Recent Developments on Viral Vaccines
Stephen K. Tyring, M.D., Ph.D., M.B.A.
University of Texas Health Science Center
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
Ph II―P005 (N=2,391)1
Proof of principle
16- to 23-year-old women
Ph II―P007 (N=1,158)2
Dose-ranging
16- to 23-year-old women
May
2000
Ph III―FUTURE I (P013) CIN/EGL
16- to 24-year-old women (N=5,455)3
Ph III―FUTURE II (P015) CIN 2/3
15- to 26-year-old women (N=12,167)4
Duration of Efficacy Registry Study
Nordic Region
Norwegian HPV Surveillance and
Disease Burden/Population Effectiveness Study
Ph III―P016, P018 (N=1,958)5,6
Safety/immunogenicity
9- to 15-year-old girls
Jan
1998
Jan
2003
Jan
2004
Jan
2005
Jan
2006
Jan
2007
Jan
2008
Jan
2009
Jan
2010
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.
Efficacy Against HPV 6/11/16/18–
Disease in Per-Protocol Population
FUTURE I
Number of
HPV 6/11/16/18–Related Cases
100
GARDASIL
Placebo
90
80
65
70
60
60
50
n=2,258
n=2,279
40
30
100%
efficacy
100%
efficacy
20
10
n=2,241
0
n=2,261
0
0
CIN or AIS
VIN/VaIN/Genital Warts
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.
Garland SM et al. New Engl J Med. 2007;356:1928–1943.
Number of
HPV 6/11/16/18–Related Cases
Efficacy Against HPV 6/11/16/18–
Disease In Unrestricted Susceptible
Population
100
90
GARDASIL
FUTURE I
89
Placebo
81
80
70
60
n=2,684
50
40
30
20
10
n=2,684
98%
efficacy
n=2,667
2
95%
efficacy
n=2,667
4
0
CIN or AIS
VIN/VaIN/Genital Warts
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.
Garland SM et al. New Engl J Med. 2007;356:1928–1943.
GARDASIL® [Quadrivalent Human Papillomavirus (Types 6, 11, 16, 18) Recombinant Vaccine]
Summary of Safety
FUTURE I1
FUTURE II2
GARDA
GARDA
Placebo
Placebo
SIL
SIL
(n=2,672)
(n=6,031)
(n=2,673)
(n=6,019)
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
Injection-site AE
–Pain
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: CHICKENPOX
• RECURRENCE IN 20% OF
OTHERWISE HEALTHY PERSONS:
SHINGLES
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
Enrolled
38,546
Zoster vaccine
19,270
Terminated before end of study
793 (4.1%) Died
57 (0.3%) Withdrew
61 (0.3%) Lost to follow-up
Completed study
18,359 (95.3%)
Oxman MN et al. N Engl J Med. 2005;352:2271-2284.
Placebo
19,276
Terminated before end of study
792 (4.1%) Died
75 (0.4%) Withdrew
52 (0.2%) Lost to follow-up
Completed study
18,357 (95.2%)
Vaccine Efficacy
for Incidence of Herpes Zoster
51.3%
63.9%
37.6%
(95% CI)
(44.2%–57.6%)
(ND)
(ND)
Incidence of herpes zoster
Efficacy
14
P<.001
Vaccine
12
Placebo
10
8
6
4
2
0
All
60-69
Age (years)
ND=not determined.
Oxman MN et al. N Engl J Med. 2005;352:2271-2284.
70
Vaccine Efficacy for Incidence of
PHN
Efficacy
66.5%
65.7%
66.8%
(95% CI)
(47.5%–79.2%)
(20.4%–86.7%)
(43.3%–81.3%)
Incidence of PHN
2.5
2.0
Vaccine
P<.001
Placebo
1.5
1.0
0.5
0
All Subjects
60-69
Age (years)
Oxman MN et al. N Engl J Med. 2005;352:2271-2284.
70
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
New Genital Herpes Disease
HSV 1-/2- Subjects
Men
Percentage without GHD
100
95
95
90
90
Placebo
Vaccine
85
0
10
Women
100
Placebo
Vaccine
85
20
30
Observation period [months]
0
10
20
30
Observation period [months]
Vaccine Efficacy
p-value
Vaccine Efficacy
p-value
32.2%
0.47
74.4%
0.02
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 was 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?