The idea of using T-cell epitope-containing allergen peptides for AIT originally has been pursued by ImmuLogic Pharmaceutical Corp. a company, which had been located in Waltham, Massachusetts and was founded in 1987. Scientists from ImmuLogic were among the first to isolate allergen-encoding DNA and succeeded to clone the major cat allergen, Fel d 1 and the major ragweed allergen, Amb a 1 [49,50]. The T-cell peptide concept was based on studies carried out in mice showing that peripheral T cell tolerance against the major cat allergen, Fel d 1 could be induced by injection of T-cell epitope-containing short peptides . As the T-cell epitope-containing peptides were short and lacked IgE reactivity, it was expected that the treatment would not induce immediate allergic side effects but induce T-cell tolerance, which was hoped to have effects on allergen-specific IgE production (Table 1). Interestingly, T-cell peptide-based AIT for cat allergy was the first to enter clinical studies, which were conducted soon after the cloning of the major cat allergen [52–54]. However, it turned out that the treatment was clinically not effective and treated patients did not develop allergen-specific IgG antibodies because the peptides were too short to induce allergen-specific IgG responses. ImmunoLogic was then closed in 1999. Despite the disappointing clinical study results, the T-cell epitope peptide approach was continued. Again T-cell peptide treatment did not induce robust allergen-specific IgG production and clinical effects were observed mainly regarding late-phase allergic symptoms in exposure chamber studies whereas it remained unclear if the treatment had strong effects on immediate symptoms because of mast cell and basophil degranulation [55–57]. The T-cell peptide approach was pursued by the company Circassia to a large phase III field study for cat allergy but the study was not successful, although more than 1000 patients were included (Table 2).
Also another company, Anergis based in Switzerland, used allergen-derived synthetic peptides (Tables 1 and 2). In contrast to the Circassia approach, Anergis used longer peptides, which were adjuvanted using aluminum hydroxide. Interestingly, the longer adjuvanted peptides, termed contiguous overlapping peptides, induced allergen-specific IgG antibodies and showed clinical efficacy even in field trials (Table 2) [58,59,60▪]. This AIT approach was thus very similar to the treatment with hypoallergenic recombinant Bet v 1 fragments, which had induced allergen-specific IgG blocking antibodies and had shown beneficial clinical effects . However, when analyzing the results obtained with the adjuvanted recombinant Bet v 1 fragments, it became clear that the induction of allergen-specific IgG antibodies is important for clinical efficacy. This assumption is also supported by the fact, that passive vaccination with allergen-specific IgG-blocking antibodies was effective in reducing allergic symptoms in a clinical trial [62▪▪].
The concept of using allergen-encoding nucleic acids for AIT goes back to two studies, which demonstrated in murine models that immunization with allergen-encoding DNA induced allergen-specific Th1 responses and reduced allergen-specific IgE production [63,64]. DNA vaccination for AIT was then developed by the company Dynavax but concerns arose when experimental animal studies showed that DNA vaccination can lead to uncontrolled allergen transcription in different tissues . The development of DNA vaccines for AIT was, therefore, not further pursued by Dynavax and instead the company focused on conjugating immunomodulatory DNA (CpG) sequences to allergens with the goal to obtain conjugates with reduced allergenic activity and Th1-inducing properties . The latter concept of using CpG-conjugated allergen for AIT was then moved into clinical trials. It could be shown that CpG-conjugated major ragweed allergen, Amb a 1, induced allergen-specific IgG responses, had clinical effects and reduced boosting of allergen-specific IgE production caused by seasonal allergen exposure . However, consecutive clinical trials were not as successful and it seems that the chemical coupling of CpG motifs to the allergens was technically challenging. This approach was, therefore, not further pursued. Instead it was tried to use CpG motifs without added allergen for unspecific immunomodulation.
In order to reduce the risk of uncontrolled synthesis of allergen-encoding DNA in tissues, other research groups have developed concepts for genetic AIT based on mRNA vaccination . However, up to now, there are only few clinical phase I studies performed with DNA-based AIT from which no conclusions can be drawn if DNA-based AIT induces a protective allergen-specific immune response and regarding possible clinical effects (Table 2) . mRNA vaccination has not yet been evaluated in clinical trials so far (Tables 1 and 2) [70▪].
Second generation recombinant hypoallergens are based on hypoallergenic and/or nonallergenic peptides with a length of approximately 20-40 amino acids, which are derived from the IgE-binding sites of allergens, and which are rendered immunogenic by coupling to a per se non-allergenic carrier protein [91,92]. Originally, we have suggested this approach as one possibility for construction hypoallergenic AIT vaccines  and demonstrated that one can covalently couple nonallergenic allergen peptides chemically to carrier molecules, such as Keyholelimpet hemocyanin to obtain a vaccine, which will induce upon immunization allergen-specific IgG antibodies, which block allergic patient's IgE binding to the allergen and block allergen-IgE-mediated basophil activation [94,95]. In order to obtain a generally applicable method for the production of peptide carrier-based AIT vaccines suitable for large-scale GMP production, we developed recombinant peptide carrier-based vaccines, which are based on recombinant fusion proteins consisting of a nonallergenic carrier protein fused to nonallergenic allergen-derived peptides to induce blocking IgG antibodies with T-cell help from the carrier thus reducing allergen-derived T-cell epitopes in the vaccine [96,97]. As carriers we used viral proteins because they would induce eventually also a protective virus-specific immune response that would be rather beneficial for the patient and not harmful . The grass pollen allergy vaccine BM32 consisting of four recombinant fusion proteins including hepatitis B-derived PreS fused to nonallergenic peptides of the four major timothy grass pollen allergens  showed an excellent safety profile, induced robust allergen-specific blocking IgG responses with few injections and had good clinical efficacy (Tables 1 and 2) [100–102,103▪▪]. Interestingly, BM32 induced also IgG responses, which block hepatitis B infection of liver cells in vitro and the component BM325 is currently being evaluated in a clinical trial for vaccination against hepatitis B (NCT03625934). The concept of using PreS-bound allergen-derived peptides for the development of AIT vaccines seems to be broadly applicable for all allergen sources. Importantly, PreS-based allergy vaccines do not boost allergen-specific IgE responses, and therefore may be very useful for prophylactic allergy vaccination [101,103▪▪].
