (day +7-28) for eac
pairs signed rank test (n = 17 Nlac-coloni
****
0
2
4
6
8
10
12
14
16
18
20
22
0 +7-28
0
2
4
6
8
10
12
14
16
18
20
22
Anti-Nlac
Y92-1009-dOMV
IgA
SFU/2
x
10
5
PBMCs
Anti-Nmen
H44/76-dOMV
IgA
SFU/2
x
10
5
PBMCs
Anti-TT
IgA
SFU/2
x
10
5
PBMCs
Anti-Nlac
Y92-1009-dOMV
IgA
SFU/2
x
10
5
PBMCs
Anti-Nmen
H44/76-dOMV
IgA
SFU/2
x
10
5
PBMCs
Anti-TT
IgA
SFU/2
x
10
5
PBMCs
Days after inoculation
(Nlac Y92-1009)
Days after inoculation
(Nlac Y92-1009)
Days after inoculation
(PBS)
Days after inoculation
(PBS)
A
B
C
D
E
F
**
A
B
C
D
(+/+) (+/-) or (-
0
1
2
3
4
5
6
7
8
9
10
11
Anti-Nmen
H44/76-dOMV
IgG
SFU/2
x
10
5
PBMCs
A *
Anti-Nmen/Nlac IgG B
status (day 0)
(+/+)
0
1
2
3
4
5
6
7
8
9
10
11
Anti-Nmen
H44/76-dOMV
IgG
SFU/2
x
10
5
PBMCs
A
Anti-Nmen
statu
Re
Key:
Nlac colonised (blue)
Nmen colonised (red)
TS (oropharyngeal swab)
NW (nasal wash)
Study design:
• Healthy adults randomised 2:1 to
received intra-nasal inoculation with
intervention (Nlac, 105 CFU) or
control (PBS).
• Nlac/Nmen colonisation status
assessed at 0, 7, 14 and 28 days
(culture of oropharyngeal swab and
nasal wash).
• Blood taken at all time points to
assess cellular responses.
****
0 +7-28
0
2
4
6
8
10
12
14
16
18
20
22
0 +7-28
0
2
4
6
8
10
12
14
16
18
20
22
0 +7-28
0
4
8
12
16
20
24
28
0 +7-28
0
4
8
12
16
20
24
28
Anti-Nlac
Y92-1009-dOMV
IgA
SFU/2
x
10
5
PBMCs
Anti-Nmen
H44/76-dOMV
IgA
SFU/2
x
10
5
PBMCs
Anti-TT
IgA
SFU/2
x
10
5
PBMCs
Anti-Nlac
Y92-1009-dOMV
IgA
SFU/2
x
10
5
PBMCs
Anti-Nmen
H44/76-dOMV
IgA
SFU/2
x
10
5
PBMCs
Anti-TT
IgA
SFU/2
x
10
5
PBMCs
Anti-Nlac
Y92-1009-dOMV
IgG
SFU/2
x
10
5
PBMCs
Anti-Nmen
H44/76-dOMV
IgG
SFU/2
x
10
5
PBMCs
Anti-TT
IgG
SFU/2
x
10
5
PBMCs
Anti-Nlac
Y92-1009-dOMV
IgG
SFU/2
x
10
5
PBMCs
Anti-Nmen
H44/76-dOMV
IgG
SFU/2
x
10
5
PBMCs
Anti-TT
IgG
SFU/2
x
10
5
PBMCs
Days after inoculation
(Nlac Y92-1009)
Days after inoculation
(Nlac Y92-1009)
Days after inoculation
(Nlac Y92-1009)
Days after inoculation
(Nlac Y92-1009)
Days after inoculation
(Nlac Y92-1009)
Days after inoculation
(Nlac Y92-1009)
Days after inoculation
(PBS)
Days after inoculation
(PBS)
Days after inoculation
(PBS)
Days after inoculation
(PBS)
Days after inoculation
(PBS)
Days after inoculation
(PBS)
A
B
C
D
E
F
G
H
I
J
K
L
**
****
*
Colonisation with Nlac induces anti-Nmen BPLAS & BMEM responses
v
* P < 0.05, ** P ≤ 0.01, **** P ≤ 0.0001 (Wilcoxon matched pairs signed rank test)
Key:
- Keyhole limpet haemocyanin (KLH)
- Nlac (Y92-1009) dOMV (Nlac)
- Nmen (H44/76) dOMV (Nmen)
- Influenza haemagglutinin (H1N1) (Flu)
IgA/IgG BPLAS ELISpot
IgG BMEM ELISpot
