RG1-VLP Vaccine for HPV-Related Cancers
Recruiting in Palo Alto (17 mi)
+5 other locations
Age: 18 - 65
Sex: Female
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase 1
Recruiting
Sponsor: National Cancer Institute (NCI)
Must not be taking: Immunosuppressants, Corticosteroids
Disqualifiers: Genital warts, Cancer treatment, Auto-immune, others
Trial Summary
What is the purpose of this trial?
This phase I trial tests the safety, side effects, and best dose of RG1-virus-like particle (VLP) in preventing human papillomavirus (HPV)-related cancers in women. RG1-VLP is a vaccine that aims to protect against rare HPV types not targeted by currently approved HPV vaccines. HPV is a common sexually-transmitted infection that can cause certain genital and oral cancers. RG1-VLP contains a protein of HPV type 16 (HPV16) with a slightly different structure than the licensed Gardasil-9 vaccine. Gardasil-9 is approved by the Federal Drug Administration to help protect against diseases caused by some types of HPV. Gardasil-9 also contains 9 different HPV proteins. Both vaccines contain alum to stimulate the immune system. The usual approach for the prevention of HPV-related cancers for patients who are at increased risk is to consider the currently approved HPV vaccine like Gardasil-9, as well as to be followed closely by their doctor to watch for the development of cancer via routine pap smears. This trial may allow researchers to find out whether the RG1-VLP vaccine can safely trigger an immune response against HPV in healthy women and if it is better or worse than the usual approach for the prevention of HPV-related cancers.
Will I have to stop taking my current medications?
The trial does not specify if you need to stop taking your current medications, but you cannot participate if you are using immunosuppressive drugs or certain vaccines around the time of the trial vaccinations.
What data supports the effectiveness of the RG1-VLP Vaccine treatment for HPV-related cancers?
Research shows that the RG1-VLP Vaccine can produce strong immune responses against a wide range of high-risk HPV types, similar to existing vaccines like Cervarix and Gardasil. It also offers cross-protection against other HPV types not covered by current vaccines, suggesting it could be effective in preventing various HPV-related cancers.12345
Is the RG1-VLP vaccine safe for humans?
How does the RG1-VLP vaccine differ from other treatments for HPV-related cancers?
The RG1-VLP vaccine is unique because it targets a broader range of HPV types, including both high-risk and low-risk types, as well as cutaneous HPV, by incorporating a conserved epitope from the minor capsid protein L2. This contrasts with existing vaccines that primarily target a limited number of HPV types using the major capsid protein L1.12345
Eligibility Criteria
This trial is for women aged 18-45 with normal blood counts and organ function, not pregnant or breastfeeding, without HPV-related diseases or abnormal Pap smears (if over 25), no history of severe allergies to vaccines, and not on immunosuppressants. Participants must agree to use contraception if they can bear children.Inclusion Criteria
Human immunodeficiency virus (HIV)-1/HIV-2 negative
All women of childbearing potential will have a pregnancy test and agree to use adequate contraception
Platelets >= 100,000/mm^3
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Exclusion Criteria
Receiving other investigational agents
I am scheduled to receive certain vaccines around the time of the trial vaccination.
I have had genital warts in the past or currently.
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Trial Timeline
Screening
Participants are screened for eligibility to participate in the trial
2-4 weeks
Treatment
Participants receive RG1-VLP or saline placebo intramuscularly for 3 doses at months 0, 2, and 6. Blood and optional vaginal swab collections are conducted.
6 months
3 visits (in-person)
Follow-up
Participants are monitored for safety and effectiveness after treatment, including optional Gardasil-9 administration at months 12, 14, and 18.
6 months
3 visits (in-person)
Long-term follow-up
Participants are followed up to 6 months post-3rd RG1-VLP vaccination/saline injection or up to 14 days post-3rd Gardasil-9 vaccination.
6 months
Treatment Details
Interventions
- RG1-VLP Vaccine (Cancer Vaccine)
Trial OverviewThe trial tests a new vaccine called RG1-VLP against rare HPV types potentially causing cancer. It's compared with the approved Gardasil-9 vaccine. The study includes questionnaires, biospecimen collection, and uses saline as a control in some participants.
Participant Groups
2Treatment groups
Experimental Treatment
Placebo Group
Group I: Arm I (RG1-VLP, Gardasil-9)Experimental Treatment4 Interventions
Patients receive RG1-VLP IM for 3 doses at months 0, 2, and 6 in the absence of unacceptable toxicity. Patients may also receive Gardasil-9 via injection for 3 doses at 6 months after the 3rd study vaccination (month 12), then at months 14 and 18 in the absence of unacceptable toxicity. Patients also undergo blood sample collection on study and may undergo vaginal swab collection on study.
Group II: Arm II (saline placebo, Gardasil-9)Placebo Group4 Interventions
Patients receive saline placebo IM for 3 doses at months 0, 2, and 6 in the absence of unacceptable toxicity. Patients may also receive Gardasil-9 via injection for 3 doses at 6 months after the 3rd saline injection (month 12), then at months 14 and 18 in the absence of unacceptable toxicity. Patients also undergo blood sample collection on study and may undergo vaginal swab collection on study.
