One-liner : Funding proposal for a project finding protective microbiota against human papillomavirus infection in climacteric women for the future production of a probiotic.
Longevity Dealflow WG team
Scientific evaluation : Diane Seimetz, Justin Olshavsky, Anonymous reviewer (professor)
Business evaluation : Diane Seimetz, Justin Olshavsky
Shepherd : Sara Ramos and Estéfano Pinilla
Other squad members : Aaron King, Jason Colasanti, Tovah
Sourced by : Sara Ramos
Project PIs : Maria-Jose Lopez-Espinosa and M. Pilar Francino
Cancer is one of the main causes of morbimortality today. Among women, cervical cancer was the 4th most prevalent cancer worldwide in 2020 with 604,127 new cases and 341,831 death. Chronic infection by oncogenic human papillomaviruses (HPVs) is the main risk factor for the development of cervical cancer as well as other anogenital and oropharyngeal cancers. The vaginal microbiota may play a role in the acquisition and persistence of oncogenic HPVs in the female reproductive tract. However, our understanding of how this microbiota might be associated with HPV infection and cervical lesions remains limited; especially in climacteric women (i.e., women around menopause), in whom hormonal and immunological changes associated to aging and loss of reproductive capability play a key role. PhD. Lopez-Espinosa and PhD. Francino’s research team aims at characterizing the changes undergone by the vaginal microbiota in climacteric women and correlating them with infections by oncogenic HPVs, HPV-related dysplasias, and the differential risk of suffering cervical lesions. Consequently, the results of the research group will contribute to the development of probiotics that facilitate the maintenance of a healthy vaginal microbiota to prevent HPV infections and decrease the risk of neoplastic lesions and cervical cancer.
As mentioned above, cervical cancer was the 4th most common cancer type in women worldwide in 2020 with a substantial increase, compared to the latest available data, in incidence and mortality of 5.7% and 8.9%, respectively1,6. Therefore, there is an increasing need to fight against this type of cancer worldwide and reaching a substantial decrease of its incidence is a priority of the World Health Organization (WHO) for 20307.
Chronic oncogenic HPV infection is a necessary cause and the main risk factor for the development of cervical cancers, as well as other anogenital and oropharyngeal cancers and further investigations on possible determinants (such as the vaginal microbiota) of HPV infection are warranted.
Moreover, women’s health issues remain underrepresented in clinical studies and in biomedical research. A strong effort is thus still required to improve the promotion of women’s health and to contribute to their empowerment, especially in relation to sexually transmitted diseases (such as HPV) and related cancers, which are still taboo from a certain age onwards.
Furthermore, there is a preponderance of research focused on reproductive-stage women whereas the climacteric phase of life is an insufficiently explored stage, despite being a very vulnerable period in which the many anatomical, hormonal, immunological, and physiological changes that occur result in significant increases of morbidity and mortality9. In relation to the present project, in climacteric women the precise repertoire and prevalence of oncogenic HPVs, the specific risk factors for infection persistence, virus latency and reactivation, the biological mechanism underlying vaginal microbiota changes and their roles in HPV susceptibility are all still poorly understood.
Although vaccination programs to reduce the population of women susceptible to becoming infected have been useful, issues like current vaccines not protecting against all cancer-causing HPV strains, lack of coverage for women over 45 years old, lack of evidence on long-lasting protection and low vaccination rates, indicate the need for new solutions.
In this sense, the project led by PhD. Lopez-Espinosa and PhD. Francino will go beyond the state-of-the-art to fill in important gaps in the current knowledge of issues which continue to be ill-defined in climacteric women, namely the changes that occur in the vaginal microbiota at this stage and their relation to HPV-infections and related dysplasias potentially leading to cancer.
Probiotics, i.e., beneficial bacteria that contribute to promote health, are a potential approach for microbiome regulation, but the development of probiotics aimed at the vaginal microbiota is in its infancy and in need of solid backup by scientific evidence. Currently, the vaginal care market includes a variety of products containing probiotic bacteria but for which no real health claim based on scientific evidence can be made. Unfortunately, research on vaginal probiotic products is lagging behind the development and selling of these products. The team’s approach wishes to contribute to shift this market from a marketing-only perspective, to one based on rational product development with requirements for proven efficiency. Vaginal bacteria that the team identify as potential probiotics will be patented for further development with the involvement of the pharmaceutical or food industry.
