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Recurrent Respiratory Papillomatosis (RRP)—Meta-analyses

on the use of the HPV vaccine as adjuvant therapy
Peter Goon 1,5,6 ✉, Odile Sauzet2,5,6, Matthias Schuermann3, Felix Oppel 3
, SenYao Shao3, Lars-Uwe Scholtz3, Holger Sudhoff3,6 and
Martin Goerner4,6

Recurrent Respiratory Papillomatosis(RRP) is a rare disease with severe morbidity. Treatment is surgical. Prevailing viewpoint is that
prophylactic HPV vaccines do not have therapeutic benefit due to their modus operandi. Studies on HPV vaccination alongside
surgery were meta-analysed to test effect on burden of disease. Databases were accessed Nov and Dec 2021 [PubMed, Cochrane,
Embase and Web of Science]. Main outcome measured was: Mean paired differences in the number of surgeries or recurrences per
month. Analyses was performed using: Random effect maximal likelihood estimation model using the Stata module
Mataan(StataCorp. 2019. Stata Statistical Software: Release 16. College Station, TX:StataCorp LLC.) Our results found n = 38 patients,
suitable for syntheses with one previous meta-analyses (4 published, 2 unpublished studies) n = 63, total of n = 101 patients.
Analyses rendered an overall reduction of 0.123 recurrences or surgeries per month (95% confidence interval [0.064, 0.183]). Our
meta-analyses concludes that HPV vaccine is a beneficial adjunct therapy alongside surgery
npj Vaccines (2023)8:49 ; https://doi.org/10.1038/s41541-023-00644-8
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INTRODUCTION Reported incidence rates for JORRP and AORRP are estimated at
Recurrent Respiratory Papillomatosis is a rare disease that can have 0.17–1.34 per 100,000 and 0.18–0.54 per 100,000 respectively11–15.
severe morbidity, due to recurrent growth of papillomata that In the adult population, the 2 peaks appear to correlate to the oral
threaten to obstruct the airways. Its aetiology has been clearly cavity HPV infection prevalences as reported by Gillison et al. in
defined, and over 90% of cases are thought to be due to Human 201216. Adult HPV transmission appear mainly to be via intimate
contact. Gender distribution in adults appear to follow that of HPV
Papillomavirus (HPV) types 6 and 111,2, which are also the dominant
oral infection also (2–3 males to 1 female). JORRP appear to be
types causing ano-genital warts, but high risk subtypes have also
predominantly via vertical transmission (mother to child during
been identified3–5. The morbidity results from numerous repeated labour and vaginal delivery) with a 200-fold increase in risk for
surgeries and can cause scarring of the vocal cords resulting in mothers with a history of genital wart infection17. However,
hoarseness and/or change in voice generation. elective caesarean section to prevent vertical transmission is
The development of the HPV prophylactic vaccines has been a controversial and has not been shown to definitively reduce
major advance in the field. There is currently a nonavalent vaccine transmission18,19. Early age of presentation with papillomatosis in
(Gardasil 9—licensed 2014) in use in the US, and the UK is due to a child (<3 years) appears to be a risk factor for severe disease and
change from Gardasil (tetravalent vaccine since 2012) to Gardasil 9 increased recurrences20. Interestingly, infection with the HPV 11
for its national HPV vaccination programme imminently. Safety type appears to be associated with more severe disease, more
profiles and efficacy rates in infection prevention have been recurrence, distal spread into the larynx, and even malignant
similarly excellent. Recent UK data reporting on the national HPV transformation20–22. This is in contra-distinction with HPV 6, which
vaccination programme6 have now demonstrated the efficacy of is the dominant type found in ano-genital disease.
these vaccines to prevent the development of cervical cancer at the HPV are small (~8 kb) non-enveloped viruses, but have an
population level. Australia has reported on the impressive reduction icosahedral protein capsid formed out of 72 L1 (with monomeric
of RRP within their highly vaccinated population7, and preliminary L2 protein embedded within the centre) pentamers. Electron
data from the US show a similar trend8. microscopy measurements estimate a virion size of 52–55 nm, and
The age at onset of RRP was previously thought to possess a there are 8–10 genes (median of 8) encoded by a double stranded
bimodal distribution with juvenile onset (JORRP) and adult onset DNA genome. HPV tend to produce papillomata at the
transformation zones (where there is transition between squa-
(AORRP) peaks at approximately 5 and 30 years respectively (Cohn
mous and columnar epithelia) but can infect anywhere in the
et al. has been recurrently cited but does not actually give any
aero-digestive tract or ano-genital mucosa or skin anywhere on
evidence for those assumptions9), but a study in 2015 from 12 the body. L1 protein was found to self-assemble into their native
European hospitals10 with n = 639, has now demonstrated that conformation (Jian Zhao et al.23 in 1991), and proved highly
there is a trimodal distribution with peaks at median ages of 7, 35 immunogenic in producing neutralizing antibodies. These dis-
and 64 years of age10. coveries have proved to be the basis of the highly successful L1

