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5 WHO preferred product characteristics

6 for therapeutic HPV vaccines
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9 NOTE: This draft document is being posted for the purpose of inviting public comments and
10 suggestions on the content contained herein, before the document will be considered by
11 WHO's Product Development for Vaccines Advisory Committee (PDVAC) for endorsement.
12 Written comments proposing modifications to this text must be received by 6 October 2023
13 and entered in the Comment Form (available separately) and should be addressed to
14 Dr Holly Prudden at [email protected] with the subject line “Comment: WHO PPCs for
15 therapeutic HPV vaccines”.

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17 Table of Contents
18 Acknowledgements....................................................................................................................................... 3
19 Abbreviations ................................................................................................................................................ 5
20 Executive Summary .......................................................................................................... 6
21 1. Purpose of WHO preferred product characteristics .................................................... 8
22 2. HPV therapeutic vaccines – global public health need. ............................................... 8
23 3. Background on HPV and cervical cancer .................................................................. 10
24 3.1 HPV infection and routes of transmission ............................................................................. 10
25 3.2 High-risk HPV types associated with cervical and other cancers ........................................... 10
26 3.3 Natural history of HPV infection ........................................................................................... 10
27 3.3.1 General population ............................................................................................................................ 10
28 3.3.2 Women living with HIV....................................................................................................................... 11
29 3.4 Epidemiology of HPV infection.............................................................................................. 11
30 3.7 Other HPV-related cancers.................................................................................................... 12
31 4. Existing interventions for cervical cancer management and control ......................... 12
32 4.1 Primary prevention ............................................................................................................... 12
33 4.2 Secondary prevention ........................................................................................................... 13
34 4.3 Tertiary prevention ............................................................................................................... 14
35 5. Public health need for therapeutic HPV vaccines in the context of existing
36 interventions .................................................................................................................. 14
37 5.1 Implementation and scale-up of prophylactic HPV vaccine programmes ............................. 14
38 5.2 Implementation and scale-up of cervical cancer screening and treatment ........................... 15
39 5.4 Identified public health needs for therapeutic HPV vaccines ................................................ 16
40 6. Therapeutic HPV vaccine development .................................................................... 16
41 6.1 Feasibility of therapeutic HPV vaccine development ............................................................ 16
42 6.2 Therapeutic HPV vaccine pipeline and development approaches ......................................... 17
43 6.3. Clinical development considerations ................................................................................... 18
44 6.3.1 Vaccine candidates designed primarily to clear HPV infection .......................................................... 18
45 6.3.2 Vaccine candidates designed primarily to cause regression of CIN2/3 lesions ................................. 19
46 6.3.3 Considerations for both vaccine approaches ..................................................................................... 20
47 7. Potential public health value of therapeutic HPV vaccines ....................................... 20
48 7.1 Potential approaches for therapeutic HPV vaccines to meet public health needs ................ 20
49 7.2 Public health value considerations for therapeutic HPV vaccines ......................................... 21
50 7.3 Modelling of therapeutic HPV vaccine impact ...................................................................... 22
51 8. Considerations for vaccine implementation ................................................................. 22
52 8.1 Target populations................................................................................................................ 23
53 8.2 Vaccine characteristics .......................................................................................................... 23
54 8.3 Programmatic and delivery considerations........................................................................... 24

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55 9. Preferred product characteristics for HPV therapeutic vaccines ................................... 25

56 Table 9.1 Preferred product characteristics for therapeutic HPV vaccines used to clear oncogenic
57 HPV infections. ........................................................................................................................... 26
58 Table 9.2 Preferred product characteristics for therapeutic HPV vaccines used to treat cervical
59 precancers .................................................................................................................................. 30
60 Table 9.3 Parameters common to both types of therapeutic HPV vaccines. ............................... 34
61 References...................................................................................................................... 35
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65 Acknowledgements
66
67 The Departments of Sexual and Reproductive Health and Research (SRH), Immunization,
68 Vaccines and Biologicals (IVB), Research for Health (RFH), and Non-Communicable Diseases
69 (NCD) at the World Health Organization (WHO) would like to thank the many individuals
70 who contributed to the development of this document. The consultation process of
71 developing therapeutic HPV vaccine preferred product characteristics (PPCs) and
72 preparation of this publication were led by Sami Gottlieb and Holly Prudden, WHO SRH, with
73 assistance from Celina Schocken (Consultant for the Bill and Melinda Gates Foundation
74 [BMGF]).
75
76 An initial therapeutic HPV vaccine PPC consultation was convened virtually in October 2021,
77 and a follow-up consultation was convened in Nairobi, Kenya, in November 2022. Additional
78 expert input was obtained during a series of virtual meetings on therapeutic HPV vaccine
79 modelling and a workshop at the International Papillomavirus Conference in Washington,
80 DC, USA in April 2023. These meetings played an important role in the development of this
81 therapeutic HPV vaccine PPC document. WHO would like to sincerely thank the following
82 individuals who attended one or more of these consultations and commented on drafts of
83 this document.
84
85 External attendees:
86
87 Laith Abu-Raddad, Weill-Cornell, Qatar; Sharon Achilles, BMGF, USA; Azadeh Baghaki,
88 Unitaid, Switzerland; Sudharasanam Balasubramaniam, Scope Impact, Finland; Neerja
89 Bhatla, All India Institute of Medical Sciences, India; Marc Brisson, Université Laval, Canada;
90 Emily Burger, Harvard University, USA; Karen Canfell, The Daffodil Centre, University of
91 Sydney, Australia; Michael Caruana, University of Sydney, Australia; Ru-fong Cheng, BMGF,
92 USA; Z. Mike Chirenje, University of Zimbabwe, Zimbabwe, and University of California, San
93 Francisco (UCSF), USA; Raveena Chowdhury, MSI, UK; Jamie Cohen, Institute for Disease
94 Modeling (IDM), BMGF, USA; Michael Chung, University of Washington, USA; Sinead Delany-
95 Moretlwe, Wits RHI, South Africa; Lynette Denny, University of Cape Town, South Africa;
96 Mamadou Diop, Joliot Curie Cancer Institute, Senegal; Peter Dull, BMGF, USA; Linda Eckert,
97 University of Washington, USA; Eleanor Edson, BMGF, USA; Deepa Gamage, Ministry of
98 Health, Sri Lanka; Patricia Garcia, Cayetano Heredia University, Peru; Bothwell Guzha,
99 University of Zimbabwe, Zimbabwe; Michaela Hall, University of Sydney, Australia; Rolando
100 Herrero, Agencia Costarrricense de Investigaciones Biomédicas, Fundación INCIENSA, Costa
101 Rica; Holger Kanzler, BMGF, USA; David C. Kaslow, PATH, USA (co-chair); Adam Keane,
102 University of Sydney, Australia; Jane Kim, Harvard University, USA; Luisa Lina Villa,
103 Universidade de São Paulo, Brazil; Lyou-Fu Ma, BMGF, USA; Kelle Moley, BMGF, USA; Nelly
104 Mugo, Kenya Medical Research Institute, Kenya; Raul Murillo Moreno, Hospital Universitario
105 San Ignacio, Colombia; Valerian Mwenda, Ministry of Health, Kenya; Saidatul Norbaya BT
106 Buang, Ministry of Health, Malaysia; Gina Ogilvie, University of British Colombia, Canada
107 (co-chair); Kate Ramsey, Scope Impact, Finland; Helen Rees, Wits RHI, South Africa; Veronica
108 Reis, Jhpiego, USA; Gracia Violeta Ross Quiroga, Bolivian Network of People Living with
109 HIV/AIDS, Bolivia; Sarah Saleem, Aga Khan University, Pakistan; Peter Sasieni, King's College

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110 London, UK; Marion Saville, the Australian Centre for the Prevention of Cervical Cancer,
111 Australia; Maike Scharp, BMGF, USA; John Schiller, NCI, USA; Celina Schocken, BMGF
112 consultant, USA; Kate Simms, University of Sydney, Australia; Liz Smith, BMGF, USA; Jenny
113 Spencer, University of Texas, USA; Margaret Stanley, University of Cambridge, UK; Marleen
114 Temmerman, Aga Khan University Hospital, Kenya; Ted Trimble, NCI, USA; Cari van
115 Schalkwyk, DST-NRF Centre of Excellence in Epidemiological Modelling and Analysis
116 (SACEMA), South Africa; Deborah Watson-Jones, Mwanza Intervention Trials Unit/London
117 School of Hygiene and Tropical Medicine, Tanzania/UK; Fanghui Zhao, National China Cancer
118 Center, China.
119
120 All external attendees completed WHO Declaration of Interests statements, and their
121 participation in the meeting and commenting on PPC document drafts were in accordance
122 with the Organization’s guidelines for Declaration of Interests for WHO experts.
123
124 WHO Headquarters, Regional Office, and Country Office attendees:
125
126 Hiroki Akaba, IVB; ; Pascale Allotey, SRH; Maribel Almonte Pacheco, NCD; Phionah
127 Atuhebwe, WHO Regional Office for Africa (AFRO); Nyambat Batmunkh, WHO Regional
128 Office for the Western Pacific (WPRO); Armando Baena, International Agency for Research
129 on Cancer (IARC); Partha Basu, IARC; Iacopo Baussano, IARC; Paul Bloem, IVB; Nathalie
130 Broutet, SRH; Sarah Charnaud, RFH; Shona Dalal, Global HIV, Hepatitis and STI Programmes
131 (HHS); Jean-Marie Dangou, AFRO; Lucia Helena de Oliveira, WHO Regional Office of the
132 Americas (AMRO); Kamal Fahmy, WHO Regional Office for the Eastern Mediterranean
133 (EMRO); Birgitte Giersing, IVB; Sami Gottlieb, SRH; Raymond Hutubessy, IVB; André Ilbawi,
134 NCD; Sharon Kapambwe, WHO Zimbabwe Country Office; Silvana Luciano, AMRO; Mauricio
135 Maza, AMRO; Maeve B. Mello, HHS; Liudmila Mosina, WHO Regional Office for Europe
136 (EURO); Elick Narayan, WPRO; Emmanuel Njambe, WHO Regional Office for South-East Asia
137 (SEARO); Nasim Pourghazian, EMRO; Holly Prudden, WHO SRH consultant; Anna Laura Ross,
138 RFH; Naishwa Skaik, NCD; Cherian Varghese, SEARO.
139
140 Industry observers at the meetings:
141
142 Joan Benson, Merck Vaccines; Tom Evans, Vaccitech; Matt Hawryluk, Gritstone; Laurent
143 Humeau, Inovio; Jules Millogo, Merck Vaccines; Diane Morgenstern, Inovio; Miriam
144 Reuschenbach, Merck Vaccines; Nicole Rich, Inovio; Ed Saltus, Merck Vaccines; Priti Shah,
145 AstraZeneca; Dereck Tait, Vaccitech; Vicky Wheeler, Vaccitech.
146
147 Funding
148
149 This work was supported by the Bill and Melinda Gates Foundation (Grant INV-021904) and
150 by the UNDP-UNFPA-UNICEF-WHO-World Bank Special Programme of Research,
151 Development and Research Training in Human Reproduction (HRP).
152

