Wednesday, November 18, :00 PM ET. Agenda

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1 Addressing Antimicrobial Resistance through Vaccines Wednesday, November 18, :00 PM ET Agenda Agenda Welcome and Introduction Thomas M. File, Jr., MD, NFID Immediate Past-President Addressing Antimicrobial Resistance through Vaccines Scott K. Fridkin, MD, Senior Advisor, Antibiotic Resistance in Healthcare, Division of Healthcare Quality Promotion, National Center for Emerging and Zoonotic Infectious Diseases, Centers for Disease Control and Prevention Jane M. Knisely, PhD, Program Officer, Bacteriology and Mycology Branch, Division of Microbiology and Infectious Diseases, National Institutes of Health Open Discussion/Questions and Answers 1

2 General Information Please note that today s webinar is being recorded All phone lines will be placed on mute throughout the program To hear audio: Computer: Follow directions Phone: ; Access Code After both presentations, there will be a Question and Answer period Use the Chat box on the lower left side of your screen to type your question At the end of the webinar, participants will be directed to an online evaluation CME Credit/Webinar Evaluation The National Foundation for Infectious Diseases (NFID) is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education (CME) for physicians. NFID designates this enduring material for a maximum of 1.0 AMA PRA Category 1 Credit TM. Online evaluation and post-test will be available following the webinar at: Certificate will be available for print or download following successful completion of online evaluation and post-test 2

3 Disclosures Marla Dalton (NFID staff, content reviewer) owns stock, stock options, or bonds from Merck & Co., Inc. Thomas M. File, Jr., MD (content reviewer) served as an advisor or consultant for Actavis, Cempra, Merck & Co., Inc. Melinta, MotifBio, Nabriva, Pfizer Inc., Tetraphase, and Venatorx; and received grants for clinical research from Cempra and Pfizer Inc. All other faculty, activity planners/reviewers, and staff for this activity have no relevant financial relationships to disclose Learning Objectives At the conclusion of this webinar, participants will be able to: Recognize the promise of vaccines for reducing the burden of resistant bacterial infections and enhancing antimicrobial stewardship Describe the status of vaccine development for key resistant pathogens Consider optimal target populations for vaccination against different pathogens 3

4 About NFID Non-profit 501(c)(3) organization established in 1972, dedicated to educating the public and healthcare professionals about causes, treatment, and prevention of infectious diseases across the lifespan Reaches consumers, healthcare professionals, and media through: Coalition-building activities Public and professional educational program Scientific meetings, research, and training Longstanding partnerships to facilitate rapid program initiation and increase programming impact Flexible and nimble organization Addressing Antimicrobial Resistance through Vaccines Scott K. Fridkin, MD Senior Advisor, Antibiotic Resistance in Healthcare Division of Healthcare Quality Promotion National Center for Emerging and Zoonotic Infectious Diseases Centers for Disease Control and Prevention Atlanta, GA 4

5 Epidemiologic Insights into Vaccine Impact on Antibiotic Resistance Vaccines as a tool for reducing the burden of resistant bacterial infections and enhancing antimicrobial stewardship Describe the status of vaccine development for key resistant pathogens Consider optimal target populations for vaccination against different pathogens Spread of Antibiotic-Resistant Germs Antibiotic-resistant germs cause more than 2 million illnesses and at least 23,000 deaths each year Half of the antibioticresistant threats are predominately healthcareassociated infections 5

6 Urgent and Serious Threats Objectives Illustrate how vaccines are a tool for reducing the burden of resistant bacterial infections and enhancing antimicrobial stewardship Describe the status of vaccine development for key resistant pathogens Consider optimal target populations for vaccination against different pathogens 12 6

7 What to Strive For: Pneumococcal Vaccine Has Reduced AR Infections and Antibiotic Use In 2000 Conjugate 7 valent pneumococcal vaccine introduced in US for children 13 Kyaw et al, NEJM, 2006,354, Pneumococcal Vaccine Has Reduced AR Infections and Antibiotic Use PCV given to children successfully eliminates of 94 known pneumococcal serotypes including 90% of antibiotic resistant strains Added Benefit by reducing transmission of antibiotic resistant strains (from kids to adults!) 14 Kyaw et al. N Engl J Med. 2006; 354:

