Next generation immunotherapy for tree pollen allergies

Figures & data

Table 1. Novel approaches for tree pollen allergies.

Approaches	Allergen	Route	Formulation and treatment	Stage	Proposed MoA	References
Natural pollen extract or purified component based AIT	Chemically modified birch pollen extract	SC	Allergoids + MPL 4 weekly injections	Phase III	Induction of Treg and Tr1 cells, and IgG	46
	Purified natural Bet v 1	SC	Bet v 1+ Al(OH)3 Conventional SCIT build-up and maintenance in 2 years	Phase II	Induction of IgG	58
	Purified natural Cry j 1	ID	Cry j 1 entrapped in OMLs (mice: 2 weekly ID injections)	Preclinical	Th1 deviation	50
	Purified natural Cry j 1	SC	Cry j 1 conjugated with CpG (mice: 3 weekly SC injections)	Preclinical	Th1 deviation	52
Recombinant protein or synthetic peptide based AIT	rBet v 1	SC	Bet v 1 + Al(OH)3 Conventional SCIT build-up and maintenance in 2 years	Phase II	Induction of IgG	58
	rBet v 1	SL	rBet v 1 tablet once daily for 5 months	Phase II	Not determined in the reference 59	59
	Hypoallergenic rBet v 1	SC	Bet v 1 + Al(OH)3 Conventional SCIT build-up and maintenance in 1 year	Phase II	Induction of IgG, reduction of IgE	63,64
	Synthetic Bet v 1 COPs	SC	Synthetic peptides + Al(OH)3 5 injections in 2 months	Phase III	Induction of IgG4, Th1 deviation, and IL-10	72,73
	Synthetic Cry j 2 T cell epitope	SC	T-cell epitope conjugated with CpG (mice: 1 or 2 weekly SC injections)	Preclinical	Suppression of Th2 response	53
	Bet v 1 B cell epitopes	SC	B-cell epitopes + carrier (KLH, PreS) + Al(OH)3 (mice: 3 SC injections in 3 week intervals; rabbits: 3 monthly injections)	Preclinical	Induction of IgG blocking Ab	81,85,86
	Hypoallergenic rCry j 1/2 fusion protein	SC	Hypoallergenic rCry j 1/2 fusion protein conjugated with PEG (monkeys: 4 weekly SC injections)	Preclinical	Induction of IgG and Th1 deviation	88
DNA vaccines	Cry j 1 Cry j 2	IM	Cry j 1-LAMP and Cry j 2-LAMP MHC II targeting DNA plasmids 4 biweekly injections	Phase II	Th1 deviation and induction of IgG antibody	109,110
	Bet v 1a or Cry j 1	ID or IM	DNA plasmid (mice: 1 ID injection or 4 weekly IM injections)	Preclinical	Induction of IgG2a and Th1 deviation	99-101
	Bet v 1	ID	MHC I or II targeting DNA plasmid (mice: 3 weekly ID injections)	Preclinical	Treg induction	103
	T cell epitope of Cry j 2	IM	MHC II targeting DNA plasmid (mice: 4 or 5 weekly IM injections)	Preclinical	Th1 cellular immunity	102
Alternative routes	Purified natural Cry j 1	Oral	Cry j 1 conjugated to galactomannan, Daily administration for 10 weeks (build-up and maintenance)	Phase II	Induction of IgG4 and IL-10	116-119
	Cry j 1 COPs and hypoallergenic Cry j 2 by Transgenic rice:	Oral	Milled transgenic rice seed powder (mice: freely feed for 7 days or 20 days)	Preclinical	Suppression of Th2 and Th1 responses	122-124,127
	Synthetic T cell epitopes of Cry j 2 and/or Cry j 1	Oral	Synthetic peptides (mice: 4 oral doses in 2 weeks)	Preclinical	Suppression of Th2 and Th1 responses	128-130
	T cell epitopes of Cry j 2 and/or Cry j 1 by Transgenic chicken	Oral	Transgenic chicken egg white (mice: 5 days/week for 4 consecutive weeks)	Preclinical	Suppression of Th2 responses	131
	Birch or grass pollen extract	Intralymphatic	Extract + Al(OH)3 3 injections in 3–4 week intervals	Phase II	Induction of high affinity of IgG4 antibody and Th1 deviation	133,134
	rBet v 1, rBet v 1B2	Epicutaneous	Allergen + Th1 adjuvant (mice: 8 weekly EP treatments; guinea pigs: 3 biweekly patches)	Preclinical	Th1 deviation and reduction of IgE	144-146

