How Vaccine Have Been ManagingNew Type Of Diseases In Human History,And Its Social And Economic Benefits

June 18, 2015

Cem Özesen, M.DMedical Director, MSD Korea

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Agenda

• Vaccine Development; History and Impacts

– Case I; HPV Vaccine

– Case II; Ebola Virus

• Closing

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Vaccine Development; History and Impacts

• ~ 430 B.C: Peloponesian War, Thucydides describes plague – the ones who had recovered from the disease could nurse the sick without getting the disease a second time

• 15th centurry: Chinese and Turks use dried crusts of smallpox as ”vaccine”

• 1798: Edward Jenner – smallpox vaccine

History of Vaccine

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1798 1885 1900 1910 1920 1930 1940 1950 1960 1970 1980 1990 2000 2008

Smallpox

Rabies

TyphoidCholera

DiphtheriaPertussis

Tetanus

Influenza

Rickettsia

DTwP DTaP

IPV

OPV

Measles

MMR

Varicella

Rubella

Hib

HBV

BCG

Meningococcus

Pneumococcus

JEV PCV

MCV

HPV

RotavirusZoster

BCG (Bacille Calmette-Guerin vaccine)JEV (Japanese enthephalitis vaccine)DTwP (Diphtheria, Tetanus, whole cell per-tussis)DTaP (Diphtheria, Tetanus, acellular pertus-sis)IPV (Inactivated polio vaccine)OPV (Oral polio vaccine)MMR (Measles, Mumps, Rubella)Hib (Haemophilus influenzae type b vaccine)HBV (Hepatitis B vaccine)PCV (Pneumococcal conjugate vaccine)MCV (Meningococcal conjugate vaccine)HPV (Human papillomavirus vaccine)

History

History of Vaccine Development

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References: 1. Centers for Disease Control and Prevention. Ten Great Public Health Achievements — United States, 1900–1999 . Morbidity and Mortality Weekly Report (MMWR).1999; 48(12): 241-264.;2. Centers for Disease Control and Prevention. Epidemiology and Prevention of Vaccine-Preventable Diseases. Washington, DC: Public Health Foundation; 2012.;3. WHO, UNICEF, World Bank. State of the World’s Vaccines and Immunization, 3rd ed. Geneva, World Health Organization; 2009.; 4. World Health Organization. Immunization Coverage. April 2013; Fact Sheet 378. http://www.who.int/mediacentre/factsheets/fs378/en. Accessed February 19, 2014.

2 to 3 millionlives are saved worldwide each year

through vaccination4

According to the World Health Organization, vaccines help

prevent more than common infectious diseases3 30

Vaccine,from treatment to prevention

• Vaccines are one of the greatest public health success stories of the last two centuries,

• eradicating smallpox1 and nearly eliminating other diseases like polio worldwide.2

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Vaccine Has Made Profound Effects

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Vaccine Preventable Diseases

• Tuberculosis

• Diphtheria

• Pertussis

• Tetanus

• Polimyelitis

• Measles

• Mumps

• Rubella

• Japanese en-cephalitis

Decreased Incidence of Vaccine Preventable Diseases in Korea (~2006)

Impact of vaccines in Korea

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Benefits of Disease Prevention

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Developing Vaccine is long and costly process

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Recent Trends in Vaccine

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• Adult Vaccines (Zoster vaccine, Pneumococcal vaccine, Influenza) • Vaccine for cancer prevention (HPV Vaccine)• New vaccines for Viral disease (Rota Virus, Ebola, Dengue, etc)• Expansion of vaccine type coverage (4vHPV ->9vHPV)

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MSD licenses first measles vaccine in the US

1963

MSD’s Dr. Hilleman isolates the mumps virus to create the first mumps vaccine

M-M-R® trivalent vaccine introduced

1971

1995

2005

1960s

MSD licenses the first vaccine against mumps

1967

MSD licenses the first vaccine against rubella

1969

1970s

MSD licenses a vaccine against pneumococcal disease

1977

1981

1983

1978

1980s

1986

1990s 2000s

2006

First plasma-derived hepatitis B vaccine licensed, Heptavax-B (Hepatitis B Vaccine)

1996

1990

1890s

1898

H.K. Mulford Co. introduces its smallpox vaccine

* MSD and its predecessor companies have a history with vaccines that dates back more than 100 years. In 1898, the H. K. Mulford Company pro-duced its first batch of smallpox vaccine. In 1929, the H. K. Mulford Company was purchased by the Sharp & Dohme (S&D) Company of Baltimore. In April 1953, Sharp & Dohme merged with MSD & Company, Inc., becoming MSD Sharp & Dohme.

