2164-5515 Human Vaccines vaccines Austin, Tx Landes Bioscience monthly January 2005 - http://dx.doi.org/10.4161/hv http://www.landesbioscience.com/journals/vaccines/ 2164-5515 Alex Kudrin vaccines Business models and opportunities for cancer vaccine developers Landes Bioscience 2012-10-01 1431 - 1438 Human Vaccines & Immunotherapeutics 8-10 Landes Bioscience 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. http://dx.doi.org/10.4161/hv.20629 http://www.landesbioscience.com/journals/vaccines/article/20629/ article Commentary 2164-5515 Wayne R. Thomas vaccines House dust allergy and immunotherapy Landes Bioscience 2012-10-01 1469 - 1478 Human Vaccines & Immunotherapeutics 8-10 Landes Bioscience 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. http://dx.doi.org/10.4161/hv.20812 http://www.landesbioscience.com/journals/vaccines/article/20812/ article Special Focus Review 2164-5515 Laurie M. McWilliams Talal Mousallem and A. Wesley Burks vaccines Future therapies for food allergy Landes Bioscience 2012-10-01 1479 - 1484 Human Vaccines & Immunotherapeutics 8-10 Landes Bioscience 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. http://dx.doi.org/10.4161/hv.20868 http://www.landesbioscience.com/journals/vaccines/article/20868/ article Special Focus Review 2164-5515 Thomas Eiwegger Saskia Gruber Zsolt Szépfalusi and Cezmi A. Akdis vaccines Novel developments in the mechanisms of immune tolerance to allergens Landes Bioscience 2012-10-01 1485 - 1491 Human Vaccines & Immunotherapeutics 8-10 Landes Bioscience 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. http://dx.doi.org/10.4161/hv.20903 http://www.landesbioscience.com/journals/vaccines/article/20903/ article Special Focus Review 2164-5515 Ramesh Verma and Pardeep Khanna vaccines Tetanus toxoid vaccine: Elimination of neonatal tetanus in selected states of India Landes Bioscience 2012-10-01 1439 - 1442 Human Vaccines & Immunotherapeutics 8-10 Landes Bioscience 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. http://dx.doi.org/10.4161/hv.21145 http://www.landesbioscience.com/journals/vaccines/article/21145/ article Commentary 2164-5515 Shyh-Jen Wang vaccines The "real world" barriers and solutions to Candida vaccine patent prosecutions: An analysis of US Patent and Trademark Office actions on related applications Landes Bioscience 2012-10-01 1443 - 1449 Human Vaccines & Immunotherapeutics 8-10 Landes Bioscience 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. http://dx.doi.org/10.4161/hv.21184 http://www.landesbioscience.com/journals/vaccines/article/21184/ article Commentary 2164-5515 Luiz R. Travassos and Carlos P. Taborda vaccines Paracoccidioidomycosis vaccine Landes Bioscience 2012-10-01 1450 - 1453 Human Vaccines & Immunotherapeutics 8-10 Landes Bioscience 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. http://dx.doi.org/10.4161/hv.21283 http://www.landesbioscience.com/journals/vaccines/article/21283/ article Commentary 2164-5515 Xiao-Ling Li Yan-Xia Zhao Li-Rong Sun Jing Yang and Hui-Juan Xu vaccines The preparation of HL-60 cells vaccine expressing BCG heat shock protein 70 and detection of its immunogenicity in vitro Landes Bioscience 2012-10-01 1376 - 1381 Human Vaccines & Immunotherapeutics 8-10 Landes Bioscience 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. http://dx.doi.org/10.4161/hv.21321 http://www.landesbioscience.com/journals/vaccines/article/21321/ article Research Paper 2164-5515 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 vaccines Teaching tolerance: New approaches to enzyme replacement therapy for Pompe disease Landes Bioscience 2012-10-01 1459 - 1464 Human Vaccines & Immunotherapeutics 8-10 Landes Bioscience 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. http://dx.doi.org/10.4161/hv.21405 http://www.landesbioscience.com/journals/vaccines/article/21405/ article Commentary 2164-5515 Olav Zilian vaccines Scope for innovation in immunotherapy from the financial market’s point of view: Phacilitate Immunotherapy Leaders’ Forum 2012 Landes Bioscience 2012-10-01 1370 - 1372 Human Vaccines & Immunotherapeutics 8-10 Landes Bioscience 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. http://dx.doi.org/10.4161/hv.21413 http://www.landesbioscience.com/journals/vaccines/article/21413/ article Meeting Report 2164-5515 Audrey Le Gouëllec Xavier Chauchet Benoit Polack Laurent Buffat and Bertrand Toussaint vaccines Bacterial vectors for active immunotherapy reach clinical and industrial stages Landes Bioscience 2012-10-01 1454 - 1458 Human Vaccines & Immunotherapeutics 8-10 Landes Bioscience 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. http://dx.doi.org/10.4161/hv.21429 http://www.landesbioscience.com/journals/vaccines/article/21429/ article Commentary 2164-5515 Klaus Breiner vaccines Phacilitate Immunotherapy Leaders‘ Forum: <bold>How to tap into dilutive and non-dilutive funding sources for immunotherapy projects—</bold>Barcelona, May 9–11, 2012 Landes Bioscience 2012-10-01 1373 - 1375 Human Vaccines & Immunotherapeutics 8-10 Landes Bioscience How to tap into dilutive and non-dilutive funding sources for immunotherapy projects. http://dx.doi.org/10.4161/hv.21446 http://www.landesbioscience.com/journals/vaccines/article/21446/ article Meeting Report 2164-5515 Tan Yonggang Meng Yiming Zhang Heying Sun Cheng Wang Qiushi Yang Xianghong Zheng Wei Zhou Huawei and Fengping Shan vaccines Maturation and upregulation of functions of murine dendritic cells (DCs) under the influence of purified Aromatic-Turmerone (AR) Landes Bioscience 2012-10-01 1416 - 1424 Human Vaccines & Immunotherapeutics 8-10 Landes Bioscience 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. http://dx.doi.org/10.4161/hv.21526 http://www.landesbioscience.com/journals/vaccines/article/21526/ article Research Paper 2164-5515 Pawel Grzesiowski Raquel Aguiar-Ibáñez Aleksandra Kobryń Laure Durand and Pierre-Emmanuel Puig vaccines Cost-effectiveness of polysaccharide pneumococcal vaccination in people aged 65 and above in Poland Landes Bioscience 2012-10-01 1382 - 1394 Human Vaccines & Immunotherapeutics 8-10 Landes Bioscience 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. http://dx.doi.org/10.4161/hv.21571 http://www.landesbioscience.com/journals/vaccines/article/21571/ article Research Paper 2164-5515 Amy B. Middleman Mary B. Short and Jean S. Doak vaccines Focusing on flu: Parent perspectives on school-located immunization programs for influenza vaccine Landes Bioscience 2012-10-01 1395 - 1400 Human Vaccines & Immunotherapeutics 8-10 Landes Bioscience 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. http://dx.doi.org/10.4161/hv.21575 http://www.landesbioscience.com/journals/vaccines/article/21575/ article Research Paper 2164-5515 Way Seah Lee Benjamin Tze Ying Lim Pei Fan Chai Carl D. Kirkwood and Jimmy Kok Foo Lee vaccines Rotavirus genotypes in Malaysia and Universal rotavirus vaccination Landes Bioscience 2012-10-01 1401 - 1406 Human Vaccines & Immunotherapeutics 8-10 Landes Bioscience 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. http://dx.doi.org/10.4161/hv.21577 http://www.landesbioscience.com/journals/vaccines/article/21577/ article Research Paper 2164-5515 Sandra Dudareva-Vizule Judith Koch Matthias an der Heiden Doris Oberle Brigitte Keller-Stanislawski and Ole Wichmann vaccines Impact of rotavirus vaccination in regions with low and moderate vaccine uptake in Germany Landes Bioscience 2012-10-01 1407 - 1415 Human Vaccines & Immunotherapeutics 8-10 Landes Bioscience 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. http://dx.doi.org/10.4161/hv.21593 http://www.landesbioscience.com/journals/vaccines/article/21593/ article Research