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Open AccessArticle

Antibiotic Resistance Determinant-Focused Acinetobacter baumannii Vaccine Designed Using Reverse Vaccinology

by Zhaohui Ni, Yan Chen, Edison Ong and Yongqun He

Int. J. Mol. Sci. 2017, 18(2), 458; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms18020458 - 21 Feb 2017

Cited by 50 | Viewed by 9351

As one of the most influential and troublesome human pathogens, Acinetobacter baumannii (A. baumannii) has emerged with many multidrug-resistant strains. After collecting 33 complete A. baumannii genomes and 84 representative antibiotic resistance determinants, we used the Vaxign reverse vaccinology approach to [...] Read more.

As one of the most influential and troublesome human pathogens, Acinetobacter baumannii (A. baumannii) has emerged with many multidrug-resistant strains. After collecting 33 complete A. baumannii genomes and 84 representative antibiotic resistance determinants, we used the Vaxign reverse vaccinology approach to predict classical type vaccine candidates against A. baumannii infections and new type vaccine candidates against antibiotic resistance. Our genome analysis identified 35 outer membrane or extracellular adhesins that are conserved among all 33 genomes, have no human protein homology, and have less than 2 transmembrane helices. These 35 antigens include 11 TonB dependent receptors, 8 porins, 7 efflux pump proteins, and 2 fimbrial proteins (FilF and CAM87009.1). CAM86003.1 was predicted to be an adhesin outer membrane protein absent from 3 antibiotic-sensitive strains and conserved in 21 antibiotic-resistant strains. Feasible anti-resistance vaccine candidates also include one extracellular protein (QnrA), 3 RND type outer membrane efflux pump proteins, and 3 CTX-M type β-lactamases. Among 39 β-lactamases, A. baumannii CTX-M-2, -5, and -43 enzymes are predicted as adhesins and better vaccine candidates than other β-lactamases to induce preventive immunity and enhance antibiotic treatments. This report represents the first reverse vaccinology study to systematically predict vaccine antigen candidates against antibiotic resistance for a microbial pathogen. Full article

(This article belongs to the Special Issue Reverse Vaccinology)

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Open AccessArticle

Transfer of Anti-Rotavirus Antibodies during Pregnancy and in Milk Following Maternal Vaccination with a Herpes Simplex Virus Type-1 Amplicon Vector

by Anita F. Meier, Mark Suter, Elisabeth M. Schraner, Bruno M. Humbel, Kurt Tobler, Mathias Ackermann and Andrea S. Laimbacher

Int. J. Mol. Sci. 2017, 18(2), 431; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms18020431 - 16 Feb 2017

Cited by 5 | Viewed by 5235

Abstract

Rotaviruses (RVs) are important enteric pathogens of newborn humans and animals, causing diarrhea and in rare cases death, especially in very young individuals. Rotavirus vaccines presently used are modified live vaccines that lack complete biological safety. Previous work from our laboratory suggested that [...] Read more.

Rotaviruses (RVs) are important enteric pathogens of newborn humans and animals, causing diarrhea and in rare cases death, especially in very young individuals. Rotavirus vaccines presently used are modified live vaccines that lack complete biological safety. Previous work from our laboratory suggested that vaccines based on in situ produced, non-infectious rotavirus-like particles (RVLPs) are efficient while being entirely safe. However, using either vaccine, active mucosal immunization cannot induce protective immunity in newborns due to their immature immune system. We therefore hypothesized that offspring from vaccinated dams are passively immunized either by transfer of maternal antibodies during pregnancy or by taking up antibodies from milk. Using a codon optimized polycistronic gene expression cassette packaged into herpesvirus particles, the simultaneous expression of the RV capsid genes led to the intracellular formation of RVLPs in various cell lines. Vaccinated dams developed a strong RV specific IgG antibody response determined in sera and milk of both mother and pups. Moreover, sera of naïve pups nursed by vaccinated dams also had RV specific antibodies suggesting a lactogenic transfer of antibodies. Although full protection of pups was not achieved in this mouse model, our observations are important for the development of improved vaccines against RV in humans as well as in various animal species. Full article

