i211 Ves v 1

Summary

Ves v 1 is a marker allergen for genuine sensitization to Vespula vulgaris (common wasp or yellow jacket) venom (YJV). The sensitization rate to Ves v 1 in YJV allergic patients varies from 9 to 79%.  In patients sensitized to both YJV and honeybee venom (HBV) extracts, demonstration of Ves v 1-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 1 is a phospholipase A₁ (PLA1) with a molecular weight of 34 kDa. Ves v 1 cross-reactivity with Pol d 1 precludes its use for discrimination between YJV and Polistes dominula (European paper wasp) venom sensitization.

Epidemiology

Worldwide distribution

The prevalence of Ves v 1 sensitization depends on the population that is considered: 9-79% in YJV allergic patients [1-3], 60-70% of subjects with detectable IgE to YJV extract [4], 21-30% of asymptomatic adult subjects having experienced at least one Hymenoptera sting [4, 5]. In the paediatric general population, Ves v 1 sensitization is infrequent, as demonstrated in a recent serologic study conducted in nine European birth cohorts [6].

Environmental characteristics                       

Source and tissue

Ves v 1, an enzyme belonging to the PLA1 family, is secreted into the venom sac of Vespula vulgaris, where it contributes 6-14% of the venom dry weight [7].

Risk factors

Sensitization to Ves v 1 occurs through injection (YJ sting). Being stung simultaneously by a large number of wasps increases the risk of systemic manifestations in sensitized, but also non-sensitized subjects, as Ves v 1 exerts toxic effects independent of its allergenic potency [7, 8].

Clinical relevance

Specific molecules

Ves v 1 is a marker allergen of genuine sensitization to Vespid venom [1]. Ves v 1 sensitization can be demonstrated in YJV allergic patients without detectable Ves v 5 sensitization [2, 4]. The combined use of Ves v 5 and Ves v 1 for the diagnosis of YJV sensitization achieves a high diagnostic sensitivity of 90% or higher, yet fails to identify 2-8% of confirmed YJV allergic patients [1, 9, 10].

Ves v 1 does not cross-react with phospholipases of the PLA2 family found in HBV, therefore, Ves v 1 is a marker allergen allowing to discriminate between HBV and Vespid venom sensitization [1].

Cross-reactive molecules

Other PLA1 venom allergens, exhibiting variable degrees of sequence identity and serological cross-reactivity with Ves v 1, have been characterized in wasp, hornet and ant venoms, but not in HBV [1, 7]. Ves v 1 does not allow discrimination between YJV and PWV sensitization [1].

Disease severity

Neither the prevalence of Ves v 1 sensitization, nor the levels of Ves v 1-specific IgE are predictive of the severity of YJV-induced reactions [1, 3].

Molecular aspects                  

Biochemistry

Ves v 1 is a PLA1 with a molecular weight of 34 kDa in its mature form, displaying multiple disulfide bonds but no glycosylation site [1, 7, 11]. PLA1 hydrolyzes phospholipids and produces 2-acyl-lysophospholipids and fatty acids [7]. Although they share a common substrate, phospholipase A₁ and phospholipase A₂ demonstrate differences in their site of hydrolysis, molecular weight and structural characteristics, as well as limited sequence identity [7].

Cross-reactivity

Ves v 1 has high cross-reactivity with Pol d 1 preventing discrimination between Vespula vulgaris (common wasp) and Polistes dominula (European paper wasp) venom sensitization [1].

Isoforms, epitopes, antibodies

As of August 13, 2023, a unique isoallergen, Ves v 1.0101, has been included in the World Health Organization (WHO) and International Union of Immunological Societies (IUIS) Allergen Nomenclature [12].

Cross-reactivity due to structural similarity

Cross-reactivity between PLA1 allergens from Vespid and ant venoms is limited due to relatively low sequence identity percentages (30% - 77%) and to variations in the tertiary structure [1, 7].

Diagnostic relevance              

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

Ves v 1 is a marker allergen for genuine YJV sensitization. Therefore, the demonstration of specific IgE to Ves v 1 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 [1].

Cross-Reactivity

Cross-reactivity within the PLA1 family and the lack of availability of other PLA1 allergens for routine diagnosis hamper Ves v 1 use for the differential diagnosis of YJV versus PWV genuine sensitization. No marker allergen is currently available for proper differentiation of Vespula versus Polistes genuine sensitization in routine assays [1]. However, it has been suggested that the relative amount of specific IgE to distinct PLA1 allergens, or the use of CAP inhibition assays, might help identifying the primary venom sensitizer [1].

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 1, 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, 13]. Thus, the diagnostic sensitivity of specific IgE to Ves v 1 ranges from 9 to 79% in YJV-allergic patients [1-3, 5, 13]. The choice of the cut-off value for reporting detectable Ves v 1-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, 10]. Using a lower cut-off improves the diagnostic sensitivity and has been proposed in patients with mast cell disorders [10]. 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 1 sensitization has been reported in confirmed YJV allergic patients without detectable sensitization to YJV extract [4]. This rare occurrence has become exceptional, from 4.5% to 0.3% of YJV-negative sera, since the spiking of YJV extract with antigen 5 has improved the detection performance of the YJV extract [4].

Ves v 1 sensitization can be detected with commercially available singleplex and multiplex methods.

Diagnostic specificity

Detection of Ves v 1-specific IgE is a hallmark of genuine sensitization to Vespid venom, exhibiting a diagnostic specificity of 94-100% in this case [3, 14]. However, Vespid venom sensitization is not synonymous with Vespid venom allergy. The prevalence of YJV and therefore of Ves v 1 sensitization among asymptomatic subjects in the general population explains the lack of diagnostic specificity of Ves v 1 as a screening test in this context [1, 5]. Finally, Ves v 1 sensitization in YJV allergic patients does not differ between those with systemic reactions to YJV stings (eligible for YJV VIT) and those without systemic reactions [1, 3, 5].

AIT Prescription

Demonstrated sensitization to Ves v 1 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 1 is a PLA1 with a molecular weight of 34 kDa that exerts IgE-dependent and IgE-independent effects. It is produced by the yellow jacket (common wasp) Vespula vulgaris and secreted into the venom, where it represents 6 – 14% of the dry weight.

Clinical information

Ves v 1 is a marker allergen for YJV genuine sensitization, reported as a major allergen in YJV allergic patients although its prevalence may vary from 9 to 79% as a function of the cohort. HBV lack Ves v 1 homologues. Thus, Ves v 1-specific IgE identifies genuine Vespid sensitization and discriminates it from HBV sensitization in patients who are double positive to YJV and HBV extracts.

Cross-reactivity

Ves v 1 has variable cross-reactivity with PLA1 allergens from other wasps, hornets and ants, thus preventing its use for the discrimination between Vespula vulgaris and Polistes dominula venom sensitization.

Author: Dr. Joana Vitte

Reviewer: Dr. Michael Spangfort