[Frontiers in Bioscience S4, 1381-1392, June 1, 2012]
Peptides: an arrival point in cancer vaccinology
Joerg Willers1, Giovanni Capone2, Alberta Lucchese3
1
TABLE OF CONTENTS
1. ABSTRACT
During the past few decades, numerous approaches towards therapeutic vaccines have been investigated. In addition to traditional prophylactic vaccines against infectious microorganisms, there have been attempts to develop therapeutic vaccines for indications as complex as autoimmunity and cancer. Driven by an increasing understanding of the underlying mechanisms, researchers have attempted to interfere with complex molecular cascades during disease progression. Monoclonal antibodies have gained more importance, and their specificity has become more predictable. However, in spite of the advances in our knowledge, crucial problems linger unsolved in vaccinology, such as the major histocompatibility complex (MHC) degeneration phenomenon, the escape from immune surveillance of cancer and microbes, and the possibility of adverse events, perhaps linked to peptide cross-reactivity. In essence, it seems that in order to understand immune responses the peptide-peptide interactions have yet to be clearly defined. These issues will be discussed in the frame of current approaches to vaccine development with special focus on cancer vaccines.
2. VACCINES: AN HISTORICAL OUTLINE
Vaccine research began with the early vaccination trials of Edward Jenner and Louis Pasteur at the end of the 19th century. Since those early days, vaccines have been developed for many infectious diseases that were once major afflictions of mankind. For example, vaccine use has dramatically reduced the incidence of diphtheria, measles, mumps, pertussis, rubella, poliomyelitis, tetanus, and many more. Clearly, vaccination is a cost-effective weapon for disease prevention. An important example is the smallpox vaccine, the use of which has basically eradicated the disease (1). Experience with the smallpox vaccine has been recognized worldwide and has affected many contemporary disease control programs. Besides classical prophylactic vaccines, new treatment modalities have been explored.
At present, there is also growing interest in the development of therapeutic vaccines to treat already established infections or endogenous diseases, as is reflected in growing numbers of recent publications (2). In this respect, detailed knowledge of the differences in the epitopes recognized by T cells and B cells is of utmost importance and has enabled immunologists to design vaccines that activate the humoural and/or the cell-mediated branches of the immune system (3). In order to be successful, the activation of the immune system has to provoke a response that specifically recognizes the disease-associated pathogen. Furthermore, vaccines should stimulate the immune system to develop a long-lasting response that is both curative and protective. An example of an experimental approach that combines both characteristics is an isolated human monoclonal antibody (MAb) against the influenza antigen M2 (4). The MAb was able to protect vaccinated mice from a lethal challenge with influenza virus and cured infected mice as long as the MAb was given 2 to 3 days after infection. However, when the numerous approaches and encouraging preliminary data are translated to clinical practice, the results have not been as successful. For example, vaccine-based attempts to reprogram the immune system so that it will control tumour cell growth or fight infectious diseases have been failing so far (5, 6). With this background, the current review aims to explore the many approaches that have led to the current state of the art in vaccine development with special focus on cancer vaccines.
3. GENERAL CONCEPTS OF VACCINES
3.1. Active versus passive immunization
Before focusing on specific treatments it is necessary to define the various vaccine types. Immunity to infectious microorganisms can be achieved by either active or passive immunization. Furthermore, immunity can be acquired by natural processes or by artificial means involving administration of Abs or vaccines. Detailed knowledge of the mechanism of action is a prerequisite for beneficial interference in situations where the immune system is out of balance.
Active immunization with a dead or attenuated viral pathogen generally provokes a long-term protective memory. Similar results are observed using vaccinations with virus-like particles (VLPs) against human papilloma virus (HPV) infections (7) or with bacterial toxoids, such as tetanus (8). Therefore, active vaccination has the goal of stimulating the immune system to generate a specific and sustained response. Such a response can consist of Abs (humoural immune response), T cells (cellular immune response), or both (combined immune response).
In contrast, passive immunization with polyclonal serum (9)or MAbs (10, 11) against the pathogen provides instant help in situations where the disease or infection has already manifested in the body. However, no long-term protection can be achieved since the treatment does not generate an immunological memory and the effect vanishes with the decay of the therapeutic (12).
3.2. Prophylactic versus therapeutic vaccines
Vaccinations can be distinguished according to the time point of application. An active vaccination can be performed prophylactically, that is before infection or with the purpose of treating an existing disease. In contrast to prophylactic vaccines that are extensively known and used (1, 7), therapeutic use of active vaccination is a relatively new approach. In this respect, it is important to closely examine the target antigens. Targets for therapeutic vaccines can be either foreign- or self-antigens. Depending on the nature of the antigen, the vaccine has to fulfil different criteria. A vaccine against tumour cells (self-antigen), for instance, should stimulate specific T cells in order to be effective (13), while a vaccine against microbes (foreign antigens) should lead to the generation of neutralizing Abs (14).
3.3. B cell versus T cell responses
It is expected that Abs will deal with the pathogen itself (i.e., bacteria, free viruses, and parasites) and T cells act upon infected cells. With this paradigm in mind, what would be the best or appropriate attack against malignant cells or pathologically over-expressed self-structures such as tumour necrosis factor alpha (TNF-alpha) in inflammatory autoimmune diseases? Researchers are trying different approaches. Let us take a closer look at tumour cells. With their tumour-antigen expression profile, do they resemble more parasites, bacteria or viruses, or are they more like infected cells? In the first case, a humoural immune response would be appropriate to deal with the disease. In fact, numerous therapeutic Abs are under investigation (15). The success of these Abs, either passively given or actively stimulated, is diverse. It seems that Abs are a powerful weapon to identify and eliminate single circulating tumour cells, resulting in a prolongation of tumour-free time. However, as a therapeutic to decrease the tumour burden, they are rather disappointing (16).
However, if tumour cells are considered to be more like infected cells, then a cell-mediated immune response would be appropriate. As is the case for infected cells, the immune system requires the presentation of the tumour antigen in association with MHC class I or II; only then can T cells be activated. In this respect, a T cell vaccine is more likely to reduce a tumour mass. Taking both options into consideration, one comes to the conclusion that malignant cells bear both features, those of invading pathogens as well as of infected cells, thus suggesting that a combination therapy consisting of both humoural and cellular attacks will likely be the most effective.
4. ANTIGENS USED FOR VACCINATION
4.1. Carbohydrates
Carbohydrates or polysaccharide antigens are large molecules consisting of repeating epitopes that are not processed by antigen-presenting cells (APC), but interact directly with B cells, inducing antibody synthesis in the absence of T cells (thus designated T-independent antigens). T-independent responses are restricted in a number of ways. For example, they fail to induce significant and sustained amounts of antibody in young children (17). While polysaccharides are immunogenic in older children and adults, the characteristics of the antibody responses are rather restricted. They are dominated by IgM and IgG2, are relatively short lived, and a booster response cannot be elicited on repeated exposure. This failure to induce immunological memory is also reflected in the absence of demonstrable affinity maturation.
4.2. Proteins
While attenuated pathogens provide effective protection from viral infections (18), it is rare to see an attenuated version of a bacterial or parasitic pathogen used as vaccine (19). Thus, the choice is generally limited to immunization with killed pathogens. Activation of both the humoural and cellular immune responses is important (20-22). As the genome sequences of many pathogenic bacteria have become available, a new systematic approach for identification of vaccine candidates, termed reverse vaccinology, has been developed (23). The process begins with the identification of all putative surface proteins, which are a logical choice for vaccine candidates. The surface proteins can be predicted from genomic sequences using computer programs based on signal peptides, transmembrane helices, and other surface protein prediction algorithms (24). The candidate genes are then cloned and the proteins expressed in Escherichia coli. The immune responses of animals are determined after injection of the purified proteins. This approach was successfully applied to identify vaccine candidates in Neisseria meningitidis and has since been applied to identify vaccine candidates for other bacterial pathogens. However, the developed vaccines are constantly challenged by continuous adaptation of surface meningococcal structures to external stimuli resulting in a genetic shift of the epitopes initially recognized by immune responses (25).
