i209 Ves v 5

Summary

Ves v 5 is a major allergen of Vespula vulgaris (common wasp or yellow jacket) venom (YJV) and a marker allergen for genuine sensitization to this venom. The sensitization rate to Ves v 5 in YJV allergic patients is 82-98%. In patients sensitized to both YJV and honeybee venom (HBV) extracts, demonstration of Ves v 5-specific IgE confirms genuine sensitization to YJV, helps to differentiate true double positivity to YJV and HBV from cross-reactivity, and to identify adequate venom immunotherapy (VIT) in eligible patients.

Ves v 5 exhibits extensive cross-reactivity with other antigen 5 proteins from Vespid venoms such as Polistes dominula (paper wasp) venom (PWV) and hornet (e.g. Vespa crabro, Dolichovespula spp) venom, therefore it cannot be used to discriminate between Vespid sensitization or cross-reactivity.

Epidemiology

Worldwide distribution

The sensitization rate to Ves v 5 in YJV allergic patients is 82-98% (reviewed in [1]). Ves v 5 sensitization is found in 75-90% of YJV-sensitized subjects, including those without a history of Hymenoptera sting reaction [2, 3].

In line with the high prevalence of up to 40% of asymptomatic sensitization to Vespid venom extracts in the general population [1], asymptomatic Ves v 5 sensitization is a common finding. Ves v 5 sensitization was demonstrated in 8.6% (259/3001) adults and children receiving allergen multiplex investigation in Slovenia and the Czech Republic [4]. In people with high exposure to Hymenoptera stings, such as those involved in hunting and fishing, the prevalence of Ves v 5 asymptomatic sensitization was 16-31% [5].

Ves v 5 sensitization may be observed at a young age, as demonstrated in children from nine European birth cohorts, using allergen multiplex investigation [6]. In this study, Ves v 5 sensitization displayed a North-South gradient, with 7 - 20% of teenagers in Western and Central European cohorts exhibiting Ves v 5 sensitization [6]. Geography and environmental exposure patterns, including to non-Hymenopteran allergenic sources such as ticks, may explain the high rate of asymptomatic YJV and Ves v 5 sensitization in the general population [6, 7].

Environmental characteristics                       

Source and tissue

Ves v 5, a member of the venom antigen 5 family, is secreted into the venom sac of Vespula vulgaris, where it is found in high abundance [1, 8].

Risk factors

Sensitization to Ves v 5 occurs through injection (YJV sting) [1, 9].

Clinical relevance

Specific molecules

Ves v 5 is a marker allergen for sensitization to Vespid venom antigen 5 [1]. Ves v 5-specific IgE can be demonstrated in 82-98% of YJV allergic patients [1].

Of the five YJV allergens currently included in the IUIS/WHO Allergen nomenclature [9], Ves v 5 is considered the most prominent in terms of prevalence of sensitization, levels of Ves v 5-specific IgE and quantitative correlation between Ves v 5 and YJV whole extract specific IgE. Ves v 5 does not cross-react with HBV allergens, therefore, Ves v 5 is a marker allergen allowing to discriminate between YJV and HBV sensitization [1].

Cross-reactive molecules

A member of the venom antigen 5 family, Ves v 5 cross-reactivity is well established with homologues from other Vespid venoms, most notably Pol d 5 from Polistes dominula (paper wasp), but also hornets. Thus, the demonstration of Ves v 5-specific IgE does not allow discrimination between YJV and other Vespid venom sensitization [1, 10].

The degree of clinically relevant cross-reactivity between Ves v 5 and other allergens of the antigen 5 family from the venom or saliva of ants, hematophagous insects (horse fly, tsé tsé fly, mosquito) and various arthropods such as the centipede Scolopendra mutilans is largely unknown [1, 3, 8, 11-13].

Disease severity

Neither the prevalence of Ves v 5 sensitization, nor the levels of Ves v 5-specific IgE are predictive of the severity of YJV-induced reactions [1, 2].

Molecular aspects                  

Biochemistry

Ves v 5, also known as YJV antigen 5, is a  member of the CAP (CRISP, antigen 5 and PR1) superfamily of proteins with a molecular weight of 23 kDa (227 aminoacids), displaying multiple disulfide bonds and lacking N-glycosylation sites [8, 9, 12]. Although antigen 5 family members are among the most abundant proteins in Vespoidea venom, their biological function is currently unknown [1, 10].

Isoforms, epitopes, antibodies

As of August 26, 2023, a unique isoallergen, Ves v 5.0101, has been included in the World Health Organization (WHO) and International Union of Immunological Societies (IUIS) Allergen Nomenclature [9].

Cross-reactivity due to structural similarity

A sequence identity percentage of 50% or higher between Ves v 5 and many of its homologues from other Vespid venoms is associated with the clinically relevant high cross-reactivity of Ves v 5 and other Vespid venoms [1, 12]. Lower sequence identity, variable IgE-binding and scarce clinical data are available for cross-reactivity between Ves v 5 and non-Vespid allergenic members of the antigen 5 family [11].

