Recent Developments on Viral Vaccines

Stephen K. Tyring, M.D., Ph.D., M.B.A.

University of Texas Health Science Center

Houston, Texas

Prevention=Public Health + Vaccination

• Vaccination began with Jenner: cowpox (now vaccinia) to prevent smallpox: 1797 to 1977: first and only infectious disease eradicated

• Next targeted virus: polio, but goal to eradicate polio by 2005 (50th anniversary of 1st polio vaccine) not met

• Measles/mumps/rubella: now rare diseases in USA and Europe

HPV• >100 types identified• 30–40 anogenital

– Nononcogenic† types include: 6, 11, 40, 42, 43, 44, 54

• HPV 6 and 11 are most often associated with external genital warts.

– 15–20 oncogenic types, including 16, 18, 31, 33, 35, 39, 45, 51, 52, 58

• HPV 16 (54%) and HPV 18 (13%) account for the majority of worldwide cervical cancers.

HPV Types 16 and 18

• HPV Types 16/18 cause 70% of Cervical cancer and > 50% of other anogenital cancers

Human Papillomavirus (HPV) Vaccines

HPV-6/11/16/18 VLPs (Gardasil)• L1 capsid proteins HPV Types 6, 11,

16, 18 L1 VLPs manufactured in Saccharomyces cerevisiae (yeast)– Yeast-derived vaccines given to millions of

children and adults

• Formulated with alum and MPL

• 3-doses: months 0, 2, 6

• Elicits neutralizing antibody to HPV- Th1 dominant CMI

HPV-16 L1 VLPs

Phase II/III Gardasil Studies: >23,000 female subjects

FUTURE = Females United To Unilaterally Reduce Endo/Ectocervical Disease; CIN = cervical intraepithelial neoplasia; EGL = external genital lesions.

1. Mao C et al. Obstet Gynecol. 2006;107:18–27. 2. Villa LL et al. Lancet Oncol. 2005;6:271–278. 3. Garland SM et al. New Engl J Med. 2007;356:1928–1943. 4. The FUTURE II Study Group. New Engl J Med. 2007;356:1915–1927. 5. Block SL et al. Pediatrics. 2006;118:2135–2145. 6. Reisinger KS et al. Pediatr Infect Dis J. 2007;26:201–209.

Jan2003

Jan2004

Jan2005

Jan2009

Jan2006

Jan2008

Jan2007

Jan2010

Ph II―P007 (N=1,158)2 Dose-ranging16- to 23-year-old women

Ph II―P005 (N=2,391)1

Proof of principle 16- to 23-year-old women

Ph III―FUTURE I (P013) CIN/EGL16- to 24-year-old women (N=5,455)3

Ph III―FUTURE II (P015) CIN 2/315- to 26-year-old women (N=12,167)4

Duration of Efficacy Registry StudyNordic Region

Ph III―P016, P018 (N=1,958)5,6

Safety/immunogenicity9- to 15-year-old girls

Norwegian HPV Surveillance andDisease Burden/Population Effectiveness Study

Jan1998

May 2000

Efficacy Against HPV 6/11/16/18–Disease in Per-Protocol Population

Nu

mb

er o

f H

PV

6/1

1/16

/18–

Rel

ated

Cas

es

FUTURE I

Garland SM et al. New Engl J Med. 2007;356:1928–1943.

95% confidence interval: 94%–100%.CIN = cervical intraepithelial neoplasia; AIS = adenocarcinoma in situ; VIN = vulvar intraepithelial neoplasia; VaIN = vaginal Intraepithelial neoplasia; FUTURE = Females United To Unilaterally Reduce Endo/Ectocervical Disease.

100% efficacy

100% efficacy

0 0

6560

0

10

20

30

40

50

60

70

80

90

100

CIN or AIS VIN/VaIN/Genital Warts

GARDASIL

Placebo

n=2,258

n=2,241

n=2,279

n=2,261

2 4

8981

0

10

20

30

40

50

60

70

80

90

100

CIN or AIS VIN/VaIN/Genital Warts

GARDASIL

Placebo

Efficacy Against HPV 6/11/16/18–Disease In Unrestricted Susceptible

PopulationN

um

ber

of

HP

V 6

/11/

16/1

8–R

elat

ed C

ases

FUTURE I

Garland SM et al. New Engl J Med. 2007;356:1928–1943.

95% confidence interval: 92%–100% for CIN and AIS and 87%–99% for VIN/VaIN/genital warts. CIN = cervical intraepithelial neoplasia; AIS = adenocarcinoma in situ; VIN = vulvar intraepithelial neoplasia; VaIN = vaginal Intraepithelial neoplasia; FUTURE = Females United To Unilaterally Reduce Endo/Ectocervical Disease.

n=2,684

n=2,667

n=2,684

n=2,667

95% efficacy

98% efficacy

GARDASIL® [Quadrivalent Human Papillomavirus (Types 6, 11, 16, 18) Recombinant Vaccine]

Summary of SafetyFUTURE I1 FUTURE II2

GARDASIL

(n=2,673)

Placebo

(n=2,672)

GARDASIL

(n=6,019)

Placebo

(n=6,031)

Injection-site AE–Pain

86.8

85.3

77.4

75.4

84.4

83.0

77.9

75.8

Systemic AE 65.3 63.7 61.4 60.0

Serious AE 1.8 1.7 0.7 0.9

Serious vaccine-related AE

<0.1 0.0 <0.1 <0.1

Discontinuation due to serious AE

0.1 0.1 0.1 0.1

Discontinuation due to serious vaccine-related AE

0.0 0.0 0.0 <0.1

Discontinuation due to death*

0.1 0.1 0.1 0.1

GARDASIL® [Quadrivalent Human Papillomavirus (Types 6, 11, 16, 18) Recombinant Vaccine]

Gardasil Conclusions

• GARDASIL is highly safe and effective in preventing cervical cancer, CIN 2/3, AIS, and other anogenital diseases, including genital warts caused by HPV 6, 11, 16, and 18 in 16- to 26-year-old women naïve to the relevant HPV types.