ID: intradermal, IM: intramuscular, SC: subcutaneous, SL: sublingual, EP: epicutaneous

Rosewich M , Lee D , Zielen S . Pollinex Quattro: an innovative four injections immunotherapy in allergic rhinitis. Hum Vaccin Immunother. 2013;9:1523-31. https://doi.org/10.4161/hv.24631. PMID:23584250

 PubMed Web of Science ®Google Scholar

Pauli G , Larsen TH , Rak S , Horak F , Pastorello E , Valenta R , et al. Efficacy of recombinant birch pollen vaccine for the treatment of birch-allergic rhinoconjunctivitis. J Allergy Clin Immunol. 2008;122:951-60. https://doi.org/10.1016/j.jaci.2008.09.017. PMID:19000581

 PubMed Web of Science ®Google Scholar

Ishii M , Koyama A , Iseki H , Narumi H , Yokoyama N , Kojima N . Anti-allergic potential of oligomannose-coated liposome-entrapped Cry j 1 as immunotherapy for Japanese cedar pollinosis in mice. Int Immunopharmacol. 2010;10:1041-6. https://doi.org/10.1016/j.intimp.2010.06.003. PMID:20584630

 PubMed Web of Science ®Google Scholar

Kaburaki Y , Fujimura T , Kurata K , Masuda K , Toda M , Yasueda H , et al. Induction of Th1 immune responses to Japanese cedar pollen allergen (Cry j 1) in mice immunized with Cry j 1 conjugated with CpG oligodeoxynucleotide. Comp Immunol Microbiol Infect Dis. 2011;34:157-61. https://doi.org/10.1016/j.cimid.2010.06.005. PMID:20638725

 PubMed Web of Science ®Google Scholar

Nony E , Bouley J , Le Mignon M, Lemoine P , Jain K , Horiot S , et al. Development and evaluation of a sublingual tablet based on recombinant Bet v 1 in birch pollen-allergic patients. Allergy. 2015;70:795-804. https://doi.org/10.1111/all.12622. PMID:25846209

 PubMed Web of Science ®Google Scholar

Niederberger V , Horak F , Vrtala S , Spitzauer S , Krauth MT , Valent P , et al. Vaccination with genetically engineered allergens prevents progression of allergic disease. Proc Natl Acad Sci U S A. 2004;101 Suppl 2:14677-82. https://doi.org/10.1073/pnas.0404735101. PMID:15310844

 PubMed Web of Science ®Google Scholar

Spertini F , Perrin Y , Audran R , Pellaton C , Boudousquie C , Barbier N , et al. Safety and immunogenicity of immunotherapy with Bet v 1-derived contiguous overlapping peptides. J Allergy Clin Immunol. 2014;134:239-40 e13. https://doi.org/10.1016/j.jaci.2014.04.001

 Web of Science ®Google Scholar

Suzuki M , Ohta N , Min WP , Matsumoto T , Min R , Zhang X , et al. Immunotherapy with CpG DNA conjugated with T-cell epitope peptide of an allergenic Cry j 2 protein is useful for control of allergic conditions in mice. Int Immunopharmacol. 2007;7:46-54. https://doi.org/10.1016/j.intimp.2006.08.010. PMID:17161816

 PubMed Web of Science ®Google Scholar

Focke M , Linhart B , Hartl A , Wiedermann U , Sperr WR , Valent P , et al. Non-anaphylactic surface-exposed peptides of the major birch pollen allergen, Bet v 1, for preventive vaccination. Clin Exp Allergy. 2004;34:1525-33. https://doi.org/10.1111/j.1365-2222.2004.02081.x. PMID:15479266

 PubMed Web of Science ®Google Scholar

Marth K , Breyer I , Focke-Tejkl M , Blatt K , Shamji MH , Layhadi J , et al. A nonallergenic birch pollen allergy vaccine consisting of hepatitis PreS-fused Bet v 1 peptides focuses blocking IgG toward IgE epitopes and shifts immune responses to a tolerogenic and Th1 phenotype. J Immunol. 2013;190:3068-78. https://doi.org/10.4049/jimmunol.1202441. PMID:23440415

