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Paragraph: RPLs can subsequently be used in many applications including the identification of peptide ligands by receptors, the mapping of substrate sites for enzymes, and the creation of antibody peptide libraries . These applications are reviewed elsewhere [38, 46, 47] . Inovirus display technology has also been used for epitope mapping and vaccine design purposes. RPLs can be used to characterize the epitope of an antibody of interest through biopanning with a monoclonal antibody of interest, which can result in the isolation of mimotopes; these are oligopeptides that mimic the native antibody epitope. The selected recombinant inoviruses that carry mimotopes can then be isolated in order to determine the DNA and amino acid sequence of the displayed oligopeptides. DNA sequencing of such inserts as well as structure prediction analysis can potentially identify the previously unknown target of an antibody. Besides antibody characterization, inoculation of recombinant inoviruses isolated through this approach can potentially be used as vaccine carriers. For example, if a neutralizing antibody against a pathogen is used to screen an RPL, the selected peptides (fused to inoviruses) would mimic the original antibody epitope. Vaccination of animals with these inoviruses could ultimately induce the production of similar antibodies by the vaccinated individual, offering protection from infection against the pathogen. Inovirus display technology has been successfully applied in the development of vaccines against various pathogens (Tables 1 and 2 ). The potential for inovirus display technology to facilitate the mapping of antibody epitopes is of great importance, especially in the case of HIV-1. Epitopes of broadly neutralizing monoclonal anti-HIV-1 antibodies could be rare, vulnerable spots on the surface of a frequently mutating virus such as HIV-1 and therefore, their identification and further study could lead to new drug therapies or vaccine targets. This review focuses particularly on the applications of inovirus display technology that utilizes capsid proteins gp3 and gp8, as those have been used in vaccine development. Schematic representations of antigen display on the surface of Ff inovirus-associated vectors (IAVs). Foreign antigens are shown as red spheres. The designation on the left denotes the inoviral gene, which can be genetically modified to express an antigen on the outer architecture of the virion. IAVs that contain both the wild type and antigen display capsid proteins are designated by "m" which indicates that the virion is a mosaic. Each Ff virion contains about 2700 copies of major capsid protein gp8, and five copies of each of the minor capsid proteins, gp3, gp6, gp7 and gp9. inovirus-associated vector (bottom) showing the major coat protein gp8 subunits arranged with a combined five-fold rotation axis and an approximate two-fold screw axis [28] . Right, the corresponding surface lattices, identical to those previously published [30] . The lattice diagrams show the relative position of each gp8 subunit on the outer virion surface. The five gp8 subunits of each of the two interlocking pentamers constituting the helical symmetry of the virion are indicated by blue and green dots respectively. The relative virion surface area (about 1400 Å 2 ) associated with each gp8 subunit is marked in yellow. The virion perimetrical (azimuthial) distance is calculated based on a virion diameter of about 65 Å. The displayed antigens, represented by red spheres, are arranged on the surface of the Ff.g8 inovirus-associated vector according to helical symmetry of the virion outer architecture (bottom). IAVs are effective vaccine carriers and, as shown in Tables 1 and 2 , they have been used successfully in numerous vaccine development studies. They have been utilized in the development of vaccines against a wide variety of viral, protozoan and worm parasites and also against non-infectious diseases like Alzheimer and various types of cancer. All these attempts can be divided in two main sub-categories. The first sub-category, inovirus display technology was used to screen RPLs with monoclonal antibodies and then to select the immunogenic peptides of interest. The selected peptide was used as a vaccine in its soluble form or in conjugation with carrier proteins [55,66,70,81-84, 86-88,90-92,98] . In the second sub-category, similar to the first sub-category, inovirus display technology has been used for epitope mapping and isolation, but in this case, inoviruses were also used as the vaccine carriers