T cells influence antibody responses to protein antigens. The consequence of this T cell help is that antibody responses to protein antigens can be elicited in immature immune systems. In addition, immunity is long lived due to the generation of immunological memory. Antibody responses to protein antigens are dominated by the IgG1 and IgG3 subclasses, and affinity maturation influenced by B-cell receptor-antigen binding can be demonstrated over time (26).
4.3. Peptides
Small peptides and in particular self-peptides are poorly immunogenic by themselves and require co-administration with strong adjuvants. For example, Kel et al. (27) administered a self-peptide derived from the proteolipid protein together with complete Freund's adjuvant to mice with experimental encephalomyelitis and observed an inhibition of disease progression. In contrast, self-peptides derived from the glucose-6-phosphate isomerase protein have been shown to induce autoimmune arthritis in a murine model (28). The use of self-peptides also carries the risk of enhancing the pre-existing disease instead of healing it.
4.4. Conjugates
A conjugate vaccine is created by covalently attaching a poorly immunogenic antigen to a carrier protein, thereby conferring the immunological attributes of the carrier on the attached antigen. This technique for creating an effective immunogen can be applied to peptides, small chemical entities, and last but not least to bacterial polysaccharides for the prevention of invasive bacterial disease.
The ability to enhance the immunogenicity of polysaccharide antigens was first noted by Avery and Goebel in 1929 (29, 30). They demonstrated that the poor immunogenicity of purified Streptococcus pneumoniae type 3 polysaccharide in rabbits could be enhanced by conjugation of the polysaccharide to a protein carrier. Their observations have formed the foundation for the modern development of conjugate vaccines.
Recent investigations of HIV-1 infections have demonstrated that virus-like particle (VLP)-carbohydrate conjugates are even more immunogenic when the carbohydrate motif has been slightly altered (31). A vaccine composed of a VLP-carrier conjugated to gp120-derived glycans was able to elicit specific Abs that recognized the altered gp120. Additionally, binding could be inhibited by the known anti-HIV-1 MAb 2G12. However, generated Abs did not show cross-reactivity with wild-type gp120 (31).
Following animal studies, initial human infant studies confirmed the immunogenicity of Haemophilus influenzae type b (Hib) capsular polysaccharide (polyribosylribitol phosphate (PRP)) conjugate vaccines. Formulations of Hib conjugates with different protein carriers, including tetanus toxoid, diphtheria toxoid, mutant diphtheria toxin, and outer membrane protein, have been developed and have been shown to vary both quantitatively and qualitatively in their immunogenicity (32). For example, the PRP antigen conjugated to outer membrane protein has been shown to be immunogenic following a single dose in infancy, while the other formulations have only demonstrated significant immunogenicity after two or three doses. Antibody avidity induced by different Hib conjugates has also been shown to vary, as has Hib variable region gene usage. Prototypes of the pneumococcal and meningococcal conjugate vaccines demonstrated enhanced immunogenicity compared with plain polysaccharide formulations in infants and young children. Furthermore, formulations using different carrier proteins have similarly been shown to vary in their avidity.
The relative importance of memory versus circulating antibody levels for clinical protection by conjugate vaccines is unclear; however, it is interesting to note that even the least immunogenic of the Hib conjugates, PRP-D, has been shown to be efficacious in reducing the incidence of invasive Hib infection in Finland. The efficacy of such formulations may thus be related to the ability of the conjugate vaccines to prime for memory, even in the face of poor primary immunogenicity (33). Demonstration of the presence of immunological memory is thus increasingly being used in the evaluation of further formulations. The success of the Hib conjugate vaccines in reducing the incidence of invasive Hib disease in childhood has accelerated the development of conjugate vaccines designed to prevent infection by other encapsulated bacteria. The imperative driving the development of such vaccines has been the need to find a vaccine formulation that renders bacterial capsular polysaccharides immunogenic in those patients who are most at risk for infection.
5. TREATMENT MODALITIES
5.1. Antibodies against self-antigens
During the past few decades, increasing numbers of MAbs against self-structures have been developed to cope with various diseases. Initially very successful, these MAbs turned out to carry increasing risks of unwanted side effects. One of the best-investigated examples is rheumatoid arthritis (RA) where MAbs against TNF-alpha reduce inflammatory symptoms in the patient, but also increase the patient's susceptibility to infections like tuberculosis (34). In this context some researchers are sceptical of the safety and efficacy of such approaches (35).
Vaccination against self-structures is an old concept adopted from the area of cancer therapeutics. Here, researchers tried for a long time to stimulate Abs effective against cancer cells. Cancer cells are basically self-structures with a misdirected cell program and the immune system has learned to tolerate such altered tissue. This tolerance was originally thought to be manifested by the absence of autoreactive immune cells; however, recent research has shown that it is more likely due to regulation/suppression of existing autoreactive cells (36, 37). This self-tolerance has to be overcome if an effective anti-tumour therapy is to be achieved. As a consequence, one has to try to develop an artificial autoimmune disease in the cancer patient where immune cells are directed against self-structures. If the self-tolerance has been broken, the important task in this scenario is how to control the resulting immune response, so that it is not overacting and/or causing negative side effects.
Immunosuppressive MAbs act by one of two general mechanisms. Some MAbs trigger the destruction of lymphocytes in vivo, and are referred to as depleting (e.g., Rituximab (38)), while others are non-depleting and act by blocking the function of their target protein without killing the cell that bares it (e.g., Ipilimumab (39)).
Autoimmune disease is only detected once the autoimmune response has caused tissue damage or disturbed specific functions. There are three main approaches to treatment. First, anti-inflammatory therapy (e.g. IL1) can reduce tissue injury caused by an inflammatory autoimmune response; second, immunosuppressive therapy (e.g. steroids) may be aimed at reducing the autoimmune response; and third, treatment may be directed specifically at the organ systems damaged by the disease. The diabetes induced by autoimmune attack on pancreatic cells is treated with insulin. Insulin is used to directly compensate for the loss of beta-cells while most recently anti-IL-1b therapy has shown additional benefit of anti-inflammatory action. Anti-inflammatory therapy for autoimmune diseases includes the use of anti-cytokine Abs; anti-TNF-alpha, or more recently anti IL-17 Abs induce striking temporary remissions in rheumatoid arthritis (40, 41). Abs can also be used to block cellular migration to sites of inflammation. For example, anti-CD18 Abs prevent tight leukocyte adhesion to vascular endothelium and reduce inflammation in animal models of disease (42). In contrast to passive immunization with MAbs, several approaches have explored to break self-tolerance and thereby to stimulate a therapeutic immune response. Approaches, such as a combination of chemotherapy and protein vaccination (murine cancer model (43)) or a virus-like particle conjugate (human hypertension (44)) positively interfere with the immune system. Additionally in cancer, the tumour microenvironment can be modified with transforming growth factor-beta to increase susceptibility of the immune system towards the vaccine (45-47). Selective inhibition of IgE may benefit patients with allergies. In animal models, for example, MAbs to IL-4 have been used to decrease IgE production (48).
5.2. Cellular vaccines
Cellular vaccines using antigen-presenting cells, such as dendritic cells (DCs), are known to reliably generate effective T cell immunity. Recently, virus-infected DCs that express Her-2/neu have been reported to induce stronger Her-2/neu-specific cytotoxic T lymphocytes (CTLs) than did DNA vaccination (49). Furthermore, several reports have shown that mature DCs can break self-tolerance against tumour-associated antigens, thus inducing activated self antigen-specific CTLs (50-53). Although a peptide-loaded DC immunization can break self-tolerance at the cellular level by activating autoreactive CTLs, host levels of antitumor responses are governed by a diverse regulatory mechanism established between the host and tumour environments.
