Merck

Vaccines for

Older Adults

Eddy A. Bresnitz, MD, MSCE

Executive Director, Adult Vaccines

WHO Meeting on Immunization in the Elderly

March 22, 2017

Geneva, Switzerland

Topics Covered

• Currently licensed vaccines

– Herpes Zoster (HZ) Vaccine: ZOSTAVAX® (Zoster Vaccine Live)

– Pneumococcal Polysaccharide Vaccine: PNEUMOVAX®23

(Pneumococcal Vaccine Polyvalent)

– Hepatitis B Vaccine: RECOMBIVAX HB® Hepatitis B Vaccine

(Recombinant)

• Vaccine pipeline for adults

– Phase II: Pneumoconjugate Vaccine (V114)

– Phase III: Herpes Zoster Inactivated VZV vaccine (V212)

– Phase III: Ebola vaccine (rVSV-ZEBOV-GP; V920)

• Drivers and barriers to vaccine uptake in adults

ZOSTAVAX™ [Zoster Vaccine Live (Oka/Merck)] Product Profile

• Live, attenuated VZV vaccine

• Minimum of 19,400 PFU per dose1

– 14 times the minimum potency of VARIVAX™ [Varicella Virus

Vaccine Live (Oka/Merck)]

• No preservative

• Lyophilized product

• Single subcutaneous dose

• Licensed in 58 countries

• More than 36 million doses distributed globally since 2006

PFU=plaque-forming unit; VZV=varicella-zoster virus.

1. Oxman MN et al. N Engl J Med. 2005;352:2271–2284.

Zoster Vaccine Live (Oka/Merck) Indications and Contraindications

Indications*

Contra-

indications

• ZOSTAVAX is indicated for vaccination of adults

aged 50 years and older for

- Prevention of herpes zoster (HZ)

- Prevention of postherpetic neuralgia (PHN)

- Reduction of acute and chronic HZ-associated pain

• History of anaphylactic/anaphylactoid reaction to

gelatin, neomycin, or any other component of the

vaccine

• Immunosuppression or immunodeficiency

• Active untreated tuberculosis

• Pregnancy

HZ Vaccine (Zostavax) Efficacy/Effectiveness

Efficacy1,2:

– HZ: 50-59: 70%; 60-69; 64%; 70+: 38%

– Post Herpetic Neuralgia: 60-69: 66%; 70+: 67%

Effectiveness3-5 (%):

1.Oxman MN et al. N Engl J Med. 2005;352:2271–2284.

2. Schmader KE et al. Clin Infect Dis. 2012;54:922–928;

3. Tseng HF et al. J Infect Dis. J Infect Dis 2016;213 (12) 1872-1875.

4. Langan et al. 2013;10(4):e1001420. doi: 10.1371/journal.pmed.1001420. Epub 2013 Apr 9

5. Baxter R et al. Presented at ID Week. New Orleans, October, 2016

Low Rates of Severe (Grade 3)

Injection-Site and Systemic

Adverse Events within 7 days

Postvaccination with Live

Attenuated HZ Vaccine, a Post

Hoc Analysis of Two Pivotal Phase

3 Trials Using FDA Grading Scale

Presented at the 26th European Congress of Clinical Microbiology and

Infectious Diseases (ECCMID), Amsterdam, The Netherlands,

April 9–12, 2016.

Zoran Popmihajlov, MD, MS

Director, Clinical Research

FDA Toxicity Grading Scale Tables

7

Utilizing FDA Toxicity Grading Scale in the Shingles Prevention Study1 and the ZOSTAVAX Efficacy & Safety Trial2

• Severe injection-site reactions within 7 days postvaccination were 1% or less

• Severe systemic AEs within 7 days postvaccination were very rarely reported

• The results of this post-hoc analysis confirm that severe injection-site and systemic AEs occurred infrequently after subcutaneous vaccination with ZOSTAVAX in the pivotal clinical trials to support licensure

• The rates of events categorized as severe injection-site reactions and fever would be even lower if the current FDA Toxicity Grading Scale were applied

• These results are consistent with the safety profile of ZOSTAVAX observed in real-world use and postlicensure surveillance (Merck internal data)

• Routine application of the FDA Toxicity Grading Scale across different vaccine development programs provides a common tool to enable comparison between products

1. Oxman MN et al. N Engl J Med. 2005;352:2271–2284 2. Schmader KE et al. Clin Infect Dis. 2012;54:922–928. .

Use of Polysaccharide

Pneumococcal Vaccine23

(PCV23)

and Pneumoconjugate Vaccine13

(PCV13) in Adults

Summary of STIKO 2016 Pneumococcal Vaccination Recommendations for Adults Aged ≥60 Years1

• The majority of IPD in Germany is caused by serotypes contained in

PPSV23

• Vaccine efficacy results from STIKO meta-analysis:

– IPD: 73% for PPSV23 and 76% for PCV13

– NBPP: 37%–64% for PPSV23 and 17%–41% for PCV13

• Health economic modeling found one-time vaccination with PPSV23

to be most cost-effective

• STIKO 2016 recommendations: – Routine vaccination with PPSV23 for all adults aged ≥60 years

– STIKO does not recommend sequential vaccination with PCV13

and PPSV23 as a standard vaccination regimen for older adults

IPD=invasive pneumococcal disease; NBPP=nonbacteremic pneumococcal disease; PCV13=13-valent pneumococcal conjugate

vaccine; PPSV23=23-valent pneumococcal polysaccharide vaccine: PNEUMOVAX®23 (Pneumococcal Vaccine Polyvalent);

STIKO=German Standing Committee on Vaccination.

