A Path to Reducing Antibiotic Resistance.pptx

Great ExPEC’tations: A Path to
Reducing Antimicrobial Resistance
Supported by an educational grant from Janssen Therapeutics,
Division of Janssen Products, LP.

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Program Director
Lilian Abbo, MD, FIDSA
Associate Chief Medical Officer in Infectious Diseases
Jackson Health System
Professor of Infectious Diseases
Department of Medicine & Miami Transplant Institute
University of Miami Miller School of Medicine
Miami, Florida

Disclosures
The faculty reported the following relevant financial relationships or
relationships to products or devices they have with ineligible companies
related to the content of this educational activity:
Lilian Abbo, MD, FIDSA: consultant/advisor/speaker: Ferring.

Emerging ExPEC Vaccine Technologies

ExPEC Vaccine Targets
 Surface polysaccharides
(eg, O and K surface antigens)1
 Fimbrial adhesins1
‒ FiMH: possible target; allows for E coli colonization in bladder and
enables formation of biofilms
 Outer membrane vesicles2
 Outer membrane iron receptors1
 Toxins1
1. Brumbaugh. Expert Rev Vaccines. 2012;11:663. 2. who.int/publications/i/item/9789240052451.
3. Terlizzi. Front Microbiol. 2017;8;1566. 4. Chapman. Science. 2002;295:851. 5. Barnhart. Ann Rev Microbiol. 2006;60:131.

ExPEC: Surface Polysaccharide Vaccine Targets
 Goal: identify factors expressed by pathogenic E coli and not by commensal E coli
to avoid detrimental effects against the gut flora1,2
Surface Antigens O K H
Location Part of LPS Polysaccharide capsule Flagellum
No. of types ˃180 ˃80 ˃50
1. Brumbaugh. Expert Rev Vaccines. 2012;11:663. 2. Poolman. J Infect Dis. 2016;213:6.
 Virulence factors allow E coli to evade host immune assaults
(eg, opsonophagocytosis, complement-mediated killing)1
 May cloak subcapsular epitopes on bacterial surface,
blocking recognition by host antibodies1
O antigens appear to be
promising target for
ExPEC vaccines2
K1-antigen considered but
resembles glycoproteins found
on human neural tissue2

4 valent 10 valent
Included in Vaccines
 Analysis of O-serotype distribution among ICU
patients with E coli BSI in the Netherlands (N = 70)
‒ 68 isolates serotyped
‒ Most common isolates: O25 (16%), O8 (7%), O2 (6%),
O6 (6%), O15 (6%)
ICU Distributions of O-Serotype in ExPEC
Verboom. Vaccine. 2021; 39:1670.
0
25 6 2 1 8 15 75 16 18 4 17 101 78 9 107 111117 13 153 161 162169 21 23 24 3 44 45 58 68 73 77 86
Non-
typeable
Occurrence
Vaccine coverage
O-Serogroups
O-Serogroups of E Coli Bloodstream Isolates
 Theoretical coverage of 10-valent
ExPEC vaccine: 54%
‒ 56% for community acquired
‒ 53% for nosocomial BSI
60
40
20
Theoretical
Vaccine
Coverage
or
Infection
Occurrence
(%)
Other Serogroups
100
80

Global Distribution of O-Serotypes in ExPEC
 Analysis of 3217 ExPEC blood culture isolates from Europe, North America, Asia-Pacific,
and South America from 2011-2017
‒ Overall, MDR frequency was 10.7%, of which O25 was most prevalent (63.2%)
Weerdenburg. Clin Infect Dis. 2022; ciac421.
O25 O2 O6 O1 O75 O15 O8 O16 O4 O18 O77
Group
O153 O9 O101/
O162
O86 O13
40
30
20
10
0
Prevalence
(%)
100
80
60
40
20
0
Cumulative
Prevalence
(%)
1.1
1.4
1.6
1.6
2.0
2.5
2.8
3.0
3.2
3.2
3.4
4.5
7.9
8.1
8.3
22.9
O Serotype
Individual: agglutination
Cumulative: agglutination
Individual: agglutination and genotyping
Cumulative: agglutination and genotyping