MSD Vaccine- More than A Century of Commitment

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Case I; HPV Vaccine

Dr. Harald Zur Hausen2008 Nobel Prize (Physiology or Medicine)

Discovered the role of Human papillomavirus in cervical neoplasia.

• >190 types identified

• ≥30–40 anogenital- ~15–20 oncogenic*,

- HPV 16 and HPV 18 types account for the majority of all cervical cancers.

- Non-oncogenic** types- HPV 6 and 11 are responsible for >90% of

genital warts.

Human Papillomavirus

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90+%

~40%

~100%

60-90%

90+%

HPV

Cervical Cancer

Vulvar Cancer

Vaginal Cancer

Anal Cancer

12-70%Head & Neck

Cancer

45%Penile

Cancer

Genital Warts

Other Possible Disease burden

RRP

Preterm birth?

PROM?

Preeclampsia?

Male infertility?

Esophageal can-cer?

* RRP: Recurrent Respiratory Papillomatosis* PROM: Premature rupture of membranes

HPV Related disease

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Worldwide HPV-related disease burden

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Lee EH et al., J Korean Med Sci 2012; 27: 1091-1097

Of the 60,775 Korean women aged between 18 and 79 yr,

• Overall HPV positive rate of total patients was 34.2%.

• Age-specific HPV infection prevalence peaked at 49.9% in 18-29 year olds.

HPV Prevalence in Korea

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• 3,299 new cervical cancers are diagnosed annually in Korea.- Crude incidence rate: 13.5/100,000 women per year. - Cervical cancer is the 4th most common female cancer in women

aged 15 to 44 years in Korea.

Morbidity

WHO/ICO, Human papillomavirus and related disease report, Korea, republic of, version posted on www.hpvcentre.net in Mar 20th, 2015.

Mortality

Epidemiology of Cervical Cancer in Korea

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• 1,113 new cervical cancer deaths occur annually in Korea.- Crude Mortality Rate: 4.6/100,000 women per year- Cervical cancer is the 3rd leading cause of cancer deaths in women

aged 15 to 44 years in Korea.

Gardasil,The first vaccine to prevent cancer

• First vaccine, approved in the US on June 8, 2006 by FDA

• Contains the VLP (Virus-like Particles) of the recombinant major capsid (L1) protein of HPV types 6, 11, 16 and 18.

• Indicated for prevention of HPV 6, 11, 16, 18-related cervical, vulvar, vaginal and anal cancer & precancerous lesions and genital warts.

Introduction of HPV Vaccine

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L1 VLPs Mimic the HPV Virion(Type-Specific)

Viral DNA

Infectious HPVNoninfectious HPV VLP

Capsid proteins:L1

L2

Lacks viral DNA

LacksL2 protein

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3

North America:

USACanada Mexico

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South America:Brazil Bolivia+Argentina UruguayPeru EcuadorColombia ChileParaguay

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Middle East & Africa:

Gabon NamibiaIsrael C.A.R.+Morocco MauritiusKenya+ KuwaitMauritania UAE Guinea Eq. Ethiopia+Uganda+ Togo+Malawi+ Congo Brazzaville Congo Kinsh (DRC)+Jordan Egypt Niger+Cote d’Ivoire+ Burkina Faso+ Ghana+Chad+ Bahrain BotswanaLebanon Tanzania+ Zambia+

South Africa Cameroon+ Nigeria+Tunisia Mali+ QatarGuinea Conakry+ Saudi Arabia Rwanda+

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Asia Pacific & Japan:Kyrgyzstan+Uzbekistan+KazakhstanAustraliaIndonesia KoreaTaiwanHong KongSingaporeNew ZealandMacauMalaysiaPhilippinesThailandIndia+Vietnam+FijiBhutanJapanSri LankaBruneiAzerbaijanPakistan+TurkmenistanBangladeshCambodia

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Europe:

Germany Cyprus Ireland France Czech Republic

LatviaUK Denmark LithuaniaSpain Estonia LuxembourgItaly Finland MaltaAustria Greece NetherlandsBelgium Hungary NorwayBulgaria Iceland PolandPortugal Romania SlovakiaSlovenia Sweden SerbiaMontenegro Switzerland LiechtensteinBosnia/Herzegovina+ RussiaBelarus Croatia Turkey UkraineMacedonia AlbaniaGeorgia Kosovo

