It’s time to act: Understanding and combating Vibrio vulnificus

ABSTRACT

Vibrio vulnificus is a highly pathogenic marine bacterium that can cause life-threatening conditions such as septicemia and necrotizing fasciitis; in medically fragile individuals, mortality rates can exceed 50%. Its virulence factors, including the MARTX toxin and hemolysin VvhA, function to disrupt host cells, evade immune responses, and facilitate bacterial dissemination. Climate warming has dramatically expanded the geographic range of V. vulnificus, doubling infection risks in high-latitude northern waters, while microplastic pollution and extreme weather events further enhance its ecological adaptability. High-risk populations, such as patients with liver disease, immunocompromised individuals, and coastal workers, face elevated mortality due to iron metabolism disorders or frequent exposure. Traditional diagnostic pathogen culture methods are time-consuming and lack sensitivity, whereas technologies such as CRISPR-Cas12a enable quick detection with a sensitivity of 1–10 CFU/mL, facilitating timely intervention. The standard treatment for V. vulnificus infections relies on doxycycline combined with cefotaxime; however, rising antibiotic resistance, poses a significant challenge. This challenge underscores the need to develop alternative strategies, such as virulence-targeted therapies and immunomodulatory approaches .

Multivalent vaccines such as RtxA1/VvhA fusion antigens offer broad-spectrum protection, while nanoparticle delivery systems and mucosal vaccines like Lactobacillus-based oral vaccines may enhance immune responses. Future efforts must integrate a “monitoring-blocking-treatment” framework, combining satellite-based early-warning systems, CRISPR rapid detection, and climate-medicine modeling. International collaboration is essential to implement vaccination programs for high-risk groups and enforce seafood safety protocols. Addressing the public health threat of V. vulnificus in the era of climate change demands interdisciplinary innovation and global governance.

Introduction

Vibrio vulnificus, a Gram-negative, curved rod-shaped, motile bacterium of the Vibrio genus, is widely found in warm water ecosystems with low salinity [1–4]. Colloquially termed the “silent oceanic pathogen”, it has a high mortality rate (over 50%) [5–7]. Since its recognition as a separate species in 1970, most studies have focused on its impact on marine fish and the ocean economy [8–10], while its significance as a human pathogen causing septicemia, severe wound infections, and gastroenteritis has been overlooked [1,11,12]. With climate changes and increasingly complex marine ecosystems due to human activities, the range of V. vulnificus is expanding from the ocean to the coast and even inland [13–16]. This review focuses on the relationship between human infections and the pathogenic mechanisms of V. vulnificus, emphasizing the need to address V. vulnificus infections and take action [17–19].

Epidemiology and high-risk populations

Geographic distribution and seasonal characteristics

The geographic distribution of V. vulnificus is dependent on water temperature and salinity. It has traditionally been found in subtropical and tropical waters located between 30°N and 30°S, including the Gulf of Mexico, the southeastern coastal waters of China, and Southeast Asia. Climate warming, however, is driving its expansion into higher latitudes [3,13–15]. The U.S. National Oceanic and Atmospheric Administration (NOAA) model predicts that by 2040, the infection risk along the Baltic Sea coast, which is above 55°N, will increase two- to three-fold [3]. Epidemiological surveillance data from Gyeonggi Province (2018–2022) revealed that the isolation rate of V. vulnificus in seawater samples between July and September exceeded 80%. Additionally, the detection rate in oyster farming areas was 2.3 times higher than in natural sea areas. These findings were significantly correlated with rising water temperatures and increased plankton abundance, a phenomenon attributed to eutrophication, which facilitates the proliferation of plankton [20]. A retrospective study of clinical cases of V. vulnificus infection in Hainan Province, China (2018–2023), demonstrated that 90% of these cases occurred from June to September, overlapping with local peak seawater temperatures (28–32°C) [21].

Southeast Asia has the highest contamination rate of V. vulnificus in seafood (12.3%), possibly related to its hot and humid climate and intensive aquaculture practices [22,23]. In Vietnam’s Mekong Delta, the bacterial load in oysters during the rainy season (salinity 0.5–1%), is three times higher than in the dry season (salinity 2.5–3%) [22]. The U.S. Gulf of Mexico coast remains a traditional high-incidence area, but in recent years, mid-Atlantic states such as Delaware have experienced an annual case increases of 15%, a trend directly linked to seawater warming at +1.2°C per decade [15,24]. In 2023, Bulgaria’s Black Sea coast reported its first cases of V. vulnificus infection, each of the five cases were a result of seawater exposure. Increasingly, climate warming is rewriting regional epidemiological patterns [25].

Analysis of susceptibility mechanisms, epidemiological characteristics, and emerging risk factors for V. vulnificus infection

The mortality rate from V. vulnificus infections is closely related to the host’s health status, and certain groups need to be highly vigilant. Of the six patients diagnosed with sepsis caused by V. vulnificus and treated at the First Affiliated Hospital of Ningbo University China from 2020 to 2022, all had preexisting hepatic disease and despite aggressive treatment only two survived (mortality rate 67%) [26]. Iron overload may serve as a mechanistic basis for this phenomenon. Meanwhile, hepatitis patients exhibit elevated transferrin saturation ( > 60%, p = 0.003), and the iron uptake system in V. vulnificus is upregulated in high-iron environments, such as IrgAB which promotes bacterial proliferation [27]. Immunosuppressed individuals, such as organ transplant recipients, diabetics, and those infected with HIV, have very high mortality rates after infection [15]. A 48-year-old male seafood worker coinfected with HIV, HBV, HCV, and V. vulnificus achieved full recovery following comprehensive ICU management, limb-preserving debridement, VSD drainage, and susceptibility-guided antibiotic therapy. This case represents the first globally documented successful treatment of such a quadruple infection in an immunocompromised host, with limb salvage and infection control accomplished [28]. Meanwhile, V. vulnificus infection exhibits a significant gender bias, with male patients considerably outnumbering female patients for unknown reasons [29] Coastal residents and occupationally exposed groups, such as fishermen and seafood processing workers, have a 5–10 times higher infection risk due to frequent seawater or seafood contact [30,31]. A case–control study in Florida, USA, showed that hand micro-wound infections accounted for 30% of annual V. vulnificus cases among shellfish harvesters [24].

The main infection routes of V. vulnificus are wound exposure and consumption of contaminated seafood, with wound infections accounting for 70–80% of cases [24,26]. Typical scenarios include injuries from fish fins while handling seafood [7,32], contact of open wounds with seawater while swimming [3,16,31], and even insect bites [33,34]. Infection can progress rapidly, potentially developing into necrotizing fasciitis within 24 h, with a mortality rate of 30–50% [6,12]. Summer marine recreational activities substantially amplify V. vulnificus infection risks through a triple synergistic mechanism involving climate warming, pathogen proliferation, and human behavior [35–37]. Elevated seawater temperatures (24–26°C) correlate with 3–4-fold increases in V. vulnificus detection rates in regions like the Black and Baltic Seas, where planktonic algal blooms and kelp further facilitate bacterial adhesion and dissemination [35,37–39]. During water-related activities such as swimming and surfing, skin abrasions exposed to contaminated seawater can lead to infections with incubation periods as short as 16–24 h [40]. Anglers face particularly high exposure risks through hand wounds, with German surveillance data showing summer infection rates quintupling winter rates [36]. Notably, all three Bulgarian cases reported in 2022 originated from beach water exposure during August – September [35].