Big advantages of recombinant hypoallergenic derivatives for a potential use in preventive AIT approaches are that they represent defined molecules with known properties, which can be produced under GMP conditions in a reproducible manner [21,22,121▪,122]. In fact, hypoallergenic allergen derivatives have already been used for immunization in nonallergic individuals in two small clinical trials [123,124▪▪]. In a recently published double-blind, placebo-controlled study, it could be shown that vaccination with recombinant hypoallergenic fragments of the major birch pollen allergen, Bet v 1 induced IgG antibodies in nonallergic individuals, which could block IgE binding of birch pollen allergic patients to Bet v 1 [124▪▪]. Thus these derivatives should be useful for preventive vaccination because they induce a protective IgG response. In this context, it should be mentioned that another study provided evidence that maternal allergen-specific IgG may prevent against allergic sensitization in the offspring [125▪▪]. Children from mothers containing high levels of allergen-specific IgG did not develop IgE sensitizations against these allergens when followed up to the age of 5 years [125▪▪]. One may, therefore, speculate that it may be possible to increase the levels of allergen-specific IgG in pregnant women by AIT with hypoallergenic allergen derivatives to prevent the development of allergic sensitization in the offspring.
Although AIT with peptides containing allergen-specific T-cell epitopes was so far not successful, peptides may be considered for the induction of preventive T-cell tolerance . One possibility to induce prophylactic allergen-specific tolerance is oral tolerance induction shortly after birth . This possibility is discussed in the context of early studies showing effective prophylactic oral tolerance in experimental animal models [22,130]. However, also systemic administration of tolerogenic peptides may be considered as a prophylactic strategy for allergy as it is already considered for other hypersensitivity diseases .
The administration of hematopoetic stem cells expressing transplant antigens, autoantigens and allergens for long-lasting prophylactic tolerance induction has been successfully demonstrated in experimental animal models [132–136]. Such a stem cell-based prophylactic approach may be feasible for allergy because the molecular structures and sequences of the most important allergens are known and it should be technically feasible to prepare constructs for the transformation of hematopoetic stem cells obtained from cord blood to be introduced into newborns for tolerance induction. However, additional major hurdles need to be overcome. For example, it will be necessary to develop methods for expression of the antigens on the stem cells, which are well tolerated. Furthermore, suitable protocols for stem cell transplantation need to be developed, which are not immunosuppressive.
AIT is an extremely effective, inexpensive and the only disease-modifying therapy for allergy. Moreover, AIT can be used for specific prophylaxis. However, the further development of AIT is severely hampered by the quality of natural allergen extracts and can only be achieved with molecular AIT strategies. Most of the disease-causing allergen molecules have been identified and several molecular forms of AIT have been developed, which have the potential to revolutionize AIT and eventually allergen-specific prevention. However, resources are needed to develop the new molecular approaches in clinical trials to become available in daily allergy care. Clinical studies performed with molecular approaches indicate that the success of AIT depends strongly on the induction of allergen-specific IgG antibodies, which inhibit allergic patient's IgE binding to the allergen and consecutive immediate and late phase allergic reactions. Moreover, it has been recently shown that passive immunotherapy with recombinant allergen-specific human monoclonal IgG antibodies is effective in reducing allergic symptoms. Molecular AIT approaches, therefore, should induce allergen-specific IgG-blocking antibodies to be successful in clinical trials. AIT approaches, such as T-cell peptide therapy targeting only allergen-specific T cells without inducing allergen-specific IgG antibodies have so far not been successful; however, such approaches may have a high potential for prophylactic tolerance induction whenever given in early life. Further molecular approaches for prevention of allergy include preventive vaccination with recombinant hypoallergenic allergen derivatives, passive immunization with allergen-specific blocking antibodies and eventually stem cell-based therapy approaches.
Papers of particular interest, published within the annual period of review, have been highlighted as:
1▪. Valenta R, Karaulov A, Niederberger V, et al. Molecular aspects of allergens and allergy
. Adv Immunol 2018; 138:195–256.
Comprehensive, text-book-like overview on what is known and not known regarding molecular mechanisms in allergy.
2. Anto JM, Bousquet J, Akdis M, et al. Mechanisms of the Development of Allergy
(MeDALL): introducing novel concepts in allergy
phenotypes. J Allergy
Clin Immunol 2017; 139:388–399.