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153 Abbreviations
154
155 ART: anti-retroviral therapy
156 CIN: cervical intraepithelial neoplasia
157 CIN2/3: cervical intraepithelial neoplasia grade 2 and grade 3
158 CKC: cold knife conization
159 DART: development and reproductive toxicology
160 HDI: human development index
161 HICs: high-income countries
162 HIV: human immunodeficiency virus
163 HPV: human papillomavirus
164 LEEP: loop electrosurgical excision procedure
165 LLETZ: large loop excision of the transformation zone
166 LMICs: low- and middle-income countries
167 MSM: men who have sex with men
168 NAATs: nucleic acid amplification tests
169 PPCs: preferred product characteristics
170 SAGE: WHO’s Strategic Advisory Group of Experts on Immunization
171 STI: sexually transmitted infection
172 VIA: visual inspection with acetic acid
173 WHO: World Health Organization
174 WLHIV: women living with HIV
175

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176 Executive Summary

177
178 Development of therapeutic vaccines for human papillomavirus (HPV) may provide an
179 important addition to the current methods to prevent and treat cervical cancer. Cervical
180 cancer, caused almost exclusively by sexual transmission of oncogenic types of HPV, is an
181 important public health problem globally (1). In 2020, an estimated 604,000 women 1 were
182 diagnosed with cervical cancer, and approximately 342,000 women died from the disease
183 (2). Nearly 90% of cervical cancer-associated deaths occurred in women in low- and middle-
184 income countries (LMICs), largely due to inequitable access to effective cervical cancer
185 prevention and management measures.
186
187 The World Health Organization (WHO) has published a Global Strategy to Accelerate the
188 Elimination of Cervical Cancer as a Public Health Problem (3). On the path to elimination, the
189 Strategy could result in more than 62 million lives saved by 2120 (4) if three key targets are
190 achieved by 2030: vaccination of 90% of girls with prophylactic HPV vaccines; screening of
191 70% of women for cervical cancer with a high-performance test twice in their lifetime; and
192 provision of treatment to 90% of women with cervical precancers and invasive cancers.
193
194 Implementation of the global strategy currently lags far behind 2030 targets. The cost and
195 complexity of cervical cancer screening and treatment programmes, which may require
196 several visits for women testing positive for oncogenic HPV infection, and persistent
197 inequities in access to cervical cancer prevention programmes are major hurdles to reaching
198 the Strategy goals, particularly in LMICs (5).
199
200 Therapeutic HPV vaccines are currently in early clinical development and might offer an
201 additional tool to address gaps in cervical cancer programmes. Unlike existing prophylactic
202 HPV vaccines, which prevent new infections, therapeutic vaccines would be designed to
203 clear or treat existing HPV infections, HPV-associated precancers, or invasive cervical cancer.
204 This document focuses on potential therapeutic vaccines for HPV infection and/or cervical
205 precancers, which could be part of cervical cancer prevention efforts.
206
207 WHO preferred product characteristics (PPCs) documents provide guidance to vaccine
208 developers, policy makers, and programme implementers on preferences for new vaccines
209 in priority disease areas, including from the perspective of LMICs. Articulation of product
210 attributes that meet the needs of LMICs, while also addressing concerns of high-income
211 countries (HICs), can advance development of vaccines that are suitable for global use.
212
213 As a first step in defining therapeutic HPV vaccine PPCs, a WHO-convened group of experts
214 assessed the public health needs that might be addressed by therapeutic HPV vaccines,

1
All individuals have the right to sexual and reproductive health care. In this document, we recognize that
most of the available evidence on cervical cancer is based on study populations of cisgender women, and we
also recognize that cisgender women, transgender men, non-binary, gender-fluid and intersex individuals born
with a female reproductive system require cervical cancer prevention services. However, to be concise and
facilitate readability, we use the term “women” to refer to all gender-diverse people at risk for cervical cancer.
Cervical cancer prevention services must consider the needs of – and provide equitable care to – all individuals
independently of gender identity or its expression.

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215 considering the goal of saving additional lives on the path to cervical cancer elimination,
216 especially within the next 3 to 4 decades as prophylactic vaccination is scaled up. They
217 identified two overarching contexts:
218
219 • In settings where it has been difficult to scale up cervical cancer screening and
220 treatment, there is a need to reach women who have likely not received prophylactic
221 HPV vaccines to reduce the overall proportion that will develop or already have
222 cervical precancers, and
223
224 • In settings where screening and treatment is occurring, there is a need for an
225 alternative, simpler treatment to reduce loss-to-follow-up and increase the overall
226 proportion of women that are effectively treated following a positive test.
227
228 Ideally, therapeutic HPV vaccines would have high efficacy in both clearing high-risk HPV
229 infection to prevent development of cervical precancers and in treating (causing regression
230 of) high-grade precancers that have already developed. However, depending on their
231 mechanisms of action, the vaccines may have differential activity against these outcomes.
232 Thus, this document describes PPCs for two types of therapeutic HPV vaccines:
233
234 • Therapeutic HPV vaccines that primarily clear oncogenic HPV infection: For initial
235 licensure, these vaccines would be expected at a minimum to clear infection and/or
236 prevent high-grade cervical precancer due to HPV types 16 and 18, but activity
237 against additional HPV types and in treating existing precancers would broaden
238 impact and be desirable. These vaccines could be used in adult women (e.g., ages 25-
239 49 years) through population-based vaccine delivery without a preceding diagnostic
240 test. They could also be used to clear infection after a positive HPV test.
241
242 • Therapeutic HPV vaccines that primarily cause regression of high-grade cervical
243 precancers, at a minimum those associated with HPV types 16 and 18: These
244 vaccines would be used mainly as an alternative or adjunct to existing cervical
245 treatments among women who have, or who might have, cervical precancer
246 according to positive screening tests. However, depending on their attributes and
247 the setting, these vaccines could be used more broadly, with or without testing.
248
249 Both types of vaccine could potentially play a role in addressing each of the identified gaps
250 in cervical cancer prevention programmes. The choice of target population, including the
251 optimal age range, and the delivery strategy in a given setting, e.g., broad population-based
252 vaccination as opposed to targeted vaccination based on HPV testing, will not only depend
253 on vaccine characteristics such as efficacy in clearing infection versus causing regression of
254 high-grade precancers, but also on factors such as: the extent to which prophylactic HPV
255 vaccination and cervical cancer screening and treatment programmes have been scaled up;
256 the prevalence of cervical precancers at different ages, which may vary according to the
257 proportion of women living with HIV (WLHIV); cost-effectiveness; and programmatic and
258 health systems factors.
259

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260 1. Purpose of WHO preferred product characteristics

261
262 The World Health Organization (WHO) has a mandate to accelerate the development and
263 optimal use of safe and effective vaccines that could have global public health impact.
264 Priority areas include facilitating advancement of desirable vaccine candidates towards
265 licensure and generating evidence to inform future policy recommendations and vaccine
266 introduction. Identifying and articulating vaccine preferences that meet global health needs,
267 early in product development, is fundamental to this mission.
268
269 WHO vaccine preferred product characteristics (PPCs) documents describe such parameters
270 as vaccine indications and target populations, considerations for safety and efficacy
271 evaluation, and delivery strategies (6). WHO PPCs are intended to encourage product
272 innovation and facilitate vaccine development, particularly for use in low- and middle-
273 income countries (LMICs), which often have the largest unmet public health need. Because
274 vaccine manufacturers often develop vaccines for initial use in high-income countries (HICs),
275 first-generation vaccines may not be suitable for use in LMICs, and broader vaccine
276 introduction and impact can be substantially delayed. WHO PPCs emphasize LMIC
277 perspectives, in addition to those for HICs, to encourage development of vaccines for global
278 use.
279
280 PPCs are pathogen-specific rather than product-specific and are intended to provide
281 guidance early in product development. As such, the PPC guidance is intended to be broad,
282 to encourage innovation and stimulate further dialogue regarding the desired product
283 attributes that will optimally address the public health need and facilitate real-world use.
284 PPCs can inform subsequent target product profiles as product development progresses.
285 PPCs can also be updated with more specific guidance when further clinical trial data
286 become available, or in the event of changes in the identified need or in the research and
287 development landscape.
288
289 The primary target audience for WHO PPCs is any entity intending to develop a vaccine for
290 LMIC use and planning to seek WHO policy recommendations and prequalification for their
291 products (7). The PPCs also aim to reach policy makers and programme implementers to
292 highlight data needs and other considerations for future use. However, while PPCs define
293 aspirational goals for vaccine attributes, they do not supersede the evidence-based
294 assessment by WHO’s Strategic Advisory Group of Experts on Immunization (SAGE) or other
295 existing WHO guidance on vaccines (8)(9).
296

297 2. HPV therapeutic vaccines – global public health need.

298
299 Addressing cervical cancer is a global health priority. Despite being a preventable disease,
300 cervical cancer remains one of the most common causes of cancer-related death in women
301 worldwide. One woman dies of cervical cancer every two minutes (10). Furthermore, few
302 diseases reflect global inequities as much as cervical cancer, with 90% of cervical cancer
303 deaths occurring in LMICs (10).
304

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305 In 2020, the World Health Assembly, comprised of 194 WHO Member States, approved a
306 Global Strategy to Accelerate the Elimination of Cervical Cancer as a Public Health Problem
307 (3). The WHO Strategy set a goal of reducing cervical cancer cases below a global threshold
308 of 4 cases per 100 000 women-years. Because cervical cancer is almost exclusively caused by
309 cervical infection with oncogenic types of human papillomavirus (HPV), key components of
310 the Strategy include efforts to prevent, detect and treat precancerous cells infected with
311 HPV.
312
313 Cervical cancer can be eliminated as a public health problem within the next century, with
314 the potential to save 62 million lives in the process, if three key 2030 targets are successfully
315 reached by 2030 and sustained (4)(11):
316
317 • 90% of girls are fully vaccinated with a prophylactic HPV vaccine by the age of 15;
318
319 • 70% of women are screened using a high-performance test (e.g., HPV DNA testing)
320 by the age of 35, and again by the age of 45;
321
322 • 90% of women identified with cervical disease receive treatment (90% of women
323 with precancer treated, and 90% of women with invasive cancer managed).
324
325 Although prophylactic vaccination against HPV and screening and treatment for HPV-related
326 precancerous lesions are cost-effective methods to prevent cervical cancer, significant
327 challenges exist in scaling-up these interventions. Many countries, particularly LMICs, are far
328 from reaching Strategy targets for implementation of these interventions. Thus, while
329 efforts are redoubled to improve scale-up of existing interventions, the Strategy also calls
330 for exploration of new innovations, including advances in developing new medicines,
331 vaccines, diagnostics, and treatment modalities, to reach global goals (3).
332
333 One such potential innovation is development of therapeutic HPV vaccines designed to clear
334 or treat existing HPV infections or HPV-associated cervical disease, unlike prophylactic
335 vaccines that prevent infection. During October 2021 to November 2022, WHO convened a
336 series of global multidisciplinary consultations comprised of basic scientists, clinicians,
337 epidemiologists, vaccinologists and public health programme and policy experts from LMICs
338 and HICs, to discuss the need, goals, and potential value of therapeutic HPV vaccines and
339 key considerations for developing therapeutic HPV vaccine PPCs (12). The consultations
340 focused on potential therapeutic vaccines for HPV infection and/or cervical precancers.
341 Vaccines to treat invasive cervical cancer are beyond the scope of this document.
342
343 Experts agreed that the strategic public health goal of therapeutic HPV vaccines should be
344 aimed at saving additional lives on the path to cervical cancer elimination, particularly in the
345 next 30-40 years, the interim period before the impact of prophylactic HPV vaccine scale-up
346 is likely to be seen. Development of therapeutic vaccines would also aim to address gaps in
347 scaling-up cervical cancer screening and treatment programmes, as many LMICs currently
348 have virtually no national programmes in place. The full rationale for the public health goals
349 and key background considerations for therapeutic HPV vaccine PPCs can be found in the
350 meeting report from the WHO consultations (12).
351