Obstacles in ExPEC Vaccine Development
 Need to generate robust mucosal
adaptive immune response1
‒ Long-term dormancy of E coli in
bladder and on epithelial surfaces
results in intracellular bacterial
communities and biofilms2
‒ Require novel approaches
(eg, antigen delivery systems,
use of adjuvants)1
 Severe local and systemic
reactions by O polysaccharides
have required detoxification (ie,
removal of lipid-A via hydrolysis)
prior to human administration1,3
‒ Limits immunogenicity3
‒ Requires either protein
conjugation or adjuvant to induce
an adequate immune response3
1. Brumbaugh. Expert Rev Vaccines. 2012;11:663. 2. Rojas-Lopez. Front Microbiol. 2018;20:440.
3. Huttner. Clin Microbiol Infect. 2018;24:1046.

Prophylactic vs Therapeutic Vaccines
Prophylactic
Used for prevention
Vaccines initially created to
prevent childhood illnesses
Therapeutic
For at-risk populations either
already colonized or infected
with pathogen
who.int/publications/i/item/9789240052451

The Pipeline: Active Clinical Trials
Vaccine1 Approach
Prophylactic/
Therapeutic
Route of
Administration
Phase
ExPEC9V
Subunit; conjugate
O-polysaccharide with
P aeruginosa exoprotein A
Prophylactic Parenteral III
FimH
Subunit; conjugate
FimH (bacterial adhesin protein)
as antigen with
TLR4 agonist adjuvant
Therapeutic Parenteral II
OM-89
Subunit; outer membrane
vesicle; derived from
heat-inactivated E coli
membrane proteins
Both Oral II
ExPEC10V
Subunit; conjugate
O-polysaccharide, bioconjugated
to the carrier protein
Prophylactic Parenteral I/II
 Inclusion: patients
aged ≥60 yr with
history of UTI in
past 3 yr2
 Primary outcome:
first occurrence of
invasive ExPEC
disease (of 9V
serotypes) with
microbiological
confirmation in
blood, urine, or
other sterile sites2
https://www.who.int/publications/i/item/9789240052451
1. who.int/publications/i/item/9789240052451. 2. clinicaltrials.gov.

ExPEC4V Vaccine: Women With Recurrent UTIs
 Randomized, single-blind, placebo-controlled phase Ib trial
 Primary endpoint: AE incidence
 Other endpoints: immunogenicity and antibody functionality, UTI incidence
caused by E coli vaccine serotypes (O1A, O2, O6A, O25B)
Healthy women aged 18-70 yr with
self-reported history of recurrent UTIs
(2 infections in past 6 mo or 3 infections in past yr)
with ≥1 urine culture with E coli in preceding
5 yr and in generally good health
(N = 188)
Target-Dosed ExPEC4V
(n = 93)
Placebo
(n = 95)
Reduced-Dose ExPEC4V
(n = 6)
Huttner. Lancet Infect Dis. 2017;17:528.

ExPEC4V Vaccine: Safety in Women With Recurrent UTIs
AEs Occurring in
≥2% of Patients, n (%)
Placebo (n = 95) ExPEC4V (n = 93)
Any Severity Mild Moderate Severity Any Severity Mild Moderate Severe
Any event 47 (49) 43 (45) 12 (13) - 56 (60) 52 (56) 18 (19) -
Injection-site pain 17 (18) 15 (16) 2 (2) - 29 (31) 20 (22) 9 (10) -
Injection-site swelling 12 (13) 9 (9) 3 (3) - 18 (19) 11 (12) 7 (8) -
Headache 3 (3) 3 (3) - - 16 (17) 11 (12) 5 (5) -
Dizziness - - - - 4 (4) 3 (3) 1 (1) -
Fever - - - - 4 (4) 3 (3) 1 (1) -
Chills - - - - 3 (3) 2 (2) 1 (1) -
Diarrhea - - - - 2 (2) 2 (2) - -
Dysgeusia - - - - 2 (2) 1 (1) 1 (1) -
Extremity pain - - - - 2 (2) 2 (2) - -
Hyperhidrosis - - - - 2 (2) 1 (1) 1 (1) -
Injection-site warmth - - - - 2 ( 2) 2 (2) - -
Upper abdominal pain - - - - 2 (2) 1 (1) 1 (1) -