3. Bousquet J, Anto JM, Wickman M, et al. Are allergic multimorbidities and IgE
polysensitization associated with the persistence or re-occurrence of foetal type 2 signalling? The MeDALL hypothesis. Allergy
4. Lupinek C, Wollmann E, Baar A, et al. Advances in allergen-microarray technology for diagnosis and monitoring of allergy
: the MeDALL allergen-chip. Methods 2014; 66:106–119.
5. Westman M, Lupinek C, Bousquet J, et al. Mechanisms for the Development of Allergies Consortium. Early childhood IgE
reactivity to pathogenesis-related class 10 proteins predicts allergic rhinitis in adolescence. J Allergy
Clin Immunol 2015; 135:1199.e1–1206.e11.
6. Asarnoj A, Hamsten C, Waden K, et al. Sensitization to cat and dog allergen molecules in childhood and prediction of symptoms of cat and dog allergy
in adolescence: a BAMSE/MeDALL study. J Allergy
Clin Immunol 2016; 137:813.e7–821.e7.
7. Asarnoj A, Hamsten C, Lupinek C, et al. MeDALL Consortium. Prediction of peanut allergy
in adolescence by early childhood storage protein-specific IgE
signatures: The BAMSE population-based birth cohort. J Allergy
Clin Immunol 2017; 140:587.e7–590.e7.
8. Posa D, Perna S, Resch Y, et al. Evolution and predictive value of IgE
responses toward a comprehensive panel of house dust mite allergens during the first 2 decades of life. J Allergy
Clin Immunol 2017; 139:541.e8–549.e8.
9▪▪. Wickman M, Lupinek C, Andersson N, et al. Detection of IgE
reactivity to a handful of allergen molecules in early childhood predicts respiratory allergy
in adolescence. EBioMedicine 2017; 26:91–99.
Shows that the development of respiratory allergy can be predicted early in childhood based on IgE reactivity to a handful of allergen molecules.
10. Gandhi NA, Bennett BL, Graham NM, et al. Targeting key proximal drivers of type 2 inflammation in disease. Nat Rev Drug Discov 2016; 15:35–50.
11. Bagnasco D, Ferrando M, Varricchi G, et al. A Critical evaluation of anti-IL-13 and anti-IL-4 strategies in severe asthma. Int Arch Allergy
Immunol 2016; 170:122–131.
12. Incorvaia C, Gritti BL, Ridolo E. The economic advantage of allergen immunotherapy over drug treatment in respiratory allergy
. J Med Econ 2018; 21:553–555.
13. Curin M, Khaitov M, Karaulov A, et al. Next-generation of allergen-specific immunotherapies: molecular approaches. Curr Allergy
Asthma Rep 2018; 18:39.
14. Matricardi PM, Kleine-Tebbe J, Hoffmann HJ, et al. EAACI molecular allergology
user's guide. Pediatr Allergy
Immunol 2016; 27 (Suppl 23):1–250.
15. Curin M, Garib V, Valenta R. Single recombinant and purified major allergens and peptides: how they are made and how they change allergy
diagnosis and treatment. Ann Allergy
Asthma Immunol 2017; 119:201–209.
16▪. Saltabayeva U, Garib V, Morenko M, et al. Greater real-life diagnostic efficacy of allergen molecule
-based diagnosis for prescription of immunotherapy in an area with multiple pollen exposure. Int Arch Allergy
Immunol 2017; 173:93–98.
Demonstration that molecular allergy diagnosis helps to save treatment costs.
17▪. Garib V, Rigler E, Gastager F, et al. Determination of IgE
and IgG reactivity to more than 170 allergen molecules in paper-dried blood spots. J Allergy
Clin Immunol 2019; 143:437–440.
Demonstration that one can perform molecular chip diagnosis from paper-dried blood spots.
18. Brüggenjürgen B, Reinhold T. Cost-effectiveness of grass pollen subcutaneous immunotherapy (SCIT) compared to sublingual immunotherapy (SLIT) and symptomatic treatment in Austria, Spain, and Switzerland. J Med Econ 2018; 21:374–381.
19. Holt PG, Sly PD, Sampson HA, et al. Prophylactic use of sublingual allergen immunotherapy in high-risk children: a pilot study. J Allergy
Clin Immunol 2013; 132:991.e1–993.e1.
20. Szépfalusi Z, Bannert C, Ronceray L, et al. Preventive sublingual immunotherapy in preschool children: first evidence for safety and pro-tolerogenic effects. Pediatr Allergy
Immunol 2014; 25:788–795.
21. Valenta R, Campana R, Marth K, van Hage M. Allergen-specific immunotherapy
: from therapeutic vaccines to prophylactic approaches. J Intern Med 2012; 272:144–157.
22. Campana R, Huang HJ, Freidl R, et al. Recombinant allergen
and peptide-based approaches for allergy
prevention by oral tolerance. Semin Immunol 2017; 30:67–80.
23. Larché M, Akdis CA, Valenta R. Immunological mechanisms of allergen-specific immunotherapy
. Nat Rev Immunol 2006; 6:761–771.
24. Shamji MH, Durham SR. Mechanisms of allergen immunotherapy for inhaled allergens and predictive biomarkers. J Allergy
Clin Immunol 2017; 140:1485–1498.
