Transcript An heterologous effect of MMR vaccine will induce

Finding our way in RRP- remission can be induced
by an heterologous effect of MMR vaccine.
Nigel R.T. Pashley, MB, BS;
FRCSC; FAAP
Rocky Mountain Hospital for
Children,
At Presbyterian St. Lukes
Medical Centre, Denver,
Colorado, USA.
Historical background of heterologous effects of
vaccines.
• Bacille Calmette-Guérin (BCG) reduces non-accidental
deaths from diseases other than TB by 53% (BMJ, 1959)
- used to treat bladder carcinoma in humans.
- prevents malaria in mice.
- protects against leprosy in humans.
• Measles immunisation in children in developing countries
has a protective efficacy against death of 30-86%.
(Aaby P et al BMJ, 1995) Girls respond best - effect
disappears if DPT given after measles immunisation.
• Shann F: Heterologous immunity = activation of memory T
cells. Prior infection is protective if Th1 response. Live
BCG and measles induce this. Regulatory T cells probably
mediate response. (J. Ped.Inf.Dis 2004)
Historical background of heterologous effects of
vaccines.
 “No one is naïve…” T-cell memory pool laid down
by prior infections and successive infection.
Mumps more symptomatic in teenagers =
activation of memory T cells? Welsh R. and
Selin L. Nature Reviews / Immmunol. June 2002.
Some observed in nature:
 GBV-C flavivirus virus co - infection reduces
mortality in HIV infected patients. (Tillman H. et
al NEJM. 345. 2001)
Historical background of heterologous effects of
vaccines in RRP.
Pashley N.R.T. Can Mumps vaccine induce remission
in RRP? Arch.Otolaryngol Head Neck Surg 128: July
2002: 783-6.
(Intra-lesional mumps with laser excision)
Pilot study:11 children, 82% remission, F/U 5-19 yrs
Open series:
18 children, 78% remission, F/U 2-5 yrs
20 adults, 75% remission, F/U 2-5 yrs
Heterologous Mumps vaccine effect
Jan 2000 8 year old
female
9 prior surgeries
10 amps monovalent
Mumps x 4
Intervals 6-26 weeks
April 2001
“Exploring” RRP 2002-6
2002: Mumps withdrawn- “20%
fail to immunize”.
18-25% of Pashley’s RRP
patients not in remission with
mumps alone.
MMR converts most
monovalent mumps failures.
2006: Shann, F. “MMR effect in
RRP another example of an
heterologous effect.”
Hampson, I. “HPV blocks Tcells in cervical ca.- MMR is
unblocking memory T-cells.”
Tyson, W. “HPV found in
placenta of HPV+ patients.”
Technique
• Custom suspension laryngoscope (Sontec, Denver)
• CO2 laser: 2-5 Watts: 0.1mm spot: 5 microsec pause ultrapulse mode (SSI laser, Nashville, Tenn.)
• Laryngeal injection needle (Piling Co. Philadelphia, Pa.)
• Absolute steroid avoidance.
• Single immunisation dose given with laryngeal injection.
Heterologous effect of MMR in RRPResults
Patients
38
Age yrs
1 - 58
10 children
28 adults
MMR
#
ml’s
amps/dose 1.8-17.5
3-28
M /F
Severity score
PrePost-
3F / 7M
3F / 25M
19-28
1-8
Freq.Wks Follow up
3-28
1-4 years
Heterologous effect of MMR in RRPResults
Remission
34/38 = 89.5%
Follow up 1 - 4 years
9 “single injection” remissions
 7 monovalent mumps failures converted
 8 cidofovir failures converted
 No “non-responders”.

Remission = 2 disease free (suitably long) intervals.
Heterologous MMR vaccine effect
May 2002
38 years male
11 prior surgeries
15 amps MMR by
single injection
20 weeks later
October 2002
Remission 2 visits later.
Heterologous MMR vaccine effect
May 2002
29 years male
16 operations elsewhere
Last 5 with cidofovir
10 amps MMR/dose
6-50 week intervals
9 operations (last 2
disease free)
Remission- March 2006
Heterologous effect of MMR in RRPConclusions:
•
•
•
•
•
Adjuvant to laser excision,
both mumps and MMR have
an heterologous effect on
RRP.
MMR is significantly better
than monovalent mumps.
The technique is simple but
arduous, reproducible,
cheap, effective, and has no
identifiable risk.
MMR works elsewhere- (skin
and peri-anal warts in HIV,
laryngeal carcinoma -in- situ
with RRP).
The effect is likely mediated
by memory T-cells.
The Heterologous effect of MMR in RRP
My thanks to the courageous
patients who tried this “offlabel” use of a conventional
vaccine with no assurance
that it would be effective (or
risk free).
The Heterologous effect of MMR in RRP
6 years male
∆ Armenia as “tumour.” Age 2 yrs
Tracheostomy + L. cordectomy.
Revised in Germany. Age 4yrs.
Sub-glottic stenosis + RRP.
January 2003: LTP with A/P
costochondral grafts +
MMR(20amps)
May 2007 Remission “pending”- no
trach, near normal husky voice.
No O2 req. @ 5800’
Immigration pending! Wants to go
to medical school.
Back to basics - the HIV example
after Silverstein G. Lancet: 369: April 28 2007
• Non-self molecules elicit
inflammatory cells (T-cells
and antigen presenting
cells). Both cell types are
subject to HIV infection.
• If large #’s of inflammatory
cells present in an area,
more infections would be
anticipated (seen in HIV
patients using microbicide
cellulose sulphate vs
placebo).
Is this why GER, or local
traumatic inflammatory
response to laser char etc.
makes laryngeal HPV
worse?
Common sense - the HIV example
after Silverstein G. Lancet : 369: April 28 2007
• HIV-1 isolated 1983-4.
Proteins extracted from
tissue culture (or produced
thru genetic engineering),
unsuccessful attempts made
to develope a vaccine.
• High rate of mutation and
how HIV strains evolve now
need to be considered - a
successful immune response
to HIV has yet to be defined.
Could the same thing occur in
RRP? The quadrivalent HPV
vaccine, if used for RRP, is
only being applied in
females.
Back to basics - immunogenesis of RRP
• Patients with HPV are
already immunized (to their
maximum) by presence of
disease (= “non-self.”)
Epigenetic hypermethylation
of tumor suppressor genes
in RRP suggests gene
silencing as one mechanism
allowing growth, (but maybe
not origin.)
• MMR and monovalent
mumps vaccine may induce
remission by unblocking Tcells. A successful immune
response to HPV has yet to
be defined.
Are intra-uterine exposure to
HPV, heavy marijuana use,
and cell to cell apposition
important?