6. APPLICATION TO CANCER VACCINES
6.1. Peptide-based vaccines
Often a peptide is not sufficient to immunize, but needs to be combined with T cells and cytokines (54). In this way, the tolerant (silent) stage of autoreactive T cells can be converted (55), which is vital for development of an effective vaccine against pathologic autoantigens. Although many adjuvants have been investigated for peptide immunotherapies, to-date current strategies such as particulates, oil emulsions, toll-like receptor ligands, immunostimulatory complexes, and other biologically sourced materials utilize chemically or structurally heterogeneous materials, making their characterization, mechanistic understanding, and anticipation of side-effects challenging (56-59). In general, the development of peptide vaccines has been challenged by imprecise antigen display and the use of heterogeneous immune adjuvants whose mechanisms of action are both complex and incompletely understood (45).
Within the last decade, we and others (60-67) proposed vaccines based on low-similarity peptides (e.g., peptide sequences not present or scarcely represented in the host proteome). This approach promises to be specific, flexible, and universal. Indeed, synthetic peptides are useful as antigens because their precise chemical definition allows one to specify the exact epitopes against which an immune response has to be raised (68, 69). Moreover, short peptide modules can be easily synthetized and administered, are less likely to induce collateral adverse events (70, 71), may be selected for activity against a broad range of (sub)strains and species of a given microbe, and are quickly modifiable to fight emerging mutated types (72-74).
Finally, and of no less importance, short epitopic amino acid modules might also be of help in autoimmune disorders. Specifically, they have the potential to block circulating autoantibodies against recognizing self-molecules and tissues (75).
6.2. Immunization with mimetic peptides (mimotopes)
The definition of epitope peptide mimics, i.e., mimotopes, was made feasible by the screenings of random peptide phage display libraries (76). Immunization with mimotopes may induce epitope-specific anti-cancer Abs (77). They are capable of eliciting Abs with biologic properties comparable to those of the original MAbs, with the advantages of production by the patient him- or herself. Additionally, the resulting Abs are not restricted to one given isotype, but are of various antibody classes, and thus able to mediate the full range of immune effector mechanisms. Moreover, the induction of immunological memory could prove beneficial in the event of disease recurrence. So far only animal studies are available, but these are very promising for a variety of antigens, and warrant translation of this approach into humans.
Recent investigations have transposed the principle of vaccination against tumour antigens using carbohydrates, particularly GD2. GD2 is a ganglioside expressed on tumour cells of neuroectodermal origin, and the antigen used for vaccination is a peptide mimic of GD2. This so-called mimotope elicited GD2 cross-reactive IgG Abs, as well as MHC class I-restricted CD8+ T cells, to syngeneic neuroblastoma tumour cells (78). Furthermore, the same principle is applied to certain other carbohydrate tumour antigens. It was shown in non-human experiments that immunization with a carbohydrate-peptide conjugate resulted in a substantial humoural immune response specific for antigen-expressing tumour cells (79, 80). Additionally, small chemical entities profit from conjugation to a carrier and gain immunogenicity in humans (81).
One special type of conjugate contains a carrier component that resembles viral structures. So-called 'virus-like-particles' (VLPs) are typically protein shells with an ordered structure that displays the antigen of choice in a repetitive way. Unlike 'real' viruses, VLPs do not replicate or integrate into the host's genome. The strong immunogenicity of VLPs helps to break the self-tolerance to stimulate a humoural immune response, at least in animal disease models of clinical relevance (82, 83). Several VLP-based vaccines have been shown pre-clinical efficacy (84-86) and some have entered clinical development (44, 87, 88).
6.3. Towards low-similarity peptides in the design of vaccines
A wide array of themes has unfolded in the previous paragraphs, although they do not cover all research areas due to space constraints. Nevertheless, we have shown several pathways that scientists have explored to find 'the vaccine'. The theoretical vaccine formulation platform must be able to fight/neutralize a disease, be safe for the patient, and be globally applicable. However, looking at the numbers, it seems that despite the high hopes, the results have been scarce in terms of global health. In 2011, we still witness the emergence of new infectious diseases, the re-emergence of old diseases, and the persistence of intractable diseases. For example, influenza pandemics and West Nile virus outbreaks represent constant threats. HIV/AIDS, HCV, human B19 erythrovirus, malaria, and tuberculosis - to cite only a few diseases - show an increasing incidence, and most attempts to develop vaccines have failed (89-91). Cancer continues to be a plague (92, 93). With the due caveats and proper proportions, the current clinical situation is not so much different from that of 1905, when Ehrlich shifted from immunology to chemotherapy: "I have, generally speaking, the impression that it is necessary that I concentrate all of my energy, consistent with my innate ability, to chemical therapy. Now is the moment to confront the major types of illness (protozoan diseases) from the direction of chemical approaches, which are not very open to immunization therapy" (94), as cited by Silverstein (95). In other words, the immunological armamentarium accumulated during the last century and outlined above has not defeated cancer and infectious diseases. In this regard, the main obstacles to the translation of this immunological theoretical framework into effective clinical applications are represented by unsolved phenomena such as the heavy degeneracy of MHC molecules (96-98).
The broad binding capacity of MHC molecules and the consequent lack of discrimination expected in their peptide-binding capability are obvious obstacles to specific immune targeting. To complicate the issue, Buus et al. (99) observed that only 5-10% of affinity-purified MHC class II molecules are available to bind, the others being constitutively occupied by self-peptides. It seems that evoking effective T cell responses implies careful tests such as analysis of the TCR affinity threshold delimiting maximal CD8 T cell function (100, 101), identification of factors which accelerate the dissociation of the peptide from an unstable intermediate of the binding reaction, thus mediating the binding of the high-affinity peptide to class I (102), and measurement of the peptide-MHC class II complex stability that possibly governs CD4 T cell clonal selection.
An additional major safety question is how to control an immune response to self-peptides in a way that does not lead to overacting autoimmune disease. One major objection to vaccination protocols consists of the potential adverse effects that are ascribed to adjuvants (103-105).
It is possible that, as recently suggested (106-109), adverse effects ascribed to adjuvants and cross-reactions with the host proteins might be related. Indeed, a massive peptide overlap exists between microbes and human proteins (73, 106, 107, 110-117). Hence, it is logical to hypothesize that human anti-microbial immune reactions are prevented by the tight self-tolerance mechanisms that protect our organism. That would also explain the well-known phenomenon of microbial escape from immune surveillance and the consequent necessity of adding adjuvants to anti-microbial vaccine formulations in order to evoke immune responses. In parallel, the highest peptide redundancy exists among human proteins, thus underlying tumour escape mechanisms (113, 118). In addition, adjuvant-induced immunogenicity might also derange immune system activity and its fine modulation, therefore explaining autoimmunity, which usually accompanies cancer regression and microbe neutralization following adjuvanted vaccination (108, 119-122).
In such a complex context, analysing the structural and molecular features of the interactions between effector cells, Abs, and antigens at the peptide level might provide the tools for designing targeted vaccines. Indeed, analysis of peptide commonality between the antigen and the human host appears to be a practical method for designing safe, targeted, and effective peptide vaccines (65, 66, 71-74, 123). Selection of peptide sequences unique to microbes or tumour-associated-antigens would specifically hit the microbial agents or tumours without cross-reacting with host proteins. That is, the risk of autoimmunity would be nullified in such low-similarity peptide vaccines. The positive implications of this approach for clinical practice would obviously be paramount.
In conclusion, notwithstanding our increasing knowledge of the mechanism of vaccination, there is still a long way to go until therapeutic vaccines can be broadly used. The most critical obstacles are firstly, the multiple measures the immune system can take to prevent or circumvent autoimmunity; it is of course of eminent importance for the survival of the organism to avoid self-attacks. Secondly, one has to be able to control a potential therapeutic autoimmune response; otherwise the effects are even worse (124). This can be accomplished via neutralizing Abs or immune-suppressant treatments. However, in any case the benefits and risks have to be judged before a therapeutic vaccination is started.
Within this framework, based on the scientific and clinical problems that have constellated the field of vaccine research, Figure 1 illustrates a methodological pathway and describes already available technologies for designing safe and effective immunotherapeutic approaches against cancer, infectious diseases, and autoimmune pathologies.