8 Pneumococcal Vaccine Has Reduced AR Infections and Antibiotic Use In CA, PCV reduced antibiotic prescriptions by 5.4% (CI 4.0 to 6.7%) in all follow-up starting at 1stst Dose. From Dose 1 to age 3.5 years, PCV prevented a total of 35 antibiotic prescriptions per 100 children vaccinated per protocol. In Israel, ABX days cut in half in first year Fireman et al, PIDJ 2003; 22: RR of antibiotic use was 0.83 (95% CI , P< 0.001) Dagan et al, 2001, PIDJ, 20, A Pathway to Less AR and Antibiotic Use Direct Effect Prevention of primary or recurrent disease Indirect Effects Preventing spread of colonizing and subsequent infecting organisms from vaccinated to unvaccinated Respiratory: S. pneumoniae GI microbiota: Clostridium difficile, CRE, other GNR Skin: MRSA Prevent spread from decreased interactions with healthcare system (avoid becoming colonized/infected with AR pathogen) 8

9 Clostridium difficile Infection (CDI) Antibiotic exposure is the overwhelming most critical risk factor for CDI Preventing unnecessary antibiotic use will dramatically reduce CDI Efforts to develop a Clostridium difficile vaccine are underway Identification of patients at risk for Clostridium difficile infection (CDI) is critical to inform vaccine trials Epidemiology for Vaccine Development Distribution of Clostridium difficile Infections by Location at Time of Diagnosis, Emerging Infections Program, 2010 CDI Cases (N=10,342)* Post hospital Discharge 19% Hospital-onset 23% Community- Associated 32% 82% have had at least one outpatient healthcare exposure in the 12 weeks prior to symptoms onset; understanding these settings can inform vaccine trials Nursing-home onset 26% * EIP Sites: California, Colorado, Connecticut, Georgia, Minnesota, New York, Oregon, and Tennessee 45% of all CDI occurs in post-discharge setting or in nursing homes, making these populations important consideration for primary prevention through vaccine CDC, MMWR March 9, 2012 / 61;

10 Identifying Future Clostridium difficile Infection Following Hospital Discharge Identification of patients at risk for Clostridium difficile infection (CDI) is critical to inform vaccine trials Combining active surveillance across communities with hospital administrative data Identify groups at high risk of CDI post-discharge (during 28 days after hospital discharge) Used 28 days after discharge to take into account time needed for vaccine recipients to build an immune Validated a risk index applied at hospital discharge high risk patients at discharge were ~4-5 times greater than other patients Risk score based on few data available at discharge, demonstrated good predictability Risk Index for Combined Model with LOS Characteristic Points Characteristic Points Age LOS 1-3 Days 0 Age LOS 2-3 Days 1 Age LOS 4-9 Days 4 Age LOS 10+ Days 8 1 Past Visit 6 Fluoroquinolone ever 2 2 Past Visits 8 3 rd /4 th generation cephalosporin ever Lincosamide ever 1 3 Apply Model to Truven Health MarketScan Hospital Drug Database (HDD) Proprietary Database Contains billing records for all adult and pediatric patients from approximately 500 hospitals Years Longitudinal, relational database 10

11 Results Low Risk (score <14) High Risk (score 14) Total CDI 1,088 6,699 7,787 No-CDI 5,021,784 3,644,787 8,666,571 Total 5,022,872 3,651,486 8,674, Hospitals 42% of index visits high risk 86% of CDI cases occurred in high risk cohort OR=8.5, p < S. aureus 80,000 invasive MRSA infections each year in the US Roughly 15% are community associated without clear ties to healthcare stable rates over past 10 years Roughly 20% are hospital-onset decreasing 10% per year Most (60%) occur in post-discharge setting little change Defining risk by subpopulation can help target vaccine trial efforts 11