1- Study population. 330 women living in Valencia (Spain), with the following inclusion criteria: being between 45-65 years old, not having undergone a hysterectomy, being able to understand Spanish and belonging to one of the three populations defined below:
A) INMA population. 200 women of mostly middle or upper-middle social class who are part of the Spanish population-based cohort INMA (mean age: 48.5 years, www.proyectoinma.org). The recruitment has already finished in October 2021.
B) PAPILONG population. 100 women (sex workers, migrants, vulnerable women born in Spain, and homeless women) users of five NGOs from Valencia: Spanish Red Cross (https://www2.cruzroja.es/), “Cáritas” (https://www.caritas.es/), “Por Ti Mujer” (https://asociacionportimujer.org/), “Infàncies i Dones del Món” (https://infanciesidonesdelmon.org/), and “Amigos de la Calle” (https://amigosdelacalle.es/). The recruitment is ongoing and planned to finish in April 2022.
C) CASES POPULATION. 30 women with recent diagnosis of oncogenic HPV will be recruited from different hospitals from Valencia from February to May.
An Ethical Committee has evaluated the study design (date: 04/06/2021, number: 20210604/10/02) and women provide a signed informed consent prior to study inclusion.
- Task 1. Recruitment and fieldwork. The team has recruited up to now 200 women and will recruit the rest, up to 330, in the upcoming months. Part of the funding will be dedicated to the recruitment of extra fieldwork personnel to accelerate the collection.
- Task 2. Cervical smear analyses. To finalize the laboratory analysis of HPV and associated dysplasias.
- Task 3. Microbiota analyses. To finalize the 16S rRNA gene-based analysis of vaginal microbiota composition. Part of the funding will be dedicated to the recruitment of extra personnel to accelerate the analysis.
- Task 4. Statistical analyses. To introduce data in databases and conduct the appropriate statistical analyses. Part of the funding will be dedicated to the recruitment of extra personnel to accelerate this part.
By the completion of the study, results regarding the identification of vaginal bacteria that could be employed as potential probiotics will be presented to VITADAO. The potential commercial development of these discoveries would be pursued in partnership with VITADAO or other interested business partners.
It is expected to generate a probiotic that can be protected by patent if it has novelty and sufficient inventive step.
In the event that it could be of commercial interest, a diagnostic kit could also be generated to detect alterations of the vaginal microbiota. The diagnostic kit would be protected by another patent if it has novelty and sufficient inventive step.
Currently the Medical Device European regulation (Regulation (EU) 2017/745) does not regulate probiotics via the vagina as the previous regulation did (Regulation changed around 10 months ago). The possible regulatory routes would be as a drug or as an oral supplement. The drug route is expensive and probably not commercially viable. Therefore the best regulatory route would be as a dietary supplement if efficacy and colonization of the vaginal microbiota could be demonstrated. These trials are not included in this project.
In other territories such as USA and Canada such products are available, so a future licensee could study whether it is viable to market a vaginal probiotic in those countries.
On the other hand, if a diagnostic kit is developed, beyond this project, it would follow the regulation for in vitro diagnostic medical devices.
PhD. Maria-Jose Lopez-Espinosa (MJLE) is a senior epidemiologist at FISABIO-Public Health, head of the Environment and Health Area of said institution, and associate professor at the University of Valencia. She is currently studying the interrelationship of placental, faecal, and vaginal microbiome with human health.
PhD. Pilar Francino (PF) is a Senior Scientist at the Genomics and Health Department of FISABIO-Public Health in Valencia and Head of this Department. She is an expert on human microbiome communities, mainly those inhabiting the gut and the vagina.
PhD. Reem Abumallouh (RA) holds a doctorate in Biology from the Univ. Valencia, with extensive experience in laboratory analysis of the microbiome. Currently, she has a contract with CIBERESP and works at FISABIO-Public Health.
PhD. Ignacio Bravo (IB) is an expert on papillomavirus evolution and anogenital cancers, at both the fundamental and the clinical levels. He is head of the MIVEGEC laboratory in Montpellier.