ExPEC4V Vaccine: Immunogenicity and UTI Incidence
 ExPEC4V vaccine induced significant
IgG responses for all serotypes,
comparing D30 vs baseline (P <.0001)
‒ O1A: 4.6x higher; O2: 9.4x higher;
O6A: 4.9x higher; O25B: 5.9x higher
 Antibody functionality seen via
opsonophagocytic kill activity
 No reduction of UTI incidence with
≥103 CFU/mL vs placebo
‒ In post hoc analysis, fewer UTIs caused
by E coli of any serotype observed
(0.207 mean episodes vs 0.463 mean
episodes; P = .002)
60
50
40
30
20
10
0
Cumulative
UTI
(≥10
5
CFU/mL)
50 100 150 200 250
Placebo, E coli
ExPEC4V, E coli
ExPEC4V, E coli, vaccine serotype
Placebo, vaccine serotype
Days After Vaccination
P = .002*
P = .074*
*Compared with placebo.

ESTELLA: ExPEC4V in Healthy Adults
 Randomized, double-blind, placebo-controlled phase II trial
 Primary objectives: safety, tolerability, immunogenicity of ExPEC4V, and
determination of dose-dependent immunogenicity 15 days after vaccination
Healthy adults
≥aged 18 yr
with BMI of
35 kg/m2
(N = 848)
Group 1—4:4:4:4 µg (n = 152)
Group 3—8:8:8:8 µg (n = 151)
Group 2—4:4:4:8 µg (n = 152)
ExPEC Dosing by Antigen Content: O1A;O2:O6A:O25B
Frenck. Lancet Infect Dis. 2019;19:631.
Group 4—8:8:8:16 µg (n = 152)
Group 5—16:16:16:16 µg (n = 152)
Groups
compared with
placebo
(n = 87)

ESTELLA: ExPEC4V Safety in Healthy Adults
Placebo Group 1 Group 2 Group 3 Group 4 Group 5
Any solicited local AE, n (%)
Pain or tenderness
Erythema
Swelling or induration
Other
11 (13)
10 (12)
1 (1)
0
1 (1)
41 (27)
38 (25)
5 (3)
2 (1)
2 (1)
34 (22)
30 (20)
6 (4)
3 (2)
4 (3)
42 (28)
40 (26)
6 (4)
3 (2)
2 (1)
47 (31)
43 (29)
7 (5)
4 (3)
5 (3)
58 (38)
54 (36)
8 (5)
8 (5)
7 (5)
Median days to onset of any
solicited local AE (range)
1.0 (1-2) 2.0 (1-8) 2.5 (1-8) 2.0 (1-8) 2.0 (1-8) 6.0 (1-8)
Any solicited systemic AE, n (%)
Fatigue
Headache
Nausea
Myalgia
Malaise
Fever (≥38°C)
Other
30 (35)
13 (15)
16 (19)
7 (8)
10 (12)
9 (1)
0
0
66 (43)
48 (32)
45 (30)
13 (9)
29 (19)
28 (18)
1 (<1)
0
54 (36)
32 (21)
25 (16)
9 (6)
26 (17)
18 (12)
0
0
62 (41)
47 (31)
27 (18)
22 (15)
32 (21)
26 (17)
1 (<1)
0
65 (43)
35 (23)
37 (25)
17 (11)
34 (23)
24 (16)
0
2 (1)
78 (51)
47 (31)
48 (31)
26 (17)
34 (22)
36 (24)
3 (2)
0
Median days to onset of any
solicited systemic AE (range)
1.0 (1-8) 2.0 (1-7) 2.0 (1-8) 2.0 (1-8) 1.0 (1-8) 2.0 (1-8)