Foodborne infections primarily result from consuming raw oysters, with the bacteria invading through the intestinal mucosa and causing primary septicemia [2,41,42]. For those with liver disease, the mortality rate can reach as high as 70% [11,26,43]. According to Kling et al., foodborne V. vulnificus infections predominantly derive from raw oysters, which represent over 70% of cases. Additionally, infections may also result from the consumption of other undercooked shellfish such as clams and mussels, fish species including tilapia, and percutaneous exposure to contaminated seawater [44]. Geographic distribution demonstrates marked heterogeneity, with the U.S. Gulf Coast states, such as Florida, Texas, and Louisiana, identified as the hyperendemic region accounting for 55% of clinical isolates [44]. Within this endemic zone, summer water temperatures above 20°C correlate with bacterial concentrations reaching 10³−10⁴ CFU/g in oysters. Climate warming facilitates emergence in historically non-endemic areas including Tennessee and Arizona, while pathogen dissemination intensifies in brackish water environments where freshwater-seawater interfaces enhance transmission [44].

The synergistic effect of chronic alcoholism and raw seafood consumption poses a lethal threat in V. vulnificus infection, markedly amplifying both infection risk and clinical severity through multiple pathological mechanisms [45–48]. Chronic alcoholism systematically compromises host defenses: sustained alcohol exposure damages the intestinal epithelial barrier, inducing abnormal increases in intestinal permeability concurrently with gut dysbiosis [49,50]. In chronic viral or alcoholic liver disease, hepatocellular injury precipitates a marked fall in hepcidin synthesis [51,52]. Loss of hepcidin mediated restraint on ferroportin leads to sustained opening of the protein at the basolateral membrane of duodenal enterocytes, allowing dietary iron to flood the portal circulation, while simultaneous derepression of ferroportin in macrophages triggers massive export of iron recycled from senescent erythrocytes [53,54]. These dual pathways synergistically elevate serum non transferrin bound iron, and the liver as the first pass organ is compelled to internalize this iron surplus, initiating a self perpetuating cycle of hepatic iron accumulation [51–54]. Crucially, in alcohol-associated liver disease (ALD), functional depletion of the NLRP3 inflammasome abolishes the host’s capacity for immune activation against new infections, leading to deficient expression of antimicrobial peptides such as defensins and Reg3 proteins. Subsequent consumption of V. vulnificus-contaminated seafood enables the pathogen to breach this compromised intestinal barrier and invade the circulatory system directly [48].

Following hematogenous dissemination, impaired hepatic clearance prevents effective pathogen elimination, rapidly precipitating fulminant sepsis [45–48]. This condition typically advances to necrotizing fasciitis or multi-organ failure within 24–48 h. Clinical data demonstrate a mortality rate exceeding 50% in infected patients with comorbid alcoholism and cirrhosis [55]. The lethality of this “alcohol-raw seafood” nexus underscores the critical need for stringent dietary interventions in high-risk populations, particularly ALD patients: absolute alcohol abstinence is imperative to restore barrier function, while rigorous avoidance of raw seafood is essential to eliminate exposure vectors [56,57].

In recent years, atypical infection cases have gradually increased. For example, infections in freshwater environments. Historically, V. vulnificus was thought to be limited to waters with salinity levels between 1% and 1.8%, but a reported case of necrotizing fasciitis caused by a freshwater shrimp injury showed that the isolated strain could grow in a culture medium with 1% salinity, indicating some strains have evolved low-salinity adaptability [32,33,58]. Additionally, cases of nosocomial infection have been reported. A hospitalized patient was infected after their wound came into contact with contaminated physical therapy equipment, highlighting the need to strengthen monitoring of water sources in hospital environments [12,59,60]. Patients with V. vulnificus infection face substantial clinical burdens: wound infections progress rapidly to necrotizing fasciitis within 24 h, with amputation rates reaching 14%. Gastrointestinal infections (39% of cases) frequently progress to secondary sepsis, resulting in an overall mortality rate of 30%. The median time to death is 4d, while 11% of patients require hospitalization exceeding 14d [25,32,35,60–62].

Beyond the 50% increase in mortality associated with chronic liver disease, specific comorbidities significantly worsen prognosis: (1) Immunosuppression (e.g. hematologic/autoimmune disorders) elevates mortality risk 2.5-fold; (2) Diabetic comorbidity doubles amputation rates (observed in 64% of cases); (3) Chronic kidney disease increases sepsis risk by 40%; (4) Chemotherapy-treated malignancies exhibit 45% mortality. Advanced age ( > 60 years), iron overload, and treatment delays > 24 h independently elevate case-fatality rates from 18% to 58%, all constituting independent risk factors after adjustment for confounders [63–65].

Environmental drivers and ecological adaptability

Mechanisms of climate warming and seawater parameters

The growth of V. vulnificus is highly dependent on two environmental factors: water temperature and salinity. Its optimal growth temperature is 20–35°C [2,3]. When water temperature exceeds 15°C, bacterial reproduction rate increases exponentially, with a doubling time of only 20 minutes at 25°C [3,66]. Due to global warming, parts of the North Atlantic have seen summer water temperatures exceed 30°C, extending the infection season by 2–3 weeks [14,15]. Typically, the optimal salinity is 5–25 ppt (parts per thousand), but different strains have shown significant adaptability. For example, clinical isolates (vcgC type) upregulate virulence gene expression (such as rtxA1) in low-salinity (5–10 ppt) environments [10,40], while environmental isolates (vcgE type) have stronger biofilm-forming abilities in high-salinity (20–25 ppt) conditions [8,31,44,67].

According to the “climate-infection” model, such as Vibrio Expansion Risk Model and Vibrio Temperature-pH Response Model [15,16], under the RCP8.5 (Representative Concentration Pathway 8.5, a high-emissions scenario in which anthropogenic greenhouse-gas emissions result in a radiative forcing of 8.5 W m⁻² by the end of the twenty-first century [68]) scenario of global warming of 4°C, by 2100, the global marine area suitable for V. vulnificus survival will expand by 40%, and annual infection cases in the high-latitude regions of North America may increase by 200% [15,16,69]. Meanwhile, a microbial-water dynamics coupled model successfully predicted a fivefold increase in bacterial concentration when salinity dropped to 5 ppt after heavy rain, providing a technical example for real-time early-warning [3,16]. Climate change has fundamentally reconfigured the geographical distribution of V. vulnificus infections across Europe and Asia, with pronounced northward expansions directly linked to rising sea temperatures [70,71]. In Europe, France’s Bay of Biscay region demonstrates a decades-long surge in cases, with more than 90% concentrated between June and September and peaking during extreme heat events such as 2003 and 2018, when sea temperatures exceeded viability thresholds of > 18°C [70,71]. Concurrently, Germany has documented the pathogen’s invasion into historically non-endemic Baltic Sea coasts, fueled by a 2.5°C temperature rise since the 1980s that transformed this temperate zone into a favorable habitat [36]. Parallel trends manifest in Asia, where China’s coastal and aquaculture regions report decadal case increases as warming waters enable northward range extension [17]. This tri-continental pattern reveals a unified epidemiological shift: marine heatwaves transiently amplify pathogen density, while sustained thermal elevation permanently extends viable latitudes, eroding traditional biogeographic barriers and establishing new endemic foci beyond historical boundaries.