Caribbean & Central America:

Costa Rica Trinidad/TobagoPuerto Rico El SalvadorGuatemala HondurasCuracao Nicaragua+Bermuda PanamaBahamas Cayman IslandsBarbados ArubaJamaica Dominican Republic

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Gardasil / Silgard ApprovalsGARDASIL approved in 135 countries (includes 29 GAVI-eligible)

+GAVI – Eligible Registration Approvals (28 out of 56): Bolivia, Bosnia/Herze-govina, Burkina Faso, Cameroon, Central African Republic, Chad, Congo (DR), Cote d’Ivoire, Ethiopia, Ghana, Guinea (Conakry), India, Kenya, Kyrgyzstan, Malawi, Mali, Mauritania, Nicaragua, Niger, Nigeria, Pakistan, Rwanda, Tanzania, Togo, Uganda, Uzbekistan, Vietnam, Zambia, Bangladesh, Cambodia

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HPV Recommendations by National Expert Advi-sory Bodies on Immunization

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Cayman Is.

3North America

USA**Canada* Mexico

9South AmericaArgentina PeruGuyanaColombiaUruguayParaguaySurinamBrazilChile

9Middle East & AfricaKuwaitUAELesothoKazakhstanLibyaIsraelRwanda***South AfricaSeychelles

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Asia PacificAustralia**New Zealand*MalaysiaBruneiIndiaSingaporeJapanMacau

26EuropeAustria**BelgiumBulgariaCzech RepublicDenmarkFinlandFranceGermanyGreeceIcelandIreland*ItalyLatviaLuxemburgMacedoniaNetherlandsNorwayPortugalRomaniaSloveniaSpainSwedenSwitzerlandLiechtensteinUnited KingdomHungary

Caribbean & Central AmericaPuerto Rico PanamaBarbadosBermuda Trinidad & Tobago Cayman IslandsSt Martin (COM – part of EU)

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FUNDING

GARDASIL only

Bivalent Only

Both vaccines

No funding*Male Recommendation**Male Reco & Funding

***Through GAVI****will switch to Gardasil in 2014

GAVI Demo ProjectsGhana, Kenya, Laos, Madagascar, Malawi, Mozambique, Niger, Sierra Leone, Tanzania, Zimbabwe

For Female: 62 Countries – For Males: 6 countriesNational Funding: For Females: 60 Countries – For

Males: 3 countries

Population impact of HPV vaccination- Reduction in Genital warts

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HPV vaccination program introduced

Proportion of Genital warts diagnosis in Australia (< 21 years old)

Chow PF et al, Sex Transm Infect. 2015 May;91(3):214-9

• The largest decline in genital warts occurred from the 2007/2008 to the 2008/2009 periods in women aged <21 years, with a fall from 20.6% to 6.6%.

• Significant reductions in genital warts in men aged <21 years occurred from 2007/2008 (25.5%) to 2008/2009 (13.7%) to 2009/2010 (2.2%).

Population impact of HPV vaccination-Reduction in cervical lesions

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HPV vaccination program introduced

Impact on Cervical Abnormalities in Australia

JM Brotherton et al, Cancer Causes Control. 2015 Jun;26(6):953-4

• In women aged <20 years, rates have fallen from 10.9 per 1,000 screened women in 2006 (the year prior to vaccination) to 5.0 in 2013 (p<0.0001)

• In women aged 20-24 years, rates have fallen from 21.5 per 1,000 screened women in 2008 to 13.5 in 2013 (p<0.0001)

Atypia or worse CIN 2/3 CIN 30

0.10.20.30.40.50.60.70.80.9

1

1989–1990

1991–1992

1993–1994

1995–1996

1997–1999

Ha

zard

ra

tio

Population impact of HPV vaccination-Reduction in Cervical lesions

Risk for cervical lesions among vaccinated women vs. non-vaccinated women, October 2006–March 2012a,b

CIN=cervical intraepithelial neoplasia; qHPV=quadrivalent human papillomavirus.

1. Baldur-Felskov et al. J Natl Cancer Inst. 2014. doi:10.1093/jnci/djt460.

c

P<0.001 P=0.005

d

Birth cohortP=0.01

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Impact on Cervical lesions in Denmark

~80% Reduction

• Risk of atypia or worse and of CIN2/3 were statistically significantly reduced among vacci-nated women in birth cohorts 1991 to 1994.