7. REFERENCES
1. E Tognotti: The eradication of smallpox, a success story for modern medicine and public health: what lessons for the future? J Infect Dev Ctries 4, 264-266 (2010)
http://dx.doi.org/10.3855/jidc.1204
2. SA Plotkin: Vaccines: the fourth century. Clin Vaccine Immunol 16, 1709-1719 (2009)
http://dx.doi.org/10.1128/CVI.00290-09
3. M Sela, E Mozes: Therapeutic vaccines in autoimmunity. Proc Natl Acad Sci USA 101, 14586-14592 (2004)
http://dx.doi.org/10.1073/pnas.0404826101
4. RR Beerli, M Bauer, N Schmitz, RB Buser, M Gwerder, S Muntwiler, WA Renner, P Saudan, MF Bachmann: Prophylactic and therapeutic activity of fully human monoclonal antibodies directed against influenza A M2 protein. Virol J 6, 224 (2009)
http://dx.doi.org/10.1186/1743-422X-6-224
5. MM Davis: A prescription for human immunology. Immunity 29, 835-838 (2008)
http://dx.doi.org/10.1016/j.immuni.2008.12.003
6. RN Germain: Vaccines and the future of human immunology. Immunity 33, 441-450 (2010)
http://dx.doi.org/10.1016/j.immuni.2010.09.014
7. L Mariani, A Venuti: HPV vaccine: an overview of immune response, clinical protection, and new approaches for the future. J Transl Med 8, 105 (2010)
http://dx.doi.org/10.1186/1479-5876-8-105
8. RF Edlich, LG Hill, CA Mahler, MJ Cox, DG Becker, JH Horowitz, LS Nichter, ML Martin, WC Lineweaver: Management and prevention of tetanus. J Long Term Eff Med Implants 13, 139-154 (2003)
http://dx.doi.org/10.1615/JLongTermEffMedImplants.v13.i3.20
9. RC Kankonkar, DG Kulkurni, CB Hulikavi: Preparation of a potent anti-scorpion-venom-serum against the venom of red scorpion (Buthus tamalus). J Postgrad Med 44, 85-92 (1998)
10. CE Griffiths, BE Strober, P van de Kerkhof, V Ho, R Fidelus-Gort, N Yeilding, C Guzzo, Y Xia, B Zhou, S Li, LT Dooley, NH Goldstein, A Menter, ACCEPT Study Group: Comparison of ustekinumab and etanercept for moderate-to-severe psoriasis. N Engl J Med 362, 118-128 (2010)
http://dx.doi.org/10.1056/NEJMoa0810652
11. I Lowy, DC Molrine, BA Leav, BM Blair, R Baxter, DN Gerding, G Nichol, WD Jr Thomas, M Leney, S Sloan, CA Hay, DM Ambrosino: Treatment with monoclonal antibodies against Clostridium difficile toxins. N Engl J Med 362, 197-205 (2010)
http://dx.doi.org/10.1056/NEJMoa0907635
12. R Deng, S Iyer, FP Theil, DL Mortensen, PJ Fielder, S Prabhu: Projecting human pharmacokinetics of therapeutic antibodies from nonclinical data: What have we learned? MAbs 3, 61-66 (2011)
http://dx.doi.org/10.4161/mabs.3.1.13799
13. H Bernhard, L Salazar, K Schiffman, A Smorlesi, B Schmidt, KL Knutson, ML Disis: Vaccination against the HER-2/neu oncogenic protein. Endocr Relat Cancer 9, 33-44 (2002)
http://dx.doi.org/10.1677/erc.0.0090033
14. LM Walker, DR Burton: Rational antibody-based HIV-1 vaccine design: current approaches and future directions. Curr Opin Immunol 22, 358-366 (2010)
http://dx.doi.org/10.1016/j.coi.2010.02.012
15. AL Nelson, E Dhimolea, JM Reichert: Development trends for human monoclonal antibody therapeutics. Nat Rev Drug Discov 9, 767-774 (2010)
http://dx.doi.org/10.1038/nrd3229
16. RL Ferris, EM Jaffee, S Ferrone: Tumor antigen-targeted, monoclonal antibody-based immunotherapy: clinical response, cellular immunity, and immunoescape. J Clin Oncol 28, 4390-4399 (2010)
http://dx.doi.org/10.1200/JCO.2009.27.6360
17. P Klein Klouwenberg, L Bont: Neonatal and infantile immune responses to encapsulated bacteria and conjugate vaccines. Clin Dev Immunol 2008, 628963 (2008)
http://dx.doi.org/10.1155/2008/628963
18. AS Lauring, JON Jones, R Andino: Rationalizing the development of live attenuated virus vaccines. Nat Biotechnol 28, 573-579 (2010)
http://dx.doi.org/10.1038/nbt.1635
19. R Curtiss: Bacterial infectious disease control by vaccine development. J Clin Invest 110, 1061-1066 (2002)
http://dx.doi.org/10.1172/JCI200216941
20. RT Evans, B Klausen, HT Sojar, GS Bedi, C Sfintescu, NS Ramamurthy, LM Golub, RJ Genco: Immunization with Porphyromonas (Bacteroides) gingivalis fimbriae protects against periodontal destruction. Infect Immun 60, 2926-2935 (1992)
21. GD Healey, SJ Elvin, M Morton, ED Williamson: Humoral and cell-mediated adaptive immune responses are required for protection against Burkholderia pseudomallei challenge and bacterial clearance postinfection. Infect Immun 73, 5945-5951 (2005)
http://dx.doi.org/10.1128/IAI.73.9.5945-5951.2005
22. G Szalay, CH Ladel, SH Kaufmann: Stimulation of protective CD8+ T lymphocytes by vaccination with nonliving bacteria. Proc Natl Acad Sci U S A 92, 12389-12392 (1995)
http://dx.doi.org/10.1073/pnas.92.26.12389
23. DG Moriel, M Scarselli, L Serino, M Mora, R Rappuoli, V Masignani: Genome-based vaccine development: a short cut for the future. Hum Vaccin 4, 184-188 (2008)
http://dx.doi.org/10.4161/hv.4.3.6313
24. CD Rinaudo, JL Telford, R Rappuoli, KL Seib: Vaccinology in the genome era. J Clin Invest 119, 2515-2525 (2009)
http://dx.doi.org/10.1172/JCI38330
25. I de Filippis: Quest for a broad-range vaccine against Neisseria meningitidis serogroup B: implications of genetic variations of the surface-exposed proteins. J Med Microbiol 58, 1127-1132 (2009)
http://dx.doi.org/10.1099/jmm.0.011189-0
26. W Liu, T Meckel, P Tolar, HW Sohn, SK Pierce: Antigen affinity discrimination is an intrinsic function of the B cell receptor. J Exp Med 207, 1095-1111 (2010)
http://dx.doi.org/10.1084/jem.20092123
27. JM Kel, B Slutter, JW Drijfhout, F Koning, L Nagelkerken: Mannosylated self-peptide inhibits the development of experimental autoimmune encephalomyelitis via expansion of nonencephalitogenic T cells. J Leukoc Biol 84, 182-190 (2008)
http://dx.doi.org/10.1189/jlb.0507312
28. L Bruns, O Frey, L Morawietz, C Landgraf, R Volkmer, T Kamradt: Immunization with an immunodominant self-peptide derived from glucose-6-phosphate isomerase induces arthritis in DBA/1 mice. Arthritis Res Ther 11, R117 (2009)
http://dx.doi.org/10.1186/ar2777
29. OT Avery, WF Goebel: Chemo-Immunological studies on conjugated carbohydrate-proteins: II. Immunological specificity of synthetic sugar-protein antigens. J Exp Med 50, 533-550 (1929)
http://dx.doi.org/10.1084/jem.50.4.533
30. WF Goebel, OT Avery: Chemo-immunological studies on conjugated carbohydrate-proteins: I. the synthesis of p-aminophenol beta-glucoside, p-aminophenol beta-galactoside, and their coupling with serum globulin. J Exp Med 50, 521-531 (1929)