12 Using CDC s NHSN to Quantify Incidence of Deep or Organ Space S. aureus Infections, by Procedure Type, 2011* Procedure Percent with SSI* SSI with S. aureus Ventricular Shunt % 0.73 Refusion of Spine % 0.63 Fusion of Spine % 0.38 Hip Arthroplasty % 0.34 Knee Arthroplasty % 0.23 Abdominal Hysterectomy 0.6 8% 0.05 Attack rate (%) S. aureus SSI Common procedure with high attach rate in otherwise healthy patients; attractive for vaccine clinical trial *detected on admission or re-admission to same hospital, reported to NHSN in Full report on selected procedures at Also to be presented in 2013 CDC/HICPAC General Guidelines for the Prevention of Surgical Site Infections National Burden of Disease estimates (Adults) of Invasive MRSA Infection by Subgroup (2009) Population Estimated No. Infections Estimated Population No. per 100,000 US adults 76, ,458, years 38, ,888, years 37,972 39,571, Private household resident 41, ,371, Long-Term Care resident 15,281 1,402,000 1,090 Chronic hemodialysis 10, ,000 2,909 66% of invasive MRSA (non-dialysis patients) cases admitted from home were in hospital during the previous 12 weeks; making vaccination at hospital discharge among high risk discharges a viable vaccine administration window especially if protection is anticipated to be transient Fagan, IDWeek 2012; Dantes, JAMA Internal Medicine

13 Percent of Total Cumulative Percent Two-thirds of Patients Presenting To Hospital with Invasive MRSA Infections Were Discharged from a Hospital in the 12 Weeks before Infection*, Emerging Infections Program, % 25% 66% 100% 90% 80% 20% Percent of Total Cumulative % 70% 60% 15% 50% 10% 40% 30% 5% 20% 10% 0% >75 Weeks between Prior Hospital Discharge and MRSA culture date 0% Epidemiologic Insights into Vaccine Impact on AR: Summary Using epidemiologic data can aid in targeted high risk patients for vaccine trials CDI: Enrolling high risk patients at discharge decreases estimated no. to enroll and decreases cost of a clinical trial S. aureus: high risk may be surgical population; however considerations for high burden disease as a longer term target (post-discharge setting) Decreasing disease burden through primary prevention will reduce antibiotic use by Direct effect on primary prevention Secondary effect on preventing transmission and subsequent prescribing 13

14 Vaccines for Antimicrobial Stewardship Jane M. Knisely, PhD Program Officer, Division of Microbiology and Infectious Diseases NIAID, NIH, DHHS NFID Webinar November 18, 2015 National Strategy: 5 Goals Slow the Development of Resistant Bacteria and Prevent the Spread of Resistant Infections Strengthen National One-Health Surveillance Efforts to Combat Resistance Advance Development and Use of Rapid and Innovative Diagnostic Tests for Identification and Characterization of Resistant Bacteria Accelerate Basic and Applied Research and Development for New Antibiotics, Other Therapeutics and Vaccines Improve International Collaboration and Capacities for Antibiotic Resistance Prevention, Surveillance, Control, and Antibiotic Research and Development 14

15 NIAID Antibacterial Resistance Program Basic Research Translational Research/ Product Development Clinical Research Harnessing the Immune System to Combat Bacterial Infections Diagnosis, Prevention, and Treatment Disclaimer This information was assembled from publicly available sources and may not be comprehensive 15

16 C. difficile Infections Importance The most commonly reported pathogen responsible for health care-associated infections 1 ~ 480K people are infected each year contributing to 29K deaths 2 Clostridium difficile infections (CDI) contribute to $3B in extra US healthcare costs 3 Challenges Not always a pathogen Recurrence occurs easily and often New advances linking antibiotics, gut microbes, and metabolic function Credit: NationalGeographic.com 1 CDC; 2 Lessa, et al., 2015 NEJM 372:9; 3 Dubberke, 2012 J Hosp Med 7:S1 Current Vaccine Approaches for C. difficile Infection Vaccine Approach Subunit Toxin-based (inactivated full length toxoid) Toxin-based (inactivated recombinant toxoid) Stage of Development Phase III Phase II Sanofi Support Pfizer, Valneva Nontoxic protein chimeras Preclinical NIAID Novel virulence factors Preclinical NIAID Surface proteins/glycans Live or Vectored Preclinical Live Salmonella vector Preclinical NIAID Adenovirus vector Preclinical NIAID Novartis/Other 16

17 Toxin-Based Vaccine for C. difficile Infection Increas ed toxin producti on = C. difficile Sanofi vaccine candidate affects the disease here thus blocking the activity of the toxin. Modified from: Young & Britton, 2014 Gastroenterology 146:1547 Methicillin-resistant Staphylococcus aureus Importance Methicillin-resistant Staphylococcus aureus (MRSA) is a bacterium that is resistant to many antibiotics. Classic opportunistic infection. MRSA causes life-threatening bloodstream infections, pneumonia and surgical site infections. Challenges Strains are geographically diverse and versatile in antigenic mechanisms Different vaccine components may be needed to treat the various manifestations of infections, from skin and soft tissue infections to endocarditis, bacteremia, or implant biofilms It is unclear what immunological response is protective 17

