Table of Contents

Volume 8, Issue 10

  October 2012

  Pages 1365 - 1547

Special Focus: Allergy Vaccines and Immunotherapeutics

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 Issue Catalogue (MARC XML)

EDITOR'S CORNER

Open Access Article

Letter from the Editor

Ronald Ellis and Eva M. Riedmann
Page 1365
http://dx.doi.org/10.4161/hv.22499
Full Text | PDF




NEWS, POLICY AND PROFILES

Open Access Article

News

Eva M. Riedmann
Pages 1366 - 1369
http://dx.doi.org/10.4161/hv.22583
Abstract | Full Text | PDF

Chickenpox cases in the US drop by 80%
Novel immunotherapy for breast, ovarian and prostate cancer successfully completes Phase 1
Important progress for Inovio’s universal influenza vaccine
Vaccine against ricin exposure successful in phase 1B
BCG could help reverse Type 1 Diabetes
HPV vaccine: effective, when given early
First vaccine for visceral leishmaniasis starts human testing
CDC prepares vaccine for new swine flu strain




MEETING REPORTS

Scope for innovation in immunotherapy from the financial market’s point of view: Phacilitate Immunotherapy Leaders’ Forum 2012

Olav Zilian
Pages 1370 - 1372
http://dx.doi.org/10.4161/hv.21413
Abstract | Full Text | PDF

In the vast area of immunotherapies, the development of monoclonal antibodies as a therapeutic concept emerged as a quantum leap out of the area of traditional vaccines (Köhler and Milstein)¹ in vitro selection and optimisation made it possible to elaborate a single biological molecule from the molecular plethora of an individual adaptive immune response and to utilize such a cloned antibody repeatedly in a generalized fashion whenever the therapeutic indication is given to humans.

At present, some 25 therapeutic monoclonal antibodies are currently being marketed in oncology, exceeding sales of USD20bn in 2011. A total of about 270 antibodies are currently in Phase II and III clinical development. Working on the assumption of usually lower attrition rates for antibody candidates, we expect approximately 120 of these 270 antibodies to be finally approved. This poses some key questions. What level of differentiation is required so that the coming new antibody drugs can command premium pricing when members of the founding generation become generic and inexpensive? What will global demand for antibody drugs be in view of the rising buying power in emerging pharmaceutical (‘pharmerging’) markets, but which is still not comparable with that of developed ones? What would the next quantum leaps be that might potentially push antibody technology on to a next level by disruptive innovation? Presentations given at the Phacilitate Immunotherapy Leaders’ Forum 2012 (9–11 May in Barcelona) reflected on these questions and provided some stimulating perspectives.

Phacilitate Immunotherapy Leaders‘ Forum: How to tap into dilutive and non-dilutive funding sources for immunotherapy projects—Barcelona, May 9–11, 2012

Klaus Breiner
Pages 1373 - 1375
http://dx.doi.org/10.4161/hv.21446
Abstract | Full Text | PDF

How to tap into dilutive and non-dilutive funding sources for immunotherapy projects.




RESEARCH PAPERS

The preparation of HL-60 cells vaccine expressing BCG heat shock protein 70 and detection of its immunogenicity in vitro

Xiao-Ling Li, Yan-Xia Zhao, Li-Rong Sun, Jing Yang and Hui-Juan Xu
Pages 1376 - 1381
http://dx.doi.org/10.4161/hv.21321
Abstract | Full Text | PDF

Gene-modified cell vaccines are the best way to achieve the immunotherapy for all types of acute leukemia. In this study, the recombinant eukaryotic expression vector (pDisplay-HSP70) of heat shock protein 70 (HSP70) of Bacille Calmette-Guérin (BCG) was constructed by amplifying the whole BCG HSP70 gene using polymerase chain reaction (PCR) and sub-cloning into the polyclone endonuclease sites in pDisplay. Then the HL-60 cell vaccine expressing the protein onto the cell surface was prepared by lipofectamine transfection and its anti-tumor effect and mechanism were further studied. Results showed that the fragment of BCG HSP70 was consistent with Mycobacterium tuberculosis HSP70 gene published in GeneBank. DNA sequencing showed that the recombinant vector was correctly constructed and named pDisplay-HSP70. After BCG HSP70 gene transfection, the yellow-green fluorescence on the HL-60 cells surface was observed under a fluorescence microscope. The immunogenicity of HSP70-transfected HL-60 cells exhibited upregulated proliferation of lymphocytes, increased cytokine secretion (IFN-γ) and enhanced killing activity. These results suggested that gene transfection of BCG HSP70 could significantly enhance the immunogenicity of HL-60 cells. It may be used as a suitable candidate gene-modified cell vaccine for cancer immunotherapy.