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352 3. Background on HPV and cervical cancer

353
354 3.1 HPV infection and routes of transmission
355
356 Human papillomaviruses are DNA viruses belonging to the family Papillomaviridae. HPV
357 exclusively replicates in squamous epithelium and is mainly associated with cutaneous and
358 mucosal infections. While there are over 200 types, anogenital HPVs are broadly classified
359 into low-risk and high-risk types. The low-risk HPVs (e.g., types 6 and 11) are predominantly
360 responsible for cutaneous and anogenital warts, and the high-risk types (e.g., types 16 and
361 18) are responsible for cervical cancer, other anogenital cancers including anal, vaginal,
362 vulvar, and penile cancers, and oropharyngeal cancers (13). Multiple HPV genotype
363 infections are common, particularly in women living with HIV (WLHIV)(14).
364
365 High-risk HPV types infect basal epithelial cells of the anogenital mucosa via micro-abrasions
366 in the epithelial lining. Thus, the predominant route of transmission is through penetrative
367 sex, although transmission has also been associated with other types of sexual activity (15).
368 The probability of HPV transmission per sex act has been estimated to be around 40%
369 (range 5-100%) (16). In a large meta-analysis, among male partners of women testing HPV-
370 positive, 36% had concurrent type-specific infection, while among female partners of HPV-
371 positive men, 55% had concurrent infection (17). The risk of oropharyngeal cancer is
372 increased in women with cervical infection and in their partners, providing evidence of
373 genital-oral transmission (18).
374
375 3.2 High-risk HPV types associated with cervical and other cancers
376
377 High-risk HPV types, but not low-risk types, encode genes whose protein products can
378 transform normal healthy cells and cause cancer (i.e., are oncogenic) (19). Virtually all
379 cervical cancers are caused by infection with a high-risk HPV, of which there are at least
380 twelve (20). Two high-risk types, HPV types 16 and 18, are associated with 70% of all cervical
381 cancers (21). An additional five high-risk types, HPV types 31, 33, 45, 52 and 58, are
382 estimated to be responsible for another 20% of cervical cancers (22). In addition to cervical
383 cancer, oncogenic high-risk HPVs, particularly HPV type 16, are associated with other
384 anogenital cancers and a proportion of oropharyngeal cancers. Overall, HPV causes around
385 5% of all cancers globally (10).
386
387 3.3 Natural history of HPV infection
388
389 3.3.1 General population
390
391 Most HPV infections are asymptomatic and resolve spontaneously. Approximately 40% to
392 70% of incident HPV infections in women clear on their own in one year, depending on the
393 population studied (23). Clearance rates as high as 70–100% have been observed in young
394 women 2–5 years post-infection (24). Infections with the same HPV type tend to clear at the
395 same rate, regardless of age (25). However, high-risk HPV infections are more likely to
396 persist than low-risk HPV infections (26). Among women with persistent infection,
397 progression to cervical intraepithelial neoplasia (CIN) grade 2 or grade 3 (CIN2/3) – high-

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398 grade cervical precancer – is estimated to occur in 8–28%, depending on the HPV type. This
399 may take months to years. Without intervention in these women, an additional 3–5% will
400 progress to invasive cervical cancer (24). In women with normal immune systems, cervical
401 cancer generally takes 15–20 years to develop from the time of HPV infection.
402
403 3.3.2 Women living with HIV
404
405 For those with weakened immune systems, such as untreated women living with HIV
406 infection (WLHIV), cervical cancer may develop faster (i.e., in 5–10 years) (27). HIV infection
407 is associated with a six-fold increase in the risk of cervical cancer, in part due to HIV’s
408 modifying effect on HPV pathogenesis (24). In addition to an increased risk of HPV
409 acquisition among WLHIV, the time to clear infection is longer (28) and the chances of
410 recurrent infection are higher compared to HIV-uninfected women (29). Risk of HPV
411 acquisition and progression inversely correlates with CD4 T cell count, although this
412 association can be mitigated in those virally suppressed on anti-retroviral therapy (ART)
413 (27).
414
415 3.4 Epidemiology of HPV infection
416
417 Data from high-income settings show that between 50% to 79% of women acquire a genital
418 HPV infection over their lifetime, with 40% of women infected within the first two years of
419 sexual debut (30). Thus, adolescent girls and women under age 25 years have the highest
420 incidence rates of HPV infection (31). A summary report from 2023 showed that the
421 estimated global prevalence of HPV type 16 or 18 at any point in time was 3.9% among
422 women with normal cervical cytology, 25.8% in women with low-grade cervical lesions (i.e.,
423 CIN1), 51.9% in women with high-grade cervical lesions (i.e., CIN2/CIN3) and 69.4% in
424 women with cervical cancer (32).
425
426 The global prevalence of genital HPV infection in men is similar to that seen in women (33),
427 with increased risk of infection in men who have sex with men (MSM) and men living with
428 HIV (34). For men, HPV infection rates are high across all age groups (35).
429
430 3.5 Epidemiology of cervical cancer
431
432 In 2020 globally, there were an estimated 604,000 new cases of cervical cancer (age-
433 standardized incidence rate 13.3 per 100,000 women) and 342,000 cervical cancer deaths
434 (age-standardized mortality rate 7.3 per 100,000 women) (Figure 1) (32). However, these
435 figures reflect marked disparities in the global distribution of cases and deaths (Figure 2) (2).
436 In many HIC settings, cervical cancer incidence is below 7 cases per 100,000, while incidence
437 rates are above 29 per 100,000 in many countries in sub-Saharan Africa, where mortality
438 rates may also be over 20 times higher compared to HICs (Figure 1) (2). In some countries,
439 the majority of which are in Sub-Saharan Africa and Southeast Asia, cervical cancer is the
440 most commonly diagnosed female cancer and leading cause of women’s cancer deaths (36).
441
442 While higher rates of cervical cancer in sub-Saharan Africa may be partly explained by lower
443 rates of cervical cancer screening and treatment, a higher prevalence of HIV is also a major

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444 contributing factor (27). In southern Africa, an estimated 64% of women with cervical cancer
445 are living with HIV, as are 27% of women in Eastern Africa; HIV prevalence in these settings
446 ranges from 2% to 27% in the general population (37)(38).
447
448 3.7 Other HPV-related cancers
449
450 In addition to causing cervical cancer, HPV is also associated with anal, penile, vaginal,
451 vulvar, and oropharyngeal cancer. In 2020, the total number of non-cervical HPV-associated
452 anogenital cancers was estimated to be 150,087 in men and women. Of these, 30.1% were
453 vulvar cancer, 24.0% were penile cancer, 33.9% were anal cancers, and 12.0% were vaginal
454 cancers (32). A further 98,400 estimated HPV-related cancers are oropharyngeal (36).
455

456 4. Existing interventions for cervical cancer management and

457 control
458
459 Programmes to prevent cervical cancer morbidity and mortality currently have three
460 essential pillars: primary prevention, which includes administration of prophylactic HPV
461 vaccines; secondary prevention, which involves screening women to identify those who may
462 have HPV-related precancers and treatment to prevent progression to cervical cancer; and
463 tertiary prevention, which involves treatment of invasive cervical cancer and access to
464 palliative care. These three pillars form the basis for the targets of the WHO Global Cervical
465 Cancer Elimination Strategy (3).
466
467 4.1 Primary prevention
468
469 Clinical trials have shown prophylactic HPV vaccines to be safe and highly efficacious in
470 preventing persistent infection with vaccine-type HPV and related precancers (39)(40). The
471 first HPV vaccines were licensed in 2006. Currently available prophylactic vaccines include
472 quadrivalent vaccines protecting against HPV types 6, 11, 16 and 18, bivalent vaccines
473 protecting against HPV types 16 and 18, and nine-valent vaccines protecting against HPV
474 types 6, 11, 16, 18 ,31, 33, 45, 52 and 58 (41). Although there is evidence of some limited
475 cross-protection against acquisition of other, non-vaccine HPV types (42), the vaccines do
476 not have a therapeutic effect on pre-existing HPV infection or cervical lesions.
477
478 WHO recommends use of prophylactic HPV vaccines in early adolescence, with the primary
479 target being girls 9-14 years old, before the typical initiation of sexual activity, and the
480 primary focus being prevention of cervical cancer (43)(44). Vaccination of girls only, when
481 coverage is high, provides herd immunity to boys as well as providing direct protection
482 against cervical cancer, and is typically more cost-effective than vaccinating both sexes (41).
483 However, vaccination of both boys and girls is carried out in some settings. School-based
484 programmes are the main vaccine delivery strategy among LMICs, resulting in higher
485 coverage than facility-based programmes (45).
486

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487 Countries that have achieved high coverage of adolescent girls with prophylactic HPV
488 vaccination have observed dramatic declines in HPV prevalence, incidence of cervical
489 precancers, and invasive cervical cancers (46)(47)(48).
490
491 4.2 Secondary prevention
492
493 To prevent cervical cancer, women can be screened using several tests to identify those who
494 have, or are at risk of, cervical precancer. The three main approaches are molecular tests,
495 cytologic tests, and visual inspection. Molecular methods include nucleic acid amplification
496 tests (NAATs) for HPV DNA or mRNA. These are the most sensitive and cost-effective
497 diagnostic tests, although the current cost of the test kits and the infrastructure required for
498 processing and testing are a barrier in many settings. Cytologic tests (e.g., Papanicolaou
499 tests, liquid-based cellular assessments) require trained cytologists in addition to higher-cost
500 laboratory infrastructure. A lower-cost alternative is visual inspection with acetic acid (VIA),
501 which involves clinician visualization of the cervix after applying diluted acetic acid solution.
502 Despite the lower cost and infrastructure, the sensitivity and specificity of this method are
503 strongly dependent on the experience of the clinician, and, even with a highly skilled
504 practitioner, the sensitivity and specificity remain poor relative to molecular screening.
505
506 WHO recommends HPV DNA or mRNA NAAT testing on provider-collected cervical samples
507 as the primary screening test, starting at age 30 years for women in the general population
508 and repeated every 5–10 years (49). Women can also provide self-collected vaginal swabs
509 for HPV DNA testing. For WLHIV, HPV DNA or mRNA NAATs are also the recommended
510 primary screening test to start at age 25 years, and repeated every 3–5 years (49). For both
511 groups, after the age of 50 years, WHO recommends stopping testing following two
512 consecutive negative screening results.
513
514 For women with a positive HPV test, WHO recommends either a “screen and treat” or
515 “screen, triage and treat” approach. In the “screen and treat” approach, the decision to
516 treat is based on a positive primary screening test only, preferably an HPV DNA or mRNA
517 test. Before treatment, all women who have screened positive should undergo a visual
518 examination of the cervix to exclude cervical cancer and determine eligibility for ablative
519 treatment. In the “screen, triage and treat” approach, the decision to treat is based on a
520 positive primary screening test followed by a positive second test (“triage”) with or without
521 histologically confirmed diagnosis. The WHO recommended primary test is HPV DNA or
522 mRNA detection followed by partial genotyping, VIA or cytology as a triage test (49).
523
524 If treatment is indicated and the lesion is appropriate (small and entirely visible on the
525 ectocervix), it can be treated with ablation that destroys abnormal tissue by freezing
526 (cryotherapy) or application of heat (thermal ablation). If the lesion is not appropriate for
527 ablation, it can be surgically excised by removing the entire abnormal transformation zone,
528 using large loop excision of the transformation zone (LLETZ) 2 or cold knife conization (CKC).