Collated BPLAS data Collated BMEM data
0 28
0.000
0.025
0.050
0.075
0.100
0.125
0.150
0 28
0.000
0.025
0.050
0.075
0.100
0.125
0.150
0.2
0.4
0.6
0 28
0.000
0.025
0.050
0.075
0.100
0.125
0.150
0 28
0.000
0.025
0.050
0.075
0.100
0.125
0.150
0.2
0.4
0.6
*
0
0
10
20
30
40
50
60
70
80
0
0
10
20
30
40
50
60
70
80
Anti-Flu
HA
IgG
SFU
(%
of
total
IgG
SFU)
E
0 28
0.00
0.25
0.50
0.75
1.00
1.25
1.50
1.75
2.00
2.25
2.50
2.75
3.00
0 28
0.00
0.25
0.50
0.75
1.00
1.25
1.50
1.75
2.00
2.25
2.50
2.75
3.00
A
B
C
D F
Anti-Nlac
Y92-1009
IgG
SFU
(%
of
total
IgG
SFU)
Anti-Nlac
Y92-1009
IgG
SFU
(%
of
total
IgG
SFU)
Anti-Nmen
H44/76
IgG
SFU
(%
of
total
IgG
SFU)
Anti-Nmen
H44/76
IgG
SFU
(%
of
total
IgG
SFU)
Anti-Flu
HA
IgG
SFU
(%
of
total
IgG
SFU)
Days after inoculation
(Nlac Y92-1009)
Days after inoculation
(PBS)
****
Total
IgG
SFU
per
5x10
2
cells
G
H
Days after inoculation
(Nlac Y92-1009)
Days after inoculation
(Nlac Y92-1009)
Days after
(Nlac Y
Days after inoculation
(PBS)
Days after inoculation
(PBS)
Days after
(P
ns n
n
ns
ns
ns
Total
IgG
SFU
per
5x10
2
cells
0 28
0.000
0.025
0.050
0.075
0.100
0.125
0.150
0 28
0.000
0.025
0.050
0.075
0.100
0.125
0.150
0.2
0.4
0.6
0 28
0.000
0.025
0.050
0.075
0.100
0.125
0.150
0 28
0.000
0.025
0.050
0.075
0.100
0.125
0.150
0.2
0.4
0.6
*
Anti-Flu
HA
IgG
SFU
(%
of
total
IgG
SFU)
E
0.00
0.25
0.50
0.75
1.00
1.25
1.50
1.75
2.00
2.25
2.50
2.75
3.00
0.00
0.25
0.50
0.75
1.00
1.25
1.50
1.75
2.00
2.25
2.50
2.75
3.00
A
B
C
D F
Anti-Nlac
Y92-1009
IgG
SFU
(%
of
total
IgG
SFU)
Anti-Nlac
Y92-1009
IgG
SFU
(%
of
total
IgG
SFU)
Anti-Nmen
H44/76
IgG
SFU
(%
of
total
IgG
SFU)
Anti-Nmen
H44/76
IgG
SFU
(%
of
total
IgG
SFU)
Anti-Flu
HA
IgG
SFU
(%
of
total
IgG
SFU)
Days after inoculation
(Nlac Y92-1009)
Days after inoculation
(PBS)
****
Days after inoculation
(Nlac Y92-1009)
Day
(N
Days after inoculation
(PBS)
Days
ns
ns
0.000
0.025
0.050
0.075
0.100
0.125
0 28
0.000
0.025
0.050
0.075
0.100
0.125
0.150
0.2
0.4
0.000
0.025
0.050
0.075
0.100
0.125
0.150
0 28
0.000
0.025
0.050
0.075
0.100
0.125
0.150
0.2
0.4
0.6
B D
Anti-Nlac
Y92-1009
IgG
SF
(%
of
total
IgG
SFU)
Anti-Nlac
Y92-1009
IgG
SFU
(%
of
total
IgG
SFU)
Anti-Nmen
H44/76
IgG
SFU
(%
of
total
IgG
SFU)
Anti-Nmen
H44/76
IgG
SFU
(%
of
total
IgG
SFU)
Days after inoculation
(Nlac Y92-1009)
Days after inoculation
(PBS)
ns
0 28
0.000
0.025
0.050
0.075
0.100
0.125
0.150
0 28
0.000
0.025
0.050
0.075
0.100
0.125
0.150
0.2
0.4
0.6
0 28
0.000
0.025
0.050
0.075
0.100
0.125
0.150
0 28
0.000
0.025
0.050
0.075
0.100
0.125
0.150
0.2
0.4
0.6
*
Anti-Flu
HA
IgG
SFU
(%
of
total
IgG
SFU)
E
0.00
0.25
0.50
0.75
1.00
1.25
1.50
1.75
2.00
2.25
