Could We Develop Vaccines for Depression and Anxiety?

In response to the pandemic, scientists around the world developed COVID-19 vaccines in record-time, saving millions of lives. Vaccines have been hailed “one of the greatest medical advances of modern times”. They work by introducing a harmless form of a pathogen to the immune system, which teaches adaptive immune cells how to respond to the real pathogen if they’re ever exposed in the future. Could the same technology that trains the immune system against pathogens also be used as a preventative for depression and anxiety?

The link between inflammation and mental health

While there isn’t a specific microbe that directly causes mental illness, there are some (like SARS-CoV-2) that adversely impact the immune system, which in turn can affect mental health. The effects of COVID-19 infection – and associated stressors such as grief and lockdowns – over the last two years have likely contributed to the 25% increase in the prevalence of the most common mental illnesses in the world: depression and anxiety.

Inflammation is a key component of the body’s immune response, often activated in response to tissue damage. However, a growing amount of research is now demonstrating the role of inflammation in the pathogenesis of human diseases, including mental health disorders.

In certain subtypes of depression, scientists have identified elevated levels of the stress hormone cortisol and other inflammatory signaling molecules in the blood and the cerebrospinal fluid. One meta-analysis published in Psychological Medicine analyzed 37 studies of depression, looking for increased levels of C-reactive protein (CRP)– a molecular biomarker  of an acute inflammatory response. Depressed patients were 46% more likely to have elevated levels of this protein in their blood.

Another study published in Molecular Psychiatry found that depressed patients who responded to antidepressant treatment showed a reduction in the inflammatory cytokine TNF-alpha. While these are interesting links, more research is warranted to understand the directionality of cause-and-effect and whether these cytokines can cause depression.

There are similar findings suggesting systemic inflammation plays a role in anxiety disorders. A meta-analysis published in BMJ Open found that patients with generalized anxiety disorder had higher levels of CRP in their blood compared to controls. However, the authors noted that there is only preliminary evidence that the cytokines play a role in the development of the disease.

Could a vaccine be used to help teach the immune system to taper its response to stress?

The psychological stress response is known to contribute to the etiology of mental health illnesses, but the idea that the inflammatory response against microbial organisms can also cause similar outcomes is controversial. Researchers are hypothesizing that, if they can find a type of bacteria that stimulates a similar response to psychological stressors, then it might be possible to inoculate or vaccinate against future stressors and their consequences on mental health.

Dr. Christopher Lowry is an associate professor of integrative physiology at the University of Colorado Boulder. His research is laying the groundwork to bring this idea to fruition. “If we're going to inject the bacterium prior to a stressor, the immunization could alter the host’s immune system in a way that would prevent inflammation,” he posits. “Then we should be able to prevent any negative outcomes of stress exposures that are dependent on inflammation.”

Mycobacterium vaccae as an immune regulator

In 1999, Lowry began his research career at the University of Bristol, where he studied how the vagus nerve facilitated communication between the lungs and the brain. His supervisor at the time, Professor Stafford Lightman, and a colleague, Professor Graham Rook, had become interested in a bacterium isolated from soil in Uganda, called Mycobacterium vaccae. M. vaccae may already be capable of vaccinating humans against tuberculosis, a respiratory infection that often leads to the development of depression.

“They [Rook and his collaborators] showed that if you injected mice with this bacterium, it could prevent allergic airway inflammation in models of allergic asthma,” Lowry says. Their findings were published in Nature Medicine in 2002.

Lowry wanted to see what neurons would fire if heat-killed M. vaccae was injected into the airways of mice. “We looked at what that did to serotonin systems and found that it was highly selective for activating a group of neurons that we believed should have antidepressant properties,” he says. These neurons belong to the serotonergic system. When the researchers tested the effects in mice, they observed antidepressant-like responses in behavioral tests. M. vaccae increased the activation of serotonin neurons as well as serotonin metabolism in the prefrontal cortex, mimicking some of the effects of antidepressants. When Lowry published the findings in 2007, it captured the public’s imagination, he recalls: “It genuinely seemed to have these antidepressant-like properties, and people had a hard time getting their head around that,” Lowry says. “You're injecting a bacterium and getting antidepressant-like effects, that doesn't make sense.”

For Lowry, it was clear that the bacterium exerted anti-inflammatory effects by promoting the balanced expression of regulatory and inflammatory T-cells, which are typically associated with longer-term immune responses. Another study conducted by Rook found that the heat-killed bacterium provided protection against the allergic air-way response for more than 12 weeks after immunization. After being exposed to an airway allergen, the researchers found no change in inflammatory cytokine or antibody levels. Perhaps it could also provide long-term protection against the negative inflammatory impacts of stress?