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
University of Wisconsin Carbone Cancer Center - University HospitalMadison, WI
University of Alabama at Birmingham Cancer CenterBirmingham, AL
Johns Hopkins University/Sidney Kimmel Cancer CenterBaltimore, MD
Staten Island University HospitalStaten Island, NY
More Trial Locations
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Who Is Running the Clinical Trial?
National Cancer Institute (NCI)Lead Sponsor
References
RG2-VLP: a Vaccine Designed to Broadly Protect against Anogenital and Skin Human Papillomaviruses Causing Human Cancer. [2023]The family of human papillomaviruses (HPV) includes over 400 genotypes. Genus α genotypes generally infect the anogenital mucosa, and a subset of these HPV are a necessary, but not sufficient, cause of cervical cancer. Of the 13 high-risk (HR) and 11 intermediate-risk (IR) HPV associated with cervical cancer, genotypes 16 and 18 cause 50% and 20% of cases, respectively, whereas HPV16 dominates in other anogenital and oropharyngeal cancers. A plethora of βHPVs are associated with cutaneous squamous cell carcinoma (CSCC), especially in sun-exposed skin sites of epidermodysplasia verruciformis (EV), AIDS, and immunosuppressed patients. Licensed L1 virus-like particle (VLP) vaccines, such as Gardasil 9, target a subset of αHPV but no βHPV. To comprehensively target both α- and βHPVs, we developed a two-component VLP vaccine, RG2-VLP, in which L2 protective epitopes derived from a conserved αHPV epitope (amino acids 17 to 36 of HPV16 L2) and a consensus βHPV sequence in the same region are displayed within the DE loop of HPV16 and HPV18 L1 VLP, respectively. Unlike vaccination with Gardasil 9, vaccination of wild-type and EV model mice (Tmc6Δ/Δ or Tmc8Δ/Δ) with RG2-VLP induced robust L2-specific antibody titers and protected against β-type HPV5. RG2-VLP protected rabbits against 17 αHPV, including those not covered by Gardasil 9. HPV16- and HPV18-specific neutralizing antibody responses were similar between RG2-VLP- and Gardasil 9-vaccinated animals. However, only transfer of RG2-VLP antiserum effectively protected naive mice from challenge with all βHPVs tested. Taken together, these observations suggest RG2-VLP's potential as a broad-spectrum vaccine to prevent αHPV-driven anogenital, oropharyngeal, and βHPV-associated cutaneous cancers. IMPORTANCE Licensed preventive HPV vaccines are composed of VLPs derived by expression of major capsid protein L1. They confer protection generally restricted to infection by the αHPVs targeted by the up-to-9-valent vaccine, and their associated anogenital cancers and genital warts, but do not target βHPV that are associated with CSCC in EV and immunocompromised patients. We describe the development of a two-antigen vaccine protective in animal models against known oncogenic αHPVs as well as diverse βHPVs by incorporation into HPV16 and HPV18 L1 VLP of 20-amino-acid conserved protective epitopes derived from minor capsid protein L2.
Incorporation of RG1 epitope into HPV16L1-VLP does not compromise L1-specific immunity. [2023]The candidate pan-Human Papillomavirus (HPV) vaccine RG1-VLP are HPV16 major capsid protein L1 virus-like-particles (VLP) comprising a type-common epitope of HPV16 minor capsid protein L2 (RG1; aa17-36). Vaccinations have previously demonstrated efficacy against genital high-risk (hr), low-risk (lr) and cutaneous HPV. To compare RG1-VLP to licensed vaccines, rabbits (n = 3) were immunized thrice with 1 µg, 5 µg, 25 µg, or 125 µg of RG1-VLP or a 1/4 dose of Cervarix®. 5 µg of RG1-VLP or 16L1-VLP (Cervarix) induced comparable HPV16 capsid-reactive and neutralizing antibodies titers (62,500/12,500-62,500 or 1000/10,000). 25 µg RG1-VLP induced robust cross-neutralization titers (50-1000) against hrHPV18/31/33/45/52/58/26/70. To mimic reduced immunization schedules in adolescents, mice (n = 10) were immunized twice with RG1-VLP (5 µg) plus 18L1-VLP (5 µg). HPV16 neutralization (titers of 10,000) similar to Cervarix and Gardasil and cross-protection against hrHPV58 vaginal challenge was observed. RG1-VLP vaccination induces hrHPV16 neutralization comparable to similar doses of licensed vaccines, plus cross-neutralization to heterologous hrHPV even when combined with HPV18L1-VLP.