1
Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, and Departments of Dermatology & Otolaryngology, National University Health
System, Singapore, Singapore. 2Bielefeld School of Public Health and Department of Business Administration and Economics, University of Bielefeld, Universitätsstraße 25,
33615 Bielefeld, Germany. 3University Dept of Otolaryngology, Campus Klinikum Bielefeld Mitte, University Hospital OWL of Bielefeld University, Teutoburger Str. 50, 33604
Bielefeld, Germany. 4Dept of Haematology, Oncology and Palliative Medicine, Campus Klinikum Bielefeld Mitte, University Hospital OWL of Bielefeld University, Teutoburger
Str. 50, 33604 Bielefeld, Germany. 5These authors contributed equally: Peter Goon, Odile Sauzet. 6These authors jointly supervised this work: Peter Goon, Odile Sauzet, Holger
Sudhoff, Martin Goerner. ✉email: pkcgoon@nus.edu.sg

Published in partnership with the Sealy Institute for Vaccine Sciences

 P. Goon et al.
2
patients from new studies we were able to find since 2018 to gather
the available evidence that HPV vaccine can be used to substantial
beneficial effect for RRP (as adjunct treatment alongside surgery).
An updated meta-analyses would be most useful in rapid
dissemination of this information, since there are likely to be
28,000–150,400 patients (assuming a world population of 8 billion)
estimated to be living and suffering with RRP all across the world.

RESULTS
Results from search process and mathematical synthesis
Figure 2 illustrates the literature search process. After undergoing
this rigorous selection process, (and including the previous
published data from Rosenberg et al.26), we found several studies
which were potentially suitable for synthesis analyses. Mauz et al.
201827 and Matsuzaki et al. 201928 were then excluded due to the
lack of pre-immunisation data which was required for analyses.
Personal communications with Smahelova et al. 202229 allowed us
access to unpublished and just published data and has helped to
reduce bias. See Table 1 for details of the patients included in the
analyses.
See Fig. 3 for Forest Plot of Random Effect Maximal Likelihood
Estimation Model analysis.
Total number of patients included in the analysis was n = 12
(Yiu et al. 2018) + 26 (Smahelova et al. 2022) + 63 (Rosenberg
1234567890():,;

