Targeting the Vaginal Microbiome for Urogenital and Reproductive Health
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Researchers from the University of Maryland School of Medicine’s (UMSOM) Institute for Genome Sciences (IGS) have created VIRGO (human vaginal non-redundant gene catalog): the first genomic catalog of the vaginal microbiome. VIRGO has been released as a public resource that can be utilized by scientists exploring the role of microbes in gynecological health conditions. Its development is described in a recent publication available in Nature Communications.
LUCA Biologics, a biotechnology company founded in 2019, are harnessing data from VIRGO to develop live biotherapeutics for widespread, unmet medical needs in women's health. This includes urinary tract infections (UTIs), estimated to impact half of women globally, and pre-term birth.
Technology Networks recently spoke with Dr Jacques Ravel (Chief Scientist of LUCA Biologics) and Luba Greenwood (CEO of LUCA Biologics) to learn more about what the vaginal microbiome is, how it can contribute to human pathology and the development of novel therapeutics in this space that are approaching clinical trials.
Molly Campbell (MC): For our readers that may be unfamiliar, can you please tell us about what the vaginal microbiome is? Why is it important to understand the genetic composition of the microbiome? What constitutes an "optimal" vaginal microbiome?
Jacques Ravel (JR): The vagina represents a unique environment in which communities of microbes (the vaginal microbiome) interact with each other and with the host mucosa. The vaginal microbiome has a symbiotic relationship with the human host and plays critical roles in maintaining health. An “optimal” vaginal microbiome is often dominated by one of four known species of Lactobacillus that are uniquely found in the vagina. These Lactobacillus leverage the production of glycogen by the host mucosa to grow and produce copious amounts of lactic acid, thus acidifying the vagina to pH less than four. This highly acidic environment fends off pathogens and has anti-inflammatory properties.
For so long, it was thought that low complexity ecology (i.e, a microbiota comprised of a single dominant strain of Lactobacillus) was associated with optimal vaginal microbiota. However, our exploration of not just the composition (which is low resolution), but the genetics of the vaginal microbiome showed that an optimal vaginal microbiota is comprised of multiple strains of the same Lactobacillus species which interact to form a complex ecological network.
Our work with VIRGO has revealed just how much genetic diversity there is within a woman's vaginal microbiota, as well as within bacterial species in the vagina. This new understanding of the strains’ broad genetic composition allows us to think about how we can improve the vaginal microbiome’s overall functionality. This knowledge is changing the way we approach modulation of the vaginal microbiome through microbiota-based therapeutics to restore and sustain the protective functions of this ecosystem, and thus transforming how we prevent and treat disease.
MC: What research methods are typically adopted when studying the vaginal microbiome? Can you tell us more about VIRGO?
JR: Most researchers largely use 16S rRNA gene sequencing. All bacteria carry ribosomes that consist of proteins and RNAs. One type of RNA, the 16S ribosomal RNA (rRNA), is encoded by a gene whose sequence is highly conserved between bacterial taxa. By amplifying and sequencing the genes (DNA) encoding this ribosomal RNA, scientists obtain the names and the proportions of each bacterial species present in a microbiome (its composition). Understanding the composition of a microbiota does not provide any information about its function – what it can do or what it is actually doing. Thus, the method has many limitations and paints an incomplete picture.
New sequencing-based technologies and approaches have been developed to afford a more detailed and functional understanding of microbiome. These methodologies are metagenomics (sequencing of all genetic material, not just 16S rRNA genes) and metatranscriptomics (what genes are expressed, and therefore what function and activities are performed). In other words, tools that give us a more comprehensive view of what bacteria are present, and what they’re doing.
Powered by the largest integrated data set of vaginal metagenomes and metatranscriptomes to date, VIRGO is the first reference database to provide a gene-centric approach to describe microbiome function and vaginal intraspecies variation. It was built from a large collection of genome sequences of vaginal bacteria and metagenomes sequenced through funding from the National Institutes of Health. In building VIRGO, we catalogued all unique genes found in these samples, which amounted to about 1 million genes. This gene catalogue is highly curated so that most genes are assigned a function and the name of the bacteria that carries them.
In building VIRGO, we noticed that each species was represented by a higher number of genes than is encoded on the genome of one strain. For example, each strain of Lactobacillus crispatus, a species often associated with playing a beneficial role in vaginal health, carries on average about 2,000 genes; however, in VIRGO, Lactobacillus crispatus is represented by more than 5,500 genes. This indicates that we captured a large number of strains, mostly from the metagenomes, that each contribute a set of unique genes, the sum totaling more than 5,500. More interestingly, within a woman with Lactobacillus crispatus, we identified on average, 3,000 genes for that species, telling us that within a woman a large number of strains of Lactobacillus crispatus coexist. This was true for almost all the species we were able to identify in the vagina. This finding is novel and is changing our understanding of the vaginal ecosystem.
VIRGO was developed to be used by others to analyze their own metagenomes or metatranscriptomes by mapping their sequence data to the catalogue. This approach is fast and computationally efficient compared to traditional approaches which require expertise and large computer infrastructure.
MC: How is the vaginal microbiome implicated in certain pathological conditions?