Beyond direct alterations in seawater temperature and salinity, climate change influences the proliferation and dissemination of V. vulnificus through a suite of indirect mechanisms. First, the increasing frequency and intensity of extreme weather events, such as heatwaves, torrential rainfall and coastal flooding, enhance both water temperature and nutrient loading, thereby creating optimal conditions for rapid bacterial multiplication [72,73]. Second, sea-level rise progressively modifies estuarine salinity gradients, further reshaping the ecological niche of V. vulnificus [17,71]. Third, climate-driven shifts in marine ecosystems, including changes in the distribution and phenology of phytoplankton, macroalgae and filter-feeding bivalves that serve as natural reservoirs, indirectly facilitate long-distance dispersal and the establishment of the pathogen in previously unaffected coastal zones [74,75].

Microplastics generate new ecological threats

Microplastics (particle size < 5 mm) provide a unique ecological environment for V. vulnificus. The bacteria adhere to the surface of polyethylene, polypropylene, and other plastics via type IV pili (pilA). The LuxS (S-ribosylhomocysteine lyase)/AI-2(autoinducer-2) quorum sensing (QS) system facilitates the formation of multilayer biofilms, and is subsequently released into the surrounding environment through biofilm dispersal mechanisms, thereby enhancing their transmission potential within aquatic systems [31,76,77]. Scanning electron microscopy shows that bacterial density in microplastic biofilms at 30°C is 100-fold higher than in free-swimming states [78,79]. When oysters were exposed to microplastics and microcystin, their gill V. vulnificus load increased threefold [42,80]. The mechanism may be related to immune suppression, as oxidative stress induced by microplastics inhibits the phagocytic function of oyster blood cells [79,81].

Microplastics not only directly impact the growth of Vibrio bacteria but may also indirectly affect their ecological niche by altering the structure and function of their natural host communities [82,83]. For instance, microplastics might reduce the abundance of natural predators of Vibrio by interfering with the feeding behavior of planktonic organisms, thereby potentially promoting Vibrio growth indirectly [83]. Furthermore, biofilms formed on microplastic surfaces can serve as “refuges” for Vibrio, enabling survival in adverse environments and further enhancing their competitiveness within natural host populations [83].

The growth and spread of Vibrio correlate not only with microplastics but also with other types of pollutants. Research indicates that Vibrio growth is influenced by a combination of environmental factors, including water temperature, dissolved organic matter, and nutrient levels. For example, Vibrio is significantly more enriched in aquaculture areas such as oyster farms compared to other waters, a phenomenon likely attributed to eutrophication in these regional waters [20].

Less stringent governmental or environmental regulations may lead to increased discharge of microplastics and other pollutants, thereby creating more favorable conditions for Vibrio growth and dissemination [83]. For example, inadequate regulations on wastewater treatment and waste management could result in higher levels of microplastics and metals entering marine environments, elevating the risk of Vibrio proliferation and spread. Therefore, strengthening the governance of microplastic pollution and enhancing the enforcement of environmental regulations are imperative for controlling Vibrio transmission and safeguarding human health.

Association of extreme climate events with infection outbreaks

Data from Florida after Hurricane Ian showed a 300% increase in V. vulnificus infection cases compared to normal years, mainly because heavy rain causing a sharp drop in coastal salinity to 3–5 ppt, thereby promoting bacterial proliferation [73]. On 29 August 2005, Hurricane Katrina made landfall along the US Gulf Coast as a Category 3 storm, triggering catastrophic flooding [84]. During the subsequent two-week enhanced surveillance period, Louisiana, Mississippi, and other states reported a total of 22 cases of V. vulnificus and other Vibrio-related infections, resulting in 5 fatalities. Of these, 18 were wound-associated infections, primarily caused by V. vulnificus (14 cases) and Vibrio parahaemolyticus (3 cases), all resulting from prolonged exposure of open wounds to floodwaters. The remaining 4 cases were non-wound infections involving non-toxigenic Vibrio cholerae gastroenteritis acquired through consumption of contaminated seafood, with no fatalities. Patients ranged in age from 31 to 89 years (median: 73 years) and were predominantly male (83%); notably, 72% had underlying medical conditions such as heart disease, diabetes, alcoholic liver disease, or immunosuppression. Illustrative cases include a 60-year-old man who developed necrotizing fasciitis in both ankles after wading in New Orleans floodwaters for three days; diagnosed with V. vulnificus sepsis, he died the day after admission. Similarly, a 61-year-old man with HIV infection developed a fatal V. parahaemolyticus infection through a skin abrasion, dying within 24 h. Crucially, all cases developed symptoms within 7d of the hurricane’s landfall, indicating rapid infection following floodwater exposure. Additionally, during fires, copper ions (5–10 μM) present in wildfire ash activate the CusSR two-component system of V. vulnificus, up-regulating virulence genes such as vvpE and doubling the organism’s survival rate within the host [81].

Pathogenic molecular mechanisms and host interactions

Virulence factor mechanisms and immune evasion strategies of V. vulnificus

As a core virulence factor within the Vibrio genus, the rtxA1 gene encodes the MARTX (Multifunctional-Autoprocessing Repeats-in-ToXin) toxin, which mediates host damage through a multi-stage pathogenic process [85,86]. Its secretion depends on the T1SS system (RtxB/D/E-ToIC complex). A key breakthrough revealed in 2025 is that the Aknot domain, a 273-amino acid insertion within the toxin’s N-terminal repeat region, features dual immunoglobulin-like folds that specifically bind internal GlcNAc residues within complex biantennary N-glycans [87,88]. This binding mechanism underpins the toxin’s broad cellular tropism, as biantennary N-glycans are ubiquitous on mammalian glycoproteins. The complete avirulence of the ΔAknot mutant confirms that Aknot-N-glycan binding is an indispensable pathogenic hub. Following binding, the N- and C-terminal repeat regions assemble a β-barrel pore in the host membrane, translocating the central unfolded effector region and cysteine protease domain (CPD) into the cytosol. Host cytosolic inositol hexakisphosphate (InsP6) subsequently activates the CPD, triggering autoproteolytic cleavage and releasing free effector domains [87,88].

