THE POTENTIAL OF VACCINES TO PREVENT AMR...development, implementation •Establish the sources of...

CONFIDENTIAL

THE POTENTIAL OF VACCINES TO PREVENT AMR

Padmini Srikantiah, MD MPH

Bill & Melinda Gates Foundation

PDVAC Meeting, June 27, 2018

© Bill & Melinda Gates Foundation

1. Background: AMR at a global level

2. AMR Pathogen Priority List

3. Potential role of vaccines to impact AMR: mechanisms and factors to consider

4. Planned work to better characterize vaccine impact on AMR

© Bill & Melinda Gates Foundation | 2

OUTLINE


INCREASING BURDEN OF AMR

Source: Center for Disease Dynamics and Economic Policy, Resistance Map, 2015

Resistance of Klebsiella pnuemoniae 3rd generation cephalosporins Estimated neonatal sepsis deaths by bacteria resistant to first-line

antibiotics in five high-burden countries

Source: Laxminarayan, Lancet 2015


ANTIMICROBIAL RESISTANCE: INCREASING ATTENTION AT THE GLOBAL

LEVEL

2014: WHO AMR Global Report 2015: WHO AMR Global Action Plan 2015: AMR GLASS Manual

2016: UN General Assembly High Level Meeting on AMR

• AMR: global public health issue with

increasingly severe consequences

for human health and world

economy

• WHO Global Action Plan calls for

countries to tackle AMR across 5

pillars

• Increased awareness

• Improved surveillance

• Prevention of Infections

• Optimized use of antimicrobials

• Increased investment in

research, new medicines,

vaccines, diagnostics

• AMR discussed at UNGA 2016

• High level commitments at G20

• Follow-up high level meeting in

2019


REVIEW ON ANTIMICROBIAL RESISTANCE: O’NEILL REPORT, 2016

CONFIDENTIAL © Bill & Melinda Gates Foundation | 6



WHO AMR PRIORITY PATHOGEN LIST FOR RESEARCH AND DEVELOPMENT OF NEW ANTIBIOTICS, 2017

© 2014 Bill & Melinda Gates Foundation | 8

RANKING OF ANTIBIOTIC RESISTANT BACTERIA FOR RESEARCH AND DEVELOPMENT OF NEW ANTIBIOTICS, 2017

CONFIDENTIAL © Bill & Melinda Gates Foundation | 9


CONFIDENTIAL

Appropriate antibiotic use has the power

to save lives in the most vulnerable

communities

Our interest in AMR relates to our current

health strategies in developing countries

• How does AMR jeopardize the ability to

achieve defined health impact targets?

• How can we prevent and reduce the

burden of AMR?

We believe it’s critical to better

understand the prevalence of AMR, and

its impact on mortality, in developing

countries

The threat of AMR reinforces the

importance of prevention – vaccines and

infection control – which is a core focus of

foundation work

FOUNDATION PERSPECTIVE ON ANTIMICROBIAL RESISTANCE


CONFIDENTIAL

Focus areas:


Better characterize burden of AMR

among pathogens key to our strategies

in low-income countries

Better characterize AMR in vulnerable

populations (e.g. newborns)

Better quantify the impact of vaccines on

AMR and their role as a key lever in

addressing AMR

Identify and de-risk promising innovative

treatment and/or passive immunization

approaches, focused on targeting

antibiotic-resistant neonatal infections

VACCINES REMAIN AT THE CENTER OF OUR AMR APPROACH

• Need for a vaccine “priority” list to guide

research agenda

• How should value of vaccines be attributed

in context of AMR?