Cost-effectiveness of polysaccharide pneumococcal vaccination in people aged 65 and above in Poland

Pawel Grzesiowski, Raquel Aguiar-Ibáñez, Aleksandra Kobryń, Laure Durand and Pierre-Emmanuel Puig
Pages 1382 - 1394
http://dx.doi.org/10.4161/hv.21571
Abstract | Full Text | PDF

Introduction: Invasive pneumococcal disease is associated with substantial morbidity, mortality and cost implications, which could be reduced by vaccination.
Aim: To assess the cost-effectiveness of a 23-valent pneumococcal vaccine in the elderly (65 and older) in Poland.
Methods: A Markov model with a 1-year cycle length was developed, allowing up to 10 cohorts to enter the model over the lifetime horizon (35 years). In the base case, costs and benefits were assessed using the public health care payer (NFZ) perspective. The analysis included routine vaccination of all elderly and high-risk (HR) elderly versus no vaccination. The analysis assumed that the government would reimburse 50% of the vaccine price. Costs and benefits were discounted 5%, with costs expressed in 2009 Polish Zloty (PLN). Extensive sensitivity analyses were carried out.
Results: PPV23 vaccination targeting all elderly and HR elderly in Poland would avoid 8,935 pneumococcal infections, 2,542 hospitalisations, 671 deaths and 5,886 infections, 1,673 hospitalisations and 441 deaths respectively. The incremental cost per QALY gained would be PLN 3,382 in all elderly and PLN2,148 in HR elderly.
Conclusion: Vaccinating adults 65 and older regardless of risk status with a 23-valent pneumococcal vaccine, is cost-effective, resulting in clinical and economic benefits including a non-negligible reduction of ambulatory doctor visits, hospitalizations and, deaths in Poland.

Focusing on flu: Parent perspectives on school-located immunization programs for influenza vaccine

Amy B. Middleman, Mary B. Short and Jean S. Doak
Pages 1395 - 1400
http://dx.doi.org/10.4161/hv.21575
Abstract | PDF

School-located immunization programs (SLIP) will only be successful if parents consent to their children's participation. It is critical to understand parent perspectives regarding the factors that make them more or less likely to provide that consent. Organizations creating SLIPs will be able to capitalize on the aspects of SLIPs that parents appreciate, and address and correct issues that may give rise to parent concerns. This study involved five focus groups among the parents of school students in a large, urban school district. Findings highlight the broad range of concepts important to parents when considering participation in a SLIP. The safety and trust issues regarding vaccines in general that are so important to parents are also important to parents when considering participation in a SLIP. Effective communication strategies that include assurances regarding tracking of information and the competence and experience of immunizers will be helpful when addressing parents regarding SLIPs. In addition, parents were very cognizant of and positive regarding the public health benefits associated with SLIPs. Further study among larger populations of parents will further refine these ideas and aid in the development of successful influenza vaccine SLIPs that directly address and communicate with parents about the issues most important to them.

Rotavirus genotypes in Malaysia and Universal rotavirus vaccination

Way Seah Lee, Benjamin Tze Ying Lim, Pei Fan Chai, Carl D. Kirkwood and Jimmy Kok Foo Lee
Pages 1401 - 1406
http://dx.doi.org/10.4161/hv.21577
Abstract | PDF

Group A rotavirus (RV-A) genotypes isolated in Malaysia was studied to estimate the effectiveness of a universal RV-A vaccination in Malaysia. A simple mathematical model was used, with input from a two-year, two-center, prospective study on hospitalization of RV-A gastroenteritis (RVGE) in young children, published data on RV-A hospitalizations and genotypes, mortality on childhood GE and published genotype-specific efficacy data on two RV-A vaccines. Assuming a 95% vaccine coverage, the overall projected effectiveness was 75.7 to 88.1% for Rotateq® and 78.7 to 90.6% for Rotarix® against RVGE-related hospitalizations. The projected annual reduction in RVGE-related deaths was 27 to 32 deaths (from 34 deaths) for Rotateq® and 28 to 32 deaths annually forRotarix®. A universal RV-A vaccine is efficacious in reducing RVGE-related hospitalizations and mortality in Malaysia.