PhD. Nuria Jimenez is a senior scientist at the Genomics Health Department of FISABIO. She is an expert on human microbiome communities.
Natalia Marin (NM) is a nurse with expertise in oncology and a PhD student in FISABIO-Public Health doing her thesis with data of the present project. She holds a degree in Nursing and a MSc on Oncologic Nursing.
Maria Montagud (RA) holds a Master’s in Biostatistics from the Faculty of Mathematical Sciences (2019-2021) and work at FISABIO-Public Health.
This is an ongoing project with previous budget for some of the recruitment and analyses but we need extra funding for developing it to the point where we can identify bacteria that can be developed commercially as probiotics.
|TASK 1: Recruitment and field work||TOTAL|
|Expendable material: Cervical smear collection kit, vaginal microbiota collection kit, fungible material for field work and storage, and preservation in biobank||7,000 €|
|Fidelization of participants: A 20€ public transportation voucher (voucher + card) for transportation to the facilities and to recognize their effort.||2,000 €|
|Sanitary personnel: 6 months/full-time (Graduated + MSc + running cost).||27,000 €|
|Personnel: 6 months/full-time (Graduated + running cost).||21,000 €|
|NOTE: We need this funding for the 100 samples still to be collected.|
|TASK 2: Cervical smear analyses||TOTAL|
|Cervical smear analyses + HPV detection in Arnau of Villanova and Montpellier||16,000 €|
|Storage and shipment of samples||2,000 €|
|NOTE: We need this funding for the 100 samples still to be collected.|
|TASK 3: Vaginal microbiota analyses||TOTAL|
|Vaginal microbiota analyses||8.000 €|
|Laboratory personnel: 6 months/full time (Graduated + MSc + running cost).||27.000 €|
|NOTE: We need this funding for the 100 samples still to be collected.|
|TASK 5: Statistical analyses||TOTAL|
|Creation and depuration of data bases||22.000 €|
|Personnel for statistical analyses: 10 months/full time (postdoc + running cost)||55.000 €|
|NOTE: We need this funding for the 330 samples.|
|TOTAL TASKS 1-5||187,000 €|
|FISABIO costs and administrative tasks (15% of the total)||33,000 €|
The 3 senior reviewers have decided independently to recommend against the funding of this proposal by the VitaDAO community and are ready to give a final digest:
To quantify the level of conviction, they have provided a score on a scale of 1-5 (with 5 being the highest).
The average score was 2.37/5
Brief qualitative review summaries:
• Related to impact (brought up by 2/3 reviewers):
- Underserved population. Gender-specific studies focusing on women are attractive, both from a marketing perspective and from an empowerment perspective. Similarly, HPV most significantly impacts underdeveloped or vulnerable populations, so the main focus of the proposal is an obvious worthwhile pursuit.
- HPV infections have a second peak of prevalence, namely during the climacteric life stage, suggesting an age-related adverse health outcome. Successful commercialization of this technology would lead to increased healthspan for climacteric women.
• Related to feasibility (brought up by 3/3 reviewers):
Scientific data seems feasible, worthwhile to determine if the vaginal microbiome can be modulated to clinical benefit
• Related to team (brought up by 2/3 reviewers):
- Strong scientific team. Relevant backgrounds to conduct this research
- There is a clear commitment of the applicants to work with the DAO community in product development and commercialization.
• Related to scope (brought up by 2/3 reviewers)
- Although the target population is admirable, the focus of the study is not truly geroscience research, meaning the project operates on the periphery of the VitaDAO mission
• Related to low commercial viability (brought up by 3/3 reviewers)
- While it is still considered possible to perform the proposed study in menopausal women today, it is highly questionable if this population will be relevant for a future product development due to available HPV vaccines and vaccination programs in young women that were initiated a couple of years ago. These women will be largely protected due to the vaccination. Therefore, it is unclear what the additional benefit of a probiotic product would be in the proposed setting.
- Probiotics are a complicated therapeutic strategy and market, with many uncertainties here from an investment perspective.
• Related to unclear IP potential (brought up by 3/3 reviewers)
- Team has limited experience in commercializing therapeutics, and doesn’t seem to have particularly strong backgrounds for developing IP.
- Development of IP seems like an afterthought to the public health epidemiological focus of the research.