http://dx.doi.org/10.1084/jem.50.4.521
31. KJ Doores, Z Fulton, V Hong, MK Patel, CN Scanlan, MR Wormald, MG Finn, DR Burton, IA Wilson, BG Davis: A nonself sugar mimic of the HIV glycan shield shows enhanced antigenicity. Proc Natl Acad Sci U S A 107, 17107-17112 (2010)
http://dx.doi.org/10.1073/pnas.1002717107
32. DF Kelly, ER Moxon, AJ Pollard: Haemophilus influenzae type b conjugate vaccines. Immunology 113, 163-174 (2004)
http://dx.doi.org/10.1111/j.1365-2567.2004.01971.x
33. PH Makela, H Kayhty, T Leino, K Auranen, H Peltola, N Ekström, J Eskola: Long-term persistence of immunity after immunisation with Haemophilus influenzae type b conjugate vaccine. Vaccine 22, 287-292 (2003)
http://dx.doi.org/10.1016/S0264-410X(03)00524-3
34. G Barouta, M Karapetsa, E Kostopoulou, I Alexiou, G Koukoulis, LI Sakkas: Oral tuberculosis in a patient with rheumatoid arthritis after long treatment with methotrexate and adalimumab. J Clin Rheumatol 16, 330-331 (2010)
35. DR Getts, MT Getts, DP McCarthy, EM Chastain, SD Miller: Have we overestimated the benefit of human(ized) antibodies? MAbs 2, 682-694 (2010)
http://dx.doi.org/10.4161/mabs.2.6.13601
36. G D'Arena, L Laurenti, MM Minervini, S Deaglio, L Bonello, L De Martino, L De Padua, L Savino, M Tarnani, V De Feo, N Cascavilla: Regulatory T-cell number is increased in chronic lymphocytic leukemia patients and correlates with progressive disease. Leuk Res 35, 363-368 (2011)
http://dx.doi.org/10.1016/j.leukres.2010.08.010
37. JC Sun: Re-educating natural killer cells. J Exp Med 207, 2049-2052 (2010)
http://dx.doi.org/10.1084/jem.20101748
38. E Dotan, C Aggarwal, MR Smith: Impact of Rituximab (Rituxan) on the Treatment of B-Cell Non-Hodgkin's Lymphoma. P T 35, 148-157 (2010)
39. SM Ansell, SA Hurvitz, PA Koenig, BR LaPlant, BF Kabat, D Fernando, TM Habermann, DJ Inwards, M Verma, R Yamada, C Erlichman, I Lowy, JM Timmerman: Phase I study of ipilimumab, an anti-CTLA-4 monoclonal antibody, in patients with relapsed and refractory B-cell non-Hodgkin lymphoma. Clin Cancer Res 15, 6446-6453 (2009)
http://dx.doi.org/10.1158/1078-0432.CCR-09-1339
40. GR Burmester, G Ferraccioli, RM Flipo, I Monteagudo-Sáez, K Unnebrink, S Kary, H Kupper: Clinical remission and/or minimal disease activity in patients receiving adalimumab treatment in a multinational, open-label, twelve-week study. Arthritis Rheum 59, 32-41 (2008)
http://dx.doi.org/10.1002/art.23247
41. W Hueber, DD Patel, T Dryja, AM Wright, I Koroleva, G Bruin, C Antoni, Z Draelos, MH, Psoriasis Study Group, P Durez, PP Tak, JJ Gomez-Reino, Rheumatoid Arthritis Study Group, CS Foster, RY Kim, CM Samson, NS Falk, DS Chu, D Callanan, QD Nguyen, Uveitis Study Group, K Rose, A Haider, F Di Padova: Effects of AIN457, a fully human antibody to interleukin-17A, on psoriasis, rheumatoid arthritis, and uveitis. Sci Transl Med 2, 52ra72 (2010)
42. EI Tuomanen, K Saukkonen, S Sande, C Cioffe, SD Wright: Reduction of inflammation, tissue damage, and mortality in bacterial meningitis in rabbits treated with monoclonal antibodies against adhesion-promoting receptors of leukocytes. J Exp Med 170, 959-969 (1989)
http://dx.doi.org/10.1084/jem.170.3.959
43. HJ Ko, YJ Kim, YS Kim, WS Chang, SY Ko, SY Chang, S Sakaguchi, CY Kang: A combination of chemoimmunotherapies can efficiently break self-tolerance and induce antitumor immunity in a tolerogenic murine tumor model. Cancer Res 67, 7477-7486 (2007)
http://dx.doi.org/10.1158/0008-5472.CAN-06-4639
44. AC Tissot, P Maurer, J Nussberger, R Sabat, T Pfister, S Ignatenko, HD Volk, H Stocker, P Müller, GT Jennings, F Wagner, MF Bachmann: Effect of immunisation against angiotensin II with CYT006-AngQb on ambulatory blood pressure: a double-blind, randomised, placebo-controlled phase IIa study. Lancet 371, 821-827 (2008)
http://dx.doi.org/10.1016/S0140-6736(08)60381-5
45. ML Disis: Enhancing cancer vaccine efficacy via modulation of the tumor microenvironment. Clin Cancer Res 15, 6476-6478 (2009)
http://dx.doi.org/10.1158/1078-0432.CCR-09-2256
46. T M Terabe, E Ambrosino, S Takaku, JJ O'Konek, D Venzon, S Lonning, JM McPherson, JA Berzofsky: Synergistic enhancement of CD8+ T cell-mediated tumor vaccine efficacy by an anti-transforming growth factor-beta monoclonal antibody. Clin Cancer Res 15, 6560-6569 (2009)
http://dx.doi.org/10.1158/1078-0432.CCR-09-1066
47. R Ueda, M Fujita, X Zhu, K Sasaki, ER Kastenhuber, G Kohanbash, HA McDonald, J Harper, S Lonning, H Okada: Systemic inhibition of transforming growth factor-beta in glioma-bearing mice improves the therapeutic efficacy of glioma-associated antigen peptide vaccines. Clin Cancer Res 15, 6551-6559 (2009)
http://dx.doi.org/10.1158/1078-0432.CCR-09-1067
48. HL Spiegelberg, L Beck, HP Kocher, WC Fanslow, AH Lucas: Role of interleukin-4 in human immunoglobulin E formation in hu-PBL-SCID mice. J Clin Invest 93, 711-717 (1994)
http://dx.doi.org/10.1172/JCI117024
49. CL Efferson, J Schickli, BK Ko, K Kawano, S Mouzi, P Palese, A García-Sastre, CG Ioannides: Activation of tumor antigen-specific cytotoxic T lymphocytes (CTLs) by human dendritic cells infected with an attenuated influenza A virus expressing a CTL epitope derived from the HER-2/neu proto-oncogene. J Virol 77, 7411-7424 (2003)
http://dx.doi.org/10.1128/JVI.77.13.7411-7424.2003
50. L Fong, D Brockstedt, C Benike, JK Breen, G Strang, CL Ruegg, EG Engleman: Dendritic cell-based xenoantigen vaccination for prostate cancer immunotherapy. J Immunol 167, 7150-7156 (2001)
51. EY Nikitina, S Chada, C Muro-Cacho, B Fang, R Zhang, JA Roth, DI Gabrilovich: An effective immunization and cancer treatment with activated dendritic cells transduced with full-length wild-type p53. Gene Ther 9, 345-352 (2002)
http://dx.doi.org/10.1038/sj.gt.3301670
52. F Okano, M Merad, K Furumoto, EG Engleman: In vivo manipulation of dendritic cells overcomes tolerance to unmodified tumor-associated self antigens and induces potent antitumor immunity. J Immunol 174, 2645-2652 (2005)
53. TC Tzeng, JL Suen, BL Chiang: Dendritic cells pulsed with apoptotic cells activate self-reactive T-cells of lupus mice both in vitro and in vivo. Rheumatology 45, 1230-1237 (2006)