The MARTX toxin can be composed of different effector domains encoded by various bacterial species, with a single strain carrying up to five distinct effectors [89]. The V. vulnificus MARTX toxin integrates the functionally defined effector modules ACD, DUF1, RID, MCF, DUF5 and so on, which act individually and synergistically to create a highly efficient, modular system for immune evasion and pathogenesis [90]. By severing the actin cytoskeleton and intercellular junctions while simultaneously suppressing pro-inflammatory cytokine production, it secures potent immune evasion and widespread dissemination. Initially, the ACD (Actin Cross-linking Domain) domain catalyzes the formation of isopeptide bonds between G-actin monomers, precipitating actin cross-linking and polymerization arrest [91,92]. This rapidly dismantles the cytoskeletal scaffold, disrupts epithelial tight junctions, and compromises mucosal barrier integrity, ultimately facilitating bacterial translocation across the epithelium. The MCF (Makes Caterpillars Floppy) initially binds aden-osine diphosphate (ADP) ribosylation factors (ARFs) to trigger autoprocessing and activation, subsequently targeting and cleaving the C-terminal tails of host Rat sarcoma-related proteins (Ras) in brain (Rab) guanosine triphosphatases, leading to their degradation and functional impairment [93]. This sequence of events culminates in the loss of mitochondrial membrane potential and the release of cytochrome c, which activates the caspase cascade and induces apoptosis in host immune cells and epithelial barriers [93]. Consequently, immune defenses are markedly weakened, while disruption of the intestinal epithelial barrier facilitates bacterial translocation across the gut wall into the bloodstream, thereby driving the progression of systemic infection. DUF1 (Domain of Unknown Function 1), now renamed RID dependently trans-forming NADase domain (RDTND) [90], possesses NAD⁺ glycohydrolase activity; by hydrolyzing intracellular NAD⁺ and reducing the NAD⁺/NADH ratio, it inhibits NF-κB and MAPK signaling pathways, significantly downregulating pro-inflammatory cytokines like TNF-α [90]. RDTND functions within a “RDTND -RID synergistic module” alongside RID (Rho Inactivation Domain) [89,90]. RID specifically catalyzes the deamidation or glycosylation of RhoA(Ras homologous A), Rac1(Ras-related C3 botulinum toxin substrate 1) and Cdc42 (Cell division control protein 42 homolog), disrupting the actin cytoskeleton and cell junctions [89]. These mechanisms collectively facilitate bacterial translocation across the epithelial barrier while systemically suppressing phagocytosis and reactive oxygen species (ROS) production, thereby enabling comprehensive immune evasion. DUF5 has been redefined as a Ras/Rap1-specific endopeptidase (RRSP) that cleaves the Switch I loop of Ras and Rap1 GTPases within the host cytosol [94]. This proteolytic excision abolishes the interaction of the truncated GTPases with downstream effectors such as Raf, thereby completely abrogating ERK1/2 signaling. Consequently, cellular proliferation and immune responsiveness are markedly attenuated, significantly potentiating the virulence of V. vulnificus. The α/β-hydrolase (ABH) domain functions as a phospholipase A1 that specifically hydrolyzes phosphatidylinositol-3-phosphate (PtdIns3P), thereby disrupting autophagosome biogenesis and the endo-lysosomal pathway [95–97]. This impairment compromises the ability of immune cells to eliminate bacteria and concurrently diminishes ROS production [95–97]. Through the synergistic action of these multiple mechanisms, the MARTX toxin not only disrupts host cellular architecture and barrier integrity but also globally suppresses inflammatory responses, phagocytosis, and oxidative killing. Collectively, the toxin orchestrates a comprehensive immune-evasion strategy that facilitates bacterial dissemination and the establishment of systemic infection within the host [87–90]. Future inhibitors targeting these interactions may represent novel anti-infective strategies. In adult mice (intraperitoneal) and suckling mice (oral gavage), MARTX-knockout strains show 100–2600-fold increases in lethal dose (LD₅₀) [86,89].

Under conditions of iron sufficiency, the iron-responsive regulator Fur (Ferric Uptake Regulator) represses QS regulators such as SmcR (QS master regulator R), thereby attenuating virulence gene expression and facilitating immune evasion. Conversely, during iron limitation, derepression of SmcR promotes the activation of vulnibactin siderophore biosynthesis genes and the HupA/HvtA heme uptake systems. This adaptive response enables efficient iron acquisition from the host, supporting rapid bacterial proliferation, enhanced virulence factor production, and accelerated infection progression. Iron overload further correlates with suppressed host immune function, as elevated serum iron directly promotes V. vulnificus growth and impairs neutrophil activity [95,96].

QS via AI-2 and the cyclic dipeptide cFP provides additional fine-tuning of virulence expression, centered on LuxS/AI-2 synthesis, the LuxPQ-LuxU-LuxO phosphorelay, and the LuxR homolog SmcR. At low cell density, V. vulnificus represses the QS regulator SmcR via AI-2–LuxPQ/LuxU/LuxO signaling while up-regulating AphA (Aphidicolin resistance protein A) in response to iron limitation and IscR (Iron – sulfur cluster Regulator) in response to oxidative stress. These two stress-responsive regulators jointly induce flagella and the glucan-binding adhesin GbpA (Glucan-binding protein A), enabling stealth adhesion that postpones host immune activation [4,96]. Upon reaching high V. vulnificus density, accumulated AI-2 relieves SmcR inhibition; SmcR then upregulates invasive factors, such as VvP (V. vulnificus protease) metalloprotease, and capsular polysaccharide (CPS), while downregulating early colonization genes, driving the transition from biofilm to planktonic state to promote tissue invasion and immune evasion. Furthermore, the cyclic dipeptide cFP peaks during stationary phase, activating the ToxR-LeuO-HU-RpoS cascade to enhance catalase KatG (Catalase-peroxidase) expression, countering host oxidative bursts, and directly inhibiting the RIG-I (Retinoic acid-Inducible Gene I)-mediated interferon pathway to subvert innate immunity [95,96].

CPS constitutes one of V. vulnificus’ paramount virulence factors. CPS confers resistance to phagocytosis by host immune cells and protects against complement-mediated killing, facilitating bacterial survival and dissemination within the host. CPS-deficient mutants exhibit significantly attenuated virulence in murine models [98].

Biofilm formation substantially enhances V. vulnificus persistence within the host. Elevated levels of the second messenger c-di-GMP (cyclic diguanylate) inhibit flagellar synthesis via the PlzD (PilZ domain-containing) protein while activating cellulose synthase (Bcs) to promote biofilm matrix production [99]. The diguanylate cyclase VdcR is a key regulatory node, as its deletion reduces biofilm formation by 80%. The biofilm’s protective matrix shields bacteria from phagocytosis and antibiotic killing, enhancing both antimicrobial resistance and resilience against host immunity. Biofilms also promote colonization and dissemination, increasing infection severity [95,96].

The pathogen also exhibits tolerance to host antimicrobial peptides (AMPs), such as intestinal α-defensins (HD-5, HD-6) and β-defensins (HBD-1) in the small intestine [100]. Furthermore, it survives the acidic gastric environment via amino acid decarboxylation, such as lysine decarboxylase generating putrescine, to neutralize stomach acid; putrescine additionally scavenges superoxide anions, aiding oxidative stress tolerance [96,97].

Secreted immunomodulatory factors include phospholipase A2 (PlpA), which hydrolyzes host membrane phospholipids to impair membrane integrity and immune function, and elastase (VvpE, V. vulnificus extracellular elastase), which disrupts epithelial tight junctions to facilitate bacterial invasion and spread [86,95].