Diagnostic relevance              

Diagnosis of genuine sensitization to Vespula vulgaris (yellow jacket wasp) venom

Ves v 5 is a marker allergen for genuine YJV sensitization, with a notable prevalence of up to 98% of Ves v 5-specific IgE in YJV allergic patients. Therefore, the demonstration of specific IgE to Ves v 5 confirms genuine sensitization to YJV, helps identifying the primary sensitizer in patients with double IgE positivity to HBV and YJV extracts, and supports the initiation of YJV VIT in eligible patients [1].

Conversely, as nearly all patients who are primarily sensitized to YJV test positive to Ves v 5 and/or Ves v 1, a patient who tests negative to both Ves v 5 and Ves v 1 is unlikely to have primary YJV sensitization, regardless of IgE to other YJV components [14].

Cross-Reactivity

Ves v 5 cross-reactivity within the antigen 5 family hampers its use for the differential diagnosis of YJV versus PWV genuine sensitization. However, it has been suggested that the relative amount of specific IgE to distinct antigen 5 allergens might help identifying the primary venom sensitizer [1].

A study found that in patients with suggestive clinical history and proportion between specific IgE against recombinant (r) Ves v 5 and rPol d 5 greater than 2, the use of a CAP inhibition assay could help to achieve differential diagnosis between YJV and PWV sensitization [15].

Disease severity

In Hymenoptera venom IgE testing, the quantitative result of specific IgE to a molecular allergen or whole venom extract is neither predictive of, nor correlated to the severity of the reaction [1]. 

Sensitivity of in vitro assays

The prevalence of sensitization to individual YJV allergens, including Ves v 5, in YJV-allergic patients varies depending on multiple factors such as geography, patient inclusion criteria, single or double positivity to YJV and other Hymenoptera venoms, the use of a recombinant allergen from bacterial or insect cell expression versus a natural purified allergen, assay format, and positivity cut-off values [1-4, 16, 17]. Thus, the diagnostic sensitivity of specific IgE to Ves v 5 ranges from 82 to 98% in YJV-allergic patients [1, 2, 5, 16, 17].  The choice of the cut-off value for reporting detectable Ves v 5-specific IgE, usually debated between 0.35 kUA/L and 0.1 kUA/L, leads to important variations, up to two-fold, in the prevalence and therefore the analytical sensitivity of the test [5, 17, 18]. Using a lower cut-off improves the diagnostic sensitivity and has been proposed in patients with mast cell disorders [19]. The EAACI 2023 guidelines suggest that the 0.10 kUA/L cut-off might be clinically relevant even in patients without mast cell disorders [1].

Detectable Ves v 5 sensitization has been reported in confirmed YJV allergic patients without detectable sensitization to YJV extract [3, 18, 20]. This rare occurrence has become exceptional, from 2.7% to 0.7% of YJV-negative sera, since the spiking of YJV extract with antigen 5 [3, 18, 21]. Introducing rVes v 5-spiked YJV extract increased the detection rate from 83% to 96% with this new standard assay, allowing the diagnosis of nearly 95% of Hymenoptera venom allergic patients with the commercially available HBV and spiked YJV extracts [22].

Ves v 5 sensitization can be detected with commercially available singleplex and multiplex methods. Intermethod comparison showed good agreement between singleplex and multiplex methods for the detection of Ves v 5 sensitization [4], and between different singleplex methods for quantitative assessment of IgE to Ves v 5 [5, 16, 17, 23].

Diagnostic specificity

Detection of Ves v 5-specific IgE is a hallmark of genuine sensitization to Vespid venom, exhibiting a diagnostic specificity of 92-100% in this case [16]. However, Vespid venom sensitization is not synonymous with Vespid venom allergy.  The high prevalence of Ves v 5 sensitization among asymptomatic subjects in the general population explains the lack of diagnostic specificity of Ves v 5 as a screening test in this context [4-6]. Finally, Ves v 5 sensitization in YJV allergic patients does not allow to discriminate between those with systemic reactions to YJV stings (eligible for YJV VIT) and those without systemic reactions [2, 5, 24], with a 68% diagnostic specificity reported in a monocentric study [24].

AIT Prescription

Demonstrated sensitization to Ves v 5 confirms genuine sensitization to YJV in patients with a convincing clinical history, thus supporting the choice of YJV VIT in eligible patients [1].

Explained results

Allergen Information

Ves v 5 is the Vespula vulgaris venom (YJV) representative of the antigen 5 family, CAP superfamily. It has a molecular weight of 23 kDa and its biological function is currently unknown.

Clinical information

Ves v 5 is a marker allergen for genuine YJV sensitization and a major allergen in YJV-allergic patients. HBV lack Ves v 5 homologues. Thus, rVes v 5-specific IgE identifies genuine Vespid sensitization and discriminates it from HBV sensitization in patients who are double positive to YJV and HBV extracts. In YJV-allergic patients, the prevalence of Ves v 5 sensitization is 82-98%. Asymptomatic Ves v 5 sensitization is frequent, with up to 20% of subjects from the general population.

Cross-reactivity

Ves v 5 has high cross-reactivity with Pol d 5 and other Vespid venoms, preventing discrimination between Vespula vulgaris and Polistes dominula, but also hornet venom sensitization.

Author: Dr. Joana Vitte

Reviewer: Dr. Michael Spangfort