HPV vaccines: who and when

1
HPV vaccines who and when to vaccinate
Margaret Stanley Department of Pathology Cambridge
2
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

3
Immunity is a partnership
Innate no memory, not antigen specific activate
d 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
4
Adaptive immune responses

• Type 1/Th1
• Cell mediated
• CD4 T cells help killers
• Killer T cells
• Activated macrophages
• Cytokines
• Natural killer cells

• Type 2/Th2
• Humoral
• CD4 T cells help
• B cells make antibody
• Non cytotoxic Antibody
• IgM, IgG, IgA, IgE

innate effectors enhanced and activated by
adaptive responses
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Natural Course of Genital HPV Infection
HrHPVs 12-18months LrHPVs 4-9months


Time
infection
Seroconversion Antibody to L1
Immune Response CMI
First Lesion
Virological clearance DNA-ve

Viral persistence DNAve LSIL/HSIL
Productive viral infection, DNAve low grade
lesions
DNA-ve
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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
7
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

8
Why might vaccines generating neutralising antibod
y 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
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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
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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

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Immune Response to HPV VaccinesA Proposed
Mechanism15
1. Stanley M. Vaccine. 2005 Epub ahead of
print. 2. Batista FD, Neuberger MS. EMBO
Journal. 200019513520. 3. Tyring SK. Curr Ther
Res. 200061584596. 4. Roden RB, Hubbert NL,
Kirnbauer R, et al. J Virol. 19967032983301.
5. Chen XS, Garcea RL, Goldberg I, et al.
MolCell. 20005557567.
12

• 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

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B cell memory and long term antibody persistence
Amanna et al Imm Revs 2006 211320
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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

15
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

16
Natural Course of Genital HPV Infection
infection
Seroconversion Average time 9mo
First Lesion
Immune Response
Sustained clinical remission
Active Growth (3-6 Mo.)
Late Stage
Host Containment (3-6 Mo.)
DNA-ve Sero-ve
Persistent or recurrent disease
17
Quadrivalent HPV Vaccine Phase III Adolescent
Immunogenicity Study Neutralizing Anti-HPV GMTs
at Month 7
Females 1015 Years of Age Males 1015 Years of
Age Females 1623 Years of Age
GMT geometric mean titers

• Block SL, Nolan T, Sattler C, et al. Pediatrics.
  2006 118.2135-45

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Age Specific Neutralizing HPV-6 Antibodies 1
Month Post-Vaccination1
PPE population Neutralizing anti-HPV 6 GMTs at
month 7
Efficacy Program
Immunogenicity Bridge
1600
1500
1300
1100
Serum cLIA GMT with 95 CI, mMU/mL
900
700
500
Females Only
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.
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Demonstration of Immune Memory with an Antigen
Challenge at Month 601
HPV 16
10,000
Immune memory demonstrated after immune challenge
1000
Anti-HPV response(GMT Levels with 95 CIlog10
scale)
Quadrivalent HPV Vaccine n78
100
10
Placebo (Sero () and PCR ()) n70
?
0
2 3
7
12
18
24
30
36
54
6
60
61
Months
601week
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.
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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

21
Natural Course of Genital HPV Infection
infection
Seroconversion Average time 9mo
First Lesion
Immune Response
Sustained clinical remission
DNA-ve Serove
Active Growth (3-6 Mo.)
Late Stage
Incubation (1-6 Mo.)
Host Containment (3-6 Mo.)
DNA-ve Sero-ve
Persistent or recurrent disease
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Gardasil Phase III HPV-Naïve Modified Intention
To Treat Population
Endpoint HPV vaccine Placebo 95
C.I cases cases Efficacy
n9342 n9400

• HPV 16/18-related
• CIN 3 or AIS
• HPV 16/18-related CIN3
• HPV 16/18-related AIS

0 0 0
52 47 9
93, 100 92, 100 49, 100
100 100 100
Mean follow up 2 years

• Subjects are counted once per applicable row.

www.fda.gov/ohrms/dockets/ac/06/slides/2006-4222s-
index.htm
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Quadrivalent HPV Vaccine Yields Higher
Neutralizing Anti-HPV Antibodies in Baseline
Seropositive Subjects
Vaccine naive recipient
Scale
3000
Placebo naive recipient
2000
Vaccine seropositive and PCR negative recipient
10
Placebo seropositive and PCR negative recipient
1000
100
Geometric Mean Titer (mMU/mL) Log
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.
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Natural Course of Genital HPV Infection
infection
Seroconversion Average time 9mo
First Lesion
Immune Response
Sustained clinical remission
Active Growth (3-6 Mo.)
Late Stage
Incubation (1-6 Mo.)
Host Containment (3-6 Mo.)
DNAve Serove
DNAve Sero-ve
Persistent or recurrent disease
25
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

26
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
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Prophylactic HPV L1 VLP vaccines Efficacy
gt90 for persistent infection 100 for
disease (5 years post vaccination) in subjects
naïve for vaccine HPV types Immunogenic high
antibody concentrations up to 1000x gt than in
natural HPV infection Duration of vaccine
induced antibody levels protection maintained
over 5 years Safe no vaccine related
serious adverse events identified in the
trials to date (70,000 women)
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Protection for this generation