2.50
2.75
3.00
0.00
0.25
0.50
0.75
1.00
1.25
1.50
1.75
2.00
2.25
2.50
2.75
3.00
A
B
C
D F
Anti-Nlac
Y92-1009
IgG
SFU
(%
of
total
IgG
SFU)
Anti-Nlac
Y92-1009
IgG
SFU
(%
of
total
IgG
SFU)
Anti-Nmen
H44/76
IgG
SFU
(%
of
total
IgG
SFU)
Anti-Nmen
H44/76
IgG
SFU
(%
of
total
IgG
SFU)
Anti-Flu
HA
IgG
SFU
(%
of
total
IgG
SFU)
Days after inoculation
(Nlac Y92-1009)
Days after inoculation
(PBS)
****
Days after inoculation
(Nlac Y92-1009)
Days after inoculation
(PBS)
ns
ns
Total SFUs
(mAb-
coated)
KLH
Tetanus
toxoid
Nlac
Nmen
IgA IgG
Day 14
Clinical and Experimental Sciences, University of Southampton, Southampton, SO16 6YD, UK. 2. Public Health England,
Porton Down, Salisbury, SP4 0JG, UK.*correspondence to: a.p.dale@soton.ac.uk
n with Neisseria lactamica induces plasma
cross-reactive with Neisseria meningitidis.
ia A. Theodosiou1, Jay R. Laver1, Eleanor F. Roche1, Andrew Gorringe2, Marta E. Polak1,
Andrew T. Vaughan1, Robert C. Read1.
al of the
gnificantly
men). We
cellular
effect.
ncluding
oculation
NL/NM
Results
Total
antibody
KLH
Tetanus
toxoid
N. lac
OMV
N. men
OMV
Day 0 Day 14
IgA
Day 0 Day 7
IgM
Day 0 Day 14
IgG
Anti-N.
lac
IgA
SFUs/2x10
5
PBMCs
Anti-N.
lac
IgM
SFUs/2x10
5
PBMCs
Anti-N.
lac
IgG
SFUs/2x10
5
PBMCs
Study time point (days)
es, University of Southampton, Southampton, SO16 6YD, UK. 2. Public Health England,
ry, SP4 0JG, UK.*correspondence to: a.p.dale@soton.ac.uk
isseria lactamica induces plasma
active with Neisseria meningitidis.
Jay R. Laver1, Eleanor F. Roche1, Andrew Gorringe2, Marta E. Polak1,
w T. Vaughan1, Robert C. Read1.
ts
Day 0 Day 14
IgA
Day 0 Day 7
IgM
Day 0 Day 14
IgG
Anti-N.
lac
IgA
SFUs/2x10
5
PBMCs
Anti-N.
lac
IgM
SFUs/2x10
5
PBMCs
Anti-N.
lac
IgG
SFUs/2x10
5
PBMCs
Study time point (days)
Day 0 Day 0 Day 14
Anti-Nlac-dOMV
IgG
SFU/2x10
5
PBMCs
(day
+7-28)
Anti-Nlac-dOMV
IgA
SFU/2x10
5
PBMCs
(day
+7-28)
Anti-Nmen
H44/76-dOMV
IgG
SFU/2x10
5
PBMCs
(day
+7-28)
Anti-Nmen
H44/76-dOMV
IgA
SFU/2x10
5
PBMCs
(day
+7-28)
0
.
0
1
0
.
1
1
1
0
1
0
0
1
0
0
0
0.0
2.5
5.0
7.5
10.0
12.5
0
.
0
1
0
.
1
1
1
0
1
0
0
1
0
0
0
0
2
4
6
8
10
0
.
0
1
0
.
1
1
1
0
1
0
0
1
0
0
0
0
4
8
12
16
20
24
28
0
.
0
1
0
.
1
1
1
0
1
0
0
1
0
0
0
0
4
8
12
16
20
24
28
Nlac CFU ml-1 nasal wash (Day 28)
Nlac CFU ml-1 nasal wash (Day 28)
A C
B D
rs = -0.617* rs = -0.522 *
rs = -0.467 rs = -0.432
Nlac-specific BPLAS responses and IgG titers
are associated with Nlac colonisation density
Nlac CFU ml-1 nasal wash (Day 7)
Anti-Nlac
Y92
1009-dOMV
IgG
titer
(Day
28)
Anti-Nmen
H44/76-dOMV
IgG
titer
(Day
28)
0
.
0
1
0
.
1
1
1
0
1
0
0
1
0
0
0
0
20
40
60
80
100
120
140
0
.
