Vaccinating against depression or anxiety: is it plausible?

KEYWORDS:

• Anxiety
• clinical trials
• depression
• faecal transplantation
• inflammation
• major depressive disorder
• microbiota
• probiotics
• vaccination
• vaccine

1. Introduction

In 2012, Rook et al. [1] postulated that vaccines might be useful for preventing or treating major depressive disorder (MDD) (see also [2]). This idea was apparently ignored in the medical literature. A PubMed search found no vaccine tested in animal models of depression. A search in the ClinicalTrials.gov register found only one clinical trial of a vaccine tested against depression (NCT01533285, last accessed 6 October 2016). NCT01533285 was an exploratory study investigating the effect of Salmonella typhi vaccine (Typhim Vi) on depressive symptoms in patients with major depression. The trial was completed in November 2013, but results were still not posted to ClinicalTrials.gov.

Even though it did not capture clinical interest, the hypothesis of Rook et al. [1] deserves to be revisited because relapse is common in MDD and at least 15%–30% of patients with MDD are resistant to treatment, resulting in considerable morbidity and increased risk of suicidal behavior [3]. A vaccine can prevent episodes of MDD, as well as being safe and well tolerated in the long term.

The intestinal microbiota has been found to modulate anxiety-like behavior in rodents [4,5], but a literature search (PubMed and ClinicalTrials.gov) found no vaccine tested in animal models of anxiety or undergoing clinical trials in anxiety disorders.

Taken together, all the above arguments motivated us to explore the plausibility of a vaccine against MDD or anxiety disorders.

2. What is a vaccine against depression or anxiety?

The term ‘vaccination’ was originally coined a long time ago to characterize the immunization against smallpox, and usually refers to the administration of an antigenic material to stimulate adaptive immunity to a pathogen [6]. Therefore, the development of a vaccine against depression or anxiety likely requires the previous identification of microorganisms susceptible to induce MDD or anxiety disorders in humans.

3. Depression or anxiety induced by microorganisms

3.1. Enteric bacterial pathogens

Lyte et al. [7] reported anxiety-like behaviors in mice receiving a subclinical infection with the Gram-negative pathogen Campylobacter jejuni (C. jejuni) in the absence of an overt immune response (C. jejuni is the most prevalent causative agent worldwide of food-borne human gastroenteritis). Later, Goehler et al. [8] showed that oral inoculation with C. jejuni led to a significant neuronal increase in c-Fos expression in the vagal ganglia, in the nucleus tractus solitarius (the vagal primary relay nucleus in the brainstem), and in other brain regions (Figure 1). Notably, these activation mechanisms occurred in the absence of elevated levels of circulating pro-inflammatory cytokines [8]. Similar results were obtained with Citrobacter rodentium (an enteric mucosal pathogen of mice) [9].

Figure 1. A model for the pro-depressive or anxiogenic mechanisms of pathogenic or commensal gut bacteria.

The challenge of animals and humans with infectious microorganisms activates pro-inflammatory cytokine production, which can in turn induce depression [10] (Figure 1).

3.2. Evidence for inflammatory, depressive actions induced by gut microbiota-commensals

A large body of evidence has shown a significant association between MDD and inflammatory markers of cell-mediated immune (CMI) activation in the absence of a clear inflammatory lesion [11,12]. It appears that inflammation and CMI activation in MDD may result from intestinal translocation of Gram-negative enterobacteria due to increased gut permeability (leaky gut) [11]. Maes et al. [11] reported that patients with MDD exhibited increased IgA and IgM responses against the LPS (lipopolysaccharide, endotoxin) of Gram-negative enterobacteria, i.e. Citrobacter koseri, Hafnia alvei, Klebsiella pneumonia, Morganella morganii, Pseudomonas aeruginosa and Pseudomonas putida.

Jiang et al. [13] recently reported an altered fecal microbiota composition in patients with MDD (Proteobacteria, Bacteroidetes, and Actinobacteria were significantly more abundant, whereas levels of Firmicutes were significantly reduced; it is important to mention that patients were treated with antipsychotics, a study limitation acknowledged by the authors). The overgrowth of the phylum Proteobacteria [13] included the above inflammogenic Enterobacteriaceae identified by Maes et al. [11]. Moreover, MDD patients had increased levels of the Gram-negative Alistipes of the Rikenellaceae family [13].

3.3. Enteric bacteria modulating anxiety behavior

In 2004, Sudo et al [4] reported that germ-free mice have an exaggerated endocrine response to stress. The exaggerated stress response was reversed by reconstitution with Bifidobacterium infantis [4]. Conversely, mono-association with enteropathogenic Escherichia coli enhanced the response to stress [4]. Mono-association with Blautia (Clostridium) coccoides (the most dominant inhabitant of the human gut) reduced the anxiety level [5].

4. Conclusions

The plausibility of a vaccine against anxiety or depression requires the previous identification of the microorganisms susceptible to induce such mental disorders. A clear ‘proof of concept’ that microorganisms can induce anxiety was demonstrated in mice, by the anxiety-like behavior induced by some enteric bacterial pathogens [7–9] (Figure 1). Moreover, inflammation and CMI activation in human subjects with some types of MDD likely result from overgrowth and intestinal translocation of Gram-negative enterobacteria due to a leaky gut [11,13] (Figure 1). More research is needed to identify and/or characterize such kind of pathobionts (potentially pathological microorganisms which, under normal circumstances, live as symbionts) susceptible to induce depression or anxiety in humans.