ESTELLA: ExPEC4V Immunogenicity
 At Day 15,
≥80% participants
achieved ≥2x
increase in
serotype-specific IgG
 Immune responses
for ExPEC 4:4:4:8 µg
and 8:8:8:16 µg
dosages persisted
for 1 yr
*Percentage of participants with 2x increase in ELISA lgG at Days 15 and 360.
0
6.1
0 1.5 0
7.6
0
3.0
81.9
89.6
86.8
71.5
82.8
65.8
91.0
83.8
82.8
65
84.8
65.0
86.6
96.6
92.6
83.2
92.4
71.1
98.6
90.9 92.4
79.3
90.3
71.1
94.3 97.9 95.0
90.1
0
20
40
60
80
100
Day 15 Day 360 Day 15 Day 360 Day 15 Day 360 Day 15 Day 360
Participants*
(%)
Placebo Group 1 Group 2 Group3 Group 4 Group 5
01A 02 06A 025B

ExPEC: FiMH Vaccine
 Open-label, dose-escalation phase I study assessed FiMH vaccine safety in
67 healthy women ± histories of recurrent UTIs
‒ No SAEs resulted
‒ Vaccine induced both binding and functional antibodies
‒ Women with histories of recurrent UTIs demonstrated >150-fold increases in
antibodies against N-terminal region of FimH
Eldridge. Hum Vaccin Immunother. 2021;17:1262.

ExPEC: OM-89 Vaccine
 Multicenter, double-blind study in 52 centers in Europe found that
OM-89 significantly reduced UTI incidence during 12 mo of study vs placebo
(0.84 vs 1.28; P <.003) (N = 453)
‒ 34% UTI reduction resulted with OM-89 vs placebo
Bauer. Eur Urol. 2005;47:542.
Mo 1-3 Mo 4-6 Mo 7-9 Mo 12
End of
study
1 capsule daily No treatment
Booster course:
1 capsule first 10 days
of month

Possible Downfalls With Vaccines
 Selective pressure
‒ Eg, PCV7, emergence
of serotype 19A
(“vaccine-evading strain”)
 Emergence of vaccine
resistance (rarely observed)
‒ Typically, vaccines include
several immunogenic epitopes;
vaccine resistance requires
more mutations than
does antibiotic resistance
(eg, HBV vaccine)
Micoli. Nat Rev Microbiol. 2021;19:287.

Development of Resistance: Vaccines vs Antibiotics
Kennedy. Proc Biol Sci. 2017;284:20162562.
Antibiotics
Vaccines
Year
1920 1940 1960 1980 2000 2016
Sulfonamides
Penicillin
Streptomycin
Chloramphenicol
tetracycline
erythromycin
methicillin
cephalosporins
ampicillin
gentamicin
vancomycin
Oxyimino-beta-lactams
ceftazidime
imipenem
levofloxacin
linezolid
daptomycin
ceftaroline
Smallpox
Diphtheria
tetanus
pertussis
Influenza
Polio
Measles
Mumps
Rubella
meningococcal
pneumococcal
Hepatitis B virus
Haemophilus influenzae type b
Varicella zoster virus
Hepatitis A virus
Rotavirus
Human papillomavirus
Bacterial vaccine
Viral vaccine
First observations of resistance
Drug availability, line starts at production
introduction (except smallpox vaccine)

Reducing Antimicrobial Resistance With Vaccines
‒ Overuse and/or misuse of
antimicrobials
‒ Poor infection control
‒ Lack of hygiene
‒ Lack of new antimicrobials
Vaccines Prevent
Infections
Decrease
Antimicrobial Use
Reduce
Antimicrobial
Resistance
 Antimicrobial resistance driven by:
who.int/publications/i/item/9789240052451