et al. 2019) which is n = 101 patients. This equates to an overall

reduction of 0.123 recurrences or surgeries per month (95%
confidence interval [0.064, 0.183]).
For the Yiu et al. 2018 study, the 12 patients included had a
Fig. 1 Juvenile Recurrent Respiratory Papillomatosis. a At Surgery mean recurrence of 0.225 per month (SD 0.221) before vaccina-
(>80 surgeries in previous 4 years). b Three months Post-Surgery (1a) tion and 0.068 (SD 0.072) after vaccination. For Smahelova et al.
and HPV vaccine. 2022, this mean recurrence value for the 26 patients included was
0.098 (SD 0.082) before and 0.028 (SD 0.032) after vaccination. We
vaccines produced in bivalent (Cervarix™), quadrivalent (Gardasil™) were able to synthesise these results with those of Rosenberg
and nonavalent (Gardasil 9™) forms and which have been shown et al. 2019.
to reduce incidence rates of cervical cancer (and dysplastic Our analyses suggest that there is substantial benefit for the
precursors)6 and also RRP7 in current real world experience. intervention of HPV vaccination used as adjunct therapy in
There are numerous other L1 vaccine clinical trials ongoing:24 to conjunction with surgery and strengthen the conclusions of the
test the efficacy of a 1 dose regimen; efficacy of 3 doses in meta-analysis performed by Rosenberg et al. in 201926 by providing
20–45 year old females; usage in postpartum women and an updated estimate with increased precision.
immunocompromised individuals (HIV and transplant patients);
dosage sparing via intradermal injections; usage as therapy in
DISCUSSION
combination with a PD1 inhibitor in patients with cervical cancer;
efficacy in protecting against recurrent disease in women under- Our results support the use of HPV prophylactic vaccination in
going ablative therapy for cervical disease, persistence of conjunction with ablative surgery to remove the papillomata, and
protection and efficacy in preventing oropharyngeal cancers. when more recent studies are combined with the large meta-
L1 HPV vaccine has also been used as adjunct therapy in the analysis conducted by Rosenberg et al. 2019, the data lend weight
treatment of RRP. The evidence of efficacy in reducing recurrent to the argument favouring this intervention for all patients.
papillomata formation, reducing the number of surgeries to keep Further, the mean recurrences for Smahelova et al. 2022 before
airways patent, increasing the interval between surgeries, etc. immunisation might be a little underestimated, due to (1) a less
have been accumulating gradually over the years24. Our group as precisely recorded duration of illness (in whole years). Recording
well as others has published on this interesting observation25 (see duration of illness in whole years prior to vaccination may mean
Fig. 1). The majority of published data on HPV vaccine as adjunct that it was less precise due to rounding up to a whole number,
in RRP have been conducted in small cohort single-centre studies, rather than a precisely recorded timespan in months or days. (2)
since RRP is a rare disease. Despite the clinical evidence so far, the Their data on mean number of recurrences before immunisation is
prevailing dominant viewpoint is that L1 vaccine cannot give also much lower than in the other studies, which may explain the
therapeutic benefit since its primary function is to generate smaller effect of immunisation. Vaccination appears to reduce the
protection against infection via anti-L1 antibodies (its modus mean number of recurrences to close to zero or low numbers,
operandi). therefore a smaller average number of recurrences before
There was a meta-analyses published in 2019 by Rosenberg immunization means that the decline of the decrease line to the
et al.26 which demonstrated beneficial effects of the quadrivalent average number of recurrences (a low number) after vaccination is
HPV vaccine, in conjunction with surgery for RRP. Synthesis analyses not as steep compared to a population with a high average
from 4 published and 2 unpublished datasets yielded 63 patients number of recurrences decreasing to a low number.
suitable for meta-analyses at that time. Mean intersurgery intervals This latest meta-analysis has now calculated the effect of HPV
(ISIs) improved from 7.02 months (range 0.30–45.0 months) prior to prophylactic vaccination on the mean RRP recurrences seen
vaccination, to 34.45 months (range 2.71–82.0) post-vaccination. before and after vaccination for n = 101 patients. This is the
Here we have updated and supplemented the meta-analyses with largest number of patients meta-analysed from multiple centres

npj Vaccines (2023) 49 Published in partnership with the Sealy Institute for Vaccine Sciences
 P. Goon et al.
3
Records from Databases using search terms [PubMed 53 (PG Accessed 17-11-

Idenficaon
2021); Cochrane 11 (PG Accessed 17-11-2021); Embase 118 (OS Accessed 29-
11-2021); Web of Science 79 (OS Accessed 29-11-2021)] n = 261