1. Falkenhorst G et al. Bundesgesundheitsbl. 2016;59:1623–1657.

US ACIP’s Recommendations for Sequential Pneumococcal Vaccination

Adults Aged ≥65 Years1

2014: Sequential PCV13PPSV23 regimen is recommended by the ACIP

• 2018: ACIP recommendations will be reevaluated and revised as needed because of the potential time-limited benefit of PCV13 for adults ≥65 years

• Indirect effects from PCV13 use among children, if similar to those observed after PCV7 introduction, might further reduce the remaining burden of adult pneumococcal disease caused by PCV13-types.

ACIP=Advisory Committee on Immunization Practices; PCV13=13-valent pneumccoccal polysaccharide-protein

conjugate vaccine; PPSV23=23-valent pneumococcal polysaccharide vaccine.

1. Tomczyk S et al. MMWR Morb Mortal Wkly Rep. 2014;63(37):822–825.

Pipeline

Vaccines

Herpes Zoster

Inactivated VZV

Vaccine (ZVIN ) (V212)

V212 Phase III Program: Protocols 001 and 011

P001: auto-HCT recipients P011: Patients with STM and HM

Double-blind safety and efficacy study of V212 in auto-HCT recipients

Double-blind safety and efficacy study of V212 in subjects with STM and HM

4 dose sub-cutaneous regimen (30 days pre-transplant, 30, 60 and 90

days post-transplant)

4 dose sub-cutaneous regimen (Days 1, 30, 60 and 90)

26 countries and 135 sites 46 countries, 330 sites

Study duration: ~ 5 years

Initial results presented Feb 2017 Study duration: ~ 5 years

HCT: Hematopoetic Cell Transplant; STM= Solid Tumour Malignancy; HM= Hematologic malignancy

V212 P001 Efficacy Summary

Estimated VEHZ = 64%

Estimated VEPain = 70%

Estimated VEPHN = 84%

Estimated VEComplications = 74%

No unexpected safety issues

Winston D et. al. Presented at the American Society of Bone Marrow Transplantation , Orlando, FL Feb 24, 2017

V114

15-valent pneumococcal

conjugate vaccine

V114 Early Clinical Development Program: Completed Clinical Trials

1. V114-001: Safety and Immunogenicity in adults and toddlers – Small cohort of adults and toddlers: Single dose of V114

2. V114-002: Safety and Immunogenicity in adults ≥50 years of age

– Single dose of MAPA-adjuvanted V114 compared to PCV13 and PPSV23

3. V114-003: Safety and immunogenicity of V114 in infants – MAPA-adjuvanted and nonadjuvanted formulations of V114

compared to PCV13 – Four doses given at 2, 4, 6, and 12-15 months of age – Non-inferiority (immunogenicity) hypothesis met for 10 out of

13 shared serotypes

Conclusions

• Serotype-specific OPA GMTs and IgG GMCs at one month post vaccination (adjusted for baseline titer level) were generally comparable between recipients of PCV15 and PCV13 for the 13 common serotypes

• PCV15 induces significant increase (>10-fold rise) in OPA GMTs and IgG GMCs to serotypes 22F and 33F

• Overall, a higher number of PCV15 recipients reported injection-site and systemic AEs relative to recipients of PCV13, although differences were not clinically significant

Majority of injection-site and systemic AEs were transient and mild to moderate in intensity

Nature, frequency, and intensity of AEs reported by recipients of PCV15 were consistent with AEs previously reported for PCV7 and PCV13

Andrews CP et al. ISPPD, Hyderabad, India March 9-13, 2014

Vaccine Uptake

Herpes Zoster Vaccine

Cumulative Vaccination rates for HZ and

pneumococcal vaccines (2015) continue to trail annual

vaccination rates for influenza vaccine-US, 2015-2016

1. Centers for Disease Control and Prevention (CDC). Flu Vaccination Coverage, United States, 2015-16

Influenza Season. cdc.gov/flu/pdf/fluvaxview/2015-16/nfid-coverage-2015-16-final.pdf. Accessed February 27,

2017. Data Sources: National Immunization Survey-Flu (NIS-Flu) and Behavioral Risk Factor Surveillance

System (BRFSS) p6. 2. CDC. Vaccination coverage among adults in the United States, NHIS, 2015.

cdc.gov/vaccines/imz-managers/coverage/adultvaxview/coverage-estimates/2015.html#table5. Accessed

February 27, 2017. 3. CDC. Vaccination coverage among adults in the United States, NHIS, 2015.

cdc.gov/vaccines/imz-managers/coverage/adultvaxview/coverage-estimates/2015.html#table1. Accessed

February 27, 2017.

