Integrating complex host-pathogen immune environments into S. aureus vaccine studies

Abstract

Staphylococcus aureus (SA) is a leading cause of bacterial infection and antibiotic resistance globally. Therefore, development of an effective vaccine has been a major goal of the SA field for the past decades. With the wealth of understanding of pathogenesis, the failure of all SA vaccine trials has been a surprise. We argue that experimental SA vaccines have not worked because vaccines have been studied in naive laboratory animals, whereas clinical vaccine efficacy is tested in immune environments reprogrammed by SA. Here, we review the failed SA vaccines that have seemingly defied all principles of vaccinology. We describe major SA evasion strategies and suggest that they reshape the immune environment in a way that makes vaccines prone to failures. We propose that appropriate integration of concepts of host-pathogen interaction into vaccine study designs could lead to insight critical for the development of an effective SA vaccine.

Keywords: B cells; Staphylococcus aureus; T cells; antibodies; evasion mechanisms; original antigenic sin; pathogenesis; vaccine.

Figure 1.. B cell evasion mechanisms.

Antibody responses against immunodominant SA surface antigens are largely non-protective, whereas responses against toxins are partially protective. SpA induces B cell deletion and suppression through its super-antigenic activity, and thus creates “holes” in the B cell repertoire and primes for a skewed specific antibody response. The reason why antibodies against surface antigens are not protective is unclear.

Figure 2.. T cell evasion mechanisms.

Th1 / Th17 lymphocytes mediate anti-SA immunity. Staphylococcal toxins (α-toxin and LukED) induce cytolysis of mature and memory T cells. Various SA virulence determinants affect T cell priming by modulating antigen-presenting cell – naïve T cell interaction: PSM (induction of tolerogenic DC); SEB (Vβ-specific T cell activation), Peptidoglycan modification (suppression of Th17-related cytokines), Map (induction of Th2 cells), SpA (induction of Treg cells), LukED and LukAB (killing of DC). APC: Antigen Presenting Cells.