• Widespread vaccination of young women should help reduce cervical cancer as well as other anogenital diseases related to HPV 6, 11, 16, and 18.

HPV Vaccine Questions• Use of vaccine as therapy? Little information

available, but has scientific basis• Use in males? Studies ongoing• Use in females <9 or >26 years?• Duration of protection? 5 years+• Role of dermatologists?

– Educate pts about the link between HPV and cervical cancer

– Remind male patients about pap smears and HPV vaccine for female partners

– Identify female pts at high risk or the target age group for HPV vaccine

HPV Vaccine Questions• Acceptance? As a cancer vaccine>>STD vaccine

• Should Gardasil be mandatory? -Reduction of morbidity -Reduction of mortality -Cost savings

– Other vaccines are mandatory, but are for both sexes. – Making a vaccine mandatory increases compliance 10 fold.

VARICELLA ZOSTER VIRUS

• PRIMARY INFECTION: CHICKENPOXCHICKENPOX

• RECURRENCE IN 20% OF OTHERWISE HEALTHY PERSONS: SHINGLESSHINGLES

Varicella/Varicella Zoster

• Attenuated vaccine,Varivax, FDA approved in 1995, is safe and effect to prevent chickenpox (two injections if over 12 months)

• Varivax was FDA approved 9/6/05 to be given with MMR as “Proquad”

• Immunity appears to last 25+ years• When given to adults who had chickenpox in past, it

decreased the incidence of shingles by 51% and the incidence of PHN by 66% (N Engl J Med 352: 2271-2284; 2005). Zostavax, the 14-fold concentrated version of Varivax, was approved in May 2006 for prevention of herpes zoster in persons >60 years (without history of shingles)

Disposition of Study Subjects

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

Terminated before end of study 793 (4.1%) Died 57 (0.3%) Withdrew 61 (0.3%) Lost to follow-up

Zoster vaccine19,270

Terminated before end of study 792 (4.1%) Died 75 (0.4%) Withdrew 52 (0.2%) Lost to follow-up

Completed study18,357 (95.2%)

Placebo19,276

Enrolled 38,546

Completed study18,359 (95.3%)

P<.001

Vaccine Efficacy for Incidence of Herpes Zoster

Efficacy

(95% CI)

51.3% (44.2%–57.6%)

63.9%(ND)

37.6% (ND)

0

2

4

6

8

10

12

14

Incid

en

ce o

f h

erp

es z

oste

r

Vaccine

Placebo

ND=not determined.Oxman MN et al. N Engl J Med. 2005;352:2271-2284.

All 60-69 70

Age (years)

Vaccine Efficacy for Incidence of PHN

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

P<.001

Efficacy (95% CI)

66.5% (47.5%–79.2%)

65.7% (20.4%–86.7%)

66.8% (43.3%–81.3%)

0

0.5

1.0

1.5

2.0

2.5

All Subjects 60-69 70

Incid

en

ce o

f P

HN Vaccine

Placebo

Age (years)

Questions regarding Zostavax

• Use in persons under 60 years?

• Use in persons with history of shingles?

• Use in persons without a history of chickenpox?

• Use as therapy for shingles or PHN?

• Use in immunocompromised patients?

• Implications for therapeutic HSV vaccine?

Safety of Zostavax

• Recipients of Zostavax had higher rates of local reactions (erythema, swelling, etc.) than did recipients of placebo

• Recipients of Zostavax and placebo did not differ in systemic adverse events

Will Zostavax Decrease the Prevalence of Herpes Zoster?

• 51% efficacy; duration of benefit unknown• FDA approval for persons > 60 years• Insurance coverage?• Low compliance with recommended vaccines• Contraindicated in immunocompromised (IC)

patients• Elderly and IC populations increasing• Decreased wild type VZV: less immune boosting

Vaccine Efficacy p-value

32.2% 0.47

Vaccine Efficacy p-value

74.4% 0.02

Observation period [months] Observation period [months]

Per

cent

age

with

out G

HD

Men Women

0 2010 30

85

90

95

100

PlaceboVaccine

0 2010 30

85

90

95

100

PlaceboVaccine

New Genital Herpes DiseaseHSV 1-/2- Subjects

Future Vaccines: HIV

• >40 million persons in the world with HIV• >20 antiretroviral drugs, but no cures• First HIV vaccine safe, but not effective• Many HIV vaccines in Phase II trials: most

promising waswas replication attenuated adenovirus carrying recombinant pol, nef and gag; over 6000 persons vaccinated: safe and immunogenic, but it did not show clinical protection

What’s New in Prevention of Viral Diseases?

1. FDA approved vaccines are much safer than the viruses they prevent

2. Vaccines should be used in combination with public health

3. VZV vaccines are safe and effective in prevention of primary VZV (Varivax) as well as herpes zoster (Zostavax)

4. The HPV 6/11/16/18 vaccine (Gardasil) is safe and effective for prevention of genital warts and anogenital malignancy

QUESTIONS?QUESTIONS?