Impact of rotavirus vaccination in regions with low and moderate vaccine uptake in Germany

Sandra Dudareva-Vizule, Judith Koch, Matthias an der Heiden, Doris Oberle, Brigitte Keller-Stanislawski and Ole Wichmann
Pages 1407 - 1415
http://dx.doi.org/10.4161/hv.21593
Abstract | Full Text | PDF

In Germany, routine RV-vaccination is not adopted into the national immunization schedule as of 2012. Because RV-vaccines were already on the market since 2006, in 2010 a moderate (58%) and low (22%) vaccine uptake was observed in the 5 eastern federal states (EFS) and the 11 western federal states (WFS), respectively. To assess the impact of RV-vaccination, we compared the incidence rates (IR) of RV-related hospitalizations before (2004‒2006) and in seasons after (2008/09–2010/11) RV-vaccine introduction in Germany by utilizing data from the national mandatory disease reporting system. In the EFS, the IR was significantly reduced in age-groups < 18 mo in 2008/09 and in age-groups < 24 mo in 2009/10–2010/11. In the WFS an IR-reduction was observed only in age-groups < 12 mo in 2008/09 and in age-groups < 18 mo in 2009/10–2010/11. Overall IR-reduction in age-groups < 24 mo comparing 2008–11 with 2004–06 was 36% and 25% in EFS and WFS, respectively. In addition, we computed IR-ratios (IRR) in the seasons after mid-2006 with negative binomial regression. The effect of vaccination was independent from the geographic region. Vaccination was associated with a significant reduction in RV-related hospitalizations in the age-groups 6–23 mo. Most prominently, vaccination of 50% of infants led to an estimated decrease in age group 6–11 mo by 42%. No significant reduction was observed in age-groups ≥ 24 mo. In conclusion, in the German setting with low to moderate vaccine uptake, RV-related hospitalization incidence decreased substantially depending on the achieved vaccination coverage, but only in the first two years of life.

Maturation and upregulation of functions of murine dendritic cells (DCs) under the influence of purified Aromatic-Turmerone (AR)

Tan Yonggang, Meng Yiming, Zhang Heying, Sun Cheng, Wang Qiushi, Yang Xianghong, Zheng Wei, Zhou Huawei and Fengping Shan
Pages 1416 - 1424
http://dx.doi.org/10.4161/hv.21526
Abstract | Full Text | PDF

The aim of this work is to evaluate the effects of purified aromatic-turmerone(ar-turmerione, AR) on murine dendritic cells (DCs). These impacts of AR on DCs from bone marrow derived DCs(BMDCs) were assessed with use of conventional scanning electron microscopy (SEM), fluorescence activated cell sorting (FACS), transmission electron microscopy (TEM), cytochemistry assay, FITC-dextran, bio-assay and enzyme linked immunosorbent assay (ELISA). We found that AR induced phenotypic maturation as evidenced by increased expression of CD86, CD40, CD83, CD80 and major histocompatibility complex II (MHC II). The functional tests showed the activity of acidic phosphatase (ACP) inside the DCs were downregulated after treatment with AR (which occurs when phagocytosis of DCs were decreased). Finally, we proved that AR increased the production of IL-12 and tumor necrosis factor α (TNF-α). These data suggested that AR could promote phenotypic and functional maturation of DCs and this adjuvant-like activity may have potential therapeutic value. It is therefore concluded that AR could exert positive modulation on murine DCs.

