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Vaccine Pipeline for Prophylactic Antimicrobial Resistance Prevention Jan T Poolman, PhDHead Bacterial Vaccines Discovery & Early DevelopmentJanssen Vaccines & Prevention B.V. 26 February 2020 PACCARB, Washington DC (USA)

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Extraintestinal Pathogenic E. coli (ExPEC) and S. aureus are key pathogens thatoccur frequently & are associated with bloodstream infection and high mortality

! Nr1 pathogen E. coli/ExPEC is lacking in ESKAPE; ESKAPEE has come into use

E. coliS. aureus

Klebsiella spp.Enterococcus spp.

P. aeruginosaC. difficile

Coagulase-neg staphylococciCandida spp.

Enterobacter spp.Proteus spp.

Top 10 most frequently isolated microorganisms of reported HAI in EU/EEA study (2016-2017)

ESKAPE pathogens:EnterococcusStaphylococcusKlebsiellaAcinetobacterPseudomonasEnterobacter

Suetens et al., Surveillance and outbreak report (EU/EEA), 2018

0 5 1 0 1 5 2 0

P r o t e u s s p p .

E n t e r o b a c t e r s p p .

C a n d i d a s p p .

C o a g u l a s e - n e g a t i v e s t a p h y l o c o c c i

C . d i f f i c i l e

P . a e r u g i n o s a

E n t e r o c o c c u s s p p .

K l e b s i e l l a s p p .

S . a u r e u s

E . c o l i

F r e q u e n c y o f i s o l a t e d m i c r o o r g a n i s m s ( % )

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E. coli/ExPEC & S. aureus are the leading pathogens associated with healthcare-associated infections (HAI) in largest USA HAI epidemiology study

Weiner et al., Infect Control & Hosp Epidemiol, 2019

Modified from Weiner et al., Infect Control & Hosp Epidemiol, 2019

Staphylococcus aureus 42,132 (11.8)12

Escherichia coli 62,571 (17.5)

Distribution and rank order of the most frequently reported pathogens across all types of adult HAI -NHSN, 2015-2017

National Healthcare Safety Network (NHSN):• Managed by Centers for Disease control and

prevention (CDC)• The largest and most widely used electronic

surveillance system for tracking HAI in the UnitedStates

• Over 25,000 healthcare facilities participate inthe NHSN by entering and analyzing data on HAIs

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E. coli/ExPEC & S. aureus are the leading causes of community-onset and HAI related bacteremia in population-based study Denmark

35%

45%

20%

NosocomialCommunity acquiredHealth-care associated

Percentage of bloodstream infections by acquisition place and pathogen

Søgaard et al., CID 2011Weiner et al., Infection Control & Hospital Epidemiology 2016

E. coli

E. coli

0

S. aureus

E. coli

S. pneumoniae

S. aureus

Other enterobacteria

Other enterobacteria

S. aureus

0.1Proportion of patients

0.2

Nosocomial

Community

Health-care

0.3 0.4

Rank

ord

er

Population-based study from Denmark (2002-2006)

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Cassini et al., Lancet Infect Dis 2019 – data from EARS-Net collected between Jan 1, 2015 – Dec 31, 2015;

Burden of antibiotic-resistant E. coli/EXPEC & S. aureus/MRSA infectionsoutnumbers other AMR infections in EU and EEA

Carbapenem-resistant K. pneumoniae (CRKP) Carbapenem-

resistant Acinetobacter spp. (CRACI)

3rd generationcephalosporin-resistant E. coli (ESBL)

Methicillin-resistantS. aureus (MRSA)

Carbapenem-resistantP. aeruginosa

3rd gen. cephalosporin-resistantK. pneumoniae

- EU and European Economic Area, 2015 -

Num

ber o

f att

ribut

able

dea

ths

WHO list of priority AMR pathogensPriority 1 – critical• Carbapenem-resistant Acinetobacter

baumannii• Carbapenem-resistant P. aueruginosa• Carbapenem- and third generation

cephalosporin-resistant (ESBL) Enterobacteriaceae (predominantly ExPEC and K. pneumoniae)