 PubMed Web of Science ®Google Scholar

Linhart B , Narayanan M , Focke-Tejkl M , Wrba F , Vrtala S , Valenta R . 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. 2014;44:278-87. https://doi.org/10.1111/cea.12216. PMID:24447086

 PubMed Web of Science ®Google Scholar

Fujimura T , Fujinami K , Ishikawa R , Tateno M , Tahara Y , Okumura Y , et al. Recombinant Fusion Allergens, Cry j 1 and Cry j 2 from Japanese Cedar Pollen, Conjugated with Polyethylene Glycol Potentiate the Attenuation of Cry j 1-Specific IgE Production in Cry j 1-Sensitized Mice and Japanese Cedar Pollen Allergen-Sensitized Monkeys. Int Arch Allergy Immunol. 2015;168:32-43. https://doi.org/10.1159/000441141. PMID:26524293

 PubMed Web of Science ®Google Scholar

Su Y , Connolly M , Marketon A , Heiland T . CryJ-LAMP DNA Vaccines for Japanese Red Cedar Allergy Induce Robust Th1-Type Immune Responses in Murine Model. J Immunol Res. 2016;2016:4857869. https://doi.org/10.1155/2016/4857869. PMID:27239481

 PubMed Web of Science ®Google Scholar

Su Y , Romeu-Bonilla E , Anagnostou A , Fitz-Patrick D , Hearl W , Heiland T . 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; [Epub ahead of print]. https://doi.org/10.1080/21645515.2017.1329070

 Web of Science ®Google Scholar

Hartl A , Kiesslich J , Weiss R , Bernhaupt A , Mostbock S , Scheiblhofer S , et al. Immune responses after immunization with plasmid DNA encoding Bet v 1, the major allergen of birch pollen. J Allergy Clin Immunol. 1999;103:107-13. https://doi.org/10.1016/S0091-6749(99)70533-6. PMID:9893193

 PubMed Web of Science ®Google Scholar

Toda M , Sato H , Takebe Y , Taniguchi Y , Saito S , Inouye S , et al. Inhibition of immunoglobulin E response to Japanese cedar pollen allergen (Cry j 1) in mice by DNA immunization: different outcomes dependent on the plasmid DNA inoculation method. Immunology. 2000;99:179-86. https://doi.org/10.1046/j.1365-2567.2000.00935.x. PMID:10692034

 PubMed Web of Science ®Google Scholar

Weinberger EE , Isakovic A , Scheiblhofer S , Ramsauer C , Reiter K , Hauser-Kronberger C , et al. The influence of antigen targeting to sub-cellular compartments on the anti-allergic potential of a DNA vaccine. Vaccine. 2013;31:6113-21. https://doi.org/10.1016/j.vaccine.2013.08.005. PMID:23954383

 PubMed Web of Science ®Google Scholar

Toda M , Kasai M , Hosokawa H , Nakano N , Taniguchi Y , Inouye S , et al. DNA vaccine using invariant chain gene for delivery of CD4+ T cell epitope peptide derived from Japanese cedar pollen allergen inhibits allergen-specific IgE response. Eur J Immunol. 2002;32:1631-9. https://doi.org/10.1002/1521-4141(200206)32:6%3c1631::AID-IMMU1631%3e3.0.CO;2-O. PMID:12115646

 PubMed Web of Science ®Google Scholar

Murakami D , Kubo K , Sawatsubashi M , Kikkawa S , Ejima M , Saito A , et al. Phase I/II study of oral immunotherapy with Cry j1-galactomannan conjugate for Japanese cedar pollinosis. Auris Nasus Larynx. 2014;41:350-8. https://doi.org/10.1016/j.anl.2014.02.010. PMID:24698163

 PubMed Web of Science ®Google Scholar

Murakami D , Sawatsubashi M , Kikkawa S , Ejima M , Saito A , Kato A , et al. Effect of short-term oral immunotherapy with Cry j1-galactomannan conjugate on quality of life in Japanese cedar pollinosis patients: A prospective, randomized, open-label study. Auris Nasus Larynx. 2016;43:50-5. https://doi.org/10.1016/j.anl.2015.06.011. PMID:26197940

