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HPV vaccines: who and when
to vaccinate
Margaret Stanley
Department of Pathology
Cambridge
OUTLINE OF PRESENTATION
Immune response in the natural history
of HPV infections
Prophylactic vaccines
rationale and immune mechanisms
Who and when to vaccinate
before exposure
? post exposure
Immunity is a partnership
Innate
no memory, not antigen specific
activated by cell death
Innate immunity kick starts adaptive immunity
by activating antigen presenting cells (APC)
Adaptive
memory antigen specific
lymphocytes key players
humoral immunity
antibody mediated
neutralises extracellular pathogens
prevents re-infection
cell mediated immunity
cytotoxic effector cells
kill infected cells
Adaptive immune responses
• Type 1/Th1
Cell mediated
CD4+ T cells help killers
Killer T cells
Activated macrophages*
Cytokines*
Natural killer cells*
*innate
effectors enhanced
and activated by adaptive responses
• Type 2/Th2
Humoral
CD4+ T cells help
B cells make antibody
Non cytotoxic Antibody
IgM, IgG, IgA, IgE
Natural Course of Genital HPV Infection
HrHPVs 12-18months
Time
LrHPVs 4-9months
infection
First
Lesion
DNA-ve
Immune
Response
CMI
Productive viral
infection, DNA+ve
low grade lesions
Seroconversion
Antibody to L1
Virological
clearance
DNA-ve
Viral
persistence
DNA+ve
LSIL/HSIL
Antibody responses in natural infections are
slow and weak
only 50-60% of women sero-convert
Why are antibody responses so poor?
No viraemia
HPV does not lyse keratinocytes
no inflammation
no pro-inflammatory cytokines
poor activation of Langerhans cells and
stromal dendritic cells
Free virus particles are shed from mucosal
surfaces with poor exposure to APC
OUTLINE OF PRESENTATION
Immune response in the natural history
of HPV infections
Prophylactic vaccines
rationale and immune mechanisms
Who and when to vaccinate
before exposure
? post exposure
Why might vaccines generating neutralising
antibody be effective prophylactically ?
Systemic immunisation with infectious Cotton
tail rabbit papillomavirus (CRPV)
•did not induce visible papillomas
•generated serum neutralising antibody
•immunised rabbits were protected against
viral challenge
Shope RE 1937 Immunisation of rabbits to infectious papillomatosis
J Exp Med 65 607-24
HPV vaccines are sub-unit vaccines
made of virus like particles: VLPs
Making VLPs: molecular “cut and paste”
“cut” the L1 gene from the virus DNA
“paste” into the DNA of another microbe
such as yeast or baculovirus
grow the recombinant microbe in large
amounts
– as it grows it makes the L1 protein
The chemistry of this protein is such that
it self assembles into a virus like particle
- an empty protein shell without DNA
The VLP is morphologically and
immunologically identical to the
HPV virus particle
HPV 16 L1 VLPs
VLP vaccines: mechanisms
3 key players in the induction
of the antibody response
•Dendritic cells (antigen presenting cells) in the
muscle
•T lymphocytes in the lymph node
•B lymphocytes in the lymph node
Immune Response to HPV Vaccines:
A Proposed Mechanism1–5
1. Stanley M. Vaccine. 2005 [Epub ahead of print]. 2. Batista FD, Neuberger MS. EMBO Journal. 2000;19:513–520. 3. Tyring SK. Curr Ther
Res. 2000;61:584–596. 4. Roden RB, Hubbert NL, Kirnbauer R, et al. J Virol. 1996;70:3298–3301. 5. Chen XS, Garcea RL, Goldberg I, et al.
MolCell. 2000;5:557–567.
Th2 cell help for B lymphocytes is crucial
to
•Class switching – determines the type (IgG,etc)
and amount of antibody secreted
dictated by the Th2 cytokines – these in turn
are regulated by
antigen type
antigen dose
•The generation of memory and the efficiency
of the response to recall antigen
under the control of memory Th2 cells
B cell memory and long term antibody persistence
VLP vaccines generate high levels
of antibody to HPV L1
Why are they so immunogenic?
Delivered intramuscularly
• rapid access of VLPs to blood vessels
and local lymph nodes
•
potent activators of APC
induce good T helper responses for B cells
OUTLINE OF PRESENTATION
Immune response in the natural history
of HPV infections
Prophylactic vaccines
rationale and immune mechanisms
Who and when to vaccinate
before exposure
? post exposure
Natural Course of Genital
HPV Infection
infection
First
Lesion
Immune
Response
Seroconversion
Average time
9mo
Sustained
clinical
remission
Active Growth
Late
(3-6 Mo.)
Host Stage
Containment
(3-6 Mo.)