Relative Contribution of the 7 and 2 HPV types to HPV-positive cervical cancer and precancerous cervical lesions

Next Generation HPV vaccine- 9-valent HPV vaccine

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Approved by US FDA (Dec 2014)for the prevention of

• Cervical, vulvar, vaginal, and anal cancers caused by HPV 16, 18, 31, 33, 45, 52, and 58

• Genital Warts caused by HPV types 6 and 11.

Phase III Clinical Study Results

• Appears to be safe and effective in preventing persistent infection and precancerous lesions as well as genital warts related to HPV types 6/11/16/18/31/33/45/52/58.

Next Generation HPV vaccine- 9-valent HPV vaccine

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Case II; Ebola Virus

• Ebola virus disease first appeared in 1976

• The most largest and complex outbreak in March 2014

• Ebola virus is transmitted to people from wild animals and spreads through human-to-human transmission

• The average fatality rate is around 50% and fatality rates have varied from 25% to 90% in past outbreaks

Total 26,979 cases,

Total 11125 deaths as of May 2015

How is the Ebola virus transmitted?

Introduction of Ebola Virus

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6. Household bleach and other disinfectants kill Ebola

7. Your family members, cowork-ers, and neighbors returning from countries with Ebola out-breaks don’t pose a danger to you and your family

8. Mosquitoes are the deadliest insects in the world, but they don’t carry Ebola

9. Food and drinks imported into the United States from West Africa are safe to eat and drink

10. Your dog or cat is not spreading Ebola

1. You can’t get Ebola from a handshake or a hug

2. Ebola is only spread from one person to another after symptoms begin

3. The Ebola outbreak is not affecting the safety of air-line travel

4. Ebola is not airborne5. If you’re feeling sick, think

flu not Ebola

CDC campaign: Top 10 Things- You REALLY Need to Know about EBOLA

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Cases of Ebola Virus Disease in Africa, 1976-2015

The total reported suspected, probable, and con-firmed cases in Guinea, Liberia, and Sierra Leone provided in WHO situation reports beginning on March 25, 2014 through the most recent situation report on May 27, 2015.

Ebola Virus Disease Distribution Map

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• Supportive care-rehydration with oral or intravenous fluids-and treatment of specific symptoms, improves survival

• There is as yet no proven treatment for Ebola virus dis-ease

• No licensed vaccines are available yet, but 2 potential candidates are undergoing evaluation

• Risk reduction messaging should focus on several factors:– Reducing the risk of wildlife-to-human transmission– Reducing the risk of human-to-human transmission– Reducing the risk of possible sexual transmission– Outbreak containment measure

Prevention and Control

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• Ebola vaccine candidate, rVSV-ZEBOV-GP (V920), is now included in three large-scale clinical trials in West Africa including Sierra Leone

‒ Phase II/ III safety and effectiveness study, called STRIVE (Sierra Leone Trial to Intro-duce a Vaccine against Ebola), taking place in Sierra Leone Will involve 6,000 health and other frontline workers

‒ The Partnership for Research on Ebola Vaccines in Liberia (PREVAIL) which is Led by a Liberia-U.S. clinical research partnership and sponsored by NIAID

‒ Designed to enroll approximately 27,000 healthy men and women aged 18yrs and older

“Fighting Ebola remains a global health priority, and MSD is committed to advancing the development of our and NewLink’s vaccine candidate as part of our overall response to the crisis”

‒ Mark Feinberg, M.D., Ph.D., chief public health and science officer

R&D on Ebola Virus

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Closing

(- Much greater value in a context of new disease conquests- Reiterate beneficial effect of vaccine with the example)

IFPMA. Vaccines for Prevention. Available at http://www.ifpma.org/fileadmin/content/Resources/Vaccines/Vaccine_Pipeline_Chart.pdf accessed on Jun 1st 2015

Vaccines in development

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HPV-related cancers, HPV Vaccine (9 valent) (V503) is an investigational human papillomavirus (HPV) vaccine that targets nine HPV subtypes: 6, 11, 16, 18, 31, 33, 45, 52 and 58. V503 is being evaluated for prevention of HPV

V212 is an investigational, inactivated varicella zoster virus (VZV) vaccine candidate. It is being evaluated for the prevention of herpes zoster (HZ) and HZ-related complications in select immuno-compromised patient populations.

Data on file, MSD

MSD Vaccine pipelines

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Thank you