Duplicates removed, screened on tle +/-abstract for focus of arcles

n = 108
Screening and Eligibility

Exclusion (no new data), exclusion (single case reports),

inclusion criteria not met n = 37

Exclusion of studies already included in Rosenberg et al meta-

analysis 2019 (in order not to repeat or duplicate work) (plus 2
unpublished datasets menoned there) n = 14
Also exclusion of
Mauz et al and
Matsuzaki et al as
data required could
Inclusion for
analysis

not be extracted
Studies included for quantave synthesis/mini-meta (n = 3,
Yiu et al 2018 + 1 from hitherto unpublished data (Tachezy et
al 2022), + Rosenberg et al 2019)

Fig. 2 Flow diagram for search. PRISMA flow diagram.

so far, and represents a sum total of published and known L1 protein and neutralise the virus inoculum when contact with
unpublished data on this therapeutic option. Taken together, the the virus occurs. This effect has been shown to be highly effective
total available evidence strongly suggests there is a substantial and long-lasting, and the immune memory generated also leads
benefit for the use of adjuvant HPV vaccine in conjunction with to an anamnestic response whenever L1 is encountered in the
surgery. future. Real world data on reduction of cervical cancers and RRP
The risks and side-effect profiles of these HPV vaccines are well have now been published (as previously mentioned).
known and their safety excellent. The US Vaccine Adverse Events Adjuvants included in vaccines are many-decades old com-
Reporting System (VAERS) has reported and concluded that the pounds shown to augment and increase the immune response to
vast majority (97.4%) of reported events were non-serious, with the target, choice of adjuvant can help to increase or bias the
syncope and vaccine administration errors the commonest immune response to a specific pathway i.e. Th1 or Th2, innate
problems despite the millions of doses administered30, and that immunity and NK cell function, etc. The ideal adjuvant would
the safety profile of the HPV9 vaccine is consistent with its increase or ramp up the specificity and amplitude of the desired
predecessor HPV4 vaccine. The main benefits of the vaccine would immune response. Aluminium salts such as AAHS have been
be its proven efficacy in prophylaxis against HPV infection, and shown to increase the immune response via the T helper
thus protection against ano-genital and head and neck cancers, (Th2 > Th1) pathways and the innate immune system especially
(even if RRP continues to recur). The observations that there are through the DAMPs (Damage-Associated Molecular Patterns)
some therapeutic benefits in reducing recurrence of RRP in patients “Danger signals theory” and therefore with downstream activation
requires quantification, hence this meta-analyses. of the adaptive immune system via Dendritic cells (DCs) and
The use of HPV vaccine for therapy remains controversial, as the macrophages31–33. It is important to remember that aluminium
immune mechanisms that would explain this observed phenom- adjuvants also carry a risk of adverse effects but have been
enon is uncertain. HPV vaccines are derived from L1 proteins administered in a multitude of vaccines (HepA, HepB, Pneumovax,
which have self-assembled into virion-like particles (VLPs) and are Diphtheria-Tetanus vaccine formulations, BCG, Anthrax, Yellow
highly immunogenic but obviously do not contain any HPV DNA Fever, etc.) to billions of human beings and their safety has been
so are unable to replicate or initiate infection. The other primary monitored for many decades.
components are the adjuvant (amorphous aluminium hydroxy- The arguments for an adaptive immune response after
phosphate sulphate—AAHS), polysorbate 80 (emulsifier) and yeast vaccination with HPV L1 vaccines are two-fold. One, the above
proteins (HPV L1 grown in yeast cells to produce industrial use of adjuvant tends to cause a wider and stronger immune
quantities of proteins). response with involvement of both innate and adaptive (both
The primary function of these vaccines are to produce humoral and T-cell activation) immunity to L1 initially, but possibly
neutralizing antibody responses against L1 protein, this means with involvement of other targets through epitope spreading and
that there are high-affinity antibodies generated to bind avidly to affinity maturation later on. Two, we need to remember that HPV 6

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 P. Goon et al.
4
and 11 cause primarily productive infections, with full-cycle

2 pts excluded due to lack of

replication of the viral genome and live virus production. This is
in contra-distinction to HPV 16 and 18 (plus other high risk
subtypes) which cause productive infections initially but even-
tually integrate into the cellular genome and cause neoplasia in