Outer membrane vesicles (OMVs), about 20–200 nm in diameter, carry VvpE, hemolysin, and LPS [101]. OMVs activate the inflammasome in macrophages via the TLR4/MyD88 pathway, inducing pyroptosis while inhibiting autophagy [102]. Under low-nutrient or antimicrobial stress, V. vulnificus can enter a VBNC (viable but non-culturable state), downregulating metabolism-related genes, such as nuo and atp and altering membrane fatty acid composition to resist phagocytosis [103,104].

Chronological progression of V. vulnificus infection

V. vulnificus initiates a rapid, three-phase invasion. In Phase I, known as silent colonization, low luminal iron inactivates the Fur protein, thereby derepressing the transcription factor SmcR [27,102,105]. This enables the AphA/IscR-driven expression of flagella and the adhesin GbpA. Concurrently, CPS production cloaks surface antigens, and flagellin expression is downregulated [4,101]. These adaptations allow the bacteria to glide through the mucus and sequester within villous clefts without triggering TLR5 [103]. Upon barrier perforation in phase II, the AI-2 QS threshold is reached, which triggers the QS switch. Consequently, the transcription factor SmcR represses genes responsible for adhesion and flagellar synthesis [27,106], while simultaneously upregulating the expression of MARTX-T1SS [90], VvP-T2SS [106], the pore-forming toxin VvhA, and CPS [27,106,107]. These virulence factors collectively degrade tight junctions and basement membranes, leading to the flooding of the lamina propria and hepatic sinusoids. Phase III, hematogenous dissemination, is characterized by exponential growth fueled by vulnibactin and the heme receptors HupA/HvtA, which scavenge iron from transferrin and heme [97,101]. Concurrently, elevated c-di-GMP levels, mediated by PlzD, arrest flagellar rotation and activate Bcs-dependent exopolysaccharide production [97]. This results in the formation of a protective biofilm that accumulates toxins and resists oxidative stress. Furthermore, the cFP-LeuO cascade induces KatG expression to neutralize ROS and suppress RIG-I-mediated interferon signaling [97,101]. Interruption of any step, such as Aknot mutation, iron chelation, or c-di-GMP antagonism, elevates the LD₅₀ by 2–3 orders of magnitude, converting a lethal septicemia into a self—limiting infection [87,88,97,101,104].

Diagnostic technological innovations and challenges

V. vulnificus infection can be easily misdiagnosed due to few cases and symptoms similar to other conditions [11], yet early diagnosis is crucial as the infection progresses rapidly [108]. Currently, clinical diagnosis relies on traditional culture methods [105], while rapid detection technologies are used only for food and environmental testing [58], so developing stable, accurate, and rapid clinical detection methods is urgent (Table 1).

Table 1.

Technical comparison and applicable scenarios.

Technical Type	Sensitivity (CFU/mL)	Detection Time	Equipment Requirements	Applicable Scenarios
Traditional Culture Method	103	48-72 h	Laboratory	Confirmation and Drug Sensitivity Testing
Real-time PCR	102	2 h	Thermal Cycler	Clinical Rapid Screening
CRISPR-Cas12a	1–10	30 min	Lateral flow reader (minimal equipment)	On-site Detection
Nanozyme Colorimetric Method	10	1 h	None	Food and Environmental Sample Screening

When clinical suspicion of V. vulnificus infection arises, the principle of “sample first, treat second” must be strictly followed. Empirical antimicrobial therapy should not be initiated until blood cultures, wound swabs, or blister fluid have been collected and immediately plated onto thiosulfate-citrate-bile salts-sucrose (TCBS) selective agar. After 24–48 h of incubation, yellow-green colonies are sought, and definitive identification is completed by oxidase test, API 20E (Analytical Profile Index 20 E), or MALDI-TOF MS (Matrix-Assisted Laser Desorption/Ionization Time-of-Flight Mass Spectrometry). Although culture remains the gold standard, its sensitivity is only 30-40% and declines further after antibiotic exposure [5,25,47,60–63,73].

For culture-negative difficult cases, metagenomic next-generation sequencing (mNGS) shows unique advantages. Li et al. reported that mNGS detected V. vulnificus in 10 out of 12 suspected cases (83% positive rate), while by traditional blood culture only four positive cases were identified. Moreover, mNGS can detect mixed infections (e.g. with Acinetobacter baumannii), aiding precise treatment [105]. Without prior cultivation, mNGS can complete whole-genome alignment within 1–2 d and approaches 100% detection sensitivity, particularly valuable in sepsis or necrotizing fasciitis [105].

To compensate for the limitations of culture, molecular assays should be performed in parallel [109,110]. Nested PCR, employing two rounds of amplification targeting the vvhA or 16S rRNA gene, achieves single-copy sensitivity and can yield results within 2–3 h, making it ideal for early rapid diagnosis. Real-time fluorescent qPCR, utilizing TaqMan probes or SYBR Green chemistry to monitor amplification of vvhA and rpoS in real time, delivers results in 30 min to 2 h and enables precise quantification of bacterial load; it is currently the most frequently used supplementary test in emergency laboratories [109,110].

The following technologies may be applied to clinical rapid detection in the future (Table 1). Zhang et al. developed a RPA-CRISPR one-step detection method targeting the V. vulnificus vvhA gene, with visual detection via lateral flow strips. The limit of detection (LOD) is 1 CFU/g, and the detection time is under 30 minutes [107]. Xu et al.’s colorimetric method based on CeO₂@PtRu nanozymes uses V. vulnificus antigens to shield nanozyme activity, with color intensity inversely proportional to bacterial load. The LOD is 1 CFU/mL, and no DNA extraction is required [106]. V. vulnificus has a thick cell wall, so conventional lysis methods are inefficient. Zhang et al. developed a lysozyme-proteinase K combined lysis system, improving LAMP detection sensitivity from 10³ CFU/mL to 10 CFU/mL [111]. Pretreatment with propidium monoazide (PMA) selectively inactivates dead bacteria, enhancing the specificity of detecting live bacteria [59].

Current management and emerging advances in V. vulnificus infection: from standard antibiotics to novel anti-infective strategies

V. vulnificus infections impose not only exceptionally high case-fatality rates but also a substantial economic burden on patients and society [112–114]. In the United States, these infections generate an estimated annual economic loss of US $320 million, encompassing hospitalization, treatment, mortality-related costs, and sequelae such as amputations. Wound-associated infections alone account for more than US $28 million in yearly medical expenditures. Among seafood-borne illnesses, V. vulnificus is responsible for 66% of cases, translating into an annual economic impact of US $350 million. Nationally, the average inpatient charge exceeds US $11,700 per day; severe presentations, such as septicemia or necrotizing fasciitis, often necessitate several weeks of hospitalization, and prolonged ICU care further escalates costs. Although antimicrobial therapy with doxycycline or ciprofloxacin is comparatively inexpensive, intravenous administration, repeated surgical debridement, amputation, and extended rehabilitation markedly increase overall expenditure. Premature mortality adds another US $238 million annually in lost productivity. Collectively, V. vulnificus has emerged as one of the most economically burdensome marine pathogens, driven by its high lethality, protracted hospital stays, and complex therapeutic requirements [112–114].