http://dx.doi.org/10.1093/rheumatology/kel106
54. DJ Cole, S Gattoni-Celli, EF McClay, JS Metcalf, JM Brown, N Nabavi, DA Newton 3rd, CB Woolhiser, MC Wilson, JN Vournakis: Characterization of a sustained-release delivery system for combined cytokine/peptide vaccination using a poly-N-acetyl glucosamine-based polymer matrix. Clin Cancer Res 3, 867-873 (1997)
55. WW Overwijk, MR Theoret, SE Finkelstein, DR Surman, LA de Jong, FA Vyth-Dreese, TA Dellemijn, PA Antony, PJ Spiess, DC Palmer, DM Heimann, CA Klebanoff, Z Yu, LN Hwang, L Feigenbaum, AM Kruisbeek, SA Rosenberg, NP Restifo: Tumor regression and autoimmunity after reversal of a functionally tolerant state of self-reactive CD8+ T cells. J Exp Med 198, 569-580 (2003)
http://dx.doi.org/10.1084/jem.20030590
56. G Ragupathi, KS Yeung, PC Leung, M Lee, CB Lau, A Vickers, C Hood, G Deng, NK Cheung, B Cassileth, P Livingston: Evaluation of widely consumed botanicals as immunological adjuvants. Vaccine 26, 4860-4865 (2008)
http://dx.doi.org/10.1016/j.vaccine.2008.06.098
57. RN Coler, SL Baldwin, N Shaverdian, S Bertholet, SJ Reed, VS Raman, X Lu, J DeVos, K Hancock, JM Katz, TS Vedvick, MS Duthie, CH Clegg, N Van Hoeven, SG Reed: A synthetic adjuvant to enhance and expand immune responses to influenza vaccines. PLoS One 5, e13677 (2010)
http://dx.doi.org/10.1371/journal.pone.0013677
58. BS Graham, MJ McElrath, MC Keefer, K Rybczyk, D Berger, KJ Weinhold, J Ottinger, G Ferarri, DC Montefiori, D Stablein, C Smith, R Ginsberg, J Eldridge, A Duerr, P Fast, BF Haynes, AIDS Vaccine Evaluation Group: Immunization with cocktail of HIV-derived peptides in montanide ISA-51 is immunogenic, but causes sterile abscesses and unacceptable reactogenicity. PLoS One 5, e11995 (2010)
http://dx.doi.org/10.1371/journal.pone.0011995
59. MH Huang, SC Lin, CH Hsiao, HJ Chao, HR Yang, CC Liao, PW Chuang, HP Wu, CY Huang, CH Leng, SJ Liu, HW Chen, AH Chou, AY Hu, P Chong: Emulsified nanoparticles containing inactivated influenza virus and CpG oligodeoxynucleotides critically influences the host immune responses in mice. PLoS One 5, e12279 (2010)
http://dx.doi.org/10.1371/journal.pone.0012279
60. J Willers, A Lucchese, D Kanduc, S Ferrone: Molecular mimicry of phage displayed peptides mimicking GD3 ganglioside. Peptides 20, 1021-1026 (1999)
http://dx.doi.org/10.1016/S0196-9781(99)00095-9
61. A Mittelman, R Tiwari, G Lucchese, J Willers, R Dummer, D Kanduc: Identification of monoclonal anti-HMW-MAA antibody linear peptide epitope by proteomic database mining. J Invest Dermatol 123, 670-675 (2004)
http://dx.doi.org/10.1111/j.0022-202X.2004.23417.x
62. R Dummer, A Mittelman, FP Fanizzi, G Lucchese, J Willers, D Kanduc: Non-self-discrimination as a driving concept in the identification of an immunodominant HMW-MAA epitopic peptide sequence by autoAbs from melanoma cancer patients. Int J Cancer 111, 720-726 (2004)
http://dx.doi.org/10.1002/ijc.20310
63. A Lucchese, J Willers, A Mittelman, D Kanduc, R Dummer: Proteomic scan for tyrosinase peptide antigenic pattern in vitiligo and melanoma: role of sequence similarity and HLA-DR1 affinity. J Immunol 175, 7009-7020 (2005)
64. J Willers, A Lucchese, A Mittelman, R Dummer, D Kanduc: Definition of anti-tyrosinase MAb T311 linear determinant by proteome-based similarity analysis. Exp Dermatol 14, 543-550 (2005)
http://dx.doi.org/10.1111/j.0906-6705.2005.00327.x
65. D Kanduc: Immunogenicity in peptide-immunotherapy: from self/nonself to similar/dissimilar sequences. Adv Exp Med Biol 640, 198-207 (2008)
http://dx.doi.org/10.1007/978-0-387-09789-3_15
66. D Kanduc, G Novello, R Mazzanti: P-170 peptides with low similarity to the human proteome: tracing an effective and safe biological way towards effective and safe cancer chemotherapy. J Exp Ther Oncol 8, 151-155 (2009)
67. D Kanduc: The self/nonself issue: A confrontation between proteomes. Self Nonself 1, 255-258 (2010)
68. D Kanduc: Peptimmunology: immunogenic peptides and sequence redundancy. Curr Drug Discov Technol 2, 239-244 (2005)
http://dx.doi.org/10.2174/157016305775202946
69. D Kanduc: "Self-nonself" peptides in the design of vaccines. Curr Pharm Des 15, 3283-3289 (2009)
http://dx.doi.org/10.2174/138161209789105135
70. D Kanduc, A Lucchese, A Mittelman: Non-redundant peptidomes from DAPs: towards "the vaccine"? Autoimmun Rev 6, 290-294 (2007)
http://dx.doi.org/10.1016/j.autrev.2006.09.004
71. D Kanduc: Epitopic peptides with low similarity to the host proteome: towards biological therapies without side effects. Expert Opin Biol Ther 9, 45-53 (2009)
http://dx.doi.org/10.1517/14712590802614041
72. G Lucchese, A Stufano, D Kanduc: Proteome-guided search for influenza A B-cell epitopes. FEMS Immunol Med Microbiol 57, 88-92 (2009)
http://dx.doi.org/10.1111/j.1574-695X.2009.00582.x
73. G Lucchese, A Stufano, D Kanduc: Proposing low-similarity peptide vaccines against Mycobacterium tuberculosis. J Biomed Biotechnol 2010, 832341 (2010)
http://dx.doi.org/10.1155/2010/832341
74. G Lucchese, A Stufano A, D Kanduc: Searching for an effective, safe and universal anti-HIV vaccine: Finding the answer in just one short peptide. Self Nonself 2, 49-54 (2011)
75. G Angelini, D Bonamonte, A Lucchese, G Favia, R Serpico, A Mittelman, S Simone, AA Sinha, D Kanduc: Preliminary data on Pemphigus vulgaris treatment by a proteomics-defined peptide: a case report. J Transl Med 4, 43 (2006)
http://dx.doi.org/10.1186/1479-5876-4-43
76. GP Smith: Filamentous fusion phage: novel expression vectors that display cloned antigens on the virion surface. Science 228, 1315-1317 (1985)
77. AB Riemer, E Jensen-Jarolim: Mimotope vaccines: epitope mimics induce anti-cancer antibodies. Immunol Lett 113, 1-5 (2007)
http://dx.doi.org/10.1016/j.imlet.2007.07.008
78. D Kozbor: Cancer vaccine with mimotopes of tumor-associated carbohydrate antigens. Immunol Res 46, 23-31 (2010)
http://dx.doi.org/10.1007/s12026-009-8120-y
79. F Helling, A Shang, M Calves, S Zhang, S Ren, RK Yu, HF Oettgen, PO Livingston: GD3 vaccines for melanoma: superior immunogenicity of keyhole limpet hemocyanin conjugate vaccines. Cancer Res 54, 197-203 (1994)
80. R Lo-Man, S Vichier-Guerre, R Perraut, E Dériaud, V Huteau, L BenMohamed, OM Diop, PO Livingston, S Bay, C Leclerc: A fully synthetic therapeutic vaccine candidate targeting carcinoma-associated Tn carbohydrate antigen induces tumor-specific antibodies in nonhuman primates. Cancer Res 64, 4987-4994 (2004)