• Need to model the impact of vaccines on AMR

• Key pathogens discussed:

• TB

• Bacterial: Pneumococcus, GBS, GAS,

gonococcus, S. aureus, Pseudomonas,

Klebsiella, Chlamydia,

• Viral: Influenza, RSV, HIV


CHATHAM HOUSE MEETING ON VALUE OF VACCINES FOR AMR, MARCH 2017


IMMUNIZATION AGAINST A BACTERIAL PATHOGEN AND ITS EFFECT ON ANTIBIOTIC USE AND SPREAD OF AMR

Source: Jansen, Nature Medicine, 2018

• Within 5 years of PCV-7 introduction in children:

• non-suscpeptible strains decreased by 57%,

• invasive disease due to non-susceptible strains in

children <2yrs decreased by 84%

• PCN non-susceptible invasive disease in >65yrs

dropped by 49% (herd immunity)

• In South Africa, PCV introduction associated with

82% reduction in PCN-resistant pneumococcal

disease in children, and 47% reduction in PCN-

susceptible disease

• Introduction of PCV was associated with a reduction

in antibiotic use due to the decrease in

pneumococcal infections


IMPACT OF PNEUMOCOCCAL CONJUGATE VACCINE ON PENICILLIN NON-SUSCEPTIBLE STRAINS

Declines in proportion of PCN nonsusceptible PCV7

serotypes (70% in 2009 to 47% in 2012)

Source: von Gottburg, NEJM, 2014

• Vaccination effects:

• Prevent influenza

infections and disease

• Decrease likelihood of

secondary bacterial

infections (pneumonia

and otitis media)

• Reductions in antibiotic

prescriptions and use


UNIVERSAL INFLUENZA IMMUNIZATION PROGRAM IN ONTARIO CANADA: IMPACT ON ANTIBIOTIC PRESCRIPTIONS

Source: Kowng, CID, 2009


PATHWAYS THROUGH WHICH VACCINATION AGAINST FOCAL BACTERIA AND NONFOCAL

BACTERIA AND VIRUSES CAN IMPACT ANTIBIOTIC RESISTANCE.

Atkins, et al. Lancet Infectious Diseases, 2017


ESTIMATING THE PROPORTION OF BYSTANDER SELECTION FOR ANTIBIOTIC RESISTANCE

• Bystander selection: selective pressures exerted on microbial flora that are not the target pathogen for treatment

• US data from 2010-2011 (National Ambulatory Medical Care Survey, National Hospital Ambulatory Medical Care Survey, Human Microbiome Project)

• Estimate magnitude of bystander selection for range of clinical relevant antibiotic-species pairs

• Expressed as “proportion of bystander exposures” • Proportion of all exposures of a specific antibiotic

experienced by a species that were not intended as treatment for that pathogen

• For outpatients in U.S., estimate this proportion for all antibiotics is >80% for 8 of 9 pathogens of interest

Tedijanto, Lipsitch et al, BioRxiv 2018

• Vaccination programs demonstrated to reduce antibiotic use via several routes:

1. Incidence of infections needing antibiotic treatment is reduced

2. Fewer drug-resistant infections requiring a secondary course of antibiotics

3. Fewer viral infections for which antibiotics are given

4. Fewer viral infections leading to secondary bacterial infections for which antibiotics are needed


MODELLING THE IMPACT OF VACCINE TO PREVENT AMR

Source: Center for Disease Dynamics and Economic Policy


THE POTENTIAL IMPACT OF VACCINES ON AMR: HEALTH AND ECONOMIC OUTCOMES

Source: Chatham House Value of Vaccines on AMR Meeting Report, 2017


1. Disease targeted analyses to model and estimate the

potential vaccine impact on AMR

2. Development of value attribution framework for vaccines

impact on AMR

• Semi-quantitative estimation of vaccines against AMR

• Use of Multi-component decision analysis (MCDA)

methodology

3. Priority Guidance Document for Vaccines/AMR

VACCINES TO PREVENT AMR: MODELLING IMPACT AND DEVELOPING A

PRIORITIZATION FRAMEWORK

Pathogens with

Existing Vaccines

Pathogens with

Pipeline Vaccines

Pneumococcus RSV

Haemophilus

influenzae B

GBS

Influenza Shigella

Rotavirus Gram negative

organisms (neonatal

sepsis)

Typhoid TB


1. Develop modelling framework to integrate vaccine impact, modelling drug resistance, and economic

analysis

2. Propose analytic approach that takes into account dynamics of host-pathogen ecology in the presence of

antibiotics, and where possible, also accounts for healthcare system and antibiotic market.

