Vaccines and Dementia: Part I. Non-Specific Immune Boosting with BCG: History, Ligands, and Receptors

Abstract

Vaccines such as Bacille Calmette-Guérin (BCG) can apparently defer dementia onset with an efficacy better than all drugs known to date, as initially reported by Gofrit et al. (PLoS One14, e0224433), now confirmed by other studies. Understanding how and why is of immense importance because it could represent a sea-change in how we manage patients with mild cognitive impairment through to dementia. Given that infection and/or inflammation are likely to contribute to the development of dementias such as Alzheimer's disease (Part II of this work), we provide a historical and molecular background to how vaccines, adjuvants, and their component molecules can elicit broad-spectrum protective effects against diverse agents. We review early studies in which poxvirus, herpes virus, and tuberculosis (TB) infections afford cross-protection against unrelated pathogens, a concept known as 'trained immunity'. We then focus on the attenuated TB vaccine, BCG, that was introduced to protect against the causative agent of TB, Mycobacterium tuberculosis. We trace the development of BCG in the 1920 s through to the discovery, by Freund and McDermott in the 1940 s, that extracts of mycobacteria can themselves exert potent immunostimulating (adjuvant) activity; Freund's complete adjuvant based on mycobacteria remains the most potent immunopotentiator reported to date. We then discuss whether the beneficial effects of BCG require long-term persistence of live bacteria, before focusing on the specific mycobacterial molecules, notably muramyl dipeptides, that mediate immunopotentiation, as well as the receptors involved. Part II addresses evidence that immunopotentiation by BCG and other vaccines can protect against dementia development.

Keywords: Adjuvant; Alzheimer’s disease; Bacille Calmette–Guérin; Freund; NOD2; YB-1; immunopotentiation; muramyl dipeptide; mycobacteria; trained immunity; vaccine.

Fig. 1

Evolution of Bacille Calmette–Guérin (BCG). A) Léon Charles Albert Calmette (1863–1933; above) and Jean-Marie Camille Guérin (1872–1961; below) who first developed BCG at the Institute Pasteur de Lille, France. B) Deletion of the RD-1 region of the Mycobacterium bovis genome during passage by Calmette and Guérin. C) Further genomic polymorphisms including four deletions and two duplications during further passage of BCG vaccine strains, highlighting that different BCG strains may differ in their properties; additional detailed studies on the phylogeny of BCG strains can be found in [151]. Panel (A) reprinted, with permission, from [152]; panel (B) reprinted, with permission, from [153]; panel (C) reprinted, with permission, from [154].

Fig. 2

Titers of anti-sheep red blood cell antibodies in control and tuberculous guinea pigs. Animals were infected 21 days before the start of the experiment. At day zero animals were inoculated with a suspension of sheep red blood cells, followed by a second injection on day 33. Figure adapted, with permission, from [30].

Fig. 3

Structures of MDP (N-acetylmuramyl-L-alanyl-D-isoglutamine), GMDP (N-acetylglucosaminyl-MDP, and nG-MDP (N-glycolyl-MDP) based on muramic acid (carboxyethyl-D-glucosamine). Figure modified from [113]. The site in MDP for phosphorylation (P) by NAGK [125] is indicated by an arrow.