HIV-1 Tat B-cell epitope vaccination was ineffectual in preventing viral rebound after ART cessation: HIV rebound with current ART appears to be due to infection with new endogenous founder virus and not to resurgence of pre-existing Tat-dependent viremia

Gideon Goldstein, Eve Damiano, Mardik Donikyan, Malika Pasha, Erik Beckwith and John Chicca
Pages 1425 - 1430
http://dx.doi.org/10.4161/hv.21616
Abstract | Full Text | PDF

CD4 T cell activation, essential for productive HIV infection, is provided initially in acute HIV infection by innate immune system secretion of activating cytokines. This cytokine response wanes with time and long-term activation of CD4 cells is maintained by HIV Tat protein secreted by HIV infected cells. Structured treatment interruption (STI) in well-controlled antiretroviral-treated (ART) subjects was explored a decade ago with a consensus finding that, in most subjects, HIV levels rebounded within four weeks to pre-ART levels. Based on these observations we initiated a randomized placebo-controlled study of a universal anti-Tat epitope vaccine, TUTI-16, to determine if immunological blockade of Tat would prevent HIV rebound after ART cessation. TUTI-16 immunization was safe, with predominantly mild local and systemic injection-related adverse reactions. TUTI-16 was also immunogenic, with high levels of anti-Tat antibodies compared with levels previously shown to reduce HIV replication in vivo. Of 21 subjects analyzed, 13 (62%) had HIV rebounds vs. 8 (38%) that remained aviremia, but this distribution was not vaccine-related (p = 0.61 log-rank (Mantel-Cox) test), nullifying our hypothesis that anti-Tat antibodies would block rebound of Tat-dependent set-point HIV viremia after ART cessation. Our present findings are consistent with recent molecular findings that rebounding virus following STI is homogeneous and unrelated to previous circulating HIV, suggesting that rebounding HIV represents new founder virus, akin to the original acute HIV infection. We propose, therefore, that STI may have potential as a practical and economical approach to testing the safety and efficacy of candidate prophylactic HIV vaccines.




COMMENTARIES

Business models and opportunities for cancer vaccine developers

Alex Kudrin
Pages 1431 - 1438
http://dx.doi.org/10.4161/hv.20629
Abstract | Full Text | PDF

Despite of growing oncology pipeline, cancer vaccines contribute only to a minor share of total oncology-attributed revenues. This is mainly because of a limited number of approved products and limited sales from products approved under compassionate or via early access entry in smaller and less developed markets. However revenue contribution from these products is extremely limited and it remains to be established whether developers are breaking even or achieving profitability with existing sales. Cancer vaccine field is well recognized for high development costs and risks, low historical rates of investment return and high probability of failures arising in ventures, partnerships and alliances. The cost of reimbursement for new oncology agents is not universally acceptable to payers limiting the potential for a global expansion, market access and reducing probability of commercial success. In addition, the innovation in cancer immunotherapy is currently focused in small and mid-size biotech companies and academic institutions struggling for investment. Existing R&D innovation models are deemed unsustainable in current “value-for-money” oriented healthcare environment. New business models should be much more open to collaborative, networked and federated styles, which could help to outreach global, markets and increase cost-efficiencies across an entire value chain. Lessons learned from some developing countries and especially from South Korea illustrate that further growth of cancer vaccine industry will depends not only on new business models but also will heavily rely on regional support and initiatives from different bodies, such as governments, payers and regulatory bodies.

Tetanus toxoid vaccine: Elimination of neonatal tetanus in selected states of India

Ramesh Verma and Pardeep Khanna
Pages 1439 - 1442
http://dx.doi.org/10.4161/hv.21145
Abstract | Full Text | PDF

Tetanus is caused by a neurotoxin produced by Clostridium tetani (C. tetani), a spore-forming bacterium. Infection begins when tetanus spores are introduced into damaged tissue. Tetanus is characterized by muscle rigidity and painful muscle spasms caused by tetanus toxin’s blockade of inhibitory neurons that normally oppose and modulate the action of excitatory motor neurons. Maternal and neonatal tetanus (MNT) are caused by unhygienic methods of delivery, abortion, or umbilical-cord care. Maternal and neonatal tetanus are both forms of generalized tetanus and have similar clinical courses. About 90% of neonates with tetanus develop symptoms in the first 3–14 d of life, mostly on days 6–8, distinguishing neonatal tetanus from other causes of neonatal mortality which typically occur during the first two days of life. Overall case fatality rates for patients admitted to the hospital with neonatal tetanus in developing countries are 8–50%, while the fatality rate can be as high as 100% without hospital care. Tetanus toxoid (TT) vaccination of pregnant women to prevent neonatal tetanus was included in WHO’s Expanded Program on Immunization (EPI) a few years after its inception in 1974. In 2000, WHO, UNICEF, and UNFPA formed a partnership to relaunch efforts toward this goal, adding the elimination of maternal tetanus as a program objective, and setting a new target date of 2005. By February 2007, 40 countries had implemented tetanus vaccination campaigns in high-risk areas, targeting more than 94 million women, and protecting more than 70 million subjects with at least two doses of TT. In 2011, 653 NT cases were reported in India compared with 9313 in 1990. As of February 2012, 25 countries and 15 States and Union Territories of India, all of Ethiopia except Somaliland, and almost 29 of 34 provinces in Indonesia have been validated to have eliminated MNT.