5. Expert opinion

The discovery of new medicinal agents is a ‘show me’ situation, and no data were found in the literature showing therapeutic efficacy of a vaccine in MDD or anxiety disorders. The studies of Maes et al. [11] and Jiang et al. [13] suggest that some inflammatory forms of MDD can be seen as a microbial infection. Several Gram-negative gut commensals have been identified as potential candidates for inducing inflammation and CMI activation in MDD [11,13] (Table 1). These already identified pathobionts could be likely candidates for preparing vaccines against MDD.

Table 1. Commensal gut microbiota candidates for formulating a vaccine against major depressive disorder.

Phylum	Family	Species or genus	References^b
Proteobacteria	Enterobacteriaceae	Citrobacter koseri Hafnia alvei Klebsiella pneumonia Morganella morganii	Maes et al. [11]
	Pseudomonadaceae	Pseudomonas aeruginosa Pseudomonas putida	Maes et al. [11]
Bacteroidetes	Rikenellaceae	Alistipes^a	Jiang et al. [13]

^aIndicates genus.

^bGram-negative gut commensals associated with major depressive disorder.

5.1. Suggestions for mid- to long-term research

The study of Maes et al. [11] suggests that some inflammatory forms of MDD could be associated with a polymicrobial infection. Periodontitis is also a polymicrobial infection, and after years of experience in developing vaccines, no periodontal vaccine trial has satisfied all the requirements of an ideal periodontal vaccine [14]. Targeting not only a single pathogen, but polymicrobial organisms, has been postulated as a more successful therapeutic strategy [15]. These and other emerging concepts regarding periodontal vaccine development could be of help in the search for a vaccine against some inflammatory forms of MDD.

A biological preparation (‘vaccine’) could be prepared with the microbial candidates suggested by current (Table 1) and future studies, and then tested in patients with elevated C-reactive protein levels (a marker of inflammatory forms of MDD). Gut pathobionts may only account for one inflammatory upstream path for immune activation leading to MDD (see also the complex interaction of pro-inflammatory cytokines with kynurenine metabolism in depression [16]). Technological advances in sequencing the human microbiome, and reductions in costs, could make it possible in the near future to use a personalized medicine approach, targeting known pathobionts identified in individuals with MDD. On the other hand, vaccination is normally used to prevent infection. Therefore, the efficacy of such a vaccine should be tested in stabilized patients, to prevent relapse of depressive episodes.

Care should be taken to avoid inflammatory reactions against the employed vaccines or to avoid adverse effects due to unlikely changes in the composition of the gut microbiota.

Understanding the mechanisms of mental disturbances induced by microorganisms are important steps for the development of vaccines, including new evaluation criteria in clinical trials. In this respect, it is interesting to mention that manipulation of the mouse intestinal microbiota was able to transfer anxiety-like behavior and hippocampal expression of brain-derived neurotrophic factor (a biomarker of anxiolytic and antidepressant actions) independently of the autonomic nervous system, gastrointestinal-specific neurotransmitters, or inflammation [17].

Mice studies suggest that gut microbiota commensals may play a role in anxiety disorders. However, to the best of our knowledge, the enteric microorganisms positively associated with anxiety disorders in humans have not yet been identified. Moreover, the murine and human gut microbiota possess clear differences at the level of specific genus/species [18]. Therefore, further research is required to identify the enteric microorganisms positively associated with anxiety disorders in humans.

5.2. Abusive use of the term ‘vaccine’ for depression or anxiety?

As pointed out earlier, the term ‘vaccine’ likely refers to the administration of an antigenic material to stimulate adaptive immunity to a pathogen. Therefore, the term ‘vaccine’ does not apply to the ‘Internet-based behavioral vaccine’ developed to prevent adolescent depression [19], or to the anesthetic and antidepressant agent ketamine, which was proposed as a ‘vaccine for depression’ [20].

Reber et al. [21] recently reported that repeated immunization with a heat-killed preparation of the non-pathogenic environmental microorganism Mycobacterium vaccae (M. vaccae)-induced anxiolytic or fear-reducing effects in mice. Based on these results, some authors claimed that a ‘vaccine’ was found to alleviate anxiety and fear in rodents [22,23]. However, Reber et al. [21] never mentioned the term ‘vaccine’ or ‘vaccination’ in their article. The heat-killed preparation of M. vaccae [21] is not a ‘vaccine’ [22,23], but an immunomodulator, since depletion of regulatory T cells negates its protective effects on anxiety-like or fear behaviors [21]. M. vaccae is not known as a causal agent of human anxiety, but as an ‘old friend’ from the mud, whose reintroduction in humans was proposed to promote optimal health and wellness [21].

5.3. Biological therapeutic alternatives

Unlike vaccines, a number of other biological therapeutic alternatives are undergoing clinical development for mental disorders. These include probiotic supplementation, fecal transplantation, as well as reintroducing ‘old friends’ such as M. vaccae [1]. Intestinal alkaline phosphatase, which detoxifies LPS and limits the translocation of gut bacteria to mesenteric lymph nodes, is undergoing clinical development in patients with sepsis [24] and other disorders and could be a therapeutic option for inflammatory forms of MDD.

Declaration of interest

RP Garay is president of Craven, Villemoisson-sur-Orge, France, a non-profit association for therapeutic innovation. They have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Acknowledgment

We are grateful to Pierre-Michel Llorca (Head of Centre Médico-Psychologique B, CHU, Clermont-Ferrand, France) for his helpful comments and discussion.

Additional information

Funding

This manuscript has not been funded.