2 In some countries, this terminology was changed to LEEP (loop electrosurgical excision procedure), and the two terms are often
used interchangeably.

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529 Women with suspected cancers must be referred for further evaluation and management
530 (49).
531
532 4.3 Tertiary prevention
533
534 Cervical cancer case management is based on staging of the disease. Early-stage cervical
535 cancer has long-term survival and cure rates of around 80% where timely diagnosis and
536 high-quality treatments are available (50). WHO recommends surgery and/or radiotherapy,
537 with or without chemotherapy, for early stages of cervical cancer (49). WHO also
538 recommends integrating palliative care into the treatment plan throughout the disease
539 course. Effective early-stage treatment is paramount, as standard of care radio- and
540 chemotherapies of late-stage cervical cancers tend to have low cure and survival rates (51).
541

542 5. Public health need for therapeutic HPV vaccines in the context
543 of existing interventions
544
545 Current and predicted future gaps in scaling up existing interventions provide a potential
546 role for therapeutic HPV vaccines, with the overarching aim of reducing global cervical
547 cancer deaths over the next three to four decades.
548
549 5.1 Implementation and scale-up of prophylactic HPV vaccine programmes
550
551 As of July 2023, a total of 131 countries had introduced HPV prophylactic vaccines into their
552 national immunization programmes (52). However, only an estimated 13% of young girls are
553 fully vaccinated globally (10), and HPV vaccines have not reached those settings most in
554 need: 60% of cervical cancer cases occur in countries that have not yet introduced
555 prophylactic HPV vaccines (37).
556
557 Among the 47 countries in the WHO African region, which has the highest r ates of cervical
558 cancer in the world, only 23 countries have introduced HPV prophylactic vaccine into their
559 national immunisation programmes as of April 2022, with coverage ranging from 0-77%.
560 Challenges associated with meeting vaccination targets have included insufficient global
561 supply of vaccines, costs of the programme, low acceptance of the vaccine, and additional
562 resources required to engage stakeholders. Challenges in areas such as cold-chain
563 management and integration into existing vaccination programmes have also been
564 reported.
565
566 Nonetheless, it has been demonstrated that it is feasible to achieve high coverage of
567 prophylactic HPV vaccines, even in resource-poor settings (53). Furthermore, a Strategic
568 Advisory Group of Experts on Immunization (SAGE) meeting held in April 2022 advised that
569 countries may now choose a one- or two-dose schedule for 9–14-year-old girls, the primary
570 target cohorts, and for women aged 15–20-years-old (44) that will simplify immunization
571 implementation, increase supply, and reduce production bottlenecks and overall costs (54).
572

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573 5.2 Implementation and scale-up of cervical cancer screening and treatment
574
575 Access to cervical cancer screening is very limited in many LMICs (Figure 3). Only around a
576 third of countries have managed to screen over 70% of women at least once in their
577 lifetimes, with any method; 126 countries have screening coverage below this level (5). On
578 average, only around 10% of women in LMICs have ever received cervical cancer screening
579 (5).
580
581 Of those countries with cervical screening recommendations, only 35% (48 out of 139)
582 recommend primary HPV-based screening. Visual inspection with acetic acid is the most
583 recommended test in LMICs (5). Given the poor sensitivity and specificity of VIA compared
584 to other screening methods, high-grade precancers and early stages of cervical cancer may
585 be missed, and high false-positive rates may lead to unnecessary treatment. Thus, reported
586 levels of coverage likely still fall short of impact goals for this pillar of the cervical cancer
587 elimination strategy.
588
589 Complexity and cost of screening and treatment programmes, which may require several
590 visits, have been the primary barriers in many LMICs. Many settings report challenges in
591 switching to primary HPV DNA testing, including inadequate laboratory facilities and
592 staffing, high costs of the diagnostic assay, and weak communication systems to contact and
593 refer women who test positive. Even when screening does occur, the biggest gap within the
594 cascade of care is often from screening to treatment, with substantial loss to follow-up after
595 a positive screening test or limited capacity of the system to deliver quality treatment.
596
597 A lack of trained clinicians and difficulties with quality control in referral centres have also
598 been challenging. Peri-operative and pregnancy complications following LLETZ and other
599 excision methods such as potential scarring and stenosis of the cervix, or risk of sexually
600 transmitted infection (STI) acquisition during the healing period are also a concern (55).
601
602 In countries with high HIV prevalence, major barriers to cervical cancer prevention include
603 high recurrence rates of dysplasia following treatment in WLHIV (56). There are also
604 difficulties in treating larger lesions or lesions that occur predominantly inside the
605 endocervical canal. These lesions tend to have higher failure rates and are more common in
606 unscreened populations in LMICs (57). Building capacities to perform LLETZ to treat such
607 large lesions in LMIC settings can be quite challenging.
608
609 5.3 Implementation and scale-up of cervical cancer management
610
611 Cancer diagnostic and treatment services show wide disparities. Coverage levels of cervical
612 cancer management services in the public sector are generally above 90% in HICs; however,
613 coverage of such services is generally under 30% in low-income countries and ranges from
614 around 40% to 70% for access to cancer centres, surgery, radiotherapy, chemotherapy and
615 pathology services in lower-middle-income countries (3). Cost, complexity, and lack of
616 health system infrastructure and human resources remain barriers to effective widespread
617 implementation.
618

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619 5.4 Identified public health needs for therapeutic HPV vaccines
620
621 Large gaps exist in scale-up of current cervical cancer prevention interventions. Prophylactic
622 HPV vaccines are expected to prevent tens of millions of deaths on the road to cervical
623 cancer elimination (58). However, given the long natural history of HPV infection leading to
624 cervical cancer, the full benefits of prophylactic HPV vaccination programmes will not be
625 observed for several decades. Modelling has reinforced how crucial cervical cancer
626 screening is for the many age cohorts of women not vaccinated in adolescence, to identify
627 and treat those who may already have cervical precancers or invasive cancers, and thus to
628 save millions of additional lives (59). Although coverage for both prophylactic vaccination
629 and screening and treatment is currently low globally, experts felt that there was much
630 more promise to rapidly scale up adolescent prophylactic HPV vaccination in the coming
631 years. However, scaling up screening and treatment programmes was felt to be much more
632 challenging and predicted to lag further behind global targets.
633
634 These challenges present an opportunity in the shorter-term for new innovations to
635 contribute to cervical cancer prevention, whilst existing interventions are scaled up. The
636 WHO-convened group of experts identified two overarching contexts with public health
637 needs for potential therapeutic HPV vaccines:
638
639 • In settings where it has been difficult to scale up quality cervical cancer screening
640 and treatment, particularly areas where prophylactic HPV vaccine programmes have
641 been delayed, there is a need to reach women who have likely not received
642 prophylactic vaccination to reduce the overall proportion that will develop or already
643 have cervical precancers (and thus invasive cancers), and
644
645 • In settings where screening and treatment is being implemented, there is a need for
646 an alternative, simpler, and more accessible treatment following a positive test to
647 decrease loss-to-follow-up and increase the overall proportion of women with high-
648 risk HPV infections and/or precancers who are effectively treated.
649

650 6. Therapeutic HPV vaccine development

651
652 Experts explored the potential feasibility, pipeline, and clinical development considerations
653 for future therapeutic HPV vaccines that could meet identified public health needs. The
654 focus was on vaccines that primarily clear high-risk HPV infection and/or cause regression of
655 high-grade cervical precancers. Therapeutic vaccines for treatment of invasive cervical
656 cancer were beyond the scope of the consultations.
657
658 6.1 Feasibility of therapeutic HPV vaccine development
659
660 Therapeutic HPV vaccines are intended to act in the setting of ongoing, active infection.
661 Thus, they have different mechanisms than prophylactic vaccines, which prevent infection.
662 All HPV types encode “early” proteins (E-proteins: E1, E2, E4-E7), and “late” virion structural
663 proteins (L-proteins: L1, L2) (Figure 4). To cause infection, HPV virions bind to basal cells in
664 the epithelium using the viral capsid protein L1. All current highly efficacious prophylactic

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665 HPV vaccines target L1. In infected cells, E1 and E2 proteins are responsible for viral
666 replication and transcription, and E6 and E7 proteins drive cell proliferation. As E6 and E7
667 play a significant role in cellular transformation, these viral proteins have been the main
668 targets of most therapeutic vaccine candidates to date, designed to treat later stages of
669 HPV-driven disease such as precancer and invasive cervical cancer (60). However, for
670 therapeutic vaccines intended to target early stages of pathogenesis such as persistent
671 infection, inclusion of proteins such as E1 and E2, which are more highly expressed at these
672 early stages, may be critical for successful termination of HPV infection and prevention of
673 precancer (61)(62).
674
675 Therapeutic HPV vaccine development is challenging for several reasons. HPV has a
676 relatively slow life cycle that is non-cytolytic, actively evades the innate and adaptive
677 immune response, and does not induce a high level of inflammation that would alert the
678 host to infection (63). Antibodies are insufficient to clear persistent HPV infection or reduce
679 precancerous lesions (64). Thus, while current prophylactic HPV vaccines rely on antibody-
680 mediated protection, post-exposure therapeutic vaccines will likely require induction of cell-
681 mediated immunity with effective T cell responses against early viral proteins across
682 genetically diverse populations.
683
684 In addition, advanced cervical lesions have often undergone immune selection and display a
685 highly immunosuppressive local environment that presents scientific and immunological
686 challenges to achieving an efficacious vaccine (65). Thus, it may be easier to develop
687 efficacious therapeutic HPV vaccines that target HPV infection or low-grade precancerous
688 lesions than vaccines that target high-grade precancers or invasive cervical cancer, because
689 the vaccines focused on earlier stages will be acting upon cells that are more conducive to
690 clearance by robust immune responses.
691
692 Experts felt that, for a vaccine targeting either persistent high-risk HPV infection or more
693 advanced cervical disease, an effective single-dose vaccine is unlikely. Mucosal delivery,
694 such as oral or intravaginal, for either initial or booster dosing might improve the immune
695 response and could also allow self-administration (66). Intravaginal administration may have
696 the added benefit of recruiting T cells into the relevant tissue site.
697
698 6.2 Therapeutic HPV vaccine pipeline and development approaches
699
700 No licensed therapeutic HPV vaccines currently exist. However, the clinical pipeline is active,
701 and a wide variety of approaches have been used to develop therapeutic HPV vaccine
702 candidates, including peptide, protein, DNA, RNA, and bacterial- and viral-vectored vaccine
703 platforms (67).
704
705 To date, therapeutic HPV vaccine development has primarily focused on candidates
706 targeting regression of CIN2/3 lesions and invasive cervical cancer, although a few
707 candidates focusing on clearance of high-risk HPV infection are now in phase 1 and 2
708 studies.3 A systematic review of completed phase 2 and 3 clinical trials of therapeutic HPV
709 vaccine candidates targeting CIN2/CIN3 lesions identified 12 published studies through

3
www.clinicaltrials.gov: NCT04607850; NCT03913117; NCT04490512; accessed 27 June 2023.