63 pts included by
patients with long-term infections (which were not cleared). This

Rosenberg et al.
26 pts included tendency to continuously produce live virus in RRP ensures that
Comments

viral proteins other than L1 are exposed to the immune response,

follow up

and can be expected to cause a wide and strong immune

response to the pathogenic HPV type since there has been
activation of both the innate and adaptive arms of the immune
system.
US study but not mentioned

The evidence for a beneficial effect in RRP has been accruing

slowly over the years since the quadrivalent HPV L1 was licensed
Not mentioned but likely

NA but all studies were

in 2006. The lack of therapeutic effect in cervical cancer and its

central/east European

precursors was noted in 200734. Use of the quadrivalent L1

vaccine in RRP patients was initially for its predicted prophylactic
Race/ethnicity

effect (which has now been confirmed with reduction of incidence

rates at population levels) but it is likely that the beneficial
European

therapeutic effect was noticed shortly after more RRP patients

began to get vaccinated.
The most definitive and accepted method of confirming this
effect is to conduct a multi-centre randomised double-blinded
and placebo-controlled trial with the placebo arm switching over
to the HPV vaccine arm after 1st recurrence of papillomata, or after
Approx 41: 27
39: 11 (total

an accepted period of time of 3–6 months (whichever is first).

Sex (M: F)

Conducting such an RCT is likely to be prohibitive in cost and time,

cohort)

and so far, has not been done. Here in this updated perspective on
46 years (34–56) 10: 4

HPV viral immunology and vaccinology, we have presented the

virological and immunological logic behind the observed ther-
Men 44 (21–73)

apeutic effect, and updated the meta-analyses to include the

Pts who received other Adjuvants Median Age

latest studies (including unpublished) with available and synthe-

Women 39

sizable data to give increased precision.

(37–48)
(range)

This latest tranche of evidence is to provide clinicians in the

field, with the most up-to-date knowledge on the benefits versus
NA

risks of using HPV vaccine as an adjunct treatment, and therefore

for consideration of the inclusion of HPV vaccine as adjunct
therapy alongside surgery in national and international guidelines.
Cidofovir and Bevacizumab

Implementation of such clinical practice change is therefore likely

6 (3—Cidofovir alone), 3—

only in the richer countries of the world to begin with, but

implementation of single dose regimes in lower resource
countries should be considered.
None mentioned

METHODS
Systematic literature review and meta-analysis performed
HPV-vaccinated patients included in meta-analysis.

with PRISMA guidelines

NA

Ethical approval not required. A Population, Intervention, Compar-

ison, Outcome and Study design (PICOS) strategy was undertaken,
4: 38 but all 12 patients included

Rosenberg et al. Approx 20: 38 (not mentioned in

and patients with RRP looked for. HPV vaccination as adjunct

Smehalova et al. Ratio not mentioned but likely

therapy was the intervention searched for. Outcomes were the

numbers of recurrences or surgeries before and after HPV
vaccination, calculated to the mean recurrences per month. We
have taken into consideration the natural history of RRP which
appear to be AORRP

tends to a reduction in recurrences and surgeries over time,

especially in the young. Therefore, results will be expressed as
JORRP: AORRP

most AORRP

mean reductions per month, since this is easier to calculate for the
shorter pre-vaccine periods seen in young children. We excluded
1 study)

case reports or studies with less than 5 patients as anecdotal

single case reports have a high risk of assessment and publication
bias. The search terms with inclusion and exclusion criteria are
included here.
Search terms = (HPV vaccine OR human papillomavirus vaccine
OR papillomavirus vaccines OR alphapapillomavirus vaccines) AND
Yiu et al.
Table 1.