25. Valenta R, Karaulov A, Niederberger V, et al. Allergen extracts for in vivo diagnosis and treatment of allergy
: is there a future? J Allergy
Clin Immunol Pract 2018; 6:1845.e2–1855.e2.
26▪▪. Vickery BP, Vereda A, et al. PALISADE Group of Clinical Investigators. AR101 oral immunotherapy for peanut allergy
. N Engl J Med 2018; 379:1991–2001.
Large study for oral immunotherapy for peanut allergy.
27. Koppelman SJ, Peillon A, Agbotounou W, et al. Epicutaneous immunotherapy for peanut allergy
modifies IgG4 responses to major peanut allergens. J Allergy
Clin Immunol 2019; 143:1218.e4–1221.e4.
28▪. Uotila R, Kukkonen AK, Greco D, et al. Peanut oral immunotherapy increases IgG4 to Ara h 1, 2, and 6 but does not affect IgG4 to other allergens. Pediatr Allergy
Immunol 2019; 30:248–252.
Important study showing the limitations of peanut allergen extracts for AIT.
29▪▪. Chen KW, Zieglmayer P, Zieglmayer R, et al. Selection of house dust mite-allergic patients by molecular diagnosis may enhance success of specific immunotherapy. J Allergy
Clin Immunol 2019; 143:1248.e12–1252.e12.
Demonstration that molecular allergy diagnosis can enhance the selection of patients for AIT.
30▪. Dzoro S, Mittermann I, Resch-Marat Y, et al. House dust mites as potential carriers for IgE
sensitization to bacterial antigens. Allergy
Demonstration that house dust mites carry bacteria, which can be contaminations in house dust mite extracts and may be responsible for IgE sensitization to bacterial allergens.
31. Valenta R, Campana R, Focke-Tejkl M, Niederberger V. Vaccine development for allergen-specific immunotherapy
based on recombinant allergens and synthetic allergen peptides: lessons from the past and novel mechanisms of action for the future. J Allergy
Clin Immunol 2016; 137:351–357.
32. Valenta R, Ferreira F, Focke-Tejkl M, et al. From allergen genes to allergy
vaccines. Annu Rev Immunol 2010; 28:211–241.
33. Jutel M, Jaeger L, Suck R, et al. Allergen-specific immunotherapy
with recombinant grass pollen allergens. J Allergy
Clin Immunol 2005; 116:608–613.
34. Klimek L, Schendzielorz P, Pinol R, Pfaar O. Specific subcutaneous immunotherapy with recombinant grass pollen allergens: first randomized dose-ranging safety study. Clin Exp Allergy
35. Pauli G, Larsen TH, Rak S, et al. Efficacy of recombinant birch pollen vaccine for the treatment of birch-allergic rhinoconjunctivitis. J Allergy
Clin Immunol 2008; 122:951–960. Erratum in: J Allergy
Clin Immunol 2009; 123: 166.
36. Nony E, Bouley J, Le Mignon M, et al. Development and evaluation of a sublingual tablet based on recombinant Bet v 1 in birch pollen-allergic patients. Allergy
37▪. Kinaciyan T, Nagl B, Faustmann S, et al. Efficacy and safety of 4 months of sublingual immunotherapy with recombinant Mal d 1 and Bet v 1 in patients with birch pollen-related apple allergy
. J Allergy
Clin Immunol 2018; 141:1002–1008.
One of the few recombinant allergen-based AIT studies.
38. Grönlund H, Bergman T, Sandström K, et al. Formation of disulfide bonds and homodimers of the major cat allergen Fel d 1 equivalent to the natural allergen by expression in Escherichia coli. J Biol Chem 2003; 278:40144–40151.
39. Wopfner N, Bauer R, Thalhamer J, et al. Immunologic analysis of monoclonal and immunoglobulin E antibody epitopes on natural and recombinant Amb a 1. Clin Exp Allergy
40. Twaroch TE, Focke M, Civaj V, et al. Carrier-bound, nonallergenic Ole e 1 peptides for vaccination against olive pollen allergy
. J Allergy
Clin Immunol 2011; 128:178.e7–184.e7.
41. Linhart B, Hartl A, Jahn-Schmid B, et al. A hybrid molecule resembling the epitope spectrum of grass pollen for allergy
vaccination. J Allergy
Clin Immunol 2005; 115:1010–1016.
42▪. Douladiris N, Garib V, Focke-Tejkl M, et al. Detection of genuine grass pollen sensitization in children by skin testing with a recombinant grass pollen hybrid. Pediatr Allergy
Immunol 2019; 30:59–65.
Demonstration that skin prick test diagnosis of grass pollen allergy is possible with one single recombinant hybrid allergen.
43. González-Rioja R, Ferrer A, Arilla MC, et al. Diagnosis of Parietaria judaica pollen allergy
using natural and recombinant Par j 1 and Par j 2 allergens. Clin Exp Allergy
44. Chruszcz M, Chapman MD, Vailes LD, et al. Crystal structures of mite allergens Der f 1 and Der p 1 reveal differences in surface-exposed residues that may influence antibody binding. J Mol Biol 2009; 386:520–530.
45▪. Huang HJ, Resch-Marat Y, Rodriguez-Dominguez A, et al. Underestimation of house dust mite-specific IgE
with extract-based ImmunoCAPs compared with molecular ImmunoCAPs. J Allergy
Clin Immunol 2018; 142:1656.e9–1659.e9.