0
1
0
.
1
1
1
0
1
0
0
1
0
0
0
0
10
20
30
40
50
60
70
80
0
.
0
1
0
.
1
1
1
0
1
0
0
1
0
0
0
0
20
40
60
80
100
120
140
0
.
0
1
0
.
1
1
1
0
1
0
0
1
0
0
0
0
10
20
30
40
50
60
70
80
0
.
0
1
0
.
1
1
1
0
1
0
0
1
0
0
0
1
0
0
0
0
0
20
40
60
80
100
120
140
0
.
0
1
0
.
1
1
1
0
1
0
0
1
0
0
0
1
0
0
0
0
0
10
20
30
40
50
60
70
80
Anti-Nmen
H44/76-dOMV
IgG
titer
(Day
28)
Anti-Nmen
H44/76-dOMV
IgG
titer
(Day
28)
Anti-Nlac
Y92
1009-dOMV
IgG
titer
(Day
28)
Nlac CFU ml-1 nasal wash (Day 14)
Anti-Nlac
Y92
1009-dOMV
IgG
titer
(Day
28)
A D
B E
C F
rs = -0.156 rs = 0.105
rs = -0.469 rs = -0.386
rs = -0.638* rs = -0.216
Nlac CFU ml-1 nasal wash (Day 28)
(+/+) (+/-) or (-/-)
0
500
1000
1500
2000
2500
3000
5000
10000
15000
20000
Baseline Nmen/Nlac IgG
BMEM status
Nlac colonisation density
vs. IgA BPLAS responses
Nlac colonisation density
vs. day-28 IgG responses (plasma)
Nlac colonisation density vs. baseline
Nlac/Nmen IgG BMEM responses
*
AUC
Nlac
CFU
ml
-1
(nasal
wash)
Correlations assessed with Spearman’s Rho (rs) (* P < 0.05)
†
† Mann-Whitney (*P <0.05)
Conclusions
v Colonisation with Nlac induced BPLAS and BMEM responses specific to Nlac and Nmen, suggesting that the previously observed
protective effect of Nlac on Nmen may have an immunological basis.
v Nlac colonisation density negatively correlated with anti-Nlac IgG titers and anti-Nlac IgA-secreting BPLAS frequencies
suggesting that the magnitude of these responses may play a role in controlling Nlac colonisation density.
v We predict that protection against Nmen colonisation may only occur in those where Nlac colonisation results in the
formation of anti-Nmen B cell and antibody responses.
Acknowledgements
Read Group:
Robert Read
Jay Laver
Anastasia Theodosiou
Alison Hill
Eleanor Roche
Carl Webb
Mukhtar Ibrahim
Muhammed Ahmed
Diane Gbesemete
Hans De Graaf
Southampton Clinical Research Facility (CRF)
Saul Faust
Victoria Buxton
Rachel Miller-Price
Sara Hughes
CRF administration & research nursing team
Public Health England,
Porton Down:
Andrew Gorringe
Holly Humphries
Systems Immunology Group:
Marta Polak

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Dr Adam dale

  • 1. Neisseria lactamica induces anti-Neisseria meningitidis B-cell responses Adam P. Dale*, Anastasia A. Theodosiou, Jay R. Laver, Eleanor F. Roche, Andrew Gorringe, Marta E. Polak, Robert C. Read *NIHR Academic Clinical Lecturer University of Southampton, UK MBChB, PhD, MRCP, FRCPath
  • 2. Background: • There is an inverse relationship between pharyngeal colonisation with Neisseria lactamica (Nlac) and Neisseria meningitidis (Nmen). Aims: • To assess whether Nlac colonisation induces anti-Nmen B cell responses. • To assess whether B cell response frequencies were associated with Nlac colonisation density. • Controlled human infection with Nlac displaces Nmen and prevents new Nmen colonisation events. • The mechanism underlying this phenomenon is not yet elucidated. If it was understood, it could be exploited to develop novel strategies to prevent Nmen colonisation +/- disease. • Nlac colonisation does not induce anti-Nmen serum bactericidal activity (SBA). • We propose that the induction of cross-reactive adaptive cellular or humoral responses, independent of SBA, may be responsible for observed effect.