(This article belongs to the Special Issue Reverse Vaccinology)

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Open AccessArticle

An In Silico Identification of Common Putative Vaccine Candidates against Treponema pallidum: A Reverse Vaccinology and Subtractive Genomics Based Approach

by Arun Kumar Jaiswal, Sandeep Tiwari, Syed Babar Jamal, Debmalya Barh, Vasco Azevedo and Siomar C. Soares

Int. J. Mol. Sci. 2017, 18(2), 402; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms18020402 - 14 Feb 2017

Cited by 39 | Viewed by 7894

Abstract

Sexually transmitted infections (STIs) are caused by a wide variety of bacteria, viruses, and parasites that are transmitted from one person to another primarily by vaginal, anal, or oral sexual contact. Syphilis is a serious disease caused by a sexually transmitted infection. Syphilis [...] Read more.

Sexually transmitted infections (STIs) are caused by a wide variety of bacteria, viruses, and parasites that are transmitted from one person to another primarily by vaginal, anal, or oral sexual contact. Syphilis is a serious disease caused by a sexually transmitted infection. Syphilis is caused by the bacterium Treponema pallidum subspecies pallidum. Treponema pallidum (T. pallidum) is a motile, gram-negative spirochete, which can be transmitted both sexually and from mother to child, and can invade virtually any organ or structure in the human body. The current worldwide prevalence of syphilis emphasizes the need for continued preventive measures and strategies. Unfortunately, effective measures are limited. In this study, we focus on the identification of vaccine targets and putative drugs against syphilis disease using reverse vaccinology and subtractive genomics. We compared 13 strains of T. pallidum using T. pallidum Nichols as the reference genome. Using an in silicoapproach, four pathogenic islands were detected in the genome of T. pallidum Nichols. We identified 15 putative antigenic proteins and sixdrug targets through reverse vaccinology and subtractive genomics, respectively, which can be used as candidate therapeutic targets in the future. Full article

(This article belongs to the Special Issue Reverse Vaccinology)

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Open AccessArticle

Immunoinformatics Features Linked to Leishmania Vaccine Development: Data Integration of Experimental and In Silico Studies

by Rory C. F. Brito, Frederico G. Guimarães, João P. L. Velloso, Rodrigo Corrêa-Oliveira, Jeronimo C. Ruiz, Alexandre B. Reis and Daniela M. Resende

Int. J. Mol. Sci. 2017, 18(2), 371; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms18020371 - 10 Feb 2017

Cited by 21 | Viewed by 6347

Abstract

Leishmaniasis is a wide-spectrum disease caused by parasites from Leishmania genus. There is no human vaccine available and it is considered by many studies as apotential effective tool for disease control. To discover novel antigens, computational programs have been used in reverse vaccinology [...] Read more.

Leishmaniasis is a wide-spectrum disease caused by parasites from Leishmania genus. There is no human vaccine available and it is considered by many studies as apotential effective tool for disease control. To discover novel antigens, computational programs have been used in reverse vaccinology strategies. In this work, we developed a validation antigen approach that integrates prediction of B and T cell epitopes, analysis of Protein-Protein Interaction (PPI) networks and metabolic pathways. We selected twenty candidate proteins from Leishmania tested in murine model, with experimental outcome published in the literature. The predictions for CD4⁺ and CD8⁺ T cell epitopes were correlated with protection in experimental outcomes. We also mapped immunogenic proteins on PPI networks in order to find Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways associated with them. Our results suggest that non-protective antigens have lowest frequency of predicted T CD4⁺ and T CD8⁺ epitopes, compared with protective ones. T CD4⁺ and T CD8⁺ cells are more related to leishmaniasis protection in experimental outcomes than B cell predicted epitopes. Considering KEGG analysis, the proteins considered protective are connected to nodes with few pathways, including those associated with ribosome biosynthesis and purine metabolism. Full article

(This article belongs to the Special Issue Reverse Vaccinology)