The "real world" barriers and solutions to Candida vaccine patent prosecutions: An analysis of US Patent and Trademark Office actions on related applications

Shyh-Jen Wang
Pages 1443 - 1449
http://dx.doi.org/10.4161/hv.21184
Abstract | Full Text | PDF

The US Patent and Trademark Office (USPTO) adopts recent patent courts’ opinions (such as KSR In re Fisher and Ariad v. Lilly) in patent examinations, which would certainly create barriers to biotech patent prosecution. To identify the barriers to Candida vaccine patent prosecution, we analyzed 99 US-granted patents from January 2001 to May 2012 related to Candida vaccines. The rejections were based on factors that included obviousness, novelty, indefiniteness, double patenting, enablement, written description and utility. Based on this investigation, we find that some of these rejections were actually avoidable, and then further provide workable solutions to avoid some of the barriers, especially those related to patentability. These principles recited in this study should also be applicable to other fields of vaccines and immunotherapeutics.

Paracoccidioidomycosis vaccine

Luiz R. Travassos and Carlos P. Taborda
Pages 1450 - 1453
http://dx.doi.org/10.4161/hv.21283
Abstract | Full Text | PDF

Paracoccidioidomycosis is a granulomatous pulmonary infection that is generally controlled by chemotherapy. The efficacy of treatment, however, is limited by the status of the host immune response. The inhibition of a Th-2 immunity or the stimulation of Th-1 cytokines generally increases the efficacy of antifungal drugs.¹ This has been achieved by immunization with an internal peptide of the major diagnostic antigen gp43 of Paracoccidioides brasiliensis. Peptide 10 (QTLIAIHTLAIRYAN) elicits an IFN-γ rich Th-1 immune response that protects against experimental intratracheal infection by this fungus. The combination of chemotherapy with P10 immunization showed additive protective effect even after 30 d of infection or in anergic mice, rendering in general, increased production of IL-12 and IFN-γ and reduction of IL-4 and IL-10. Immunotherapy with P10 even in the absence of simultaneous chemotherapy has been effective using various protocols, adjuvants, nanoparticles, P10-primed dendritic cells, and especially a combination of plasmids encoding the P10 minigene and IL-12. Gene therapy, in a long-term infection protocol succeeded in the virtual elimination of the fungus, preserving the lung structure, free from immunopathological side effects.

Bacterial vectors for active immunotherapy reach clinical and industrial stages

Audrey Le Gouëllec, Xavier Chauchet, Benoit Polack, Laurent Buffat and Bertrand Toussaint
Pages 1454 - 1458
http://dx.doi.org/10.4161/hv.21429
Abstract | Full Text | PDF

Active immunotherapy based on live attenuated bacterial vectors has matured in terms of industrial development and develops through a combination of three phenomena. First, active immunotherapy that stimulates an antigen-specific cytotoxic T-cell immune response has become a reality after several years of work. Second, there is still a need to identify vectors that can deliver antigens to the cytosol of antigen-presenting cells in vivo. Third, the recent progress in the understanding of bacterial lifestyle and in developing genetic engineering tools has enabled the design of bioengineered bugs that are capable of delivering antigens. Here, we review the mechanisms by which clinical bacterial vectors deliver antigens into the cytosol of antigen-presenting cells and summarize the development strategy of the three identified firms in this field.