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 WHO/Draft for public comment/V0.1/September2023

710 2022: 6 studies with vector-based vaccines, 3 with peptide and protein-based vaccines, and
711 3 with nucleic acid-based vaccines (68). In addition, at least 6 therapeutic vaccine products
712 were registered as being in active Phase 1 or 2 studies as of June 2023.4
713
714 Several of the completed studies have demonstrated regression of high-grade (CIN2/3) to
715 low-grade (CIN1) or no precancer following therapeutic HPV vaccination, with modest but
716 significant differences when compared with natural regression (67)(68). In a meta-analysis
717 of the controlled studies, the proportion achieving regression after vaccination was about
718 50% higher than that observed in the placebo group (68). These findings provide proof of
719 concept that a therapeutic vaccine can generate immune responses that can cause
720 regression of high-grade precancer, although efficacy will need to be improved. In addition,
721 existing early phase studies have demonstrated that clearance of infection, operationally
722 defined as loss of HPV detection using a sensitive NAAT, also occurs at the same time as
723 regression of precancers (68).
724
725 All candidates to date have been multiple-dose products (most commonly 3 doses),
726 administered at set intervals over several months. The most common route of
727 administration in clinical studies has been parenteral (subcutaneous and intramuscular)
728 delivery. Other delivery methods have included oral delivery and direct injection at the site
729 of the cervix.
730
731 6.3. Clinical development considerations
732
733 6.3.1 Vaccine candidates designed primarily to clear HPV infection
734
735 Primary clinical endpoints for trials of therapeutic HPV vaccine candidates focusing on
736 infection might include clearance of vaccine type-specific HPV infection, prevention of high-
737 grade cervical precancer, or a composite of both outcomes.
738
739 Clearance of infection can be defined as a negative follow-up test (using a highly sensitive
740 and specific test, such as type-specific HPV DNA NAAT) at a pre-determined point in time
741 (e.g., at 12 months) in someone who had a positive test at baseline. Evaluating prevention
742 of high-grade cervical precancer will require serial histological evaluation and calculation of
743 rates of progression from low-grade (e.g., CIN1) or no precancer to high-grade (e.g., CIN2/3)
744 precancer. The appropriate clinical endpoints, including the precise time frame for
745 evaluating clearance or progression, and whether infection clearance will require two
746 negative tests (e.g., at 12 and 15 months), will need to be determined in discussions with
747 regulators. Although complete resolution of oncogenic infection following therapeutic
748 vaccination would be expected to prevent progression to high-grade cervical precancers,
749 which in turn would be expected to prevent progression to cervical cancer, regulatory
750 guidance will be needed to confirm whether durable clearance of infection and/or
751 prevention of high-grade precancers, as measured in trials, is an acceptable surrogate for

4
www.clinicaltrials.gov: NCT04607850; NCT03913117; NCT04490512; NCT00788164; NCT04131413;
NCT03911076, accessed 27 June 2023.

18
 WHO/Draft for public comment/V0.1/September2023

752 prevention of cervical cancer, as has been established with prevention of infection for
753 prophylactic HPV vaccines (69). Conversely, a vaccine might prevent progression to high-
754 grade cervical precancer without entirely clearing infection.
755
756 Secondary endpoints should be collected where possible, including clearance of non-vaccine
757 HPV types, incidence of reinfections or recurrences, and clearance of vaccine-type infections
758 at non-cervical sites (e.g., oropharynx, anus). Evaluation of therapeutic HPV vaccines may
759 also occur compared with or in combination with prophylactic HPV vaccination.
760
761 For evaluating therapeutic HPV vaccines with an infection clearance endpoint, adequately
762 powered clinical trials can be conducted with fewer participants, and more quickly, than for
763 prophylactic HPV vaccine trials. This is because all participants will have already acquired
764 high-risk HPV infection, and outcomes can be based on the continued presence or absence
765 of HPV infection on serial testing, over a defined period. Because a large proportion of
766 infections will clear naturally, a control group will be important in understanding efficacy.
767 No therapy is currently recommended for HPV infection when high-grade precancer has
768 been ruled out, so a placebo comparator is acceptable. Including only those with persistent
769 HPV infection at baseline, defined by the presence of type-specific HPV DNA on repeated
770 clinical biological samples over a period (typically 6 months), would decrease the number
771 who would clear infection naturally but would lengthen the screening portion of the study.
772
773 Even with vaccine candidates primarily designed to clear infection, separate evaluation of
774 the efficacy of these vaccines against high-grade cervical precancers would be useful in
775 understanding whether their use can be broadened to increase potential public health
776 value.
777
778 6.3.2 Vaccine candidates designed primarily to cause regression of CIN2/3 lesions
779
780 Clinical trials of therapeutic HPV vaccine candidates focusing on regression of high-grade
781 cervical precancers will need to be carefully designed to ensure they are ethically and
782 methodologically sound. Important considerations for clinical trial design specialists and
783 regulators include the timeline of the follow-up period, whether the comparator group
784 would be placebo or an alternative treatment, and appropriate primary and secondary
785 outcomes. Of critical importance is the need to ensure women with high-grade cervical
786 precancers are not left untreated. WHO guidelines recommend treatment is initiated no
787 later than 6 months following a positive screening. Trials comparing with an alternative
788 treatment would need large study sizes because of the high efficacy of current alternative
789 treatments that would act as comparators.
790
791 In previous clinical studies of therapeutic HPV vaccines, women with histologically
792 confirmed CIN2 and/or CIN3 associated with HPV types 16 and 18 have received therapeutic
793 HPV vaccines with or without a placebo control arm and typically followed for
794 histopathological regression of cervical lesions to CIN1 or no dysplasia (68). Clearance of
795 viral infection should also be evaluated; however, discussion with regulators can determine
796 whether associated viral clearance is an essential component of the primary outcome and
797 how to assess it, and whether endpoints will require biopsy or could be based on an
798 alternative, such as HPV testing in the setting of negative colposcopy results.

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799
800 Several trials to date have measured clearance of HPV infection as part of the primary
801 outcome along with regression of high-grade precancers, and several have evaluated viral
802 clearance as a secondary endpoint (68). Experts speculate that vaccines capable of
803 regressing CIN2/3 lesions are also likely to have efficacy against clearing high-risk HPV
804 infection, which is the precursor to precancer. Additional secondary endpoints may include
805 evaluation of cross-protection against cervical precancers associated with other oncogenic
806 HPV types, clearance of non-vaccine type HPV infection or low-grade cervical lesions,
807 prevention of recurrent cervical lesions and reinfections, and clearance of HPV infection at
808 multiple anatomical sites.
809
810 While initial licensure may be as a standalone treatment, future vaccines with primary
811 indications of regression of cervical precancers may also be considered as an adjunct to
812 existing ablative treatments, or in combination with newer immune checkpoint inhibitors or
813 genetically engineered T-cell therapy (70)(71), to enhance overall treatment outcomes
814 and/or reduce disease recurrence rates. This may be particularly interesting for WLHIV, who
815 have lower efficacy and higher recurrence rates with existing treatment.
816
817 6.3.3 Considerations for both vaccine approaches
818
819 Some outcomes could be evaluated post-licensure, e.g., progression to precancer in
820 vaccines with a primary indication of clearance of infection, or extension of benefits to other
821 anatomic sites, cross-protection, co-administration with prophylactic HPV vaccines, or
822 different dosing regimens. If a multi-dose regimen is evaluated, efficacy data should be
823 gathered whenever possible from those who only receive one-dose to inform potential
824 possibilities for improving dosing regimens, e.g., if women don’t return for a second dose,
825 they should still be followed for outcomes. Research will also be needed on whether
826 therapeutic vaccination affects future assessment and diagnosis of cervical precancers or
827 invasive cancer.
828
829 Consideration should be given for including in clinical trials populations of end-users that
830 would accrue the greatest potential benefit from the vaccine, in particular individuals from
831 LMICs. Clinical trials should include adequate planning for implementation priority for trial
832 populations, in instances where the vaccine is later approved and licensed. In addition,
833 inclusion of pregnant women in an ethical fashion whenever possible is desirable.
834

835 7. Potential public health value of therapeutic HPV vaccines

836
837 7.1 Potential approaches for therapeutic HPV vaccines to meet public health needs
838
839 Aligning the potential mechanisms of action of future therapeutic HPV vaccines with the
840 public health needs, the use of vaccines that primarily clear infection would be more
841 favoured for clearing infection and preventing precancers on a population basis in relatively
842 younger age groups, perhaps at or before the recommended starting age for screening,
843 which is age 30 years in the general population and age 25 years among WLHIV. Those
844 designed primarily to treat existing precancers may be more appropriate following testing in

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845 relatively older ages as part of cervical cancer screening and treatment efforts. However,
846 these approaches are not mutually exclusive, and efficacious therapeutic HPV vaccines with
847 either of these actions – or preferably some degree of both – might be useful additions to
848 cervical cancer prevention efforts in both contexts, depending on their attributes and how
849 they are used within existing health infrastructure.
850
851 7.2 Public health value considerations for therapeutic HPV vaccines
852
853 Multiple factors will need to be simultaneously considered to understand the potential
854 value of therapeutic HPV vaccines, and their optimal characteristics, within the context of
855 broader cervical cancer prevention programmes. Overarching factors include:
856
857 • Timeline for development: The value of therapeutic HPV vaccines will be higher
858 when the timeline to develop and implement them is shorter, relative to ongoing
859 scale-up of prophylactic vaccination programmes, aging of cohorts vaccinated with
860 prophylactic HPV vaccines in adolescence, and efforts to broaden access to cervical
861 cancer screening and treatment programmes in different settings.
862
863 • Background epidemiology and intervention scale-up: The potential added value of
864 therapeutic HPV vaccines will be greater in the setting of lower coverage of existing
865 interventions and higher background rates of vaccine-type oncogenic HPV infection,
866 cervical precancers, and invasive cancers. These factors also affect the number of
867 women needed to be vaccinated to prevent a cervical cancer case or death and thus
868 vaccine cost-effectiveness.
869
870 • Vaccine characteristics: A key factor in determining potential value will be specific
871 vaccine attributes, particularly the overall and relative efficacy in clearing or
872 controlling high-risk HPV infection to prevent precancerous lesions versus causing
873 regression of existing lesions. Efficacy or cross-protection against oncogenic HPV
874 types beyond types 16 and 18 will broaden value (72), as will the presence of
875 immune memory to clear future reinfections or prevent lesion recurrences. Factors
876 that will ease delivery and increase coverage are important, particularly for LMICs,
877 such as decreased number of doses, a simple route of administration, few side
878 effects, a schedule that aligns with existing care infrastructure, and simplified cold
879 chain and storage requirements.
880
881 • Health system and programmatic factors: These considerations will necessarily
882 intersect with vaccine characteristics to determine the most appropriate delivery
883 approach for therapeutic HPV vaccines and the ability to achieve high coverage,
884 which impacts potential added value. This includes healthcare access for those at risk
885 and the capacity to provide vaccination and/or other cervical cancer interventions at
886 points of care, the availability of HPV diagnostics, and social and community factors
887 affecting awareness, communication, and acceptability of therapeutic HPV vaccines.
888
889
890

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891 7.3 Modelling of therapeutic HPV vaccine impact