3. Endpoints:

Antimicrobial consumption

Antimicrobial resistance

Health outcomes

Economic consequences– cost effectiveness analysis to estimate financial risk protection benefits of

vaccination (estimated out of pocket treatment costs averted– which include cost of appropriate

treatment, cost of antibiotics; money metric value of insurance– sum a household is willing to pay to

avoid financial risk associated with treatment)

MODELLING THE VALUE OF VACCINES IN REDUCING THE BURDEN OF ANTIMICROBIAL RESISTANCE


MODELLING THE VALUE OF VACCINES IN REDUCING THE BURDEN OF ANTIMICROBIAL RESISTANCE

Source: Center for Disease Dynamics and Economic Policy


Develop overarching guidance document highlighting priority needs to guide decision making on optimal use

of vaccines against AMR

Technical advisory group to determine support the development of a policy document that provides

background and high-level mapping of necessary activities in field, aimed at decision makers in vaccine

R&D and policy

Anticipate the guidance document will highlight a broad array of issues related to vaccines/AMR:

• Financing, global coordination, industry engagement, political, regulatory/legal framework, incentive

schemes, clinical development pathways, access/use, programmatic challenges

Expect outputs to include guidance on:

• incorporating AMR reduction into decision-making (including methodology for calculating economic

value)

• incentivising vaccine development for pathogens that would reduce AMR

• addressing data gaps (including recommendations for collecting data on AMR and antibiotic usage

during vaccine trials)

DEVELOPING A PRIORITIZATION FRAMEWORK FOR VACCINES TO PREVENT AMR


Develop Vaccine Prioritization Framework for AMR

Expands on previous experience where WHO supported GAVI to define vaccine investment strategy

• Consensus development of:

- Pathogens and vaccines to consider: existing, pipeline; vaccines with direct vs indirect effects on

bacterial pathogens

- Use case/stakeholders for outputs of exercise

• Consensus development of attributes to be included in prioritization exercise, and metrics to establish how

value will be assigned to each of these attributes, and how attributes will be weighted

- Criteria could include: global burden (mortality/DALYs), potential to reduce antibiotic, feasibility of

vaccine development, investments required, ethical considerations, time trends, cost considerations of

development, implementation

• Establish the sources of data to populate the attributes/elements of the framework. Key gaps will be

identified during this process.

• Application of the value attribution framework to vaccines/pathogens of interest

• Development of prioritization list/document(s) for key stakeholders including: vaccine delivery,

implementation, vaccine R&D, product developers, policy makers.

• Goal for vaccine impact on AMR to become a systematic and standard consideration in evaluation of

potential vaccine impact on health

DEVELOPING A VALUE ATTRIBUTION FRAMEWORK FOR VACCINES TO PREVENT AMR

• Prevention of infections is central to effectively combatting AMR and the excess mortality associated with it

• Vaccines have the potential to play an important role

• Relationships between vaccine, pathogen (focal and non-focal), antibiotic use, and AMR are complex

• Important to work toward quantifying this impact through mathematical modelling, aware of limitations

Planned work with WHO, CDDEP, in coordination with Wellcome Trust

• Modelling impact of vaccine on AMR (antibiotic use, AMR, mortality)

• Value attribution framework to support vaccine prioritization for AMR (leeping in mind health,

economic, regulatory factors)

• WHO Guidance document: broad goal of incorporating AMR reduction/outcomes into vaccine related

decision making


SUMMARY

• BMGF

• Keith Klugman

• Calman Mclennan

• Samia Saad

• CDDEP

• Ramanan Laxminarayan

• Wellcome Trust

• Charlie Weller

• Elizabeth Klemm

• Zoe Seager

• WHO

• Johan Vekemans

• Martin Friede


ACKNOWLEDGEMENTS

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