Open Access Article

Teaching tolerance: New approaches to enzyme replacement therapy for Pompe disease

Leslie P. Cousens, Federico Mingozzi, Sander van der Marel, Yan Su, Richard Garman, Valerie Ferreira, William Martin, David W. Scott and Anne S. De Groot
Pages 1459 - 1464
http://dx.doi.org/10.4161/hv.21405
Abstract | Full Text | PDF

Babies born with Pompe disease require life-long treatment with enzyme-replacement therapy (ERT). Despite the human origin of the therapy, recombinant human lysosomal acid α glucosidase (GAA, rhGAA), ERT unfortunately leads to the development of high titers of anti-rhGAA antibody, decreased effectiveness of ERT, and a fatal outcome for a significant number of children who have Pompe disease. The severity of disease, anti-drug antibody (ADA) development, and the consequences thereof are directly related to the degree of the enzyme deficiency. Babies born with a complete deficiency GAA are said to have cross-reactive immunologic material (CRIM)–negative Pompe disease and are highly likely to develop GAA ADA. Less frequently, GAA ADA develop in CRIM-positive individuals. Currently, GAA-ADA sero-positive babies are treated with a combination of immunosuppressive drugs to induce immunological tolerance to ERT, but the long-term effect of these regimens is unknown. Alternative approaches that might redirect the immune response toward antigen-specific tolerance without immunosuppressive agents are needed. Methods leading to the induction of antigen-specific regulatory T cells (Tregs), using peptides such as Tregitopes (T regulatory cell epitopes) are under consideration for the future treatment of CRIM-negative Pompe disease. Tregitopes are natural T cell epitopes derived from immunoglobulin G (IgG) that cause the expansion and activation of regulatory T cells (Treg). Teaching the immune system to tolerate GAA by co-delivering GAA with Tregitope peptides might dramatically improve the lives of CRIM-negative babies and could be applied to other enzyme replacement therapies to which ADA have been induced.

Vaccine for the mind: Immunity against self at the choroid plexus for erasing biochemical consequences of stressful episodes

Michal Schwartz and Kuti Baruch
Pages 1465 - 1468
http://dx.doi.org/10.4161/hv.21649
Abstract | Full Text | PDF

Stressful episodes or chronic stress can shape our brain, leaving behind their biochemical signature on the neural tissue parenchyma. Mitigating such detrimental effects on the central nervous system (CNS) would be advantageous for coping with stress. While the underlying mechanisms that facilitate this response are still a mystery, recent studies demonstrate that boosting specific components of circulating immunity can potentially enhance our ability to deal with stressors. Yet, the fact that the adaptive arm of the immune system is largely excluded from directly interacting with the healthy CNS raises a key question as to how these cells exert their beneficial effects. Boosting immunity against self by active immunization with CNS-derived peptides was shown to reduce anxiety levels and to modulate hippocampal plasticity. These effects correlate with increased immune surveillance at the borders of the brain; specifically, at the choroid plexus (CP), an epithelial layer that resides at the junction between the blood circulation, and the brain and plays a key role in maintaining and restoring brain homeostasis, regulating cerebrospinal-fluid (CSF) production and neurotropic factors composition. Here, we suggest that immunomodulation of this site by active immunization could protect against stressful episodes, thereby providing a therapeutic, as well as preventive, vaccine for the mind against stress and depression.





Allergy Vaccines and Immunotherapeutics

SPECIAL FOCUS REVIEWS

Open Access Article

House dust allergy and immunotherapy

Wayne R. Thomas
Pages 1469 - 1478
http://dx.doi.org/10.4161/hv.20812
Abstract | Full Text | PDF

HDM allergy is associated with asthma, allergic rhinitis and atopic dermatitis. In many countries childhood asthma is predominantly found in HDM-allergic children with their probability of developing disease being proportional to their IgE antibody titers and the early development of Th2 responses. While the pathogenesis is complex and increasingly linked to infection the immunologically-based allergen immunotherapy and anti-IgE antibody therapy are highly beneficial. Immunotherapy could be a short-term treatment providing lifelong relief but the current regimens depend on repeated administration of allergen over years. Immunological investigations point to a contribution of responses outside the Th2 pathway and multiple potential but unproven control mechanisms. Over half of the IgE antibodies are directed to the group 1 and 2 allergens with most of remainder to the group 4, 5, 7 and 21 allergens. This hierarchy found in high and low responders provides a platform for introducing defined allergens into immunotherapy and defined reagents for investigation.