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Enhancing the Biological Relevance of Machine Learning Classifiers for Reverse Vaccinology

by Ashley I. Heinson, Yawwani Gunawardana, Bastiaan Moesker, Carmen C. Denman Hume, Elena Vataga, Yper Hall, Elena Stylianou, Helen McShane, Ann Williams, Mahesan Niranjan and Christopher H. Woelk

Int. J. Mol. Sci. 2017, 18(2), 312; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms18020312 - 01 Feb 2017

Cited by 35 | Viewed by 6395

Abstract

Reverse vaccinology (RV) is a bioinformatics approach that can predict antigens with protective potential from the protein coding genomes of bacterial pathogens for subunit vaccine design. RV has become firmly established following the development of the BEXSERO® vaccine against Neisseria meningitidis serogroup B. [...] Read more.

Reverse vaccinology (RV) is a bioinformatics approach that can predict antigens with protective potential from the protein coding genomes of bacterial pathogens for subunit vaccine design. RV has become firmly established following the development of the BEXSERO® vaccine against Neisseria meningitidis serogroup B. RV studies have begun to incorporate machine learning (ML) techniques to distinguish bacterial protective antigens (BPAs) from non-BPAs. This research contributes significantly to the RV field by using permutation analysis to demonstrate that a signal for protective antigens can be curated from published data. Furthermore, the effects of the following on an ML approach to RV were also assessed: nested cross-validation, balancing selection of non-BPAs for subcellular localization, increasing the training data, and incorporating greater numbers of protein annotation tools for feature generation. These enhancements yielded a support vector machine (SVM) classifier that could discriminate BPAs (n = 200) from non-BPAs (n = 200) with an area under the curve (AUC) of 0.787. In addition, hierarchical clustering of BPAs revealed that intracellular BPAs clustered separately from extracellular BPAs. However, no immediate benefit was derived when training SVM classifiers on data sets exclusively containing intra- or extracellular BPAs. In conclusion, this work demonstrates that ML classifiers have great utility in RV approaches and will lead to new subunit vaccines in the future. Full article

(This article belongs to the Special Issue Reverse Vaccinology)

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Review

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Open AccessReview

Reverse Vaccinology: An Approach for Identifying Leptospiral Vaccine Candidates

by Odir A. Dellagostin, André A. Grassmann, Caroline Rizzi, Rodrigo A. Schuch, Sérgio Jorge, Thais L. Oliveira, Alan J. A. McBride and Daiane D. Hartwig

Int. J. Mol. Sci. 2017, 18(1), 158; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms18010158 - 14 Jan 2017

Cited by 44 | Viewed by 11414

Abstract

Leptospirosis is a major public health problem with an incidence of over one million human cases each year. It is a globally distributed, zoonotic disease and is associated with significant economic losses in farm animals. Leptospirosis is caused by pathogenic Leptospira spp. that [...] Read more.

Leptospirosis is a major public health problem with an incidence of over one million human cases each year. It is a globally distributed, zoonotic disease and is associated with significant economic losses in farm animals. Leptospirosis is caused by pathogenic Leptospira spp. that can infect a wide range of domestic and wild animals. Given the inability to control the cycle of transmission among animals and humans, there is an urgent demand for a new vaccine. Inactivated whole-cell vaccines (bacterins) are routinely used in livestock and domestic animals, however, protection is serovar-restricted and short-term only. To overcome these limitations, efforts have focused on the development of recombinant vaccines, with partial success. Reverse vaccinology (RV) has been successfully applied to many infectious diseases. A growing number of leptospiral genome sequences are now available in public databases, providing an opportunity to search for prospective vaccine antigens using RV. Several promising leptospiral antigens were identified using this approach, although only a few have been characterized and evaluated in animal models. In this review, we summarize the use of RV for leptospirosis and discuss the need for potential improvements for the successful development of a new vaccine towards reducing the burden of human and animal leptospirosis. Full article

(This article belongs to the Special Issue Reverse Vaccinology)

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Reverse Genetics Approaches for the Development of Influenza Vaccines

by Aitor Nogales and Luis Martínez-Sobrido

Int. J. Mol. Sci. 2017, 18(1), 20; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms18010020 - 22 Dec 2016

Cited by 84 | Viewed by 17762

Abstract

Influenza viruses cause annual seasonal epidemics and occasional pandemics of human respiratory disease. Influenza virus infections represent a serious public health and economic problem, which are most effectively prevented through vaccination. However, influenza viruses undergo continual antigenic variation, which requires either the annual [...] Read more.

