Unraveling Helicobacter pylori: Insights into Pathogenesis, Immune Evasion, and Progress Toward Effective Vaccination

Abstract

Helicobacter pylori (H. pylori) is one of the most prevalent chronic bacterial infections globally, significantly contributing to gastritis, peptic ulcers, and gastric malignancies. Its pathogenesis involves a complex array of virulence factors-including cagA, vacA, and urease-which facilitate mucosal colonization, immune evasion, and persistent inflammation. A major challenge in vaccine development is the bacterium's ability to manipulate both innate and adaptive immune responses, resulting in limited natural clearance and long-term persistence. This review synthesizes H. pylori pathogenesis and host immune dynamics, highlighting their implications for vaccine design. By elucidating the molecular and cellular mechanisms underlying host-pathogen interactions, we explore how these insights inform antigen selection, adjuvant optimization, and delivery strategies. By integrating basic science with translational objectives, this review aims to support the development of an effective H. pylori vaccine, addressing global health needs, particularly in regions with a high infection burden and limited access to treatment.

Keywords: Helicobacter pylori; antigen delivery; mucosal immunity; public health; subunit vaccine; vaccine development.

Figure 1

Mechanisms of gastric microbiota displacement by H. pylori. This conceptual illustration depicts how H. pylori establishes colonization by competing with the native gastric microbiota. Key mechanisms include (1) urease-mediated alkalinization of the gastric environment, which reduces acid-dependent microbial competitors; (2) secretion of antimicrobial peptides targeting commensals; (3) disruption of epithelial tight junctions to facilitate mucosal infiltration; and (4) selective adhesion via glycan-binding adhesins to displace resident microbes. These strategies collectively promote gastric dysbiosis, enabling chronic infection and impairing immune priming, with potential consequences for host–pathogen interactions and vaccine efficacy.

Figure 2

H. pylori strategies for colonization and survival in the gastric environment. This figure illustrates key virulence factors, including the helical morphology and unipolar flagella, which facilitate motility through gastric mucus and chemotaxis toward urea and pH gradients. Acid neutralization is achieved through urease activity, which converts urea into ammonia and carbon dioxide. Outer membrane adhesins (e.g., babA and sabA) mediate adherence to the gastric epithelium, whereas the T4SS delivers effector proteins such as cagA into host cells, promoting inflammation and altering signaling pathways. Additional features include biofilm formation and antigenic variation, both of which contribute to immune evasion and persistent colonization.

Figure 3

Illustration of H. pylori-induced host interactions and inflammatory pathways. Upon colonization, H. pylori activates toll-like receptors (TLR2, TLR4, and TLR9), triggering the NF-κB and MAPK signaling pathways and the subsequent release of pro-inflammatory cytokines (IL-8, TNF-α, and IL-1β). The cagA protein is translocated into host epithelial cells via the T4SS, where it becomes phosphorylated and interferes with SHP-2 and β-catenin signaling, promoting tight junction disruption, EMT, and carcinogenesis. VacA induces mitochondrial dysfunction, apoptosis, and immune evasion. These events collectively recruit neutrophils, macrophages, and lymphocytes; amplify oxidative damage; and sustain chronic inflammation, which can progress to gastric atrophy and cancer.

Figure 4

Overview of major clinical outcomes associated with H. pylori infection. This information summarizes key gastrointestinal conditions associated with H. pylori infection, including chronic gastritis, peptic ulcer disease, MALT lymphoma, and gastric cancer. It distinguishes between duodenal ulcers—typically linked to high acid output in the antrum—and gastric ulcers, which arise in the corpus due to impaired mucosal defense. The figure highlights the progression from bacterial colonization to diverse gastric pathologies.