The combination of doxycycline (100 mg, every 12 h) and cefotaxime (2 g, every 8 h) remains the first-choice regimen [111]. A study in Hainan, China, demonstrated that administering treatment within 6 h of symptom onset reduced mortality from 65% to 28% [21]. For those allergic to beta-lactams, fluoroquinolones (e.g. levofloxacin) combined with aminoglycosides (e.g. gentamicin) can be used as alternatives, but renal toxicity needs monitoring [115].

It is reassuring that currently used antibiotics have good bactericidal effects [26]. However, with increasing cases of infection, many resistant strains have been found in clinical isolates [116]. Long et al. performed whole-genome sequencing (WGS) on 150 V. vulnificus strains, revealing that these isolates universally harbor multiple antibiotic resistance genes [70]. The findings demonstrate significant genetic diversity and elucidate key resistance mechanisms in V. vulnificus, providing novel insights into its ecological and evolutionary dynamics.

A key resistance factor identified is the β-lactamase enzyme encoded by the varG gene. This enzyme hydrolyzes β-lactams, including penicillins, carbapenems, and cephalosporins, thereby disrupting the antibiotic structure and rendering it inactive [117,118].

Furthermore, V. vulnificus employs biofilm formation as a protective strategy against antibiotics [70]. The polysaccharide matrix encapsulating bacteria within the biofilm impedes antibiotic penetration, significantly reducing drug effectiveness [119]. The bacterium also utilizes membrane efflux pumps, such as VexAB (Vibrio efflux system A and B), VexCD , and VexEF, to actively expel diverse antibiotics from the cell [120]. This efflux mechanism lowers intracellular antibiotic concentrations, diminishing drug toxicity. Finally, spontaneous mutations introduce genetic changes that render some bacteria resistant to specific antibiotics; once the vast majority of nonresistant cells are eliminated, these resistant strains can proliferate rapidly and become the dominant population [121]. In Ningbo, China, tetracycline resistance in strains reached 42%, mainly due to plasmid-borne tetB gene spread [118].

Gong et al. found that NPPB (5-nitro-2-phenylpropionamide) disrupts the integrity of the outer bacterial membrane by blocking TolCV1 function, reducing cefotaxime’s MIC from 8 to 2 μg/mL [122]. Qiao et al. used QS inhibitors, the natural compound bergamottin inhibits AI-2 signal synthesis, reducing V. vulnificus biofilm formation by 70% [123]. Pan et al. successfully treated a pediatric sepsis case using hemopurification along with continuous renal replacement therapy. These modalities attenuated systemic inflammation through an 80% decline in IL-6 and related factors, supporting multiorgan function [124]. Lipo et al. used 40% benzoic acid for chemical debridement in patients with multidrug-resistant infections, reducing wound bacterial load by 99% thus avoiding the need for amputation [125].

Prevention strategies and public health interventions

Climate-adaptive monitoring systems

Given the complex and dynamic ecological environment, creating a Vibrio early-warning system is key to preventing infections [14]. MODIS (Moderate Resolution Imaging Spectroradiometer), a key remote-sensing instrument aboard NASA’s Terra and Aqua satellites, is designed for comprehensive Earth-system observations and provides real-time global data on sea-surface temperature, chlorophyll concentration, and salinity [126]. Combining machine learning models, such as random forests, a powerful machine learning algorithm capable of robustly classifying or performing regression in high-dimensional, noisy data and able to automatically reveal which features are most important, can be used to predict high-risk infection areas [127]. Schutt et al. built a near-real-time prediction model in the Baltic Sea with an error rate of less than 15%; this model has been applied to Sweden’s public health early-warning system [128].

The U.S. Gulf of Mexico coast’s “community sampling network” pilot project is worth noting, especially for coastal areas [77]. In order to monitor Vibrio strain enrichment portable PCR devices are used to test seawater samples, with data uploaded in real time to the CDC.

Aquaculture, food processing safety innovations, and targeted education for high-risk groups

As food is a major infection route, preventing contamination is crucial [66].

The distribution of V. vulnificus is closely associated with water temperature and salinity. Global warming, leading to rising seawater temperatures, has significantly expanded both the geographical range of this bacterium and the associated infection risk [69,71]. Consequently, aquaculture and fishing operations must prioritize sourcing from officially monitored waters with confirmed low pollution risk and acceptable water quality. Particularly during the warmer summer months, regular monitoring of V. vulnificus concentrations in water bodies should be intensified. Harvesting of susceptible foods, such as shellfish, from high-risk areas should be avoided.

Maintaining low temperatures is critical for inhibiting V. vulnificus proliferation [104]. A stringent cold chain system must be established throughout the entire process, from harvest to consumption, ensuring seafood is consistently held at ≤4°C. Temperature fluctuations or delayed cooling significantly increase bacterial counts and can even activate the bacteria into an infectious state [14]. Therefore, harvested seafood should undergo immediate pre-cooling, with continuous temperature monitoring maintained during transport and storage to prevent cold chain interruptions.

For filter-feeding aquatic products like shellfish, depuration is currently the only viable post-harvest treatment that effectively reduces internal pathogenic bacteria while maintaining the product in a live state [5,22]. Literature reviews indicate optimized depuration parameters include: a processing duration of 4-6d, water temperature below 20°C, salinity between 25–32.2 ppt, and the use of flow-through or recirculating water systems. Furthermore, combining depuration with ultraviolet (UV) or electrolyzed water disinfection can achieve a 3–4 log reduction in bacterial load within 48 h [129]. Static depuration systems should be avoided due to their propensity for bacterial recontamination and inferior efficacy. Electrolyzed water at pH 2.5, applied for 10 minutes, can inactivate 99.9% of V. vulnificus in oysters without affecting meat quality [130]. High-pressure processing (HPP) at 600 MPa for two minutes reduces bacterial load by 5 log CFU/g, suitable for ready-to-eat seafood [41].

Anti-V. vulnificus vaccination in fish is more developed than for humans [131]. In 2016, China developed a V. vulnificus vaccine for large-scale tongue sole with remarkable results. This article focuses on V. vulnificus infections in humans, so details on fish vaccines are omitted.

For high-risk groups, the U.S. CDC advises against raw seafood consumption, recommends wearing puncture-resistant gloves when handling fish, and suggests monthly serum ferritin monitoring [132]. In coastal areas, during typhoon or red tide seasons, mobile phone SMS early-warning systems send infection risk alerts [14].

Development of human V. vulnificus vaccines

The effectiveness of traditional antibiotic therapy for V. vulnificus infections falls short due to drug resistance and the rapid infection progression. Development of vaccines and immunomodulatory strategies are critical for prevention and control [118]. Recent research has made significant progress in the selection of virulence factor targets, adjuvant engineering, and delivery system optimization [131]. Here, based on recent representative studies, we describe the core strategies for V. vulnificus vaccine development and the innovative directions of immunopreparations (Figure 1) [19].

Figure 1.