Past Success in Antimicrobial Resistance
Reduction With Vaccines: PCV13
Dramatic mortality reduction observed in US and Europe when
compared with locations vaccine is not widely available/used1
Jansen. Hum Vaccin Immunother. 2018;14:2142.
10
8
6
4
2
0
Invasive
Pneumococcal
Disease
Cases
in
US
per
100,000
2005 2006 2007 2009 2010
2008 2011 2012 2013
Introduction
of PCV13
63%
Macrolides
81%
Cephalosporins
81%
Tetracyclines
83%
Penicillins
Change in Antibiotic-
Resistant Cases Between
2009 and 2013

Other Vaccine Success Stories
 Antimicrobial resistance reduced with Hib vaccine1
‒ Reduction seen in β-lactamase–positive strains2
 Influenza vaccine decreased
inappropriate antibiotic
prescriptions and secondary
bacterial infections3
‒ ~64% decline in antibiotic
prescriptions after employing
universal influenza vaccines in
Ontario compared with other
Canadian providences4
1. Gilsdorf. J infect Dis. 2021;224:S321. 2. Jansen. Human Vaccin Immunother. 2018;14:2142. 3. who.int/publications/m/item/
leveraging-vaccines-to-reduce-antibiotic-use-and-prevent-antimicrobial-resistance. 4.
30
25
20
10
5
0
Hib
Incidence
in
Children
Aged
<5
Yr
in
US
(1980-2012)
1980
15
1982 1984 1986 1988 1990 1992 1994 1996 1998 2000 2002 2004 2006 2008 2010 2012
Yr
First polysaccharide Hib vaccine licensed
for use in children aged ≥18 mo
First conjugate Hib vaccine licensed for use
in children aged ≥18 mo
First Hib vaccines licensed for use in infants
aged ≥2 mo

WHO Action Framework for Licensed Vaccines to
Maximize Impact on Antimicrobial Resistance
Vekemans. Clin Infect Dis. 2021;73:e1011.
Increase
coverage of
vaccines
with impact
on AMR
Update
recommendations
and guidance to
include the role of
vaccines
Improve
awareness &
understanding
of the role of
vaccines in
limiting AMR
Funding for R
& D of new
vaccines
Develop
regulatory &
policy to
accelerate
approval & use
of vaccines
Improve
methodologies
and increase
collection
and analysis of
relevant data
Develop
estimates of
vaccine value to
avert burden
1
2
3
4
5
6
7

Importance of Antimicrobial Stewardship
 Improve clinical outcomes
 Minimize harms by improving antimicrobial prescribing
 Increase infection cure rates while reducing:
‒ Treatment failures
‒ C difficile infection
‒ Adverse events
‒ Antimicrobial resistance
‒ Hospital costs and length of stay
5 D’s
RIGHT diagnosis
RIGHT drug
RIGHT dose
RIGHT duration
RIGHT de-escalation
cdc.gov/antibiotic-use/core-elements/hospital.html

Approaches to Contain Antimicrobial Resistance
Vekemans. Clin Infect Dis. 2021;73:e1011.
Invest in new
medicines,
diagnostic tools,
vaccines, and other
interventions
Optimize use of
antimicrobials in
humans and
animals
Improve awareness
and understanding
of antimicrobial
resistance
Strengthen
knowledge and
evidence base
through
surveillance and
research
Promote effective
sanitation, hygiene,
and infection
prevention
measures including
vaccines

Key Take-home Points
 Vaccines targeting ExPEC remain active area of research
‒ Current targets include the O-polysaccharide, FiMH, and the outer membrane vesicle
‒ Phase I, II, and III clinical trials ongoing
‒ Pending clinical outcome data
 Several benefits of vaccines include but are not limited to:
‒ ↓ infections, ↓ mortality, ↓ antibiotic use, and ↓ antimicrobial resistance
 Unlike most current vaccines, the ExPEC vaccine is predicted to target a niche
patient population
 Judicious use of antimicrobials through antimicrobial stewardship remains an
important way to prevent ExPEC infections and reduce antimicrobial resistance

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