Race/Ethnicity Estimated Vaccination Rate

White

Black

Hispanic or Latino

Asian

Other

Vaccine/Population Estimated Vaccination Rate

Herpes Zoster2

Adults 60 years of age or older (total)

Influenza1 (2015–2016 Flu Season)

Adults 50–64 years of age (High risk)

Adults 65 years of age or older

Estimated Vaccination Rate with

HZ Vaccine by Race/Ethnicity, 2015

28%

26%

16%

14%

35%

44%

63%

31%

Pneumococcal Vaccine3

Adults 19–64 years of age or older (high risk)

Adults 65 years of age or older

23%

64%

HZ Vaccine Non Cumulative Coverage in England by

Age Cohort 1/9/13 to 31/8/14 (Year 1), 1/9/14 to 31/8/15 (Year 2), and 1/9/15 to 31/8/16 (Year 3) (Full public funding)

61.8% 59.6% 59.0% 57.8% 58.5% 54.9% 55.5%

0

10

20

30

40

50

60

70

80

90

100

2013-1470 y/o

2013-1479 y/o

2014-1570 y/o

2014-1578 y/o

2014-1579 y/o

2015-1670 y/o

2015-1678 y/o

Perc

enta

ge

Upta

ke

Public Health England November, 2015 Herpes zoster (shingles) immunisation programme September 2014/2015 Report for England https://www.gov.uk/government/publications/herpes-zoster-shingles-immunisation-programme-2014-to-2015-evaluation-report Public Health England November 2016 Herpes zoster (shingles) immunisation programme September 2015 – August 2016 Report for England https://www.gov.uk/government/publications/herpes-zoster-shingles-immunisation-programme-2015-to-2016-evaluation-report

HZ Vaccine Cumulative Penetration Rates by

Province Adults aged ≥ 60 years

(as of Dec 2016, Private market)

21.0%

29.2%

10.6%

22.5%

20.6%

17.7% 18.8%

15.5%

10.1%

17.5% 16.9%

0%

5%

10%

15%

20%

25%

30%

35%

National ON Qc AB BC Man Sask NB NFLD NS PEI

% C

umul

ativ

e P

enet

ratio

n

Source: QuintilesIMS GPM, December 2016

0%

2%

4%

6%

8%

10%

12%

14%

16%

2012 2013 2014 2015 2016

0.2% 1.3%

5.1%

9.4%

14.3%

% C

um

ula

tive

Pe

ne

tration

Cumulative Shingles Vaccine Coverage in Korea

Adults > 50 (Private Market)

*Note that these rates are cumulative penetration vs. >50 Korea statistics Source: based on distribution & in-market data (data on file)

In Europe: vaccination coverage rates for recommended vaccinations in “seniors” are far lower than for recommended pediatric vaccinations in the same EU countries

Implementation

Factors Impacting Vaccine Uptake in Adults Barriers Drivers

Vaccines Attributes • Efficacy • Number of doses in series • Storage requirements

• Efficacy & effectiveness • Safety and tolerability

Stakeholders

Population • Believe vaccines are for children only • Believe vaccination can actually cause the

disease (e.g.Flu) • Complacency, Convenience & Confidence • Gaps in public knowledge and awareness • No regular visits • Personal cost

• Older Adults likely to know about the importance of vaccination

• Public health needs & rational for patients suffering from chronic diseases

• Societal value of « healthy seniors »

Healthcare professionals • Lack of leadership in recommending vaccination to patients

• Unaware of BOD or risk/benefit balance • No culture of vaccination in adults

• Strength of recommendation • Medical training on immunology & vaccinology • Community Pharmacists

Health authorities / Healthcare system

• Limited funding and access • Limited promotion of vaccination schedules • Lack of quality measures • Inconsistent monitoring of: - uptake for recommended vaccinations - vaccination coverage - disease surveillance systems

• Demographic challenge & Healthy ageing • Life course approach to vaccination • Fixed age-based ≪rendez-vous≫ • Aged based recommendation • Personal invitation & reminders • Funding & Ease of access • Program objectives, monitoring & clear

communication campaign

Manufacturers • Price • Supply constraints

• Promotional efforts

Conclusion

A resilient vaccine environment with a life course approach to vaccines development and vaccination will:

• Lead to the deployment of efficacious and safe vaccines that address current and unmet needs

• Establish and sustain robust immunisation programmes

• Increase the likelihood of high levels of vaccine uptake

• Increase confidence in vaccines through stakeholders support