18 Staph Vaccines: A History Vaccine Approach Status Manufacturer PentaStaph: 5 antigen combo of capsular polysaccharides, adhesion factor and toxins 4 antigen combo with 2 surface proteins, and 2 secreted proteins. SA75: Whole staph cells inactivated by treatment with chloroform StaphVax: capsular polysaccharides Single recombinant protein IsdB (Iron Surface Determinant B) Some Phase I data Phase I Complete Phase l complete Phase III Failed Phase III Failed NABI/GSK Novartis Vaccine Research International NABI/GSK Merck Fowler VG et al. JAMA, April 3, 2013 Vol 309, No. 13 Staph Vaccines: Current Concepts Under Investigation Vaccine Approach Stage of Development Support SA4Ag: 4 antigen combination PhII Pfizer Toxoids Preclinical NIAID Recombinant iron-regulated proteins Multicomponent S. aureus bioconjugate vaccines: capsular polysaccharides Surface polymers that promote biofilm formation Non toxigenic protein A, a modified cell surface protein Recombinant Candida protein Als3, a cell-surface adhesion factor Preclinical Preclinical Preclinical Preclinical Preclinical NIAID NIAID NIAID NIAID NIAID, NovaDigm 18

19 NDV-3: Vaccine Candidate Active Against Candida albicans and Staphylococcus aureus Cell surface proteins C. albicans S. aureus Agglutininlike sequence (Als3) Clumping factor N. gonorrhoeae Infections Importance Second most commonly reported notifiable infection in the US; easily transmitted Control relies on prompt identification and treatment Showing resistance to most antibiotics usually used to treat it Challenges Antigenic variation of bacterial surface components helps the bacteria evade the immune system Gonococci can induce antibodies that block the binding of effective antibodies Unclear what immunological response is protective 19

20 Current N. gonorrhoeae Antigens Under Investigation Approach Peptide mimetic; bactericidal lipooligosaccharide (LOS) epitope Transferrin binding proteins; iron receptors Outer membrane channel; active efflux pump system Surface-exposed enzyme; anaerobic growth, biofilm formation Stage of Development Preclinical Preclinical Preclinical Preclinical Support NIAID NIAID NIAID NIAID Peptide Mimic Vaccine Monoclonal Antibody Bacteria Polysaccharides Screen peptide (protein) library with monocolonal to find mimic Vaccine Candidate Maximize presentation platform For more information: Rice PA, et. al. Immunization against a Saccharide Epitope Accelerates Clearance of Experimental Gonococcal Infection. PLoS Pathogens Aug; PMCID: PMC

21 Other Urgent and Serious AR Threats Pathogen Basic Research Preclinical candidate(s) Clinical candidate(s) Licensed Vaccine(s) Streptococcus pneumoniae Salmonella typhi Mycobacterium tuberculosis ( ) Campylobacter Shigella Pseudomonas aeruginosa Candida Enterobacteriaceae (including CRE and ESBL) Acinetobacter Non-typhoidal Salmonella Enterococci Beyond Vaccines: Prophylactic Immune Interventions Generally, vaccines require: Large target populations Broad implementation Low cost Prophylactic immune interventions could allow for: Smaller at risk target populations Less stringent requirement for durable immune response A different business model Carole Heilman, Infectious Disease News, July

22 Prophylactic Immune Interventions: Monoclonal Antibodies in Development Chris Morrison, Nature Reviews Drug Discovery 14, (2015) Where do vaccines fit in the antimicrobial resistance puzzle? 22

23 Questions & Answers CME Credit/Webinar Evaluation The National Foundation for Infectious Diseases (NFID) is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education (CME) for physicians. NFID designates this enduring material for a maximum of 1.0 AMA PRA Category 1 Credit TM. Online evaluation and post-test will be available following the webinar at: Certificate will be available for print or download following successful completion of online evaluation and post-test 23

24 Upcoming NFID CME Webinar Influenza Vaccines: Giving the Right Dose at the Right Time Wednesday, December 9, :00 PM ET Register: Subscribe to future updates: 24