Demonstration of the poor quality of allergen extract-based IgE tests for house dust mite allergy.
46▪. Käck U, Asarnoj A, Grönlund H, et al. Molecular allergy
diagnostics refine characterization of children sensitized to dog dander. J Allergy
Clin Immunol 2018; 142:1113.e9–1120.e9.
Elegant demonstration of the advantages of molecular allergy diagnosis with recombinant dog allergens.
47. Palladino C, Breiteneder H. Peanut allergens. Mol Immunol 2018; 100:58–70.
48. Gattinger P, Lupinek C, Kalogiros L, et al. The culprit insect but not severity of allergic reactions to bee and wasp venom can be determined by molecular diagnosis. PLoS One 2018; 13:e0199250.
49. Morgenstern JP, Griffith IJ, Brauer AW, et al. Amino acid sequence of Fel dI, the major allergen of the domestic cat: protein sequence analysis and cDNA cloning
. Proc Natl Acad Sci U S A 1991; 88:9690–9694.
50. Bond JF, Garman RD, Keating KM, et al. Multiple Amb a I allergens demonstrate specific reactivity with IgE
and T cells from ragweed-allergic patients. J Immunol 1991; 146:3380–3385.
51. Briner TJ, Kuo MC, Keating KM, et al. Peripheral T-cell tolerance induced in naive and primed mice by subcutaneous injection of peptides from the major cat allergen Fel d I. Proc Natl Acad Sci U S A 1993; 90:7608–7612.
52. Norman PS, Ohman JL Jr, Long AA, et al. Treatment of cat allergy
with T-cell reactive peptides. Am J Respir Crit Care Med 1996; 154:1623–1628.
53. Simons FE, Imada M, Li Y, et al. Fel d 1 peptides: effect on skin tests and cytokine synthesis in cat-allergic human subjects. Int Immunol 1996; 8:1937–1945.
54. Maguire P, Nicodemus C, Robinson D, et al. The safety and efficacy of ALLERVAX CAT in cat allergic patients. Clin Immunol 1999; 93:222–231.
55. Patel D, Couroux P, Hickey P, et al. Fel d 1-derived peptide antigen desensitization shows a persistent treatment effect 1 year after the start of dosing: a randomized, placebo-controlled study. J Allergy
Clin Immunol 2013; 131:103–109.
56. Couroux P, Patel D, Armstrong K, et al. Fel d 1-derived synthetic peptide immuno-regulatory epitopes show a long-term treatment effect in cat allergic subjects. Clin Exp Allergy
57. Ellis AK, Frankish CW, O’Hehir RE, et al. Treatment with grass allergen peptides improves symptoms of grass pollen-induced allergic rhinoconjunctivitis. J Allergy
Clin Immunol 2017; 140:486–496.
58. Spertini F, Perrin Y, Audran R, et al. Safety and immunogenicity of immunotherapy with Bet v 1-derived contiguous overlapping peptides. J Allergy
Clin Immunol 2014; 134:239.e13–240.e13.
59. Spertini F, DellaCorte G, Kettner A, et al. Efficacy of 2 months of allergen-specific immunotherapy
with Bet v 1-derived contiguous overlapping peptides in patients with allergic rhinoconjunctivitis: results of a phase IIb study. J Allergy
Clin Immunol 2016; 138:162–168.
60▪. Kettner A, DellaCorte G, de Blay F, et al. Benefit of Bet v 1 contiguous overlapping peptide immunotherapy persists during first follow-up season. J Allergy
Clin Immunol 2018; 142:678.e7–680.e7.
Demonstration of long-term effects of peptide immunotherapy.
61. Niederberger V, Horak F, Vrtala S, et al. Vaccination with genetically engineered allergens prevents progression of allergic disease. Proc Natl Acad Sci U S A 2004; 101 (Suppl 2):14677–14682.
62▪▪. Orengo JM, Radin AR, Kamat V, et al. Treating cat allergy
with monoclonal IgG antibodies that bind allergen and prevent IgE
engagement. Nat Commun 2018; 9:1421.
Proof that allergy can be treated by passive immunization with allergen-specific IgG antibodies.
63. Raz E, Tighe H, Sato Y, et al. Preferential induction of a Th1 immune response and inhibition of specific IgE
antibody formation by plasmid DNA immunization. Proc Natl Acad Sci U S A 1996; 93:5141–5145.
64. Hsu CH, Chua KY, Tao MH, et al. Immunoprophylaxis of allergen-induced immunoglobulin E synthesis and airway hyperresponsiveness in vivo by genetic immunization. Nat Med 1996; 2:540–544.
65. Slater JE, Paupore E, Zhang YT, Colberg-Poley AM. The latex allergen Hev b 5 transcript is widely distributed after subcutaneous injection in BALB/c mice of its DNA vaccine. J Allergy
Clin Immunol 1998; 102:469–475.
66. Tighe H, Takabayashi K, Schwartz D, et al. Conjugation of immunostimulatory DNA to the short ragweed allergen amb a 1 enhances its immunogenicity and reduces its allergenicity. J Allergy
Clin Immunol 2000; 106 (1 Pt 1):124–134.
67. Creticos PS, Schroeder JT, Hamilton RG, et al. Immunotherapy with a ragweed-toll-like receptor 9 agonist vaccine for allergic rhinitis. N Engl J Med 2006; 355:1445–1455.