JR: There is a strong indication that microbiome health is correlated with resiliency of the microbial composition and function, or its ability to return to a state of balance after a disruption. We know that imbalances in the composition of the vaginal microbiome can play a role in conditions such as bacterial vaginosis, UTI, and sexually transmitted infections, including chlamydia or HIV. Absence of a robust, Lactobacillus species dominated and multi-functional vaginal microbiome leaves room for pathogens or anaerobic bacteria (as in the case of bacterial vaginosis) to move in or start growing.
Lactobacilli in the vagina play a crucial role in protecting from infection. They do this by producing lactic acid and other substances that make the environment inhospitable for other bacteria, by covering the mucosal cells so that pathogens can’t attach, and by taking up resources that “bad” bacteria need to grow. So, it is really the absence of Lactobacillus species and the presence of anaerobic bacteria (dysbiosis or imbalance) in the vaginal microbiome that is implicated in pathological conditions. Standard approaches relying on antibiotic treatment for many vaginal infections can be counterproductive in the long run by disabling our microbiome instead of building it up. At LUCA Biologics, we are developing live biotherapeutic products that will work to fight infections and also fortify the vaginal microbiome to help protect women from these conditions.
MC: Please can you tell us about the creation of the company LUCA Biologics? What are the company’s aims, and how are you using information on the genetic composition of the vaginal microbiome?
Luba Greenwood (LG): LUCA Biologics is a biotechnology company we founded in August 2019, with the mission to develop live biotherapeutics for widespread, unmet medical needs in women's health. LUCA has leveraged the VIRGO platform to identify and validate strains that modulate the vaginal and urogenital microbiome. The company's novel gene-centric model informs their pipeline of VMSCs (Vaginal Microbiota Stabilization Consortia) designed to modulate the vaginal microbiota for the prevention and treatment of disease. Some of our first targets will be recurrent UTI, bacterial vaginosis, and preterm birth—but the insight provided by the VIRGO platform really enables us to re-evaluate medical approaches to many issues of women’s vaginal health, and better design future therapies accordingly.
MC: What are microbiota-based therapeutics, and how are they manufactured?
LG: Microbiota-based therapeutics are a novel class of living medicines that deliver microorganisms for the purpose of treating or preventing conditions that are influenced by the microbiome. We have had oral probiotic supplements on the market for a long time, but Live Biotherapeutic Products (LBPs) being developed today are considered a class of drugs, and are subject to the same rigorous laboratory, clinical and regulatory evaluation to ensure their safety and efficacy for patient use.
Manufacturing typically involves growing the microbes under strictly controlled conditions, followed by preservation and integration into the final delivery format. There are a wide variety of bacteria, viruses, and even fungus that are being developed as live biotherapeutics, and the manufacturing process is unique for each.
MC: LUCA Biologics' first drug candidate targets UTIs and enters the clinic this year (Phase 1b). Please can you tell us more about this therapeutic and its current status?
LG: Our company's first therapeutic will target recurrent UTI, which is estimated by the World Health Organization to impact half of women globally, and is the most common bacterial infection in the United States. Clinical trials will be led by Harvard Medical School faculty and conducted at Massachusetts General Hospital and are expected to start this year. We will be looking at the delivery of specific microorganisms directly to the vagina as part of the treatment. This is a departure from the standard application of microbes through the oral route such as with probiotic supplements, which has consistently shown very low levels of microbes reaching the vagina after passing through the digestive system. Combining the improved delivery route with the understanding we have gained from building the VIRGO platform, we believe that our approach will provide much needed and effective new treatment options to impact the health of women around the world.
MC: Microbiota-based therapeutics are biologics. What safety considerations are there when developing such drugs?
LG: Extensive preclinical testing is performed to confirm the identity, quality, purity, safety and functionality of live biotherapeutics before they ever enter into human clinical trials. These aspects are carefully checked throughout the process of development, from laboratory to clinic. Some key considerations for bacterial therapeutics in particular are a lack of transferrable antimicrobial resistance genes, non-toxicity and non-infectivity, and confirmation of genetic identity—among many more.
MC: In your opinion, what developments do you think we will see in the vaginal microbiome research field over the next five years?
JR: Research in the field of the vaginal microbiome is just starting to progress from correlation to causation. I am excited about the further development of resources like VIRGO that provide a mechanistic understanding of what the microbiota is doing, not just what is there. We are also beginning to understand the crucial functionality of the other classes of microorganisms in the vaginal ecosystem including viruses and yeasts. With these insights we can begin to implement microbe-systems approaches and positively shift the ecosystem toward homeostasis to affect health.
LG: One of the greatest implications of this new perspective is the introduction of live biotherapeutics as alternatives to antibiotics as standard-of-care for women’s health conditions. Antibiotics are crucial in many cases, but their nonspecific killing of bacteria leaves the disrupted vaginal microbiome open to reinfection and recurrence of the disease. By providing more medical options to proactively support the vaginal microbiota we promote prevention of both disease and antibiotic use, with many positive effects for health and healthcare systems alike.
Dr. Jacques Ravel, Chief Scientist of LUCA Biologics, and Luba Greenwood were speaking to Molly Campbell, Science Writer, Technology Networks.