Lowry teamed up with a researcher from Germany named Stefan Reber next, conducting research in a mouse model of an inflammatory form of post-traumatic stress disorder (PTSD). A state of chronic anxiety is induced in the model using a colony housing (CSC) paradigm. Lowry and Reber tested whether inoculating the mice with a preparation of M. vaccae prior to CSC exposure could provide some level of protection against stressor-induced inflammatory responses. “We saw that we could prevent stress-induced colitis, stress-induced exaggeration of pro-inflammatory cytokine release from mesenteric lymph node cells, and we could prevent stress-induced exaggeration of anxiety in that model,” Lowry says.

Making sense of serendipitous findings

Why does a bacterium found in soil have such profound effects? To figure that out, scientists needed to understand where its immune-modulating activity comes from.

Normally, heating microbes denatures their proteins, rendering them inert, but M. vaccae has some unique properties allowing the bacterium and its lipids to remain intact after death. “At a scanning electron microscopy level, after you heat-kill these bacteria, they are morphologically intact,” Lowry says.

“When you pre-expose macrophages – a type of innate immune cell – to the lipid, and then challenge them with lipopolysaccharide, one specific lipid isolated from M. vaccae suppresses the inflammatory response in the macrophage,” Lowry says. “We focused on a potential receptor for the lipid which turned out to be a host receptor, a transcription factor called PPAR-alpha.”

In nature, M. vaccae might be inhaled or swallowed up by animals and then eaten by phagocytic immune cells. Then the bacteria could release lipids into the cell to shut off the inflammatory cascade and survive. “I like to point out that mammals and bacteria had 65 million years to solve these problems and co-exist together,” Lowry adds. Due to the unique properties of Mycobacterium, different species are currently being screened to determine whether they might also have similar properties.

Linking microbes and mental health

Many scientists believe that one of the reasons inflammatory disorders – including anxiety, depression and PTSD – are on the rise is due to a lack of exposure to microbes earlier in life. This idea, called the hygiene hypothesis, may explain why a soil bacterium could have the ability to inoculate against future stress exposures.

One of Lowy’s collaborators conducted a study comparing the stress responses of young men who grew on farms close to animals to those who were raised in cities. “The people that grew up in cities had an exaggerated inflammatory response to the psychosocial distress,” Lowry explains. “This supports the idea that if you grew up in the city, without exposure to animals, you're at higher risk of repeated chronic low-grade inflammation in response to purely psychological stressors.” While provocative, the study was limited because many other important factors related to the microbiome (including mode of delivery, formula or breast milk in early life, and diet) were not considered.

Even if M. vaccae doesn’t directly cause a disease, the hygiene hypothesis could provide one rationale for inoculating individuals against stress-related disorders. It has been revisited by epidemiologists in recent years, questioning the links between early microbial exposure and inflammatory disease. According to the Microbiological Society, there is little evidence that the increase in inflammatory disorders is related to personal or household hygiene and cleanliness, instead positing that exposure to beneficial microbes from the natural environment is necessary for regulating the immune system. Even then, there is substantial debate over what these beneficial microbes are and if it is even possible to define a healthy gut microbiome that would promote healthy immune development. While other studies show links between the gut microbiome and depression, it isn’t clear whether they contribute to the development of the disease, act as a confounder or are a consequence of depression itself.

Are there any vaccines that impact mental health?

A growing body of evidence suggests that regulating the immune system has an impact on the brain and behavior. This is further demonstrated by the effects that vaccines designed against infectious diseases can have on mood and mental health.

Research proposes that the impact of flu vaccines on mood is more negative in people who have anxiety or depression, suggesting another link between the immune system and our mental state. Intriguingly, the COVID-19 vaccines appear to be associated with a lower prevalence of anxiety or depression, though it is unclear why. A recent large, cross-sectional study found that people who received a vaccination were 13% less likely to develop anxiety and 17% less likely to develop depression. The nature of the study design prevents causal inference, but the data enhances our understanding of how vaccination could offer a preventative route for mental health conditions.

How long until clinical trials?

According to Lowry, it may be five years until M. vaccae is tested in humans as a potential vaccine against anxiety or depression: “The strain that we're studying has been used in many clinical trials, including phase III trials, but not in the context of psychiatry,” Lowry said, adding that the bacterium already has a good safety record, which can make  it easier to receive approval for testing the vaccine for other conditions in humans.

It may take more than a decade before there is long-term data to inform us whether M. vaccae can reduce the risk or severity of developing depression over a five-year period. But if it does work, it could become an incredible vaccine success story and jumpstart the development of more vaccines for mental health conditions in the future.