DNA-ve
Sero-ve
Persistent or
recurrent
disease
Quadrivalent HPV Vaccine Phase III Adolescent
Immunogenicity Study
Neutralizing Anti-HPV GMTs* at Month 7
1500
1500
1000
1000
500
500
0
0
Anti-HPV 11 (HPV 11 mMU/mL)
Anti-HPV 6 (HPV 6 mMU/mL)
8000
6000
4000
2000
0
1500
1000
500
0
Anti-HPV 16 (HPV 16 mMU/mL)
Females 10–15 Years of Age
Males 10–15 Years of Age
*GMT = geometric mean titers
1.
Anti-HPV 18 (HPV 18 mMU/mL)
Block SL, Nolan T, Sattler C, et al. Pediatrics. 2006: 118.2135-45
Females 16–23 Years of Age
Age Specific Neutralizing HPV-6 Antibodies 1
Month Post-Vaccination1
PPE population*
Neutralizing anti-HPV 6 GMTs at month 7
Serum cLIA GMT with
95% CI, mMU/mL
Immunogenicity Bridge
Efficacy Program
1600
1500
1300
1100
900
700
500
Males + Females
9
10 11 12 13 14 15 16 17 18 19 20 21 22 23
Age at Enrollment (Years)
*Inclusive of five study protocols; all GMTs measured using cLIA
1. Data on file, MSD.
Females Only
Anti-HPV response
(GMT Levels with 95% CI
[log10 scale])
Demonstration of Immune Memory with an Antigen
Challenge at Month 601
HPV 16
10,000
Immune
memory
demonstrated
after immune
challenge
1000
Quadrivalent HPV Vaccine
n=78
100
10
Placebo (Sero (–) and PCR (–))
n=70
↴
0 2 3 6 7
12
18
24
30
36
Months
Vaccination on day 0, at two and six months
Immune challenge at 60 months
• Similar results seen with HPV 18, 6, and 11
*In subjects naïve to the relevant HPV type from day 1 through month 60
1. Data on file, MSD.
54
60
61
60+1
week
OUTLINE OF PRESENTATION
Immune response in the natural history
of HPV infections
Prophylactic vaccines
rationale and immune mechanisms
Who and when to vaccinate
before exposure
? post exposure
Natural Course of Genital
HPV Infection
infection
First
Lesion
Incubation
(1-6 Mo.)
DNA-ve
Sero-ve
Immune
Response
Seroconversion
Average time
9mo
Active Growth
Late
(3-6 Mo.)
Host Stage
Containment
(3-6 Mo.)
DNA-ve
Sero+ve
Sustained
clinical
remission
Persistent or
recurrent
disease
Gardasil Phase III
HPV-Naïve Modified Intention To Treat Population
Endpoint
HPV vaccine Placebo
cases
cases
n=9342
n=9400
HPV 16/18-related
CIN 3 or AIS
•HPV 16/18-related CIN3
•HPV 16/18-related AIS
%
95% C.I
Efficacy
0
52
100
93, 100
0
0
47
9
100
100
92, 100
49, 100
Mean follow up 2 years
Subjects are counted once per applicable row.
www.fda.gov/ohrms/dockets/ac/06/slides/2006-4222s-index.htm
Geometric Mean Titer (mMU/mL) Log 10 Scale
Quadrivalent HPV Vaccine Yields Higher
Neutralizing Anti-HPV Antibodies in Baseline
Seropositive Subjects
Vaccine: naive recipient
3000
2000
1000
Placebo: naive recipient
Vaccine: seropositive and PCR negative recipient
Placebo: seropositive and PCR negative recipient
100
10
1
0
7
12
18
30
42
48
Months
These results suggest that women who were baseline HPV
sero-positive had a booster response to the vaccination.
Natural Course of Genital
HPV Infection
infection
First
Lesion
Incubation
(1-6 Mo.)
Immune
Response
Seroconversion
Average time
9mo
Active Growth
Late
(3-6 Mo.)
Host Stage
Containment
(3-6 Mo.)
DNA+ve
Sero+ve
DNA+ve
Sero-ve
Sustained
clinical
remission
Persistent or
recurrent
disease
OUTLINE OF PRESENTATION
Immune response in the natural history
of HPV infections
Prophylactic vaccines
rationale and immune mechanisms
Who and when to vaccinate
before exposure
? post exposure
Is there cross-protection?
Evidence for cross-protection against
incident infection with HPV 45 and 31 after
vaccination with Cervarix
Harper etal Lancet April 6th 2006
Cross neutralising antibodies to HPV 45 and 31
generated after immunisation with Gardasil
Titres of these cross-neutralising antibodies are
1-2 logs lower than the dominant type specific
neutralising antibody
Smith JF et al IPV Prague Sept 3 2006
Abstract PL 1-6
Prophylactic HPV L1 VLP vaccines
Efficacy
>90% for persistent infection
100% for disease (5 years post
vaccination) in subjects naïve for
vaccine HPV types
Immunogenic
high antibody concentrations up to
1000x > than in natural HPV infection
Duration of
protection
vaccine induced antibody levels
maintained over 5 years
Safe
no vaccine related serious adverse
events identified in the trials
to date (70,000 women)
Protection for this generation