Influenza viruses cause annual seasonal epidemics and occasional pandemics of human respiratory disease. Influenza virus infections represent a serious public health and economic problem, which are most effectively prevented through vaccination. However, influenza viruses undergo continual antigenic variation, which requires either the annual reformulation of seasonal influenza vaccines or the rapid generation of vaccines against potential pandemic virus strains. The segmented nature of influenza virus allows for the reassortment between two or more viruses within a co-infected cell, and this characteristic has also been harnessed in the laboratory to generate reassortant viruses for their use as either inactivated or live-attenuated influenza vaccines. With the implementation of plasmid-based reverse genetics techniques, it is now possible to engineer recombinant influenza viruses entirely from full-length complementary DNA copies of the viral genome by transfection of susceptible cells. These reverse genetics systems have provided investigators with novel and powerful approaches to answer important questions about the biology of influenza viruses, including the function of viral proteins, their interaction with cellular host factors and the mechanisms of influenza virus transmission and pathogenesis. In addition, reverse genetics techniques have allowed the generation of recombinant influenza viruses, providing a powerful technology to develop both inactivated and live-attenuated influenza vaccines. In this review, we will summarize the current knowledge of state-of-the-art, plasmid-based, influenza reverse genetics approaches and their implementation to provide rapid, convenient, safe and more effective influenza inactivated or live-attenuated vaccines. Full article

(This article belongs to the Special Issue Reverse Vaccinology)

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Structure-Based Reverse Vaccinology Failed in the Case of HIV Because it Disregarded Accepted Immunological Theory

by Marc H. V. Van Regenmortel

Int. J. Mol. Sci. 2016, 17(9), 1591; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms17091591 - 21 Sep 2016

Cited by 29 | Viewed by 6702

Abstract

Two types of reverse vaccinology (RV) should be distinguished: genome-based RV for bacterial vaccines and structure-based RV for viral vaccines. Structure-based RV consists in trying to generate a vaccine by first determining the crystallographic structure of a complex between a viral epitope and [...] Read more.

Two types of reverse vaccinology (RV) should be distinguished: genome-based RV for bacterial vaccines and structure-based RV for viral vaccines. Structure-based RV consists in trying to generate a vaccine by first determining the crystallographic structure of a complex between a viral epitope and a neutralizing monoclonal antibody (nMab) and then reconstructing the epitope by reverse molecular engineering outside the context of the native viral protein. It is based on the unwarranted assumption that the epitope designed to fit the nMab will have acquired the immunogenic capacity to elicit a polyclonal antibody response with the same protective capacity as the nMab. After more than a decade of intensive research using this type of RV, this approach has failed to deliver an effective, preventive HIV-1 vaccine. The structure and dynamics of different types of HIV-1 epitopes and of paratopes are described. The rational design of an anti-HIV-1 vaccine is shown to be a misnomer since investigators who claim that they design a vaccine are actually only improving the antigenic binding capacity of one epitope with respect to only one paratope and not the immunogenic capacity of an epitope to elicit neutralizing antibodies. Because of the degeneracy of the immune system and the polyspecificity of antibodies, each epitope studied by the structure-based RV procedure is only one of the many epitopes that the particular nMab is able to recognize and there is no reason to assume that this nMab must have been elicited by this one epitope of known structure. Recent evidence is presented that the trimeric Env spikes of the virus possess such an enormous plasticity and intrinsic structural flexibility that it is it extremely difficult to determine which Env regions are the best candidate vaccine immunogens most likely to elicit protective antibodies. Full article

(This article belongs to the Special Issue Reverse Vaccinology)

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