(HPV OR human papillomavirus OR alphapapillomavirus OR

papillomaviridae OR viral warts OR wart virus) AND (RRP OR
recurrent papillomatosis OR recurrent respiratory papillomatosis)

npj Vaccines (2023) 49 Published in partnership with the Sealy Institute for Vaccine Sciences
 P. Goon et al.
5

Favouring intervenon Does not favour

(HPV vaccine as adjunct treatment)

Fig. 3 Analysis - Forest Plot of Random Effect Maximal Likelihood Estimation Model. Forest plot of random effect maximal likelihood
estimation.

NOT (Cervical OR Cervical cancer OR Cervix) NOT (head and neck Risk of bias assessment
cancer OR HNSCC OR squamous cell carcinoma) NOT (AIN OR Anal PICOS and SIGN checklists completed. There is heterogeneity likely
Intraepithelial Neoplasia OR Anus OR Anal cancer) due to the following limiting factors for analyses (numerous
Databases searched with the above highly focused search studies, different methodologies, different parameters of data
terminology (and Boolean filters). We have also searched through collected and presented, limited numbers of patients (as all were
ClinicalTrials.gov for studies which were not included in the single centre studies), retrospective data collection). HPV vaccine
Rosenberg meta-analyses. We found one study for which no management in the cohort of synthesised patients were
published data was available at the time (now just published), and predominantly from HPV4 (quadrivalent vaccine) since the studies
we contacted the authors who kindly provided their data were undertaken primarily after the introduction of HPV4 in 2006,
(Smahelova et al. 202229—NCT01375868). whilst HPV9 was licensed in 2014.
Meta-analyses statistical methods are recognized for synthesiz-
Screening and checking for eligibility ing different studies with different parameters which can cause
PG searched and assessed studies for inclusion and exclusion criteria, significant heterogeneity such as different surgical techniques,
with help from OS. Duplicates removed, then study abstracts and concomitant drug administration, even criteria for initiating
titles were checked through. All non-studies, conference reports, surgery. A past history of different therapies was not an exclusion
case reports with <5 patients, reviews without new or relevant data, criterion. Different surgeons, different centres, different criteria
all non-English studies or reports (Swedish, Danish, German, and techniques for surgery were accepted as significant but
Norwegian, Chinese, Russian, Dutch all removed). unavoidable contributors to increased heterogeneity and risk
We included only studies for which it was possible to calculate of bias.
paired differences in the number of surgery or recurrences per
month. We excluded study participants for which no pre- Patient and public involvement
immunisation data were available or if patients were directly Our RRP patients and the public were initially involved as we
immunised at clinical diagnosis. This meant that we were able to planned the interventional study in 2013 which was published in
pool the data of Yiu et al. 2018, with data from Smahelova et al. 201725. The research questions for that study were developed with
2022 for synthesis with the summarised effects obtained by their benefit, wellbeing, preferences and clinical experience
Rosenberg et al. 2019. paramount in our minds. This follow-up study performed meta-
analyses and synthesis of available published and unpublished
Synthesis of results data so was more distant from the patient experience. The parents
Analyses were performed using Stata (StataCorp. 2019. Stata of the child in Fig. 1 gave informed signed consent for publication
Statistical Software: Release 16. College Station, TX: StataCorp LLC.). of the photos, and were closely involved and actively encouraged
We used a random effect maximal likelihood estimation model the publication of our study for as wide dissemination as possible,
using the Stata module Mataan35. since they feel that it is really important to publicise the availability
Majority of patients from the different studies were adults, of a beneficial adjunct therapy, now that they have seen the
although the meta-analyses and syntheses will accord equal benefit that it has given their child after a torrid time with repeat
weighting to both adults and children (<18 year old). Therefore surgeries over the last 4 years. The child remains clear of regrowth
results will tend to represent adults more than children. 12 months after the last surgery.

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 P. Goon et al.
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Reporting summary 19. Shah, K. V., Stern, W. F., Shah, F. K., Bishai, D. & Kashima, H. K. Risk factors for
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respiratory papillomatosis–is there one? Int J. Pediatr. Otorhinolaryngol. 35, 31–38 All authors have completed the ICMJE form (available on request from the
(1996). corresponding author) and declare no competing interests.

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 P. Goon et al.
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