Paper 2164-5515 Gideon Goldstein Eve Damiano Mardik Donikyan Malika Pasha Erik Beckwith and John Chicca vaccines 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 Landes Bioscience 2012-10-01 1425 - 1430 Human Vaccines & Immunotherapeutics 8-10 Landes Bioscience 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. http://dx.doi.org/10.4161/hv.21616 http://www.landesbioscience.com/journals/vaccines/article/21616/ article Research Paper 2164-5515 Antonio Cappella and Stephen R. Durham vaccines Allergen immunotherapy for allergic respiratory diseases Landes Bioscience 2012-10-01 1499 - 1512 Human Vaccines & Immunotherapeutics 8-10 Landes Bioscience 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. http://dx.doi.org/10.4161/hv.21629 http://www.landesbioscience.com/journals/vaccines/article/21629/ article Special Focus Review 2164-5515 Michal Schwartz and Kuti Baruch vaccines Vaccine for the mind: Immunity against self at the choroid plexus for erasing biochemical consequences of stressful episodes Landes Bioscience 2012-10-01 1465 - 1468 Human Vaccines & Immunotherapeutics 8-10 Landes Bioscience 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. http://dx.doi.org/10.4161/hv.21649 http://www.landesbioscience.com/journals/vaccines/article/21649/ article Commentary 2164-5515 Philippe Moingeon vaccines Adjuvants for allergy vaccines Landes Bioscience 2012-10-01 1492 - 1498 Human Vaccines & Immunotherapeutics 8-10 Landes Bioscience 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. http://dx.doi.org/10.4161/hv.21688 http://www.landesbioscience.com/journals/vaccines/article/21688/ article Special Focus Review 2164-5515 Richard Warrington vaccines Drug allergy: Causes and desensitization Landes Bioscience 2012-10-01 1513 - 1524 Human Vaccines & Immunotherapeutics 8-10 Landes Bioscience 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. http://dx.doi.org/10.4161/hv.21889 http://www.landesbioscience.com/journals/vaccines/article/21889/ article Special Focus Review 2164-5515 Pål Johansen Seraina von Moos Deepa Mohanan Thomas M. Kündig and Gabriela Senti vaccines New routes for allergen immunotherapy Landes Bioscience 2012-10-01 1525 - 1533 Human Vaccines & Immunotherapeutics 8-10 Landes Bioscience 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. http://dx.doi.org/10.4161/hv.21948 http://www.landesbioscience.com/journals/vaccines/article/21948/ article Special Focus Review 2164-5515 Marek Jutel Katarzyna Solarewicz-Madejek and Sylwia Smolinska vaccines Recombinant allergens: The present and the future Landes Bioscience 2012-10-01 1534 - 1543 Human Vaccines & Immunotherapeutics 8-10 Landes Bioscience 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. http://dx.doi.org/10.4161/hv.22064 http://www.landesbioscience.com/journals/vaccines/article/22064/ article Special Focus Review 2164-5515 Claire Mailhol and Alain Didier vaccines Specific immunotherapy in grass pollen allergy Landes Bioscience 2012-10-01 1544 - 1547 Human Vaccines & Immunotherapeutics 8-10 Landes Bioscience 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. http://dx.doi.org/10.4161/hv.22357 http://www.landesbioscience.com/journals/vaccines/article/22357/ article Special Focus Review 2164-5515 Ronald Ellis and Eva M. Riedmann vaccines Letter from the Editor Landes Bioscience 2012-10-01 1365 - 1365 Human Vaccines & Immunotherapeutics 8-10 Landes Bioscience http://dx.doi.org/10.4161/hv.22499 http://www.landesbioscience.com/journals/vaccines/article/22499/ article Editor's Corner 2164-5515 Eva M. Riedmann vaccines News Landes Bioscience 2012-10-01 1366 - 1369 Human Vaccines & Immunotherapeutics 8-10 Landes Bioscience 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 http://dx.doi.org/10.4161/hv.22583 http://www.landesbioscience.com/journals/vaccines/article/22583/ article News, Policy and Profiles