  • 3. Study flow diagram: Nlac/Nmen colonisation: Participant number 0 TS TS NW TS NW TS NW 1 2 3 5 6 8 10 11 12 x x 15 17 18 19 21 23 24 26 27 29 30 0 TS TS NW TS NW TS NW 4 7 9 13 14 16 20 22 25 28 31 Intervention (Nlac Y92-1009) 7 14 28 7 14 28 Control (PBS) Figure 1. Study flow diagram showing allocation to groups, study completion and participants included in the immunological analyses. Hb – haemoglobin concentration in whole blood. 1. To establish if pharyngeal colonisation with Nlac induces Nlac-specific B cell responses that are cross-reactive with Nmen. 2. To assess whether the magnitude of Nlac-specific B cell responses induced following Nlac colonisation were associated with Nlac colonisation density. 1. Academic Unit of Clinical and Experimental Sciences, University of Southampton, Southampton, SO16 6YD, UK. 2. Public Health England, Porton Down, Salisbury, SP4 0JG, UK.*correspondence to: a.p.dale@soton.ac.uk Colonisation with Neisseria lactamica induces plasma cells that are cross-reactive with Neisseria meningitidis. Adam P. Dale1*, Anastasia A. Theodosiou1, Jay R. Laver1, Eleanor F. Roche1, Andrew Gorringe2, Marta E. Polak1, Andrew T. Vaughan1, Robert C. Read1. oduction Results 1. Academic Unit of Clinical and Experimental Sciences, University of Southampton, Southampton, SO16 6YD, UK. 2. Public Health England, Porton Down, Salisbury, SP4 0JG, UK.*correspondence to: a.p.dale@soton.ac.uk nisation with Neisseria lactamica induces plasma hat are cross-reactive with Neisseria meningitidis. Dale1*, Anastasia A. Theodosiou1, Jay R. Laver1, Eleanor F. Roche1, Andrew Gorringe2, Marta E. Polak1, Andrew T. Vaughan1, Robert C. Read1. Results Participant number 0 TS TS NW TS NW TS NW 1 2 3 5 6 8 10 11 12 x x 15 17 18 19 21 23 24 26 27 29 30 0 TS TS NW TS NW TS NW 4 7 9 13 14 16 20 22 25 28 31 Intervention (Nlac Y92-1009) 7 14 28 7 14 28 Control (PBS) Screening Ineligible (n=18) • N. meningitidis colonised (n=6) • N. lactamica colonised (n=2) • Hb below cut off (n=8) • Other reason (n=2) Analysed (n=17) Analysed (n=10) Assessed for eligibility (n=50) Withdrawn prior to allocation (n=1) • New immunocompromised contact (n=1) Allocation Follow-up visits (days 7, 14 & 28 post-inoculation) Excluded from immunological analysis (n=3) • N. meningitidis colonisation at day 0 (n=1) • Not colonised with N. lactamica following inoculation (n=2) Excluded from immunological analysis (n=1) • N. meningitidis colonisation at day 0 (n=1) Allocated to intervention (n=20) Allocated to control (n=11) Eligible (n=32) Immunological analysis A C 7 B Nlac on Number of challenge participants % Male Age (years, median with range) D Figure 3. Colonisation with Nlac ind PBS-inoculated participants and assesse specific for Nlac Y92-1009-dOMV (A, C adjusted for non-antigen-specific SFU by 105 PBMCs is shown (day +7-28) for eac pairs signed rank test (n = 17 Nlac-coloni **** 0 2 4 6 8 10 12 14 16 18 20 22 0 +7-28 0 2 4 6 8 10 12 14 16 18 20 22 Anti-Nlac Y92-1009-dOMV IgA SFU/2 x 10 5 PBMCs Anti-Nmen H44/76-dOMV IgA SFU/2 x 10 5 PBMCs Anti-TT IgA SFU/2 x 10 5 PBMCs Anti-Nlac Y92-1009-dOMV IgA SFU/2 x 10 5 PBMCs Anti-Nmen H44/76-dOMV IgA SFU/2 x 10 5 PBMCs Anti-TT IgA SFU/2 x 10 5 PBMCs Days after inoculation (Nlac Y92-1009) Days after inoculation (Nlac Y92-1009) Days after inoculation (PBS) Days after inoculation (PBS) A B C D E F ** A B C D (+/+) (+/-) or (- 0 1 2 3 4 5 6 7 8 9 10 11 Anti-Nmen H44/76-dOMV IgG SFU/2 x 10 5 PBMCs A * Anti-Nmen/Nlac IgG B status (day 0) (+/+) 0 1 2 3 4 5 6 7 8 9 10 11 Anti-Nmen H44/76-dOMV IgG SFU/2 x 10 5 PBMCs A Anti-Nmen statu Re Key: Nlac colonised (blue) Nmen colonised (red) TS (oropharyngeal swab) NW (nasal wash) Study design: • Healthy adults randomised 2:1 to received intra-nasal inoculation with intervention (Nlac, 105 CFU) or control (PBS). • Nlac/Nmen colonisation status assessed at 0, 7, 14 and 28 days (culture of oropharyngeal swab and nasal wash). • Blood taken at all time points to assess cellular responses.