for the immunogenic peptides [48] [49] [50] [51] [52] [53] [54] 56, 57, [59] [60] [61] [62] [63] [64] [65] [67] [68] [69] [71] [72] [73] [74] [75] [76] [77] [78] [79] [80] . In contrast to IAVs, soluble peptides have the disadvantage of being less stable than the same peptides fused to inoviral particles. Soluble peptides have a flexible 3D structure and thus, do not always retain the 3D structure of the desirable epitope. As a result, soluble peptides, unlike inovirus-bound peptides, are less capable of inducing the production of the desirable antibodies [99] . Additionally, the inoviral vectors displaying peptides are highly immunogenic. Their high immunogenicity is reinforced by the ability of inoviruses to display multiple copies of peptides on their surface. Additionally, inoviruses are known for their structural simplicity, which allows the immune system to focus selectively on the displayed peptides and not on the viral carrier [100] . Furthermore, since inoviruses can replicate in E. coli cultures, the cost of vaccine production is low. In summary, IAVs can be used as efficient and cost effective vaccine carriers. A large number of research studies have focused on the application of inovirus-based vaccines against infectious diseases. A common approach in many of these efforts was to vaccinate animals with inoviruses and to then challenge them with specific pathogens, in order to assess the level of protection against the pathogens. Three of these studies focused on immunization against viral parasites. In 1997, Bastien et al. fused a 15-mer linear epitope of Human Respiratory Syncytial Virus (RSV) glycoprotein G on inovirus gp3 and used the recombinant inovirus to vaccinate mice [69] . This resulted in a specific humoral response, with the vaccinated animals having complete protection from challenge with the RSV virus [69] . In 2000, Grabowska et al. used monoclonal antibodies against Herpes Simplex Virus type 2 (HSV-2) glycoprotein G2 to screen 15-mer RPLs [65] . The selected recombinant inoviruses were used to vaccinate mice, resulting in a specific humoral response. A high survival rate of vaccinated mice after challenge with a lethal dose of the virus was observed, and the level of protection was proportional to the dose of the inoviral vaccine [65] . Additionally, in 2000, Yu et al. used monoclonal antibodies against the surface glycoprotein of Neurotropic Murine Coronavirus to screen various RPLs [67] . A selected clone displaying a 13-mer peptide induced a humoral immune response but no cellular response in mice. Even so, after lethal virus challenge, three out of six mice survived. [67] . Besides viral infections, inoviral vaccine research has also been applied for systemic candidiasis, a fungal infection caused by Candida albicans. In two separate studies, a specific six amino acid peptide epitope of the fungal heat shock protein 90 was displayed as a fusion with the inoviral coat protein gp8 [73, 74] . After infection with the parasite, mice immunized with the recombinant inoviruses had fewer colony forming units of Candida albicans in the kidney and a longer lifespan [73] . The use of inovirus as a vaccine carrier was particularly successful against Taenia solium, a parasitic worm that uses pigs as intermediate hosts and causes neurocysticercosis, a parasitic disease of the central nervous system, in humans [79] . In 2004, Manoutsarian et al. fused four antigenic peptides (GK1, KETc1, KETc7, KETc12) to inoviruses and the cocktail of recombinant inoviruses was used to vaccinate pigs; as a result, a specific cellular response was induced. Vaccination of pigs protected them against challenge with the pathogen: 1/3 of pigs were totally protected and 2/3 had reduced number of cysticerci [79] . Based on these results, large-scale vaccination of 1047 rural pigs in 16 villages of central Mexico was conducted in 2008. The immunization was successful since the vaccine conferred significant protection against the parasite. Furthermore, this inovirus-based vaccine was more economical compared with to another vaccine made of synthetic peptides. The study was particularly important, not only due to the large scale vaccination attempt with inoviruses, but also due to its effectiveness in significantly reducing the number of cysticerci in the vaccinated animals [101] . Efforts were also made to develop vaccines against the worm Schistosoma japonicum. In 2004, Tang et al. screened a 12-mer RPL with polyclonal serum from infected mice [76] . The selected recombinant inoviruses induced a specific humoral response, which conferred partial