Future therapies for food allergy

Laurie M. McWilliams, Talal Mousallem and A. Wesley Burks
Pages 1479 - 1484
http://dx.doi.org/10.4161/hv.20868
Abstract | Full Text | PDF

Food allergy affects 3.9% of US children and is increasing in prevalence. The current standard of care involves avoidance of the triggering food and treatment for accidental ingestions. While there is no current curative treatment, there are a number of therapeutic strategies under investigation. Allergen specific therapies include oral and sublingual immunotherapy with native food protein as well as recombinant food proteins. Allergen non-specific therapies include a Chinese herbal formula (FAHF-2) and the use of anti-IgE monoclonal antibody therapy. Although none of these treatments are ready for clinical use, these therapeutic strategies present promising options for the future of food allergy.

Novel developments in the mechanisms of immune tolerance to allergens

Thomas Eiwegger, Saskia Gruber, Zsolt Szépfalusi and Cezmi A. Akdis
Pages 1485 - 1491
http://dx.doi.org/10.4161/hv.20903
Abstract | PDF

Allergy is the result of a disbalanced immune response to environmental innocuous antigens. Despite of accumulating data to define the pathomechanisms that take place in case of allergic diseases a detailed understanding of sequence of events that lead to the "normal" scenario of tolerance development are still under debate. Allergen-specific immunotherapy is the only causal treatment of allergic diseases. It modifies the immune response to a particular antigen to achieve tolerance against the symptom-causing allergen. This process is considered to mirror physiological peripheral tolerance induction. A number of immunological changes have been described to occur under allergen immunotherapy, including the generation of allergen-specific regulatory T cells, the induction of allergen-specific IgG4, an increase in the Th1/Th2 cytokine ratio and decreased activation and function of effector cells such as mast cells, basophils and eosinophils.

Adjuvants for allergy vaccines

Philippe Moingeon
Pages 1492 - 1498
http://dx.doi.org/10.4161/hv.21688
Abstract | Full Text | PDF

Allergen-specific immunotherapy is currently performed via either the subcutaneous or sublingual routes as a treatment for type I (IgE dependent) allergies. Aluminum hydroxide or calcium phosphate are broadly used as adjuvants for subcutaneous allergy vaccines, whereas commercial sublingual vaccines rely upon high doses of aqueous allergen extracts in the absence of any immunopotentiator. Adjuvants to be included in the future in products for allergen specific immunotherapy should ideally enhance Th1 and CD4+ regulatory T cell responses. Imunomodulators impacting dendritic or T cell functions to induce IL10, IL12 and IFNγ production are being investigated in preclinical allergy models. Such candidate adjuvants encompass synthetic or biological immunopotentiators such as glucocorticoids, 1,25-dihydroxy vitamin D3, selected probiotic strains (e.g., Lactobacillus and Bifidobacterium species) as well as TLR2 (Pam3CSK4), TLR4 (monophosphoryl lipid A, synthetic lipid A analogs) or TLR9 (CpGs) ligands. Furthermore, the use of vector systems such as mucoadhesive particules, virus-like particles or liposomes are being considered to enhance allergen uptake by tolerogenic antigen presenting cells present in mucosal tissues.

Allergen immunotherapy for allergic respiratory diseases

Antonio Cappella and Stephen R. Durham
Pages 1499 - 1512
http://dx.doi.org/10.4161/hv.21629
Abstract | Full Text | PDF

Allergen specific immunotherapy involves the repeated administration of allergen products in order to induce clinical and immunologic tolerance to the offending allergen. Immunotherapy is the only etiology-based treatment that has the potential for disease modification, as reflected by longterm remission following its discontinuation and possibly prevention of disease progression and onset of new allergic sensitizations. Whereas subcutaneous immunotherapy is of proven value in allergic rhinitis and asthma there is a risk of untoward side effects including rarely anaphylaxis. Recently the sublingual route has emerged as an effective and safer alternative. Whereas the efficacy of SLIT in seasonal allergy is now well-documented in adults and children, the available data for perennial allergies and asthma is less reliable and particularly lacking in children. This review evaluates the efficacy, safety and longterm benefits of SCIT and SLIT and highlights new findings regarding mechanisms, potential biomarkers and recent novel approaches for allergen immunotherapy.