Development strategy of V. vulnificus vaccine. Strategies for V. vulnificus vaccine development: (1) live-attenuated and vector vaccines, construct mutant strains by targeting virulence genes or develop vector-based expression systems; (2) subunit vaccines, design vaccines based on core virulence proteins of V. vulnificus; (3) mRNA vaccines, leverage advantages of rapid development and flexible design; (4) nanoparticle adjuvants/delivery systems, utilize size-tunable nanoparticles for targeted antigen/adjuvant delivery; (5) cytokine adjuvants to enhance Th1 immune response, combine antigens with cytokines (e.g. IL-21) to enhance Th1-type immunity and pathogen clearance; (6) De-immunizaton modification of FlaB adjuvants, engineer V. vulnificus FlaB to retain TLR5 activation capacity while reducing inherent immunogenicity that compromises adjuvant efficacy; (7) multivalent vaccines and epitope chimera design, address limited cross-strain protection of single antigens through multi-antigen formulations, representing an emerging trend; (8) innate immune activators, for immunocompromised populations, employ iron chelators combined with antibiotics as a therapeutic strategy against V. vulnificus infections. Created in https://BioRender.com.

Subunit vaccine development based on virulence factors

V. vulnificus virulence factors (e.g. hemolysin, metalloproteinase, iron uptake systems) are core targets for vaccine design. Sun et al. recombinantly expressed VvhA in a mouse model and found that VvhA alone induced a 60% survival rate after challenge, but with a weak Th1 immune response such as IgG2a and IFN-γ, suggesting the need for adjuvants [133].

Single antigens often offer limited protection due to strain variation, making multivalent vaccines a trend. For example, by analyzing multiple virulence factors, Zhang et al. found that clinical strains commonly carry the rtxA, vvhA, and tonB gene clusters, suggesting that their encoded antigens could be combined to develop a broad-spectrum vaccine [19,134]. Also, epitope chimera strategies can be used. Using bioinformatics to predict B/T cell epitopes, immune-dominant epitopes from multiple virulence factors can be expressed as chimeras, potentially overcoming strain heterogeneity across different geographic origins [131,133].

Innovation and optimization of immune adjuvants

Clinical strains of V. vulnificus typically elicit a vigorous immune response in the host, leading to tissue damage and sepsis [34,61,96,135]. How V. vulnificus vaccines activate the host immune system remains a challenge; incorporating adjuvants may serve as an effective strategy. Sun et al. first used IL-21 as an adjuvant with VvhA. Antibody levels showed a threefold increase in IgG2a (Th1 marker) in the combined group compared to VvhA alone, with no significant change in IgG1 (Th2 marker). In cellular immunity, splenocyte IFN-γ production increased 2.5-fold (p < 0.01), and macrophage phagocytosis efficiency rose by 40%. Immune protection improved survival from 60% to 90% after challenge, demonstrating that IL-21 can reprogram immune response types [133].

The FlaB protein of V. vulnificus is a natural TLR5 agonist, enhancing antigen presentation by activating the NF-κB pathway, but its strong immunogenicity leads to neutralizing antibodies on repeated vaccination, reducing adjuvant efficacy. Khim et al. solved this with epitope engineering. They identified B cell linear epitopes in FlaB (e.g. amino acids 150–160) via alanine scanning and introduced point mutations (e.g. D153A). While the mutant preserved TLR5-stimulating ability through wild-type-equivalent IL-6 production, its anti-FlaB antibody generation was attenuated by 90%. When used with tetanus toxoid, after three vaccinations, antigen-specific antibody levels were similar to the wild-type adjuvant group without immune tolerance [136].

Attenuated live and vector vaccines

Knocking out virulence genes (e.g. ΔrtxA, Δvvp) creates attenuated strains, but their safety requires verification. Zhang et al. leveraged 54 years of GWAS (Genome-wide association study)/GWES (Genome-wide epistasis study) data from 518 globally distributed V. vulnificus isolates to pinpoint six virulence hubs, PurH (purine biosynthesis enzyme) and the newly identified Gmr (c-di-GMP phosphodiesterase), YiaV (inner-membrane protein), DsbD (disulfide isomerase), RamA (amidase), and WbpA (lipopolysaccharide synthase). Co-adaptive signatures delineated two ecological groups: EG1, naturally attenuated and confined to low-salinity, nutrient-poor habitats, and EG2, a high-virulence lineage that thrives under high-salinity, high-temperature conditions and forms robust biofilms. Guided by these findings, a precision vaccine strategy is proposed in which EG2 serves as the chassis for systematic deletion of core virulence genes (purH, gmr, and flgK (flagellar module)/L/E), yielding a stably attenuated yet vigorously growing strain, whereas EG1 itself can be deployed as an inherently attenuated vector [19].

Viral vector vaccines are a promising strategy; using adenovirus or lentivirus vectors to express V. vulnificus antigens, induce strong CD8⁺ T cell responses. For example, an adenovirus vector expressing VvhA has been shown to activate cytotoxic T lymphocytes (CTLs) in mice [133].

Immunomodulatory strategies and challenges

Lim et al. showed that V. vulnificus flagellin activates lipocalin2 expression via TLR5, inhibiting bacterial iron uptake and protecting neutropenic mice [137]. This strategy enables preventive intervention in high-risk groups, including chemotherapy patients. Lipocalin2 or iron chelators such as deferoxamine can inhibit V. vulnificus growth by restricting iron availability and exhibit synergistic effects when combined with antibiotics, ultimately causing host metabolic reprogramming [102]. Also, cGAS-STING pathway activation can enhance IFN-I secretion and may be combined with vaccines to boost intracellular infection resistance [133].

When developing new vaccines, species differences are a primary consideration. Gu et al. developed an antimicrobial peptide vaccine efficient in fish, but mammalian immune mechanisms such as Toll-like receptor distribution differ, requiring re-optimization [70,134]. When developing new adjuvants like FlaB, attention should be paid to the inflammatory response they induce [136]. Excessive inflammation from cytokines like IL-21 may require dose optimization or localized administration methods, including controlled-release nanoparticle systems [133,138].

To address antigenic variation and immune evasion, a real-time virulence gene database based on population genomic data should be established to inform vaccine development [19,70,134]. Through structural biology approaches, highly conserved conformational epitopes within virulence factors such as the transmembrane domains of VvhA can be identified for targeted exploitation [19,88].

The combination of “vaccination + anti-virulence” should not be overlooked. For example, using TolCV1 inhibitors while administering VvhA vaccines can lower infection thresholds [123].

Discussion

As a “silent killer in the ocean,” V. vulnificus presents a complexity in infection mechanisms and prevention strategies beyond traditional understanding [5,71,139]. This review reveals three core contradictions: between rapidly expanding ecological niches and lagging monitoring-early-warning systems; between complex virulence networks and single-treatment strategies; and between the biological vulnerability of high-risk groups and limited preventive measures. The interaction of these contradictions has escalated V. vulnificus infections from a regional threat to a global public health crisis [1,5,71].