892
893 A well-validated model in 78 LMICs was developed as part of the Cervical Cancer Elimination
894 Consortium and was instrumental in showing the potential lives that can be saved if the
895 targets in the Global Strategy to Eliminate Cervical Cancer are achieved (4). It also
896 highlighted the importance of scaling up screening and treatment in the next several
897 decades, before the benefits of prophylactic vaccine scale-up are fully observed.
898
899 Preliminary modelling of therapeutic HPV vaccine impact using this platform demonstrated
900 that population-based vaccination with a therapeutic HPV vaccine with high efficacy in
901 clearing HPV infection and high coverage can have a substantial impact in reducing cervical
902 cancer cases and mortality, particularly when there has been no scale-up of existing
903 interventions (73). These findings are reinforced by models of the impact of therapeutic HPV
904 interventions in Uganda (74) and in India (75), which showed that an HPV therapeutic
905 vaccine might avert up to 25-35% of cervical cancers over 30 years, depending upon the
906 product characteristics and level of intervention scale-up. Added benefits of therapeutic
907 HPV vaccines drop as background scale-up of interventions approaches the Global Cervical
908 Cancer Elimination Strategy 90-70-90 targets (3). The available models have demonstrated
909 that efficacy in causing regression of high-grade cervical precancer in addition to efficacy in
910 clearing infection, as well as the presence of immune memory (i.e., preventing reinfection or
911 recurrence with the same HPV type), were very influential in increasing impact. Even
912 modest additional efficacy (i.e., 50%) in regressing precancers was predicted to
913 approximately double the number of cases and deaths averted, compared with high efficacy
914 in clearing infection (i.e., 70-90%) alone (75)(73).
915
916 The LMIC model showed that providing therapeutic HPV vaccines only after a positive
917 diagnostic test can reduce the number needed to vaccinate to avert a cervical cancer case or
918 death; however, the overall impact was slightly reduced because of a drop off in the
919 assumed proportion of women receiving the test and the current test sensitivity for
920 infection. Planned cost-effectiveness analyses will better elucidate these trade-offs. For
921 vaccines primarily being used as an alternative treatment for cervical precancers within
922 screening programmes, the relative impact depends on the efficacy of the vaccine relative
923 to the efficacies of existing cervical precancer treatments (e.g., cryotherapy or thermal
924 ablation) and the degree to which each can be delivered in the fewest number of visits to
925 avoid loss to follow up, which significantly impacts treatment outcomes.
926
927 Future analyses will include further exploration of impact in the setting of different vaccine
928 characteristics and delivery considerations, realistic background intervention scale-up,
929 additional analyses for WLHIV and cost-effectiveness analyses. In addition to modeling,
930 evaluation of end-user preferences and predicted acceptability of therapeutic vaccines will
931 also be important in understanding potential value.
932

933 8. Considerations for vaccine implementation

934
935 How therapeutic HPV vaccines should be implemented to optimally meet public health goals
936 will be determined by several key factors within each setting, including the preferred target

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937 populations, the vaccine characteristics, and the capacity of the health systems to deliver
938 new and existing interventions.
939
940 8.1 Target populations
941
942 Factors needing to be considered in defining the most appropriate target populations
943 include determination of the population that would receive the greatest direct benefit of
944 vaccination, the epidemiology and natural history of the infection, the ability to reach the
945 population through programmes, cost and cost-effectiveness, and equity.
946
947 Women will receive the largest direct benefit of therapeutic HPV vaccines. Provision of
948 therapeutic HPV vaccines to men may contribute to reductions in population-wide HPV
949 transmission, and it also can afford individual benefits related to other HPV-related cancers,
950 such as anal cancers among MSM and transgender women, particularly those living with
951 HIV. Because cervical cancer has by far the largest disease burden, women are the primary
952 focus. Nonetheless, additional vaccine efficacy related to other HPV-related cancers could
953 help broaden the value of the vaccines and increase equity in prevention services for those
954 disproportionately affected by HPV-related disease.
955
956 The age of women to be targeted is an important consideration, and target age may vary
957 according to the vaccine indication and use case. For example, for broad population-based
958 delivery without testing, targeting younger ages of adult women (i.e., starting at or before
959 the typical ages of cervical cancer screening – age 30 years in general populations and age
960 25 years among WLHIV) would occur before many women have precancer lesions, but
961 would also clear many infections that would likely have cleared naturally. Vaccinating at
962 earlier ages would also run the greatest risk of new infections being acquired after
963 vaccination (assuming therapeutic HPV vaccines only act against current infections and not
964 future infections), given the age-associated incidence of infection. Targeting older ages (e.g.,
965 among those recommended for screening – age 30-49 years in general populations) would
966 capture more persistent HPV infections but may also occur in the setting of more precancer
967 lesions or invasive cancers that have already developed. Across these age targets, in the
968 absence of preceding testing, therapeutic HPV vaccines would be given to a large proportion
969 of women without vaccine-type infection.
970
971 Although the primary focus would be on women in their twenties, thirties, or forties,
972 availability of these vaccines may have benefits for special populations outside of this group,
973 such as children or adults post-sexual assault or abuse, or people on chronic
974 immunosuppressive treatments. Choice of target population will also need to take into
975 consideration existing infrastructure to reach a particular group to achieve good uptake of
976 therapeutic HPV vaccines, and its background coverage with prophylactic vaccination and
977 cervical cancer screening and treatment.
978
979 8.2 Vaccine characteristics
980
981 Decisions about when, how, and whom to vaccinate will depend on the vaccine’s
982 characteristics. Ideally HPV therapeutic vaccines would have high efficacy in clearing high-
983 risk HPV, preventing progression to precancer, and regressing precancerous lesions, with an

23
 WHO/Draft for public comment/V0.1/September2023

984 excellent safety profile, and which could be feasibly delivered to target groups within health
985 systems in both LMIC and HIC settings.
986
987 Vaccine efficacy in clearing high-risk HPV infection and/or regressing precancerous lesions,
988 cross-protection against non-vaccine HPV types, and immune memory against reinfection or
989 recurrence will help to determine population impact and cost-effectiveness according to the
990 target group(s) or delivery strategy. Ideally, vaccines will show comparable efficacy in
991 treating WLHIV and immunocompromised individuals, and they will be safe and effective in
992 pregnant women. Vaccine characteristics such as number and timing of doses, route of
993 administration, and cold chain requirements will all affect programmatic feasibility.
994
995 8.3 Programmatic and delivery considerations
996
997 Choice of delivery strategy for therapeutic HPV vaccines would depend on vaccine
998 indications and target populations, against the backdrop of existing cervical cancer
999 prevention efforts and overall health infrastructure. One delivery option is broad
1000 population-based delivery to adult women, without preceding testing, which may be the
1001 most appropriate strategy to address the public health need in settings with very limited
1002 screening and treatment access or testing capacity. In settings with ongoing screening and
1003 treatment programmes or the capacity to conduct HPV testing, targeted vaccination
1004 following a positive test could provide an important treatment approach.
1005
1006 A population-based delivery strategy would not require cervical cancer screening
1007 infrastructure but would require an adult vaccination platform. Historically there has not
1008 been an immunization platform for women of reproductive age, other than for maternal
1009 immunization, which has been varyingly implemented. However, the COVID-19 pandemic
1010 has provided adult vaccination strategies that may be a new opportunity for delivery of
1011 other vaccines. Whether they will be as successful outside of a pandemic is unclear, but the
1012 infrastructure and staff training required for delivering vaccines has been established in
1013 many settings. Campaigns may also provide an effective means to deliver such a
1014 programme. For a population-based strategy without testing, the number needed to
1015 vaccinate to prevent a single case of cervical cancer will be high, making cost-effectiveness a
1016 potential issue.
1017
1018 Inclusion of therapeutic HPV vaccines within existing screening and treatment programmes,
1019 or where some testing infrastructure exists, could increase the efficiency of vaccinating
1020 those with high-risk infection or precancer. A vaccine that is less invasive or otherwise easier
1021 to deliver than current treatments could reduce the high rates of loss-to-follow-up observed
1022 after screening in many settings. In this respect, development of improved rapid point-of-
1023 care HPV diagnostics, and use with self-collected specimens, could significantly improve
1024 programmatic outcomes (76)(77). Such tests would allow therapeutic vaccination
1025 immediately after a positive test in a single visit, even if a woman is referred for further
1026 evaluation and management. A ‘test and vaccinate’ approach that is simpler to deliver than
1027 existing programmes could also help broaden coverage and improve equity. Such an
1028 approach could be done in primary care, family planning clinics, HIV prevention and care
1029 services, postpartum or infant immunization visits, or in community-based outreach efforts.
1030

24
 WHO/Draft for public comment/V0.1/September2023

1031 Acceptability of therapeutic HPV vaccines to potential vaccine recipients will be a critical
1032 component of any delivery strategy. Many countries achieve excellent coverage rates for
1033 vaccines, with high vaccine acceptability; however, countries are now increasingly affected
1034 by vaccine hesitancy. Although demonstration of both safety and efficacy is crucial to
1035 counter vaccine hesitancy, communication strategies will also be important, in addition to
1036 raising awareness more generally around cervical cancer and prevention. Prophylactic HPV
1037 vaccines have historically been promoted as vaccines to prevent cervical cancer rather than
1038 prevention of an STI, as STI vaccines may be perceived as stigmatizing (78). In addition to
1039 distinguishing therapeutic HPV vaccines from prophylactic vaccines, consideration should be
1040 given as to whether they are discussed as “vaccines” or as “treatment,” particularly as not
1041 all those receiving therapeutic vaccines will have infection or disease. Communication and
1042 marketing strategies should be planned in advance, with careful consideration and input
1043 from potential end-user communities.
1044
1045 A variety of other programmatic factors will be important in ensuring therapeutic HPV
1046 vaccines can be delivered in LMIC as well as HIC settings. Scale-up and implementation will
1047 not only need to account for health system differences, but also cultural and social
1048 differences among countries. Requirements of vaccine procurement, cold chain and
1049 transportation, linkages with other health system services, and data systems also need to be
1050 considered. A critical factor in global access and uptake of vaccines is related to their cost-
1051 effectiveness and overall costs. A full value of vaccines assessment should evaluate the
1052 trade-offs involved in investing in development and implementation of therapeutic HPV
1053 vaccines versus increased investment in scaling up current programmes, or their expansion
1054 (e.g., delivering prophylactic HPV vaccines at older ages).
1055

1056 9. Preferred product characteristics for HPV therapeutic

1057 vaccines
1058
1059 The identified areas of unmet public health need for therapeutic HPV vaccines (section 5)
1060 and potential therapeutic HPV vaccine development approaches (section 6) form the basis
1061 for therapeutic vaccine PPCs. Ideally, therapeutic vaccines would have activity against both
1062 infection and precancers. However, vaccines that are primarily designed to clear oncogenic
1063 HPV infection and those primarily designed to cause regression of high-grade cervical
1064 precancers may have different considerations in terms of how and for whom they are used,
1065 and their optimal characteristics. Both could play a role in achieving public health goals in
1066 LMIC and HIC settings. Thus, separate PPCs have been developed for each, as described in
1067 Tables 9.1 and 9.2 below. Preferred characteristics that are common to both vaccine
1068 approaches are described in Table 9.3.
1069
1070 This PPC guidance should not supersede existing WHO guidelines related to cervical cancer
1071 prevention, nor efforts to scale up existing prevention interventions (3). In all settings, to
1072 the extent possible, women should follow WHO guidelines for cervical cancer screening and
1073 treatment: starting at age 30 years in the general population and age 25 years for
1074 WLHIV(49)(41).
1075
1076

25
 WHO/Draft for public comment/V0.1/September2023

1077 Table 9.1 Preferred product characteristics for therapeutic HPV vaccines used to clear
1078 oncogenic HPV infections.
1079
Parameter Preferred characteristic Notes
Indication For initial licensure: The goal of clearing oncogenic infection would be preventing
Clearance of HPV type 16 and progression to high-grade cervical precancers, which in turn would
18 infection and/or prevention be expected to prevent progression to cervical cancer.
of high-grade cervical
precancers associated with Regulatory guidance will be needed to confirm whether durable
these HPV types. clearance of infection as measured in clinical trials (e.g., loss of HPV
detection using a sensitive NAAT) is an acceptable surrogate for
Considerations for WHO global prevention of cervical cancer for therapeutic vaccines, as has been
policy recommendations established with prevention of infection for prophylactic HPV
include: vaccines. Discussions with regulators can also establish whether
- regression of cervical prevention of high-grade precancers should be evaluated instead of,
precancers or in addition to, clearance of infection in clinical trials.
AND/OR
- clearance of additional HPV types 16 and 18 account for 70% of cervical precancers that
oncogenic HPV type infections progress to invasive cervical cancer. Therefore, minimally viable
AND/OR first-generation vaccines should include types 16 and 18.
- prolonged responses against
reinfection or recurrences. Efficacy in causing regression of high-grade cervical precancers,
cross-protection against additional oncogenic HPV types, and/or
prolonged responses against repeat vaccine-type HPV infection
(“immune memory”) would expand the public health benefits of
therapeutic HPV vaccines and could affect recommendations for
broader use. Consideration should be given to collecting supporting
evidence on these outcomes during pre-licensure studies and
designing post-licensure studies to evaluate them.