Open Access Article

Drug allergy: Causes and desensitization

Richard Warrington
Pages 1513 - 1524
http://dx.doi.org/10.4161/hv.21889
Abstract | Full Text | PDF

Allergic drug reactions occur when a drug, usually a low molecular weight molecule, has the ability to stimulate an immune response. This can be done in one of two ways. The first is by binding covalently to a self-protein, to produce a haptenated molecule that can be processed and presented to the adaptive immune system to induce an immune response. Sometimes the drug itself cannot do this but a reactive breakdown product of the drug is able to bind covalently to the requisite self-protein or peptide. The second way in which drugs can stimulate an immune response is by binding non-covalently to antigen presenting or antigen recognition molecules such as the major histocompatibility complex (MHC) or the T cell receptor. This is known as the p-I or pharmacological interaction hypothesis. The drug binding in this situation is reversible and stimulation of the response may occur on first exposure, not requiring previous sensitization. There is probably a dependence on the presence of certain MHC alleles and T cell receptor structures for this type of reaction to occur.

New routes for allergen immunotherapy

Pål Johansen, Seraina von Moos, Deepa Mohanan, Thomas M. Kündig and Gabriela Senti
Pages 1525 - 1533
http://dx.doi.org/10.4161/hv.21948
Abstract | Full Text | PDF

IgE-mediated allergy is a highly prevalent disease in the industrialized world. Allergen-specific immunotherapy (SIT) should be the preferred treatment, as it has long lasting protective effects and can stop the progression of the disease. However, few allergic patients choose to undergo SIT, due to the long treatment time and potential allergic adverse events. Since the beneficial effects of SIT are mediated by antigen presenting cells inducing Th1, Treg and antibody responses, whereas the adverse events are caused by mast cells and basophils, the therapeutic window of SIT may be widened by targeting tissues rich in antigen presenting cells. Lymph nodes and the epidermis contain high density of dendritic cells and low numbers of mast cells and basophils. The epidermis has the added benefit of not being vascularised thereby reducing the chances of anaphylactic shock due to leakage of allergen. Hence, both these tissues represent highly promising routes for SIT and are the focus of discussion in this review.


Recombinant allergens: The present and the future

Marek Jutel, Katarzyna Solarewicz-Madejek and Sylwia Smolinska
Pages 1534 - 1543
http://dx.doi.org/10.4161/hv.22064
Abstract | Full Text | PDF

Allergen specific immunotherapy (SIT) is the only known causative treatment of allergic diseases. Recombinant allergen-based vaccination strategies arose from a strong need to both to improve safety and enhance efficacy of SIT. In addition, new vaccines can be effective in allergies including food allergy or atopic dermatitis, which poorly respond to the current treatment with allergen extracts. A number of successful clinical studies with both wild-type and hypoallergenic derivatives of recombinant allergens vaccines have been reported for the last decade. They showed high efficacy and safety profile as well as very strong modulation of T and B cell responses to specific allergens.

Specific immunotherapy in grass pollen allergy

Claire Mailhol and Alain Didier
Pages 1544 - 1547
http://dx.doi.org/10.4161/hv.22357
Abstract | Full Text | PDF

Since its description by Noon in 1911, desensitization, or allergen specific immunotherapy (SIT), has been largely used in respiratory allergic diseases treatment. It remains the only etiologic treatment for allergic diseases. The development of the sublingual route and new forms of medication, as an alternative to subcutaneous injection, has led to large scale clinical trials. Many of them had been performed with allergen tablets, particularly in the field of pollen allergy. These studies have confirmed that SIT is efficient in reducing all respiratory allergic symptoms. Data on long-term benefits and sustained efficacy after stopping treatment have also been published. These show an impact on natural history of allergic disease, in particular, a reduction in the risk of asthma in desensitized rhinitic subjects and in the acquisition of new sensitivities. The basic mechanisms of immunotherapy are becoming better understood and allow us to envisage improvements in this therapeutic method in the future. The sublingual route appears to be safer with a better safety profile. This may lead to an extension of allergen specific immunotherapy indications in patients with respiratory allergic diseases.