  • 4. **** 0 +7-28 0 2 4 6 8 10 12 14 16 18 20 22 0 +7-28 0 2 4 6 8 10 12 14 16 18 20 22 0 +7-28 0 4 8 12 16 20 24 28 0 +7-28 0 4 8 12 16 20 24 28 Anti-Nlac Y92-1009-dOMV IgA SFU/2 x 10 5 PBMCs Anti-Nmen H44/76-dOMV IgA SFU/2 x 10 5 PBMCs Anti-TT IgA SFU/2 x 10 5 PBMCs Anti-Nlac Y92-1009-dOMV IgA SFU/2 x 10 5 PBMCs Anti-Nmen H44/76-dOMV IgA SFU/2 x 10 5 PBMCs Anti-TT IgA SFU/2 x 10 5 PBMCs Anti-Nlac Y92-1009-dOMV IgG SFU/2 x 10 5 PBMCs Anti-Nmen H44/76-dOMV IgG SFU/2 x 10 5 PBMCs Anti-TT IgG SFU/2 x 10 5 PBMCs Anti-Nlac Y92-1009-dOMV IgG SFU/2 x 10 5 PBMCs Anti-Nmen H44/76-dOMV IgG SFU/2 x 10 5 PBMCs Anti-TT IgG SFU/2 x 10 5 PBMCs Days after inoculation (Nlac Y92-1009) Days after inoculation (Nlac Y92-1009) Days after inoculation (Nlac Y92-1009) Days after inoculation (Nlac Y92-1009) Days after inoculation (Nlac Y92-1009) Days after inoculation (Nlac Y92-1009) Days after inoculation (PBS) Days after inoculation (PBS) Days after inoculation (PBS) Days after inoculation (PBS) Days after inoculation (PBS) Days after inoculation (PBS) A B C D E F G H I J K L ** **** * Colonisation with Nlac induces anti-Nmen BPLAS & BMEM responses v * P < 0.05, ** P ≤ 0.01, **** P ≤ 0.0001 (Wilcoxon matched pairs signed rank test) Key: - Keyhole limpet haemocyanin (KLH) - Nlac (Y92-1009) dOMV (Nlac) - Nmen (H44/76) dOMV (Nmen) - Influenza haemagglutinin (H1N1) (Flu) IgA/IgG BPLAS ELISpot IgG BMEM ELISpot Collated BPLAS data Collated BMEM data 0 28 0.000 0.025 0.050 0.075 0.100 0.125 0.150 0 28 0.000 0.025 0.050 0.075 0.100 0.125 0.150 0.2 0.4 0.6 0 28 0.000 0.025 0.050 0.075 0.100 0.125 0.150 0 28 0.000 0.025 0.050 0.075 0.100 0.125 0.150 0.2 0.4 0.6 * 0 0 10 20 30 40 50 60 70 80 0 0 10 20 30 40 50 60 70 80 Anti-Flu HA IgG SFU (% of total IgG SFU) E 0 28 0.00 0.25 0.50 0.75 1.00 1.25 1.50 1.75 2.00 2.25 2.50 2.75 3.00 0 28 0.00 0.25 0.50 0.75 1.00 1.25 1.50 1.75 2.00 2.25 2.50 2.75 3.00 A B C D F Anti-Nlac Y92-1009 IgG SFU (% of total IgG SFU) Anti-Nlac Y92-1009 IgG SFU (% of total IgG SFU) Anti-Nmen H44/76 IgG SFU (% of total IgG SFU) Anti-Nmen H44/76 IgG SFU (% of total IgG SFU) Anti-Flu HA IgG SFU (% of total IgG SFU) Days after inoculation (Nlac Y92-1009) Days after inoculation (PBS) **** Total IgG SFU per 5x10 2 cells G H Days after inoculation (Nlac Y92-1009) Days after inoculation (Nlac Y92-1009) Days after (Nlac Y Days after inoculation (PBS) Days after inoculation (PBS) Days after (P ns n n ns ns ns Total IgG SFU per 5x10 2 cells 0 28 0.000 0.025 0.050 0.075 0.100 0.125 0.150 0 28 0.000 0.025 0.050 0.075 0.100 0.125 0.150 0.2 0.4 0.6 0 28 0.000 0.025 0.050 0.075 0.100 0.125 0.150 0 28 0.000 0.025 0.050 0.075 0.100 0.125 0.150 0.2 0.4 0.6 * Anti-Flu HA IgG SFU (% of total IgG SFU) E 0.00 0.25 0.50 0.75 1.00 1.25 1.50 1.75 2.00 2.25 2.50 2.75 3.00 0.00 0.25 0.50 0.75 1.00 1.25 1.50 1.75 2.00 2.25 2.50 2.75 3.00 A B C D F Anti-Nlac Y92-1009 IgG SFU (% of