68. Roesler E, Weiss R, Weinberger EE, et al. Immunize and disappear-safety-optimized mRNA vaccination with a panel of 29 allergens. J Allergy
Clin Immunol 2009; 124:1070.e1–1077.e11.
69. Su Y, Romeu-Bonilla E, Anagnostou A, et al. Safety and long-term immunological effects of CryJ2-LAMP plasmid vaccine in Japanese red cedar atopic subjects: A phase I study. Hum Vaccin Immunother 2017; 13:2804–2813.
70▪. Scheiblhofer S, Thalhamer J, Weiss R. DNA and mRNA vaccination against allergies. Pediatr Allergy
Immunol 2018; 29:679–688.
Useful review about the state of the art of nucleic acid-based AIT.
71. Linhart B, Valenta R. Mechanisms underlying allergy
vaccination with recombinant hypoallergenic allergen derivatives
. Vaccine 2012; 30:4328–4335.
72. Kämmerer R, Chvatchko Y, Kettner A, et al. Modulation of T-cell response to phospholipase A2 and phospholipase A2-derived peptides by conventional bee venom immunotherapy. J Allergy
Clin Immunol 1997; 100:96–103.
73. Astori M, von Garnier C, Kettner A, et al. Inducing tolerance by intranasal administration of long peptides in naive and primed CBA/J mice. J Immunol 2000; 165:3497–3505.
74. Pellaton C, Perrin Y, Boudousquié C, et al. Novel birch pollen specific immunotherapy formulation based on contiguous overlapping peptides. Clin Transl Allergy
75. Vrtala S, Hirtenlehner K, Vangelista L, et al. Conversion of the major birch pollen allergen, Bet v 1, into two nonanaphylactic T cell epitope-containing fragments: candidates for a novel form of specific immunotherapy. J Clin Invest 1997; 99:1673–1681.
76. Vrtala S, Akdis CA, Budak F, et al. T cell epitope-containing hypoallergenic recombinant fragments of the major birch pollen allergen, Bet v 1, induce blocking antibodies. J Immunol 2000; 165:6653–6659.
77. Meyer W, Narkus A, Salapatek AM, Häfner D. Double-blind, placebo-controlled, dose-ranging study of new recombinant hypoallergenic Bet v 1 in an environmental exposure chamber. Allergy
78. Klimek L, Bachert C, Lukat KF, et al. Allergy
immunotherapy with a hypoallergenic recombinant birch pollen allergen rBet v 1-FV in a randomized controlled trial. Clin Transl Allergy
79. Senti G, Crameri R, Kuster D, et al. Intralymphatic immunotherapy for cat allergy
induces tolerance after only 3 injections. J Allergy
Clin Immunol 2012; 129:1290–1296.
80. Wood RA, Sicherer SH, Burks AW, et al. A phase 1 study of heat/phenol-killed, E. coli-encapsulated, recombinant modified peanut proteins Ara h 1, Ara h 2, and Ara h 3 (EMP-123) for the treatment of peanut allergy
81. Zhu D, Kepley CL, Zhang K, et al. A chimeric human-cat fusion protein blocks cat-induced allergy
. Nat Med 2005; 11:446–449.
82. Swoboda I, Bugajska-Schretter A, Linhart B, et al. A recombinant hypoallergenic parvalbumin mutant for immunotherapy of IgE
-mediated fish allergy
. J Immunol 2007; 178:6290–6296.
83. Swoboda I, Balic N, Klug C, et al. A general strategy for the generation of hypoallergenic molecules for the immunotherapy of fish allergy
. J Allergy
Clin Immunol 2013; 132:979.e1–981.e1.
84. Zuidmeer-Jongejan L, Huber H, Swoboda I, et al. Development of a hypoallergenic recombinant parvalbumin for first-in-man subcutaneous immunotherapy of fish allergy
. Int Arch Allergy
Immunol 2015; 166:41–51.
85. Douladiris N, Linhart B, Swoboda I, et al. In vivo allergenic activity of a hypoallergenic mutant of the major fish allergen Cyp c 1 evaluated by means of skin testing. J Allergy
Clin Immunol 2015; 136:493.e8–495.e8.
86. Purohit A, Niederberger V, Kronqvist M, et al. Clinical effects of immunotherapy with genetically modified recombinant birch pollen Bet v 1 derivatives. Clin Exp Allergy
87. Haselden BM, Kay AB, Larché M. Immunoglobulin E-independent major histocompatibility complex-restricted T cell peptide epitope-induced late asthmatic reactions. J Exp Med 1999; 189:1885–1894.
88. Campana R, Mothes N, Rauter I, et al. Non-IgE
-mediated chronic allergic skin inflammation revealed with rBet v 1 fragments. J Allergy
Clin Immunol 2008; 121:528.e1–530.e1.
89. Campana R, Moritz K, Marth K, et al. Frequent occurrence of T cell-mediated late reactions revealed by atopy patch testing with hypoallergenic rBet v 1 fragments. J Allergy
Clin Immunol 2016; 137:601.e8–609.e8.
90▪. Valenta R, Campana R, Niederberger V. Recombinant allergy
vaccines based on allergen-derived B cell epitopes. Immunol Lett 2017; 189:19–26.
Useful summary of the immunological mechanisms behind B-cell epitope-based AIT.
