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Are HPV vaccines ‘evolution-proof’? Multilevel evolutionary ecology of human oncoviruses

Periodic Reporting for period 3 - EVOLPROOF (Are HPV vaccines ‘evolution-proof’? Multilevel evolutionary ecology of human oncoviruses)

Reporting period: 2018-09-01 to 2020-02-29

This project studies the long term robustness of vaccines to microbial evolution. It focuses in particular on the new vaccines protecting against human papillomaviruses (HPV).

Vaccination, together with antibiotics, have been instrumental in decreasing childhood mortality and increasing general life expectancy. As illustrated by the generalisation of antibiotic resistance, microbial evolution can threaten our ability to prevent and cure infections. Several examples also show that bacteria and viruses can evolve in response to vaccination. This evolution can render a vaccine less effective or, worse, select for more virulent parasites. In summary, society needs to be one step ahead of parasite evolution.

Our idea is to use concepts and tools from ecology and evolution to assess whether HPV vaccines are evolution-proof. This is done in two steps: first understand what happens inside a person infected by HPV and second use this knowledge to simulate the spread and evolution of the virus in the human population. Importantly, this work requires setting up a clinical study. Since currently most of the research on HPV is performed on chronic infections, we know extremely little about HPV infections occurring in young adults, even though these infections represent the vast majority of infections.

Our overall objective is to capture the ecological dynamics of HPV infections happening inside patients. Using mathematical models, we will parameterise and compare these models using clinical data and then use these results to simulate HPV epidemiology and evolution.
First, we set up a clinical study. It required conceiving a detailed study protocol and elaborating detailed questionnaires for participants before obtaining the green light from several ethics committees. We then had to find a gynaecologist and nurses to willing to participate. Finally, the last task, which is still ongoing, was to find participants. So far, we have enrolled 60 out of 150 participants. All this work was further complicated by the fact that the infection we study, that is HPV in young adults, is seen as “benign” by most doctors, who normally do not collect so much biological data on infections such as these. Finally, our goal to study the within-host ecology, is very unusual for clinical studies, so we could not rely on existing protocols.

Second, we established an experimental lab. This meant importing existing protocols but also creating new ones. The most difficult step was to establish a protocol to count immune cells in cervical smears using flow cytometry technology.

Third, we built mathematical models to capture the interactions between HPV, epithelial cells, the vaginal microbes and the immune system. The first step was to describe the dynamics of a viral infection that is not systemic (contrarily to the ones that are considered by most models). We showed that accounting for the epithelial cell life cycle is essential to understand the infection develops. We also combined our mathematical models with experimental data from experimental cell cultures obtained by another lab to further demonstrate the usefulness of our framework. Our second step was to introduce more realism in the immune response into the model, especially the innate immune response. The third step is to focus more on the microbes of the vagina and study their ecological interactions.

Fourth, we begun to investigate questions at the between-host level using existing models. In particular, we focused on the epidemiological of coinfections that is the simultaneous infection of one person by two or more HPV types.

Importantly, we have also set up a network of collaborators and advisors on several aspects of the project such as microbial dynamics, clinical studies, immunity to HPV infections and flow cytometry. We have hosted workshops and are writing a proposal to coordinate a special issue for a journal.
"We have introduced a new mathematical framework to capture parasites infecting epithelial cells. Indeed, most models assume that the within-host environment is “well mixed”. This assumption is acceptable for viruses that enter the blood stream such as HIV but, as we show, it is oversimplifying for viruses such as HPV that cause a localised and structured infection.

Our clinical study is, to the best of our knowledge, one of the most ambitious clinical study aimed at understanding the within-host ecology and evolution of a human pathogen. The amount of information and data collected at each visit (virus quantity, immune cell and protein counts, microbial composition, circulating antibodies, etc.) is also unique in the context of HPV.

In the laboratory, we have extended a method to analyse cervical samples using a cell counting technology called flow cytometry, which allows us to count several kinds of immune cells using 10 different markers.

Here are some of the results we expect to obtain by the end of the project:
- Understand the dynamics and interactions of HPV acute infections in young adults (i.e. parameterising and comparing within-host models).
- Better understand of the role of stochasticity (i.e. ""chance"") in the persistence of HPV infections.
- Describe the human immune response to HPV acute infections and its role in clearing the infection.
- Better understand vaginal microbial dynamics by fitting models to data.
- Detect early signals of HPV clearance if any.
- Understand the interactions between the virus, microbiota and human genome in the context of HPV infections.
- Automatize immune cell counts data obtained from cervical samples using clustering algorithms
- Identify susceptibility factors to HPV infections if any.
- Nest models of within-host dynamics into population-level epidemiological models to predict HPV rapid evolution in response to vaccination.
- Model the evolution of HPV virulence.
- Better understand the potential effect of coinfections by different types on HPV evolution."