total IgG SFU) Anti-Nlac Y92-1009 IgG SFU (% of total IgG SFU) Anti-Nmen H44/76 IgG SFU (% of total IgG SFU) Anti-Nmen H44/76 IgG SFU (% of total IgG SFU) Anti-Flu HA IgG SFU (% of total IgG SFU) Days after inoculation (Nlac Y92-1009) Days after inoculation (PBS) **** Days after inoculation (Nlac Y92-1009) Day (N Days after inoculation (PBS) Days ns ns 0.000 0.025 0.050 0.075 0.100 0.125 0 28 0.000 0.025 0.050 0.075 0.100 0.125 0.150 0.2 0.4 0.000 0.025 0.050 0.075 0.100 0.125 0.150 0 28 0.000 0.025 0.050 0.075 0.100 0.125 0.150 0.2 0.4 0.6 B D Anti-Nlac Y92-1009 IgG SF (% of total IgG SFU) Anti-Nlac Y92-1009 IgG SFU (% of total IgG SFU) Anti-Nmen H44/76 IgG SFU (% of total IgG SFU) Anti-Nmen H44/76 IgG SFU (% of total IgG SFU) Days after inoculation (Nlac Y92-1009) Days after inoculation (PBS) ns 0 28 0.000 0.025 0.050 0.075 0.100 0.125 0.150 0 28 0.000 0.025 0.050 0.075 0.100 0.125 0.150 0.2 0.4 0.6 0 28 0.000 0.025 0.050 0.075 0.100 0.125 0.150 0 28 0.000 0.025 0.050 0.075 0.100 0.125 0.150 0.2 0.4 0.6 * Anti-Flu HA IgG SFU (% of total IgG SFU) E 0.00 0.25 0.50 0.75 1.00 1.25 1.50 1.75 2.00 2.25 2.50 2.75 3.00 0.00 0.25 0.50 0.75 1.00 1.25 1.50 1.75 2.00 2.25 2.50 2.75 3.00 A B C D F Anti-Nlac Y92-1009 IgG SFU (% of total IgG SFU) Anti-Nlac Y92-1009 IgG SFU (% of total IgG SFU) Anti-Nmen H44/76 IgG SFU (% of total IgG SFU) Anti-Nmen H44/76 IgG SFU (% of total IgG SFU) Anti-Flu HA IgG SFU (% of total IgG SFU) Days after inoculation (Nlac Y92-1009) Days after inoculation (PBS) **** Days after inoculation (Nlac Y92-1009) Days after inoculation (PBS) ns ns Total SFUs (mAb- coated) KLH Tetanus toxoid Nlac Nmen IgA IgG Day 14 Clinical and Experimental Sciences, University of Southampton, Southampton, SO16 6YD, UK. 2. Public Health England, Porton Down, Salisbury, SP4 0JG, UK.*correspondence to: a.p.dale@soton.ac.uk n with Neisseria lactamica induces plasma cross-reactive with Neisseria meningitidis. ia A. Theodosiou1, Jay R. Laver1, Eleanor F. Roche1, Andrew Gorringe2, Marta E. Polak1, Andrew T. Vaughan1, Robert C. Read1. al of the gnificantly men). We cellular effect. ncluding oculation NL/NM Results Total antibody KLH Tetanus toxoid N. lac OMV N. men OMV Day 0 Day 14 IgA Day 0 Day 7 IgM Day 0 Day 14 IgG Anti-N. lac IgA SFUs/2x10 5 PBMCs Anti-N. lac IgM SFUs/2x10 5 PBMCs Anti-N. lac IgG SFUs/2x10 5 PBMCs Study time point (days) es, University of Southampton, Southampton, SO16 6YD, UK. 2. Public Health England, ry, SP4 0JG, UK.*correspondence to: a.p.dale@soton.ac.uk isseria lactamica induces plasma active with Neisseria meningitidis. Jay R. Laver1, Eleanor F. Roche1, Andrew Gorringe2, Marta E. Polak1, w T. Vaughan1, Robert C. Read1. ts Day 0 Day 14 IgA Day 0 Day 7 IgM Day 0 Day 14 IgG Anti-N. lac IgA SFUs/2x10 5 PBMCs Anti-N. lac IgM SFUs/2x10 5 PBMCs Anti-N. lac IgG SFUs/2x10 5 PBMCs Study time point (days) Day 0 Day 0 Day 14