 PubMed Web of Science ®Google Scholar

Takagi H , Saito S , Yang L , Nagasaka S , Nishizawa N , Takaiwa F . Oral immunotherapy against a pollen allergy using a seed-based peptide vaccine. Plant Biotechnol J. 2005;3:521-33. https://doi.org/10.1111/j.1467-7652.2005.00143.x. PMID:17173638

 PubMed Web of Science ®Google Scholar

Wakasa Y , Takagi H , Hirose S , Yang L , Saeki M , Nishimura T , et al. Oral immunotherapy with transgenic rice seed containing destructed Japanese cedar pollen allergens, Cry j 1 and Cry j 2, against Japanese cedar pollinosis. Plant Biotechnol J. 2013;11:66-76. https://doi.org/10.1111/pbi.12007. PMID:23066780

 PubMed Web of Science ®Google Scholar

Wakasa Y , Takagi H , Watanabe N , Kitamura N , Fujiwara Y , Ogo Y , et al. Concentrated protein body product derived from rice endosperm as an oral tolerogen for allergen-specific immunotherapy-a new mucosal vaccine formulation against Japanese cedar pollen allergy. PLoS One. 2015;10:e0120209. https://doi.org/10.1371/journal.pone.0120209. PMID:25774686

 PubMed Web of Science ®Google Scholar

Hirahara K , Saito S , Serizawa N , Sasaki R , Sakaguchi M , Inouye S , et al. Oral administration of a dominant T-cell determinant peptide inhibits allergen-specific TH1 and TH2 cell responses in Cry j 2-primed mice. J Allergy Clin Immunol. 1998;102:961-7. https://doi.org/10.1016/S0091-6749(98)70334-3. PMID:9847437

 PubMed Web of Science ®Google Scholar

Yoshitomi T , Hirahara K , Kawaguchi J , Serizawa N , Taniguchi Y , Saito S , et al. Three T-cell determinants of Cry j 1 and Cry j 2, the major Japanese cedar pollen antigens, retain their immunogenicity and tolerogenicity in a linked peptide. Immunology. 2002;107:517-22. https://doi.org/10.1046/j.1365-2567.2002.01534.x. PMID:12460197

 PubMed Web of Science ®Google Scholar

Kawabe Y , Hayashida Y , Numata K , Harada S , Hayashida Y , Ito A , et al. Oral immunotherapy for pollen allergy using T-cell epitope-containing egg white derived from genetically manipulated chickens. PLoS One. 2012;7:e48512. https://doi.org/10.1371/journal.pone.0048512. PMID:23144766

 PubMed Web of Science ®Google Scholar

Senti G , Prinz Vavricka BM , Erdmann I , Diaz MI , Markus R , McCormack SJ , et al. Intralymphatic allergen administration renders specific immunotherapy faster and safer: a randomized controlled trial. Proc Natl Acad Sci U S A. 2008;105:17908-12. https://doi.org/10.1073/pnas.0803725105. PMID:19001265

 PubMed Web of Science ®Google Scholar

Senti G , Crameri R , Kuster D , Johansen P , Martinez-Gomez JM , Graf N , et al. Intralymphatic immunotherapy for cat allergy induces tolerance after only 3 injections. J Allergy Clin Immunol. 2012;129:1290-6. https://doi.org/10.1016/j.jaci.2012.02.026. PMID:22464647

 PubMed Web of Science ®Google Scholar

Siebeneicher S , Reuter S , Krause M , Wangorsch A , Maxeiner J , Wolfheimer S , et al. Epicutaneous immune modulation with Bet v 1 plus R848 suppresses allergic asthma in a murine model. Allergy. 2014;69:328-37. https://doi.org/10.1111/all.12326. PMID:24329861

 PubMed Web of Science ®Google Scholar

Cabauatan CR , Campana R , Niespodziana K , Reinisch C , Lundberg U , Meinke A , et al. Heat-labile Escherichia coli toxin enhances the induction of allergen-specific IgG antibodies in epicutaneous patch vaccination. Allergy. 2017;72:164-8. https://doi.org/10.1111/all.13036. PMID:27568860

 PubMed Web of Science ®Google Scholar