91. Katz DH, Paul WE, Goidl EA, Benacerraf B. Carrier function in antihapten immune responses. I. Enhancement of primary and secondary antihapten antibody responses by carrier preimmunization. J Exp Med 1970; 132:261–282.
92. Focke M, Swoboda I, Marth K, Valenta R. Developments in allergen-specific immunotherapy
: from allergen extracts to allergy
vaccines bypassing allergen-specific immunoglobulin E and T cell reactivity. Clin Exp Allergy
93. Valenta R, Vrtala S, Focke-Tejkl M, et al. Genetically engineered and synthetic allergen derivatives
: candidates for vaccination against type I allergy
. Biol Chem 1999; 380:815–824.
94. Focke M, Mahler V, Ball T, et al. Nonanaphylactic synthetic peptides derived from B cell epitopes of the major grass pollen allergen, Phl p 1, for allergy
vaccination. FASEB J 2001; 15:2042–2044.
95. Focke M, Linhart B, Hartl A, et al. Nonanaphylactic surface-exposed peptides of the major birch pollen allergen, Bet v 1, for preventive vaccination. Clin Exp Allergy
96. Edlmayr J, Niespodziana K, Linhart B, et al. A combination vaccine for allergy
and rhinovirus infections based on rhinovirus-derived surface protein VP1 and a nonallergenic peptide of the major timothy grass pollen allergen Phl p 1. J Immunol 2009; 182:6298–6306.
97. Niespodziana K, Focke-Tejkl M, Linhart B, et al. A hypoallergenic cat vaccine based on Fel d 1-derived peptides fused to hepatitis B PreS. J Allergy
Clin Immunol 2011; 127:1562.e6–1570.e6.
98. Edlmayr J, Niespodziana K, Focke-Tejkl M, et al. Allergen-specific immunotherapy
: towards combination vaccines for allergic and infectious diseases. Curr Top Microbiol Immunol 2011; 352:121–140.
99. Focke-Tejkl M, Weber M, Niespodziana K, et al. Development and characterization of a recombinant, hypoallergenic, peptide-based vaccine for grass pollen allergy
. J Allergy
Clin Immunol 2015; 135:1207.e1–1207.e11.
100. Niederberger V, Marth K, Eckl-Dorna J, et al. Skin test evaluation of a novel peptide carrier-based vaccine, BM32, in grass pollen-allergic patients. J Allergy
Clin Immunol 2015; 136:1101.e8–1103.e8.
101. Zieglmayer P, Focke-Tejkl M, Schmutz R, et al. Mechanisms, safety and efficacy of a B cell epitope-based vaccine for immunotherapy of grass pollen allergy
. EBioMedicine 2016; 11:43–57.
102. Weber M, Niespodziana K, Linhart B, et al. Comparison of the immunogenicity of BM32, a recombinant hypoallergenic B cell epitope-based grass pollen allergy
vaccine with allergen extract-based vaccines. J Allergy
Clin Immunol 2017; 140:1433.e6–1436.e6.
103▪▪. Niederberger V, Neubauer A, Gevaert P, et al. Safety and efficacy of immunotherapy with the recombinant B-cell epitope-based grass pollen vaccine BM32. J Allergy
Clin Immunol 2018; 142:497.e9–509.e9.
Demonstration of the clinical efficacy of AIT with a recombinant B-cell epitope-based vaccine for grass pollen allergy in a 3 years field study.
104. Cornelius C, Schöneweis K, Georgi F, et al. Immunotherapy with the PreS-based grass pollen allergy
vaccine BM32 induces antibody responses protecting against hepatitis B infection. EBioMedicine 2016; 11:58–67.
105. Cooke RA, Barnard JH, Hebald S, Stull A. Serological evidence of immunity with coexisting sensitization in a type of human allergy
(hay fever). J Exp Med 1935; 62:733–750.
106. Visco V, Dolecek C, Denépoux S, et al. Human IgG monoclonal antibodies that modulate the binding of specific IgE
to birch pollen Bet v 1. J Immunol 1996; 157:956–962.
107. Van Neerven RJ, Wikborg T, Lund G, et al. Blocking antibodies induced by specific allergy
vaccination prevent the activation of CD4+ T cells by inhibiting serum-IgE
-facilitated allergen presentation. J Immunol 1999; 163:2944–2952.
108. Flicker S, Valenta R. Renaissance of the blocking antibody concept in type I allergy
. Int Arch Allergy
Immunol 2003; 132:13–24.
109. Holt PG. A potential vaccine strategy for asthma and allied atopic diseases during early childhood. Lancet 1994; 344:456–458.
110. Matricardi PM. Allergen-specific immunoprophylaxis: toward secondary prevention of allergic rhinitis? Pediatr Allergy
Immunol 2014; 25:15–18.
111. Incorvaia C, Martignago I, Ridolo E. Can the pattern of early sensitization to allergen molecules drive a new approach for prevention of allergy
? EBioMedicine 2017; 26:8–9.
112. Westman M, Asarnoj A, Hamsten C, et al. Windows of opportunity for tolerance induction for allergy
by studying the evolution of allergic sensitization in birth cohorts. Semin Immunol 2017; 30:61–66.