Priority 2 – high• Methicillin-resistant S. aureus

(MRSA)/vancomycin-resistant S. aureus• …

Carbapenem-resistant E. coli (CREC)

37.2

32.6

27.222.5

14.011.58.6

5.5

14.011.5

8.6

5.5

Infections with antibiotic-resistant bacteria

Number of casesWHO Pathogens Priority List Working group,Tacconelli et al., Lancet Infect Dis 2018

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The Staphylococcus aureus-vaccines field: a history of failures

More human-like surgical-site-infection model needed• Misled by mice in absence of accepted mode of actions

NABI/GSK - StaphVax Merck - V710 Pfizer - SA4AgCP5 and CP8 IsdB CP5, CP8 + ClfA + MntC

2006 20182012

Reasons to believe that it is possible to beat this bug:

Focus on key specific S. aureus virulence factors/immune escape mechanisms

Use of a strong Th1 adjuvant, induction of high antibody levels and CD4 bystander T cell immunity

• Focus on capsules and surface proteins and opsonophagocytosiswhilst S. aureus primarily aims at immune escape mechanisms

• Absence of adjuvant:

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E. coli/ExPEC bacteremia outpaces pneumococcal bacteremia in seniors

Jackson et al., JID 2005 Would be good to add E. coli /ExPEC on CDC’s ABC list of pathogens

https://www.cdc.gov/abcs/pathogens/pathogen-links.html

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6 5 - 6 9 7 5 - 7 9 8 0 - 8 4 8 5 - 8 9 ≥ 9 07 0 - 7 4

A g e a t b a s e l i n e ( y e a r s )

INCIDENCE OF COMMUNITY-ONSET BACTEREMIA (U.S.)Cohort of 46,238 non-institutionalized Group Health cooperative

members ≥65 years of age; followed from 1998–2001

Invasive ExPEC Disease (IED)Invasive Pneumococcal Disease (IPD)

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The development of ExPEC10V, a glycoconjugate vaccine: combination of a proven mechanism of protection and a breakthrough bioconjugation technology

In-licensed breakthrough bioconjugation technology enables production of multivalent ExPEC conjugate vaccine

Low threshold serum levels of opsonophagocytic antibodies correlate with protection against diseases caused by encapsulated bacteria

Adapted from Peeters et al., Vaccine protocols, 1996; Rappuoli & De Gregorio, Nature, 2011

Opsonophagocytic killing

PoolmanJ, et al. J Infect Dis. 2016

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OPA DATA: immunological PoC- REASON TO BELIEVE -

OPA responses comparable to Prevnar in seniors#

# Van Deursen et al., Clin Infect Dis, 2017; Bonten et al., N Engl J Med, 2015

Phase 1/2a ExPEC10V ongoing– aiming for all 60+ use

Robust Ab response with opsonophagocytic killing ExPEC4V Phase 2 dose-finding study in seniors

activity (OPA) in over 90% of subjects

Frenck et al., Lancet Infect. Dis., 2019

Janssen’s ExPEC10V vaccine in Phase 1/2a, aiming for all-60+ use

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Conclusions, where can vaccines help to address the AMR issue?

• Vaccines can prevent the consequences of AMR: prevent acute life-threatening invasive bacterial diseases in a situation where the first antibiotic regimen needs to be the right one

• Prevention of invasive bacterial disease with surface polysaccharide protein conjugate vaccines have a successful track record, this is particularly promising for E. coli/ExPEC invasive disease, the nr. 1 cause of invasive disease in adults

• S. aureus/MRSA vaccines have failed in Phase 3 trials so far

• To prevent the use of antibiotics, vaccines would need to impact mucosal bacterial diseases such as urinary tract infections, skin and soft tissue infections, pneumonia, etc; this requires enhanced immune responses, a need for CD4 bystander T-cell immunity in addition to strong antibody responses (adjuvant)

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