protection from parasite challenge in the vaccinated mice [76] . Following this study, in 2006, Wang et al. used the monoclonal antibody SSj14, which targets the parasite to screen a 12-mer RPL [77] . The recombinant inoviruses induced both humoral and cellular responses that significantly protected the vaccinated mice against the worm infection [77] . Additionally, in 2006, Wu et al. used polyclonal serum from infected rabbits to screen a 12-mer RPL [78] . A humoral response was induced in the vaccinated mice, which conferred partial protection from the parasite [78] . In 2008, Villa-Mancera et al., produced a vaccine against Fasciola hepatica, by screening a previously constructed 12-mer inovirus RLP with an anti-cathepsin L monoclonal antibody [75] . Although immunization of sheep with the selected recombinant inoviruses induced a weak, specific humoral response after challenge with the parasite, the vaccinated animals had a remarkable reduction in worm burden compared to controls [75] . An inovirus-based vaccine has been constructed against the parasitic worm Trichinella spiralis. In this case, Gu et al. used a monoclonal antibody against rTs87 antigen to screen a 12-mer RPL [80] . As a result, a humoral response was induced and the vaccinated mice gained partial protection after challenge against the parasite [80] . In summary, the results of the above studies show that the construction of an efficient inovirus-based vaccine that confers protection to the vaccinated animals against the infectious pathogen is achievable through the induction of humoral or cellular immune response or both. As previously mentioned, inovirus display technology has also been used for the design of vaccines against non-infectious diseases and in some cases, the capability of the vaccine to limit the progression of the disease was evaluated. In 2005, Fang et al. displayed an epitope of the Melanoma Antigen A1 (MAGE A1) in the surface of inovirus fused on gp8 [85] . This resulted in an induction of cellular immune response against the melanoma tumor and in the significant inhibition of tumor growth in the vaccinated mice. In addition, there was an important increase in the survival rate of vaccinated animals [85] . Similar results were obtained in 2002 by Wu et al. in an effort to design a vaccine against murine mastocytoma P815 [89] . An epitope of the P1A tumor antigen was fused to the inoviral surface and the vaccinated mice gained significant protection against tumor growth. Moreover, there was a significant increase in survival rate due to an anti-tumor cellular response that was induced [89] . Some important efforts have also been made for the design of an inovirus-based vaccine against Alzheimer's disease. The main target of these vaccines was the induction of antibodies against β-amyloid plaques. In these studies, the antigenic epitope that was displayed in the inoviral surface was the epitope EGFR, which consists of the four amino acids E, G, F and R and it is part of the β-amyloid peptide. In mice immunized with recombinant inoviruses, the researchers observed a reduction in β-amyloid plaque burden and a specific humoral response [93] [94] [95] [96] . Collectively, these studies show that it is possible to protect vaccinated animals against disease progression, thus alluding to the promising use of such vaccines against non-infectious diseases in humans. In summary, the utilization of inoviral vectors for vaccine development against infectious and non-infectious non-HIV-1 diseases has produced significant and promising results. First, in the majority of cases, the vaccine was successful since it induced specific humoral or cellular response, or both. Furthermore, in many cases, there was an attempt to evaluate the efficacy of the vaccine after challenge against the pathogen in vaccinated animals. In all cases, the vaccine could provide partial, significant or even complete protection against the pathogen. This established the effectiveness of the use of inoviruses as vaccine vectors. Our knowledge of HIV-1 neutralization epitopes initiated from the isolation of several neutralizing monoclonal antibodies (2F5, 4E10, b12 and 2G12) that were described between 1993 and 1994 [102] [103] [104] . Thus far, neutralizing monoclonal antibodies have been found to target four major epitopes on the HIV-1 envelope gp41 and gp120 glycoproteins [105] [106] [107] .

Question: How can random peptide libraries be used in applications?
the identification of peptide ligands by receptors, the mapping of substrate sites for enzymes, and the creation of antibody peptide libraries