Climate warming is driving the restructuring of transmission networks (Figure 2). Recent monitoring data confirms that climate warming is reshaping V. vulnificus’ global distribution at an unexpected rate [3]. Events like the U.S. Gulf of Mexico’s 15% annual case increase, Baltic Sea’s doubled infection risk, and the first cases along the Black Sea coast in Bulgaria support NOAA’s model predictions [24]. More alarmingly, niche complexity is increasing: microplastics promote biofilm formation, increasing bacterial density up 100x, freshwater-adapted strains are emerging, and wildfire ash activates virulence genes, forming multidimensional transmission networks [81]. Kinetic models show that when seawater temperature exceeds 28°C and salinity is below 10 ppt, V. vulnificus basic reproduction number (R₀) = 1.5, enabling self-sustained transmission chains without clear contamination sources. This explains the sudden cluster of cases in traditionally non-endemic areas like Bulgaria’s Black Sea coast [128].

Figure 2.

Multiple factors interact synergistically to expand the geographic range of V. vulnificus, thereby exacerbating the frequency and severity of human infections. 1. The exacerbation of the greenhouse effect; 2. A substantial rise in microplastic pollution in beaches and coastal waters due to human activities; 3. Large-scale abnormal proliferation of kelp and algae; 4. Eutrophication in local sea areas caused by marine aquaculture; 5. Gene mutation and a host of other factors are driving a continuous expansion of the activity range of V. vulnificus. In recent years, V. vulnificus infection incidents have emerged frequently in inland freshwater areas. It is projected that by 2040, it will pose a severe threat to seas within 50 degrees north and south latitude. V. vulnificus can invade the human body through wound contact or a foodborne route, thereby inducing a series of life-threatening symptoms, such as fever, chills, necrotizing fasciitis, sepsis, and septic shock. It is estimated that by 2100, infection rates in high-latitude regions may double current levels. Created in https://BioRender.com.

Expression of V. vulnificus’ virulence shows significant environmental responsiveness [27,97,134]. In hosts, high iron environments (e.g. hepatitis patients) drive bacterial proliferation via the Fur-IRGAB axis, while low-salinity wound microenvironments trigger RtxA1 toxin secretion [27,88,140]. This spatiotemporal specificity poses two challenges: (1) VBNC state strains evade conventional detection, causing diagnostic delays in 72% of the recurrent cases [59,103]; (2) Various strategies mediate immune evasion, making sole antibiotic therapy ineffective against cytokine storms [101,102,123]. Clinical strains of V. vulnificus found worldwide have been found to carry multiple drug resistance genes, and drug resistance is becoming increasingly prevalent [70,116,130]. More severely, 23% of the deaths were preceded by multiorgan failure after treatment initiation, highlighting the limitations of current strategies against atypical infections (e.g. nosocomial cases) [5,6,8]. In future breakthrough directions for virulence research, we can decipher virulence gene environmental response patterns. This includes addressing specific questions, such as whether low-salinity adaptation in vcgC-type strains involves sRNA regulation, and using organoid models to simulate hepatitis microenvironments to reveal how iron metabolism abnormalities reshape infection thresholds.

Over 60% of the deaths are directly related to delayed diagnosis. Traditional culture methods (48-72 h) cannot meet the timeliness needed to treat these high-lethality infections [23,71]. CRISPR-Cas12a combined with microfluidic chips enables 15-minute detection (sensitivity 1 CFU/mL), while nanozyme colorimetric methods allow visual detection via antigen–nanozyme interaction, providing a “zero-delay” diagnosis for emergency departments [1,8].

In addition to the previously described research strategies, we can also pursue the following approaches for developing a V. vulnificus vaccine: (1) mRNA vaccines can be rapidly developed and have flexible design advantages, though their application in bacterial infections is still in the early stages [131]. Potential directions include: (i). Antigen design, encoding VvhA or siderophore-binding proteins in mRNA, delivered via lipid nanoparticles (LNPs) [133]; (ii). Self-amplifying RNA, using alphavirus replicons to prolong antigen expression and enhance immune memory [19]; (2) Since V. vulnificus often invades via the gut or wounds, mucosal immunity through vaccination routes like oral or nasal delivery can provide a first-line defense [11]. Developing oral vaccines using Lactobacillus plantarum to express V. vulnificus antigens can induce gut SigA secretion [131]. Also, cross-protective antigens like FlaB, which shares homology with other Vibrio species (e.g. V. cholerae), can be used to design broad-spectrum vaccines [141]; (3) Nanoparticles (NPs) can target lymphoid tissue through size modulation and co-deliver antigens/adjuvants [5,138]. Uthaman et al. (2021) developed pH-responsive NPs for tumor immunotherapy, but their design concept can be applied to bacterial vaccines. The NP surface was modified with dendritic cell mannose receptors, enhancing antigen uptake. Near-infrared light triggers NP release of IL-12 (Th1-polarizing factor) and TGF-β inhibitor, precisely modulating the local immune microenvironment. If loaded with V. vulnificus antigens like VvhA and IL-21, they may activate mucosal immunity such as gut or skin vaccination [138]. In summary, vaccine development will center on achieving three pivotal breakthroughs: 1) Epitope chimera design, for example, the RtxA1/VvhA fusion antigen confers 90% protection in mice [131,133]; 2) Adjuvant design, for example, IL-21 adjuvant activates Kupffer cells in the liver, enhancing immune response in hepatitis patients [102]; (3) Delivery systems, for example, chitosan-nanoparticle intranasal vaccines establish respiratory barriers with a protection efficiency of 85% in mice. Meta-analyses show that 70% vaccine coverage in high-risk groups could reduce global annual deaths by an average of 4,100 (95% CI 3,200–4,900) [123].

Future prevention and control should focus on three core actions: First, establishment of a global V. vulnificus genomic monitoring network and combined it with AI prediction models to achieve early- warning and precise localization of infection hotspots [15,17,122,129]. For example, integrate MODIS satellite data (SST, salinity) with portable CRISPR detection devices to establish real-time early-warning grids at 200-meter resolution [6,23,127]; second, accelerate the clinical translation of multimodal treatment regimens, combining anti-virulence therapies, immunomodulatory strategies, and new antibiotics to form a “precision strike arsenal” for different clinical scenarios [93,114,118,128,136]. For example, develop small-molecule inhibitors targeting QS such as AI-2/LuxS and iron uptake pathways IrgAB [27,119,123]. Bergamottin and NPPB combined, reduce cefotaxime’s MIC90 value by eightfold and decrease biofilm-related persistent infections [142]; finally, improve protection mechanisms for high-risk groups through international cooperation, such as providing V. vulnificus vaccines for coastal workers, mandating high-pressure processing of seafood, and popularizing guidelines for prophylactic drug use after wound exposure in climate-vulnerable areas [72,125,126]. For example, create an epitope chimera-nano-delivery-mucosal immunity system [133,136,138]. IL-21 adjuvant specifically activates Kupffer cells in hepatitis patients, and de-immunized flagellar protein adjuvants support repeated vaccination [102]. Only through the deep integration of scientific innovation, policy innovation, and global governance can we build a resilient defense system to protect human health in the era of drastic marine ecosystem change [15,17,129,132].

Funding Statement

This research was funded by the Young Doctor Key Incubation Project of the Second Affiliated Hospital of Army Medical University (No. 2024YQB014).

Disclosure statement

No potential conflict of interest was reported by the author(s).

Data availability statement

There are no data associated with this review article.