http://dx.doi.org/10.1158/0008-5472.CAN-04-0252
81. DK Hatsukami, S Rennard, D Jorenby, M Fiore, J Koopmeiners, A de Vos, G Horwith, PR Pentel: Safety and immunogenicity of a nicotine conjugate vaccine in current smokers. Clin Pharmacol Ther 78, 456
http://dx.doi.org/10.1016/j.clpt.2005.08.007
82. B Chackerian, DR Lowy, JT Schiller: Conjugation of a self-antigen to papillomavirus-like particles allows for efficient induction of protective autoantibodies. J Clin Invest 108, 415-423 (2001)
http://dx.doi.org/10.1172/JCI200111849
83. I Sonderegger, TA Rohn, MO Kurrer, G Iezzi, Y Zou, RA Kastelein, MF Bachmann, M Kopf: Neutralization of IL-17 by active vaccination inhibits IL-23-dependent autoimmune myocarditis. Eur J Immunol 36, 2849-2856 (2006)
http://dx.doi.org/10.1002/eji.200636484
84. G Spohn, R Guler, P Johansen, I Keller, M Jacobs, M Beck, F Rohner, M Bauer, K Dietmeier, TM Kündig, GT Jennings, F Brombacher, MF Bachmann: A virus-like particle-based vaccine selectively targeting soluble TNF-alpha protects from arthritis without inducing reactivation of latent tuberculosis. J Immunol 178, 7450-7457 (2007)
85. G Spohn, I Keller, M Beck, P Grest, GT Jennings, MF Bachmann: Active immunization with IL-1 displayed on virus-like particles protects from autoimmune arthritis. Eur J Immunol 38, 877-887 (2008)
http://dx.doi.org/10.1002/eji.200737989
86. G Spohn, K Schwarz, P Maurer, H Illges, N Rajasekaran, Y Choi, GT Jennings, MF Bachmann: Protection against osteoporosis by active immunization with TRANCE/RANKL displayed on virus-like particles. J Immunol 175, 6211-6218 (2005)
87. J Cornuz, S Zwahlen, WF Jungi, J Osterwalder, K Klingler, G van Melle, Y Bangala, I Guessous, P Müller, J Willers, P Maurer, MF Bachmann, T Cerny: A vaccine against nicotine for smoking cessation: a randomized controlled trial. PLoS One 3, e2547 (2008)
http://dx.doi.org/10.1371/journal.pone.0002547
88. DE Speiser, K Schwarz, P Baumgaertner, V Manolova, E Devevre, W Sterry, P Walden, A Zippelius, KB Conzett, G Senti, V Voelter, JP Cerottini, D Guggisberg, J Willers, C Geldhof, P Romero, T Kündig, A Knuth, R Dummer, U Trefzer, MF Bachmann: Memory and effector CD8 T-cell responses after nanoparticle vaccination of melanoma patients. J Immunother 33, 848-858 (2010)
http://dx.doi.org/10.1097/CJI.0b013e3181f1d614
89. A Boasso, GM Shearer, M Clerici: The hunt for an HIV vaccine: time to rethink recent failures. Lancet 371, 1897-1898 (2008)
http://dx.doi.org/10.1016/S0140-6736(08)60812-0
90. CR Andersson, S Vene, M Insulander, L Lindquist, A Lundkvist, G Günther: Vaccine failures after active immunisation against tick-borne encephalitis. Vaccine 28, 2827-2831 (2010)
http://dx.doi.org/10.1016/j.vaccine.2010.02.001
91. J Cohen: Immunology. Painful failure of promising genital herpes vaccine. Science 330, 304 (2010)
http://dx.doi.org/10.1126/science.330.6002.304
92. JC Bailar 3rd, HL Gornik: Cancer undefeated. N Engl J Med 336, 1569-1574 (1997)
http://dx.doi.org/10.1056/NEJM199705293362206
93. A Jemal, MJ Thun, LA Ries, HL Howe, HK Weir, MM Center, E Ward, XC Wu, C Eheman, R Anderson, UA Ajani, B Kohler, BK Edwards: Annual report to the nation on the status of cancer, 1975-2005, featuring trends in lung cancer, tobacco use, and tobacco control. J Natl Cancer Inst 100, 1672-1694 (2008)
http://dx.doi.org/10.1093/jnci/djn389
94. Ehrlich letter to Althoff, 1/1/1905, Rockefeller Archives Center, RAC Ehrlich Papers, box 10, file:"Briefe von Hedwig u. Paul Ehrlich an Friedrich Althoff," pp. 82-83 (1905)
95. AM Silverstein: Paul Ehrlich's Receptor Immunology: The Magnificent Obsession. Academic Press (2002)
96. S Markovic-Plese: Degenerate T-cell receptor recognition, autoreactive cells, and the autoimmune response in multiple sclerosis. Neuroscientist 15, 225-231 (2009)
http://dx.doi.org/10.1177/1073858409332404
97. C Mazza, B Malissen: What guides MHC-restricted TCR recognition? Semin Immunol 19, 225-235 (2007)
http://dx.doi.org/10.1016/j.smim.2007.03.003
98. A Mittelman, G Lucchese, A Stufano, D Kanduc: Degenerate binding of tyrosinase peptides to MHC II Ad/Ed molecules. J Exp Ther Oncol 6, 231-239 (2007)
99. S Buus, A Sette, SM Colon, HM Grey: Autologous peptides constitutively occupy the antigen binding site on Ia. Science 242, 1045-1047 (1988)
http://dx.doi.org/10.1126/science.3194755
100. DA Schmid, MB Irving, V Posevitz, M Hebeisen, A Posevitz-Fejfar, JC Sarria, R Gomez-Eerland, M Thome, TN Schumacher, P Romero, DE Speiser, V Zoete, O Michielin, N Rufer: Evidence for a TCR affinity threshold delimiting maximal CD8 T cell function. J Immunol 184, 4936-4946 (2010)
http://dx.doi.org/10.4049/jimmunol.1000173
101. CK Baumgartner, A Ferrante, M Nagaoka, J Gorski, LP Malherbe: Peptide-MHC class II complex stability governs CD4 T cell clonal selection. J Immunol 184, 573-581 (2010)
http://dx.doi.org/10.4049/jimmunol.0902107
102. PV Praveen, R Yaneva, H Kalbacher, S Springer: Tapasin edits peptides on MHC class I molecules by accelerating peptide exchange. Eur J Immunol 40, 214-224 (2010)
http://dx.doi.org/10.1002/eji.200939342
103. RK Gupta, EH Relyveld, EB Lindblad, B Bizzini, S Ben-Efraim, CK Gupta: Adjuvants, a balance between toxicity and adjuvanticity. Vaccine 11, 293-306 (1993)
http://dx.doi.org/10.1016/0264-410X(93)90190-9
104. E Israeli, N Agmon-Levin, M Blank, Y Shoenfeld: Adjuvants and autoimmunity. Lupus 18, 1217-1225 (2009)
http://dx.doi.org/10.1177/0961203309345724
105. N Petrovsky: Freeing vaccine adjuvants from dangerous immunological dogma. Expert Rev Vaccines 7, 7-10 (2008)
http://dx.doi.org/10.1586/14760584.7.1.7
106. D Kanduc: Describing the hexapeptide identity platform between the influenza A H5N1 and Homo sapiens proteomes. Biologics 4, 245-261 (2010)
107. B Trost, G Lucchese, A Stufano, M Bickis, A Kusalik, D Kanduc: No human protein is exempt from bacterial motifs, not even one. Self Nonself 1, 328-334 (2010)
108. G Lucchese, A Stufano, M Calabrò, D Kanduc: Charting the peptide crossreactome between HIV-1 and the human proteome. Front Biosci 3, 1385-1400 (2011)
109. D Kanduc: Peptide cross-reactivity: the original sin of vaccines. Front Biosci this issue (2011)