Efficacy of RG1-VLP vaccination against infections with genital and cutaneous human papillomaviruses. [2022]Licensed human papillomavirus (HPV) vaccines, based on virus-like particles (VLPs) self-assembled from major capsid protein L1, afford type-restricted protection against HPV types 16/18/6/11 (or 16/18 for the bivalent vaccine), which cause 70% of cervical cancers (CxCas) and 90% of genital warts. However, they do not protect against less prevalent high-risk (HR) types causing 30% of CxCa, or cutaneous HPV. In contrast, vaccination with the minor capsid protein L2 induces low-level immunity to type-common epitopes. Chimeric RG1-VLP presenting HPV16 L2 amino acids 17-36 (RG1 epitope) within the DE-surface loop of HPV16 L1 induced cross-neutralizing antisera. We hypothesized that RG1-VLP vaccination protects against a large spectrum of mucosal and cutaneous HPV infections in vivo. Immunization with RG1-VLP adjuvanted with human-applicable alum-MPL (aluminum hydroxide plus 3-O-desacyl-4'-monophosphoryl lipid A) induced robust L2 antibodies (ELISA titers 2,500-12,500), which (cross-)neutralized mucosal HR HPV16/18/45/37/33/52/58/35/39/51/59/68/73/26/69/34/70, low-risk HPV6/11/32/40, and cutaneous HPV2/27/3/76 (titers 25-1,000) using native virion- or pseudovirion (PsV)-based assays, and a vigorous cytotoxic T lymphocyte response by enzyme-linked immunospot. In vivo, mice were efficiently protected against experimental vaginal challenge with mucosal HR PsV types HPV16/18/45/31/33/52/58/35/39/51/59/68/56/73/26/53/66/34 and low-risk HPV6/43/44. Enduring protection was demonstrated 1 year after vaccination. RG1-VLP is a promising next-generation vaccine with broad efficacy against all relevant mucosal and also cutaneous HPV types.
RG1-VLP and Other L2-Based, Broad-Spectrum HPV Vaccine Candidates. [2023]Licensed human papillomavirus (HPV) vaccines contain virus-like particles (VLPs) self-assembled from L1 major-capsid proteins that are remarkably effective prophylactic immunogens. However, the induced type-restricted immune response limits coverage to the included vaccine types, and costly multiplex formulations, restrictive storage and distribution conditions drive the need for next generation HPV vaccines. Vaccine candidates based upon the minor structural protein L2 are particularly promising because conserved N-terminal epitopes induce broadly cross-type neutralizing and protective antibodies. Several strategies to increase the immunological potency of such epitopes are being investigated, including concatemeric multimers, fusion to toll-like receptors ligands or T cell epitopes, as well as immunodominant presentation by different nanoparticle or VLP structures. Several promising L2-based vaccine candidates have reached or will soon enter first-in-man clinical studies. RG1-VLP present the HPV16L2 amino-acid 17-36 conserved neutralization epitope "RG1" repetitively and closely spaced on an immunodominant surface loop of HPV16 L1-VLP and small animal immunizations provide cross-protection against challenge with all medically-significant high-risk and several low-risk HPV types. With a successful current good manufacturing practice (cGMP) campaign and this promising breadth of activity, even encompassing cross-neutralization of several cutaneous HPV types, RG1-VLP are ready for a first-in-human clinical study. This review aims to provide a general overview of these candidates with a special focus on the RG1-VLP vaccine and its road to the clinic.
Chimeric L2-Based Virus-Like Particle (VLP) Vaccines Targeting Cutaneous Human Papillomaviruses (HPV). [2018]Common cutaneous human papillomavirus (HPV) types induce skin warts, whereas species beta HPV are implicated, together with UV-radiation, in the development of non-melanoma skin cancer (NMSC) in immunosuppressed patients. Licensed HPV vaccines contain virus-like particles (VLP) self-assembled from L1 major capsid proteins that provide type-restricted protection against mucosal HPV infections causing cervical and other ano-genital and oro-pharyngeal carcinomas and warts (condylomas), but do not target heterologous HPV. Experimental papillomavirus vaccines have been designed based on L2 minor capsid proteins that contain type-common neutralization epitopes, to broaden protection to heterologous mucosal and cutaneous HPV types. Repetitive display of the HPV16 L2 cross-neutralization epitope RG1 (amino acids (aa) 17-36) on the surface of HPV16 L1 VLP has greatly enhanced immunogenicity of the L2 peptide. To more directly target cutaneous HPV, L1 fusion proteins were designed that incorporate the RG1 homolog of beta HPV17, the beta HPV5 L2 peptide aa53-72, or the common cutaneous HPV4 RG1 homolog, inserted into DE surface loops of HPV1, 5, 16 or 18 L1 VLP scaffolds. Baculovirus expressed chimeric proteins self-assembled into VLP and VLP-raised NZW rabbit immune sera were evaluated by ELISA and L1- and L2-based pseudovirion (PsV) neutralizing assays, including 12 novel beta PsV types. Chimeric VLP displaying the HPV17 RG1 epitope, but not the HPV5L2 aa53-72 epitope, induced cross-neutralizing humoral immune responses to beta HPV. In vivo cross-protection was evaluated by passive serum transfer in a murine PsV challenge model. Immune sera to HPV16L1-17RG1 VLP (cross-) protected against beta HPV5/20/24/38/96/16 (but not type 76), while antisera to HPV5L1-17RG1 VLP cross-protected against HPV20/24/96 only, and sera to HPV1L1-4RG1 VLP cross-protected against HPV4 challenge. In conclusion, RG1-based VLP are promising next generation vaccine candidates to target cutaneous HPV infections.