Syphilis vaccine: challenges, controversies and opportunities

Abstract

Syphilis is a sexually or vertically (mother to fetus) transmitted disease caused by the infection of Treponema pallidum subspecie pallidum (TPA). The incidence of syphilis has increased over the past years despite the fact that this bacterium is an obligate human pathogen, the infection route is well known, and the disease can be successfully treated with penicillin. As complementary measures to preventive campaigns and early treatment of infected individuals, development of a syphilis vaccine may be crucial for controlling disease spread and/or severity, particularly in countries where the effectiveness of the aforementioned measures is limited. In the last century, several vaccine prototypes have been tested in preclinical studies, mainly in rabbits. While none of them provided protection against infection, some prototypes prevented bacteria from disseminating to distal organs, attenuated lesion development, and accelerated their healing. In spite of these promising results, there is still some controversy regarding the identification of vaccine candidates and the characteristics of a syphilis-protective immune response. In this review, we describe what is known about TPA immune response, and the main mechanisms used by this pathogen to evade it. Moreover, we emphasize the importance of integrating this knowledge, in conjunction with the characterization of outer membrane proteins (OMPs), to expedite the development of a syphilis vaccine that can protect against TPA infection.

Keywords: immune response; outer membrane proteins; syphilis; treponema pallidum; vaccine.

Figure 1

Immune response to TPA infection. (A) During primary syphilis, a local lesion called chancre appear in the site of infection. After bacteria entry, the microorganisms proliferate and disseminate to distal organs. Bacteria are phagocyted by polymorphonuclear cells (PMN) and dendritic cells that migrate to draining lymph nodes to activate CD4⁺ Th cells. Th1 T cells migrate to the bacteria proliferation foci and produce Th1 cytokines (IFN-γ) for recruiting and activate macrophages. M1 macrophages phagocyte bacteria and produce TNF-α and IL-1β that contribute to chancre development and eventually necrosis. IgM antibodies and complement contribute to bacteria opsonization favoring their removal by macrophages. (B) During secondary syphilis, TPA expands from reservoirs with systematic affectation. A typical rash appears in most cases. Anti-TPA humoral responses are mainly IgGs and plasma cells are visible in the infiltrate of secondary cutaneous lesions. CD8⁺ T-cells are more represented than CD4+ T-cells in lesion infiltrates. (C) Tertiary syphilis affects deep organs like brain and heart. A Th1/Th2 switch progressively occur and the immune response is down regulated by the presence of regulatory T cells. Plasma cells are well represented. Gummas can be developed in different locations (i.e., liver, skin, brain). Gummas are a granuloma-like structure characterized by a necrotic hyaline nucleus surrounded by immune cells (i.e. plasma cells, macrophages and giant cells) and fibroblasts.

Figure 2

Immune evasions mechanisms use by TPA. (A) During its adaptation to environment changes, including the immune system pressure, TPA modulates the expression of certain genes by a switch on/off mechanism. (B) Linked with the prior mechanism; function redundancy ensure that bacterial homeostasis is not compromised by changing the expression of proteins with vital functions. (C) OM of TPA is characterized by a paucity of protein compare with the inner membrane (IM), the lack of LPS and the presence of anti-inflammatory phospholipids (i.e., phosphatidylserine and phosphatidylcholine). (D) Some proteins experience post-translational modifications that result in variants with different location preference. (E) Proteins can accumulate sequence variations by point mutation, gene conversion or recombination. (F) TPA can persist in immune privileged organs, such as central nervous system or nerve fibers, and prolong their survival by remaining hidden to the immune system. (G) TPA may be coated by host serum proteins, reducing its immunogenicity.