Inclusion of additional HPV types in the vaccine may also add

benefit. The next priority for inclusion should be HPV types 45, 35,
31, 33, 52, and 58. However, inclusion of additional types may result
in trade-offs such as cost and complexity of manufacturing, potential
effects on immunogenicity, and higher vaccine prices.

The primary indication relates to cervical infection; however,

additional efficacy against HPV infections in other sites (e.g., anal,
vaginal, oropharyngeal) would be valuable.

Target 5 The precise age range of adult women who should receive
Adult women (e.g., ages 25 to
population 49 years) in settings where a therapeutic vaccines may vary by setting, the delivery strategy, and
high proportion have not over time, and may depend on:
already received prophylactic - Scale up and ages of delivery of prophylactic vaccines
HPV vaccine. - Scale up of cervical cancer screening and treatment
- Prevalence of existing precancer at different ages
- Proportion of women living with HIV [WLHIV] in the
setting; WLHIV may require vaccination at earlier ages
- Cost-effectiveness analyses

5
To facilitate readability, the term “women” is used throughout this document to refer to all gender-diverse
people at risk for cervical cancer, including cisgender women, transgender men, non-binary, gender-fluid and
intersex individuals born with a female reproductive system.

26
WHO/Draft for public comment/V0.1/September2023

Parameter Preferred characteristic Notes

- Vaccine attributes such as additional efficacy in regressing
precancer, and duration of action of the vaccine.

Epidemiologic data and modelling will determine age thresholds that

optimize benefits of therapeutic HPV vaccination for different
settings and populations, and the relative value of using prophylactic
HPV vaccines with or without therapeutic vaccines at different ages.

In general, vaccinating younger women will result in vaccination of

more women who would clear their HPV infections naturally or who
may acquire new infections later. Vaccinating older ages will result
in capturing more women with persistent infections, but also more
women who already have cervical precancers or invasive cancers.

Women should be encouraged to receive cervical cancer screening

and treatment where available through existing programmes, and
receipt of therapeutic vaccine should not alter this guidance.

The target population includes WLHIV, who have more frequent and
rapid progression to cervical precancers and invasive cancer
following oncogenic HPV infection, and where current treatments
are less effective. However, a therapeutic vaccine that was effective
in the general population but not WLHIV, e.g., because of immune
dysfunction, would still be valuable.

Women are the primary focus of therapeutic HPV vaccines given the
large disease burden related to cervical cancer. Nonetheless,
therapeutic vaccines might also afford individual benefits related to
other HPV-related cancers, such as anal cancers among men who
have sex with men (MSM) and transgender women, particularly
those living with HIV.

Pregnant and breastfeeding women should be considered for

inclusion in the target population as soon as possible, following early
and ethical collection of vaccine safety and efficacy/effectiveness
data related to pregnancy and lactation.

Vaccine In settings where a high The most appropriate population-level vaccine delivery strategy will
delivery proportion have not already be determined by existing health systems and vaccine delivery
strategy received prophylactic HPV platforms, including mass vaccination campaigns and delivery within
vaccine nor screening: points of contact within the health care setting. Experience with
delivery of COVID-19 vaccines to the target population and other
Population-based delivery, with
programmes including prophylactic HPV vaccines may be
no requirement for a preceding
informative.
screening test.

HPV vaccination could be incorporated into a variety of health

delivery settings, including primary care, family planning, antenatal
In settings with HPV testing
and postpartum care, HIV services, and other sexual and
capacity:
reproductive health services, and for delivery to mothers during
Targeted vaccination based on their children’s immunization visits.
positive test results may be
used. In some settings, HPV testing may be used to guide therapeutic HPV
vaccination on a population level through a “test and vaccinate”
strategy. The choice of widespread vaccination without testing or

27
WHO/Draft for public comment/V0.1/September2023

Parameter Preferred characteristic Notes

targeted vaccination based on testing will depend on programmatic
and testing infrastructure, cost-effectiveness, and other population-
specific considerations. If testing is used to target vaccination, use of
self-collected samples and point-of-care testing would be highly
desirable.

Therapeutic HPV vaccines focused on infection could also be used

within established screening programmes, e.g., after a positive HPV
test and a negative follow-up triage test or no evidence of precancer
on further evaluation.

Communication, community outreach, and marketing strategies

regarding therapeutic HPV vaccines should be considered in
advance. Distinguishing therapeutic from prophylactic vaccines will
be important, as will language around “vaccines” versus
“treatment,” particularly in settings where women without known
infection will be vaccinated. Messaging may have an important
impact on vaccine acceptability.

Schedule A two-dose primary schedule, It will likely be difficult, from a biological standpoint, to develop a
and possible booster dosing, single-dose therapeutic vaccine with a sufficient immune response.
would be considered
acceptable; a single dose for Depending on the vaccine platform and formulation, multiple doses
primary immunization would might be needed, and should be aligned with existing points of
be ideal. contact with the health care system where possible. WLHIV, in
particular, may require multiple doses to enhance efficacy.

Single-dose vaccination and/or the ability to provide a take-home

subsequent dose for self-administration will likely be important for
population-based delivery of vaccination.

Research should determine the requirements, including the timing

and intervals between doses, for primary dosing and/or booster
doses. Refinements could be made post-licensure, as for other
vaccines (e.g., prophylactic HPV vaccines, COVID-19 vaccines).

Route of Parenteral or oral delivery. Parenteral routes of administration include injection (intramuscular
administration or subcutaneous) and intradermal (needle-free transdermal or
microarray patch). Needle-free methods are preferred for ease of
administration, including self-administration.

Local mucosal immunity likely plays an important role in the

mechanism of action of therapeutic HPV vaccines. In addition to oral
delivery, other potential mucosal routes of administration include
nasal, vaginal, and rectal delivery. Although self-administered
intravaginal products are increasingly used in many contexts,
acceptability and feasibility would need to be explored within the
context of a population-based delivery strategy.

Research should determine route of administration to optimize

vaccine efficacy and delivery considerations. Feasibility and
acceptability, and other end-user preferences of formulation for

28
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Parameter Preferred characteristic Notes

vaccine administration need to be further evaluated for
consideration within a broad population-based delivery strategy.

Safety A safety profile that is Consideration should be given in advance to understanding the
comparable to current WHO- safety of therapeutic HPV vaccines during pregnancy and lactation,
recommended adult vaccines. including early DART studies and measures taken for ethical and safe
inclusion of pregnant and breastfeeding women in clinical trials.

Evidence should be generated on safety and longitudinal outcomes

when women receive therapeutic HPV vaccines in the setting of an
undiagnosed cervical precancer or invasive cervical cancer.

Natural HPV cervical infection induces an influx of activated target T

cells for HIV. Evidence should be evaluated and carefully considered
to determine whether a therapeutic vaccine might transiently
increase similar populations of HIV target cells in the genital tract.

Efficacy Minimally acceptable Initial modelling results suggest that a relatively high efficacy in
thresholds for vaccine efficacy clearing HPV 16 and 18 infection will be needed for broad
can be further informed by population impact in the setting of existing cervical cancer
vaccine impact modelling interventions. However, impact would be increased in the setting of
studies, input from key cross-protection against other HPV types, some efficacy in
stakeholders, and further regressing precancers, and ongoing immune responses that could
information about likely clear reinfections.
vaccine characteristics from
The extent of cross-protection, regression of precancers, and
ongoing research.
duration of immune memory after therapeutic vaccination will need
to be evaluated, as each of these parameters will influence the
public health value and cost-effectiveness of therapeutic HPV
vaccines.

Consideration should also be given to evaluating the impact of co-

administration of prophylactic HPV vaccine with therapeutic HPV
vaccine.

Separate studies conducted in WLHIV will need to be assessed to

determine efficacy and the potential need for additional doses.

Concomitant Demonstration of favourable Evidence should be collected on the ability to co-administer

use safety and immunologic non- therapeutic HPV vaccines with other vaccines given in similar target
interference upon co- populations, including prophylactic HPV vaccines, and with currently
administration with other recommended treatments for HPV-related precancers.
vaccines recommended for use.
Lack of clinically important interference in immunogenicity for HPV
therapeutic vaccines and for co-administered vaccines, as well as
safety of co-administration should be documented in pre- or post-
licensure studies.

1080
1081
1082

29
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1083 Table 9.2 Preferred product characteristics for therapeutic HPV vaccines used to treat
1084 cervical precancers
1085
Parameter Preferred characteristic Notes
Indication Regression of high-grade Therapeutic HPV vaccines that cause regression of cervical
cervical precancers (i.e., precancers and are preferable to existing cervical precancer
CIN2/3) associated with HPV treatments with respect to efficacy, safety, cost, delivery, and/or
types 16 and 18. acceptability to women could be a useful intervention in a variety of
settings globally.
Regression of high-grade
cervical precancers due to Therapeutic HPV vaccines might also provide benefit as an adjunct
other oncogenic HPV types or to existing treatments in improving efficacy or reducing recurrences
clearance of additional HPV (e.g., among WLHIV).
infections or low-grade cervical
lesions would have added Reduction of precancer is an established proxy for prevention of
benefit. invasive cervical cancer, which is the ultimate goal of therapeutic
HPV vaccines. Clinical endpoints will need to be refined in discussion
with regulators, including the timeframe for assessing precancer
regression and whether associated viral clearance is an essential
component of the primary outcome and how to assess it.

HPV types 16 and 18 account for 70% of cervical precancers that

progress to invasive cervical cancer. Therefore, minimally viable
first-generation vaccines should include HPV 16 and 18.

Cross-protection against cervical precancers associated with

additional oncogenic HPV types (e.g., 31, 33, 35, 45, 52, 58) or
clearance of associated HPV infection or low-grade cervical lesions
would have added benefit.

Inclusion of additional types in the vaccine may also add benefit.