113. Möller C, Dreborg S, Ferdousi HA, et al. Pollen immunotherapy reduces the development of asthma in children with seasonal rhinoconjunctivitis (the PAT-study). J Allergy
Clin Immunol 2002; 109:251–256.
114. Niggemann B, Jacobsen L, Dreborg S, et al. PAT Investigator Group. Five-year follow-up on the PAT study: specific immunotherapy and long-term prevention of asthma in children. Allergy
115. Jacobsen L, Niggemann B, Dreborg S, et al. Specific immunotherapy has long-term preventive effect of seasonal and perennial asthma: 10-year follow-up on the PAT study. Allergy
116. Du Toit G, Roberts G, Sayre PH, et al. LEAP Study Team. Randomized trial of peanut consumption in infants at risk for peanut allergy
. N Engl J Med 2015; 372:803–813.
117▪. Fisher HR, Du Toit G, Bahnson HT, Lack G. The challenges of preventing food allergy
: Lessons learned from LEAP and EAT. Ann Allergy
Asthma Immunol 2018; 121:313–319.
Useful summary of the state of the art of introducing early food allergens for prevention.
118. Dehlink E, Eiwegger T, Gerstmayr M, et al. Absence of systemic immunologic changes during dose build-up phase and early maintenance period in effective specific sublingual immunotherapy in children. Clin Exp Allergy
119. Ponce M, Schroeder F, Bannert C, et al. Preventive sublingual immunotherapy with House Dust Mite extract modulates epitope diversity in pre-school children. Allergy
120. Durham SR, Yang WH, Pedersen MR, et al. Sublingual immunotherapy with once-daily grass allergen tablets: a randomized controlled trial in seasonal allergic rhinoconjunctivitis. J Allergy
Clin Immunol 2006; 117:802–809.
121▪. Kratzer B, Köhler C, Hofer S, et al. Prevention of allergy
by virus-like nanoparticles (VNP) delivering shielded versions of major allergens in a humanized murine allergy
Elegant design of a prophylactic virus particle-based allergy vaccine.
122. Sarate PJ, Heinl S, Poiret S, et al. E. coli Nissle 1917 is a safe mucosal delivery vector for a birch-grass pollen chimera to prevent allergic poly-sensitization. Mucosal Immunol 2019; 12:132–144.
123. Kündig TM, Senti G, Schnetzler G, et al. Der p 1 peptide on virus-like particles is safe and highly immunogenic in healthy adults. J Allergy
Clin Immunol 2006; 117:1470–1476.
124▪▪. Campana R, Marth K, Zieglmayer P, et al. Vaccination of nonallergic individuals with recombinant hypoallergenic fragments of birch pollen allergen Bet v 1: Safety, effects, and mechanisms. J Allergy
Clin Immunol 2019; 143:1258–1261.
First double-blind, placebo-controlled vaccination of nonallergic subjects with recombinant hypoallergenic allergen derivatives.
125▪▪. Lupinek C, Hochwallner H, Johansson C, et al. Maternal allergen-specific IgG might protect the child against allergic sensitization. J Allergy
Clin Immunol 2019; doi: 10.1016/j.jaci.2018.11.051. [Epub ahead of print].
Evidence that maternal allergen-specific IgG can protect the child from becoming sensitized.
126. Linhart B, Narayanan M, Focke-Tejkl M, et al. Prophylactic and therapeutic vaccination with carrier-bound Bet v 1 peptides lacking allergen-specific T cell epitopes reduces Bet v 1-specific T cell responses via blocking antibodies in a murine model for birch pollen allergy
. Clin Exp Allergy
127. Uthoff H, Spenner A, Reckelkamm W, et al. Critical role of preconceptional immunization for protective and nonpathological specific immunity in murine neonates. J Immunol 2003; 171:3485–3489.
128. Flicker S, Linhart B, Wild C, et al. Passive immunization with allergen-specific IgG antibodies for treatment and prevention of allergy
. Immunobiology 2013; 218:884–891.
129. Freidl R, Gstoettner A, Baranyi U, et al. Blocking antibodies induced by immunization with a hypoallergenic parvalbumin mutant reduce allergic symptoms in a mouse model of fish allergy
. J Allergy
Clin Immunol 2017; 139:1897.e1–1905.e1.
130. Rezende RM, Weiner HL. History and mechanisms of oral tolerance. Semin Immunol 2017; 30:3–11.
131. Wraith DC. The future of immunotherapy: a 20-year perspective. Front Immunol 2017; 8:1668.
132. Bracy JL, Sachs DH, Iacomini J. Inhibition of xenoreactive natural antibody production by retroviral gene therapy. Science 1998; 281:1845–1847.
133. Tian C, Bagley J, Cretin N, et al. Prevention of type 1 diabetes by gene therapy. J Clin Invest 2004; 114:969–978.
134. Baranyi U, Linhart B, Pilat N, et al. Tolerization of a type I allergic immune response through transplantation of genetically modified hematopoietic stem cells. J Immunol 2008; 180:8168–8175.
135. Baranyi U, Gattringer M, Farkas AM, et al. The site of allergen expression in hematopoietic cells determines the degree and quality of tolerance induced through molecular chimerism. Eur J Immunol 2013; 43:2451–2460.
136. Baranyi U, Farkas AM, Hock K, et al. Cell therapy for prophylactic tolerance in immunoglobulin e-mediated allergy
. EBioMedicine 2016; 7:230–239.