  • 5. Anti-Nlac-dOMV IgG SFU/2x10 5 PBMCs (day +7-28) Anti-Nlac-dOMV IgA SFU/2x10 5 PBMCs (day +7-28) Anti-Nmen H44/76-dOMV IgG SFU/2x10 5 PBMCs (day +7-28) Anti-Nmen H44/76-dOMV IgA SFU/2x10 5 PBMCs (day +7-28) 0 . 0 1 0 . 1 1 1 0 1 0 0 1 0 0 0 0.0 2.5 5.0 7.5 10.0 12.5 0 . 0 1 0 . 1 1 1 0 1 0 0 1 0 0 0 0 2 4 6 8 10 0 . 0 1 0 . 1 1 1 0 1 0 0 1 0 0 0 0 4 8 12 16 20 24 28 0 . 0 1 0 . 1 1 1 0 1 0 0 1 0 0 0 0 4 8 12 16 20 24 28 Nlac CFU ml-1 nasal wash (Day 28) Nlac CFU ml-1 nasal wash (Day 28) A C B D rs = -0.617* rs = -0.522 * rs = -0.467 rs = -0.432 Nlac-specific BPLAS responses and IgG titers are associated with Nlac colonisation density Nlac CFU ml-1 nasal wash (Day 7) Anti-Nlac Y92 1009-dOMV IgG titer (Day 28) Anti-Nmen H44/76-dOMV IgG titer (Day 28) 0 . 0 1 0 . 1 1 1 0 1 0 0 1 0 0 0 0 20 40 60 80 100 120 140 0 . 0 1 0 . 1 1 1 0 1 0 0 1 0 0 0 0 10 20 30 40 50 60 70 80 0 . 0 1 0 . 1 1 1 0 1 0 0 1 0 0 0 0 20 40 60 80 100 120 140 0 . 0 1 0 . 1 1 1 0 1 0 0 1 0 0 0 0 10 20 30 40 50 60 70 80 0 . 0 1 0 . 1 1 1 0 1 0 0 1 0 0 0 1 0 0 0 0 0 20 40 60 80 100 120 140 0 . 0 1 0 . 1 1 1 0 1 0 0 1 0 0 0 1 0 0 0 0 0 10 20 30 40 50 60 70 80 Anti-Nmen H44/76-dOMV IgG titer (Day 28) Anti-Nmen H44/76-dOMV IgG titer (Day 28) Anti-Nlac Y92 1009-dOMV IgG titer (Day 28) Nlac CFU ml-1 nasal wash (Day 14) Anti-Nlac Y92 1009-dOMV IgG titer (Day 28) A D B E C F rs = -0.156 rs = 0.105 rs = -0.469 rs = -0.386 rs = -0.638* rs = -0.216 Nlac CFU ml-1 nasal wash (Day 28) (+/+) (+/-) or (-/-) 0 500 1000 1500 2000 2500 3000 5000 10000 15000 20000 Baseline Nmen/Nlac IgG BMEM status Nlac colonisation density vs. IgA BPLAS responses Nlac colonisation density vs. day-28 IgG responses (plasma) Nlac colonisation density vs. baseline Nlac/Nmen IgG BMEM responses * AUC Nlac CFU ml -1 (nasal wash) Correlations assessed with Spearman’s Rho (rs) (* P < 0.05) † † Mann-Whitney (*P <0.05)
  • 6. Conclusions v Colonisation with Nlac induced BPLAS and BMEM responses specific to Nlac and Nmen, suggesting that the previously observed protective effect of Nlac on Nmen may have an immunological basis. v Nlac colonisation density negatively correlated with anti-Nlac IgG titers and anti-Nlac IgA-secreting BPLAS frequencies suggesting that the magnitude of these responses may play a role in controlling Nlac colonisation density. v We predict that protection against Nmen colonisation may only occur in those where Nlac colonisation results in the formation of anti-Nmen B cell and antibody responses. Acknowledgements Read Group: Robert Read Jay Laver Anastasia Theodosiou Alison Hill Eleanor Roche Carl Webb Mukhtar Ibrahim Muhammed Ahmed Diane Gbesemete Hans De Graaf Southampton Clinical Research Facility (CRF) Saul Faust Victoria Buxton Rachel Miller-Price Sara Hughes CRF administration & research nursing team Public Health England, Porton Down: Andrew Gorringe Holly Humphries Systems Immunology Group: Marta Polak