The next priority for inclusion should be HPV types 45, 35, 31, 33,
52, and 58. However, the inclusion of additional HPV types may
result in trade-offs such as cost and complexity of manufacturing,
potential effects on immunogenicity, and higher vaccine prices.

The primary indication is related to cervical precancers; however,

additional efficacy against other HPV-related precancers (e.g.,
vaginal, anal, head and neck) would be valuable.

Target Women with a positive cervical WHO recommends screening for cervical cancer with a high-
population cancer screening test (e.g., HPV performance test (e.g., HPV DNA testing) in the general population
DNA testing) who would of women at age 30 years, with repeat screening every 5-10 years
require treatment according to through age 49 years.
current screening guidelines.
WHO recommends screening of WLHIV with a high-performance
test starting at age 25 years and repeated every 3-5 years through
49 years. The target population includes WLHIV, who have more
frequent and rapid progression to cervical precancers and invasive
cancer following oncogenic HPV infection. The efficacy and safety
profile of the vaccine might require additional evaluation in this
population.

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WHO/Draft for public comment/V0.1/September2023

Parameter Preferred characteristic Notes

The extent to which the therapeutic vaccine clears infection in
addition to effects on precancer can determine the role of
vaccination even when precancer has been ruled out (e.g,
vaccinating in a “screen-triage-and-treat” scenario with a positive
primary test and negative triage test).

Although screening with a high-performance test before vaccination

is desirable, in settings or populations with high prevalence of
cervical precancers, and with constrained accessibility for screening,
vaccination without testing could be considered. In addition to
meeting other criteria, such as programmatic feasibility and cost-
effectiveness, a more rigorous safety profile may be needed when
vaccinating those without a preceding positive HPV test, as more
women without disease will also be vaccinated.

Consideration should be given in advance to understanding the

safety of therapeutic HPV vaccines during pregnancy, including early
DART studies and measures taken for ethical and safe inclusion of
pregnant women in initial clinical trials whenever possible.

Vaccine Alignment with existing cervical The most appropriate vaccine delivery strategy in different settings
delivery cancer screening and treatment will be determined by related health systems and programmatic
strategy programmes. factors, and the extent to which cervical cancer screening
programmes are well established.
HPV testing and vaccination
may occur outside of Depending on their final attributes and how they compare to or add
structured screening to existing treatments, on balance, with respect to efficacy, safety,
programmes. cost, ease of delivery, and/or acceptability to women, therapeutic
HPV vaccines may replace or supplement current WHO-
recommended treatments within programmes.

Ideally, vaccination would occur at the time of receiving positive

HPV testing results, which is preferably the same day as testing.
Use of self-collected samples and point-of-care testing to target
vaccination would be highly desirable.

HPV testing followed by immediate therapeutic HPV vaccination for

those testing positive – a “test-and-vaccinate” approach – can be
done in a variety of settings, including primary care, family planning,
postpartum care, other sexual and reproductive health services, and
for mothers during their children’s immunization visits. For WLHIV,
delivery of therapeutic HPV vaccine could be facilitated through HIV
treatment and care services, where cervical cancer screening should
be considered an essential part of care.

Whenever possible, women with positive HPV tests should receive a

cervical evaluation to rule out invasive cancer. Immediate receipt of
a vaccine can occur as a woman is referred for cervical evaluation.

If vaccine characteristics allow, a population-based vaccination

delivery strategy, without preceding testing, may be considered in
certain settings with high prevalence of cervical precancers and/or a
lack of feasible screening services. Mass vaccination campaigns or
routine delivery could be considered. Depending on the

31
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Parameter Preferred characteristic Notes

performance of the product, women should be encouraged to
receive cervical cancer screening according to existing guidance
when services become available.

Communication, community outreach and marketing strategies

regarding therapeutic HPV vaccines should be considered in
advance, particularly in relation to current communication for
prophylactic vaccines. Messaging may affect acceptability.

Schedule Ideally, up to two doses for It will likely be difficult, from a biological standpoint, to develop a
primary immunization. single-dose therapeutic vaccine with a sufficient immune response.
Depending on the vaccine platform and formulation, two to three
Additional booster doses might doses might be needed for initial immunization or to maintain
also be acceptable for lasting longer-term disease modification.
disease modification.
Research should determine the requirements for primary dosing and
booster doses. Refinement could be done post-licensure, as for
other vaccines (e.g., prophylactic HPV vaccines, COVID-19 vaccines).

If more than one dose is required, aligning the dosing schedule with
existing delivery platforms or points of contact with the health care
system, where possible, would be preferable.

Clinical trials among WLHIV will be important to understand if

additional doses are required to achieve optimal efficacy, including
comparisons with existing treatments.

Route of Parenteral or mucosal (e.g., Parenteral routes of administration include injection (intramuscular
administration oral, vaginal) delivery. or subcutaneous) injections and intradermal (needle-free
transdermal or microarray patch). Needle-free methods are
preferred for ease of administration, including self-administration.

Mucosal routes of administration include oral, nasal, rectal, and

vaginal delivery. Mucosal formulations also enable self-
administration, and self-administered intravaginal products are
increasingly used in many contexts.

Local mucosal immunity likely plays an important role in the

mechanism of action of therapeutic HPV vaccines. Research should
determine route of administration to optimize vaccine efficacy and
delivery considerations.

Mucosal delivery other than oral administration, such as intra-

vaginal delivery, have traditionally been considered difficult to
deploy; however, this is likely less of a constraint within cervical
cancer prevention programmes. Potential intravaginal products
would require criteria for standardization, e.g., related to menses,
intercourse, use of other products.

Feasibility, acceptability, and other end-user preferences of

formulation for vaccine administration need to be further evaluated.

Safety A safety profile that compares A favourable comparison with existing treatments for cervical
favourably with current WHO- precancers might take into consideration additional factors such as

32
 WHO/Draft for public comment/V0.1/September2023

Parameter Preferred characteristic Notes

recommended treatments for relative efficacy, acceptability, ease of delivery, and overall
cervical precancers and has a benefit/risk assessment.
favourable benefit/risk
assessment. Evidence should be generated on safety and longitudinal outcomes
of therapeutic HPV vaccines, particularly when women might be
vaccinated in the setting of an undiagnosed invasive cervical cancer.
Consideration should be given to collecting supporting evidence on
these outcomes during pre-licensure studies and designing post-
licensure studies to evaluate them.

Consideration should also be given in advance to understanding the

safety of therapeutic HPV vaccines during pregnancy and lactation,
including early DART studies and measures taken for ethical and safe
inclusion of pregnant and breastfeeding women in clinical trials
whenever possible.

Natural HPV cervical infection induces an influx of activated target T

cells for HIV. Evidence should be evaluated and carefully considered
to determine whether a therapeutic vaccine might transiently
increase similar populations of HIV target cells in the genital tract,
and whether this differs from other treatments (e.g., ablation).

Efficacy Efficacy that results in a Therapeutic HPV vaccines that have lower efficacy than existing
favourable comparison with treatments in clinical trials might still have similar, or greater,
current WHO-recommended programmatic effectiveness, if they result in improved delivery and
treatments for cervical uptake.
precancers, factoring in
programmatic considerations. Minimally acceptable thresholds for vaccine efficacy can be further
informed by vaccine impact modelling studies, input from key
stakeholders, and further information about likely vaccine
characteristics from ongoing research.

Therapeutic HPV vaccines may result in ongoing immune responses

that could clear reinfections or prevent recurrences over time. The
extent to which this occurs and the duration of immune memory
after therapeutic vaccination will need to be evaluated.

Consideration should also be given to evaluating the impact of co-

administration of prophylactic HPV vaccine with therapeutic HPV
vaccine, in terms of long-term response.

1086
1087
1088

33
 WHO/Draft for public comment/V0.1/September2023

1089 Table 9.3 Parameters common to both types of therapeutic HPV vaccines.
1090
Parameter Preferred characteristic Notes
Product Stability under refrigerated Vaccine stability characteristics that facilitate storage and
stability and conditions (2–8°C) for 24 deployment in LMIC settings are preferred.
storage months would be acceptable,
but stability at room Typically, vaccines or any component presented for WHO
temperature (20°C) would be prequalification should not require storage at less than -20°C(7)(79).
ideal. However, deviations from these characteristics have occurred (e.g.,
for Ebola and COVID-19 vaccines), after assessing whether issues can
be mitigated (e.g., appropriate management of ultracold chain).

Concomitant Demonstration of favourable Evidence should be collected on the ability to co-administer

use safety and immunologic non- therapeutic HPV vaccines with other vaccines given in similar target
interference upon co- populations, including prophylactic HPV vaccines, and with currently
administration with other recommended treatments for HPV-related precancers.
vaccines or with precancer
treatments recommended for Lack of clinically important interference in immunogenicity for HPV
use. therapeutic vaccines and for co-administered vaccines, as well as
safety of co-administration should be documented in pre- or post-
licensure studies.

Value The vaccine should be cost A full value of vaccines assessment should be conducted for
assessment and effective and have a favourable therapeutic HPV vaccines, both for vaccines that primarily clear HPV
affordability value assessment relative to infections and those that primarily treat cervical precancers, and
existing cervical cancer associated delivery strategies, in the context of realistic scale-up of
prevention interventions. competing interventions.

Dosage, regimen, and cost of Future development and availability of HPV point-of-care tests, with
goods amenable to affordable increased uptake (e.g., using self-sampling), may increase the value
supply; price should not be a of therapeutic HPV vaccines, by enabling a rapid “test and
barrier to access in LMICs. vaccinate” approach. Alternatively, such tests may make existing
screening and treatment programmes more feasible and cost
effective.

The greatest value should be placed on saving additional lives on the

path to cervical cancer elimination in the next 30-40 years, the
interim period before the impact of prophylactic HPV vaccine scale-
up is likely to be seen. Thus, the value assessment will depend on
how soon therapeutic HPV vaccines could be developed and
implemented.

The impact and cost effectiveness of co-administration of

therapeutic and prophylactic HPV vaccines should also be assessed.

Prequalification The vaccine should be pre- WHO-defined criteria for programmatic suitability of vaccines should
and qualified according to the WHO be met (7)(79).
programmatic process outlined (80).
suitability

1091
1092
1093

34
 WHO/Draft for public comment/V0.1/September2023

1094 References
1095
1096 1. Okunade KS. Human papillomavirus and cervical cancer. J Obstet Gynaecol J Inst
1097 Obstet Gynaecol. 2020 Jul;40(5):602–8.
1098 2. Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, et al. Global
1099 Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide
1100 for 36 Cancers in 185 Countries. CA Cancer J Clin [Internet]. 2021 May 1;71(3):209–
1101 49. Available from: https://doi.org/10.3322/caac.21660
1102 3. World Health Organization. Global strategy to accelerate the elimination of cervical
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1386 Figure 1: Estimated age-standardized cervical cancer incidence rates and mortality rates in
1387 2020 (all ages). From GLOBOCAN 2020, IARC (32).

42
WHO/Draft for public comment/V0.1/September2023

FIGURE 2. Age-standardized incidence and mortality rates of cervical cancer, by region.

From GLOBOCAN 2020, IARC (81).

Figure 3: Distribution of lifetime screening coverage among women aged 30–49 years, by
country (2019). Adapted from Bruni et al, Lancet Global Health, 2022 (5).

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Figure 4: HPV genome organization and focus of therapeutic vaccines

Adapted from Stanley M, Clin Microbiol Rev, 2012, (63) with permission.

44