110. C Natale, T Giannini, A Lucchese, D Kanduc: Computer-assisted analysis of molecular mimicry between human papillomavirus 16 E7 oncoprotein and human protein sequences. Immunol Cell Biol 78, 580-585 (2000)
http://dx.doi.org/10.1046/j.1440-1711.2000.00949.x
111. D Kanduc: Quantifying the possible cross-reactivity risk of an HPV16 vaccine. J Exp Ther Oncol 8, 65-76 (2009)
112. A Kusalik, M Bickis, C Lewis, Y Li, G Lucchese, FM Marincola, D Kanduc: Widespread and ample peptide overlapping between HCV and Homo sapiens proteomes. Peptides 28, 1260-1267 (2007)
http://dx.doi.org/10.1016/j.peptides.2007.04.001
113. D Kanduc, A Stufano, G Lucchese, A Kusalik: Massive peptide sharing between viral and human proteomes. Peptides 29, 1755-1766 (2008)
http://dx.doi.org/10.1016/j.peptides.2008.05.022
114. R Ricco, D Kanduc: Hepatitis B virus and Homo sapiens proteome-wide analysis: A profusion of viral peptide overlaps in neuron-specific human proteins. Biologics 4, 75-81 (2010)
115. B Trost, A Kusalik, G Lucchese, D Kanduc: Bacterial peptides are intensively present throughout the human proteome. Self Nonself 1, 71-74 (2010)
116. SL Bavaro, D Kanduc: Pentapeptide commonality between Corynebacterium diphtheriae toxin and the Homo sapiens proteome. Immunotherapy 3, 49-58 (2011)
http://dx.doi.org/10.2217/imt.10.83
117. SL Bavaro, M Calabrò, D Kanduc: Pentapeptide sharing between Corynebacterium diphtheria toxin and the human neural protein network. Immunopharmacol Immunotoxicol 33, 360-372 (2011)
http://dx.doi.org/10.3109/08923973.2010.518618
118. D Kanduc, G Capone, VP Delfino, G Losa: The fractal dimension of protein information. Adv Stud Biol 2, 53-62 (2010)
119. MW Cunningham, SM Antone, JM Gulizia, BM McManus, VA Fischetti, CJ Gauntt: Cytotoxic and viral neutralizing antibodies crossreact with streptococcal M protein, enteroviruses, and human cardiac myosin. Proc Natl Acad Sci U S A 89, 1320-1324 (1992)
http://dx.doi.org/10.1073/pnas.89.4.1320
120. KL Hardgrave, BR Neas, RH Scofield, JB Harley: Antibodies to vesicular stomatitis virus proteins in patients with systemic lupus erythematosus and in normal subjects. Arthritis Rheum 36, 962-970 (1993)
http://dx.doi.org/10.1002/art.1780360713
121. Z Yu, NP Restifo: Cancer vaccines: progress reveals new complexities. J Clin Invest 110, 289-294 (2002)
http://dx.doi.org/10.1172/JCI200216216
122. RR Caspi: Immunotherapy of autoimmunity and cancer: the penalty for success. Nat Rev Immunol 8, 970-976 (2008)
http://dx.doi.org/10.1038/nri2438
123. A Stufano, G Capone, B Pesetti, L Polimeno, D Kanduc: Clustering of rare peptide segments in the HCV immunome. Self Nonself 1, 154-162 (2010)
124. F Baggi, A Annoni, F Ubiali, M Milani, R Longhi, W Scaioli, F Cornelio, R Mantegazza, C Antozzi: Breakdown of tolerance to a self-peptide of acetylcholine receptor alpha-subunit induces experimental myasthenia gravis in rats. J Immunol 172, 2697-2703 (2004)
125. A Lernmark: Autoimmune diseases: are markers ready for prediction? J Clin Invest 108, 1091-1096 (2001)
http://dx.doi.org/10.1172/JCI200114234
126. B Ayoglu, A Häggmark, M Neiman, U Igel, M Uhlén, JM Schwenk, P Nilsson: Systematic antibody and antigen-based proteomic profiling with microarrays. Expert Rev Mol Diagn 11, 219-234 (2011)
http://dx.doi.org/10.1586/erm.10.110
127. JY Kim, JE Do, KJ Ahn, S Noh, HJ Jee, SH Oh: Detection of melanocyte autoantigens reacting with autoantibodies in vitiligo patients by proteomics. J Dermatol Sci 62, 202-204 (2011)
http://dx.doi.org/10.1016/j.jdermsci.2011.03.004
128. A Lucchese, A Mittelman, L Tessitore, R Serpico, AA Sinha, D Kanduc: Proteomic definition of a desmoglein linear determinant common to Pemphigus vulgaris and Pemphigus foliaceous. J Transl Med 4, 37 (2006)
http://dx.doi.org/10.1186/1479-5876-4-37
129. L Polimeno, A Mittelman, L Gennero, A Ponzetto, G Lucchese, A Stufano, A Kusalik, D Kanduc: Sub-epitopic dissection of HCV E1315-328HRMAWDMMMNWSPT sequence by similarity analysis. Amino Acids 34, 479-484 (2008)
http://dx.doi.org/10.1007/s00726-007-0539-7
130. D Kanduc, R Serpico, A Lucchese, Y Shoenfeld: Correlating low-similarity peptide sequences and HIV B-cell epitopes. Autoimmun Rev 7, 291-296 (2008)
http://dx.doi.org/10.1016/j.autrev.2007.11.001
131. D Kanduc: Correlating low-similarity peptide sequences and allergenic epitopes. Curr Pharm Des 14, 289-295 (2008)
http://dx.doi.org/10.2174/138161208783413257
132. A Lucchese, R Serpico, V Crincoli, Y Shoenfeld, D Kanduc: Sequence uniqueness as a molecular signature of HIV-1-derived B-cell epitopes. Int J Immunopathol Pharmacol 22, 639-646 (2009)
133. A Stufano, D Kanduc: Proteome-based epitopic peptide scanning along PSA. Exp Mol Pathol 86, 36-40 (2009)
http://dx.doi.org/10.1016/j.yexmp.2008.11.009
134. E Balasse, G Gatouillat, D Patigny, MC Andry, C Madoulet: In vivo anti-melanoma activities of the Melan-A/MART-1(101-115) T CD4+ cell peptide. Vaccine 27, 6107-6109 (2009)
http://dx.doi.org/10.1016/j.vaccine.2009.07.109
135. M Tomita, K Tsumoto: Hybridoma technologies for antibody production. Immunotherapy 3, 371-380 (2011)
http://dx.doi.org/10.2217/imt.11.4
136. D Kanduc, A Lucchese, A Mittelman: Individuation of monoclonal anti-HPV16 E7 antibody linear peptide epitope by computational biology. Peptides 22, 1981-1985 (2001)
http://dx.doi.org/10.1016/S0196-9781(01)00539-3
137. D Kanduc, FP Fanizzi, G Lucchese, S Stevanovic, AA Sinha, A Mittelman: NMR probing of in silico identification of anti-HPV16 E7 mAb linear peptide epitope. Peptides 25, 243-250 (2004)
http://dx.doi.org/10.1016/j.peptides.2003.12.004
138. A Lucchese, A Mittelman, MS Lin, D Kanduc, AA Sinha: Epitope definition by proteomic similarity analysis: identification of the linear determinant of the anti-Dsg3 MAb 5H10. J Transl Med 2, 43 (2004)
http://dx.doi.org/10.1186/1479-5876-2-43
Key Words: Vaccine approaches, Active versus passive immunization, Peptide-based vaccines, Immunogenic peptides, Low-similarity peptides, Review
Send correspondence to: Alberta Lucchese, Department of Odontostomatological, Orthodontics and Surgical Disciplines, Second University of Naples, SUN, Via L. De Crecchio 6, 80138 Naples, Italy, Tel: 0039 081 5667675, Fax: 0039 081 5667674, E-mail:alberta.lucchese@unina2.it