Vaccine focusing to cross-subtype HIV-1 gp120 variable loop epitopes

Cardozo, Timothy; Wang, Shixia; Jiang, Xunqing; Kong, Xiang‐Peng; Hioe, Catarina E.; Krachmarov, Chavdar

doi:10.1016/j.vaccine.2014.07.026

Cited by 9 publications

(6 citation statements)

References 61 publications

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“…Thus, even though conventional nAbs are limited in their breadth and potency, they are commonly made by HIV-positive individuals (32), by immunized humans (24), and by immunized animals (33,34), and the previously mentioned studies suggest that they can reduce infection rates. Therefore, such Abs, induced by vaccines, have substantial potential for influencing the course of the HIV epidemic.…”

Section: Types Of Antibodies Conventional Absmentioning

confidence: 99%

Antibodies Targeting the Envelope of HIV-1

Mayr

Zolla‐Pazner²

2015

Microbiol Spectr

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Antibodies (Abs) are a critical component of the human immune response against viral infections. In HIV-infected patients, a robust Ab response against the virus develops within months of infection; however, due to numerous strategies, the virus usually escapes the biological effects of the various Abs. Here we provide an overview of the different viral evasion mechanisms, including glycosylation, high mutation rate, and conformational masking by the envelope glycoproteins of the virus. In response to virus infection and to its evolution within a host, "conventional Abs" are generated, and these can also be induced by immunization; generally, these Abs are limited in their neutralization breadth and potency. In contrast, "exceptional Abs" require extended exposure to virus to generate the required hypermutation in the immunoglobulin variable regions, and they occur only in rare HIV-infected individuals, but they display impressive breadth and potency. In this review, we describe the major regions of the HIV envelope spike that are targeted by conventional and exceptional Abs. These include the first, second, and third variable loops (V1, V2, and V3) located at the apex of the envelope trimer, the CD4 binding site, and the membrane-proximal external region of the gp41 ectodomain. Lastly, we discuss the challenging task of HIV immunogen design and approaches for choosing which immunogens might be used to elicit protective Abs.

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Section: Types Of Antibodies Conventional Absmentioning

confidence: 99%

Antibodies Targeting the Envelope of HIV-1

Mayr

Zolla‐Pazner²

2015

Microbiol Spectr

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“…Similarly, thorough consideration and design would be necessary for TbpB. Indeed, a structure-based design to develop chimeric antigens to circumvent pathogen diversity has been successful in experimental vaccines against both bacterial and viral pathogens (82)(83)(84)(85).…”

Section: Resultsmentioning

confidence: 99%

Comprehensive Bioinformatic Assessments of the Variability of Neisseria gonorrhoeae Vaccine Candidates

Baarda

Zielke

Holm

et al. 2021

mSphere

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A protective vaccine is the only viable way to stop the spread of gonorrhea in the face of rising antibiotic resistance. However, the notorious phase and antigenic variation of Neisseria gonorrhoeae surface proteins remains one of the challenges in vaccine development. To facilitate vaccine advancement efforts, we carried out comprehensive bioinformatic analyses of sequence variation by comparing 34 gonorrhea antigen candidates among >5,000 clinical N. gonorrhoeae isolates deposited in the Neisseria PubMLST database. Eight protein antigens showed exceptional conservation by having a single allele variant distributed in >80% of isolates. An additional 18 vaccine candidates were represented by ≤3 alleles in >50% of N. gonorrhoeae isolates globally. Phylogenetic analyses highlighted closely related antigen variants and additionally showed that AniA and FetB were the closest between N. gonorrhoeae and N. meningitidis. Up to 44% of N. meningitidis alleles for both antigens have premature stop codons, suggesting differential expression. Mapping polymorphisms to the available three-dimensional structures of 12 antigens revealed low-frequency surface polymorphisms. PorB and TbpB possessed numerous high-prevalence polymorphic sites. While TbpA was also highly variable, conserved loops were nonetheless identified. A high degree of sequence conservation, the distribution of a single antigen variant among N. gonorrhoeae strains globally, or low-frequency sequence polymorphisms in surface loops make ACP, AniA, BamA, BamE, MtrE, NspA, NGO0778, NGO1251, NGO1985, OpcA, PldA, Slam2, and ZnuD promising candidates for a gonorrhea vaccine. Finally, the commonly used N. gonorrhoeae FA1090 strain emerges as a vaccine prototype, as it carries antigen sequence types identical to the most broadly distributed antigen variants. IMPORTANCE Neisseria gonorrhoeae, the Gram-negative bacterium responsible for the sexually transmitted infection gonorrhea, is categorized as a high-priority pathogen for research and development efforts. N. gonorrhoeae’s “superbug” status, its high morbidity, and the serious health impact associated with gonorrhea highlight the importance of vaccine development. One of the longstanding barriers to developing an effective vaccine against N. gonorrhoeae is the remarkable variability of surface-exposed antigens. In this report, we addressed this roadblock by applying extensive bioinformatic analyses to 34 gonorrhea antigen candidates among >5,000 clinical N. gonorrhoeae isolates. Our studies are important, as they reveal promising, conserved gonorrhea vaccine candidates and aid structural vaccinology. Moreover, these approaches are broadly applicable to other infectious diseases where surface antigen variability impedes successful vaccine design.

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“…The solubility of Luk sequences that were predicted from the above analysis to be continuous surface exposed loop subregions was estimated using a solubility estimation tool (http://www.innovagen.com/proteomics-tools). If the solubility was acceptable, each sequence was subjected to biased probability Monte Carlo computational ab initio folding (55), which was used to predict the 3D conformation of the identified subsequences as free peptides in solution (56)(57)(58)(59)(60)(61)(62)(63)(64)(65)(66)(67), with each searched conformation assessed for thermodynamic and physics-based energy components (68)(69)(70)(71). Thereby, the lowest energy conformation that was biologically relevant was identified, along with the dynamic ensemble that enables assessment of the flexibility of the peptide structure.…”

Section: Methodsmentioning

confidence: 99%

Unbiased Identification of Immunogenic Staphylococcus aureus Leukotoxin B-Cell Epitopes

et al. 2020

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Unbiased identification of individual immunogenic B-cell epitopes in major antigens of a pathogen remains a technology challenge for vaccine discovery. We therefore developed a platform for rapid phage display screening of deep recombinant libraries consisting of as few as one major pathogen antigen. Using the bicomponent pore-forming leukocidin (Luk) exotoxins of the major pathogen Staphylococcus aureus as a prototype, we randomly fragmented and separately ligated the hemolysin gamma A (HlgA) and LukS genes into a custom-built phage display system, termed pComb-Opti8. Deep sequence analysis of barcoded amplimers of the HlgA and LukS gene fragment libraries demonstrated that biopannng against a cross-reactive anti-Luk monoclonal antibody (MAb) recovered convergent molecular clones with short overlapping homologous sequences. We thereby identified an 11-amino-acid sequence that is highly conserved in four Luk toxin subunits and is ubiquitous in representation within S. aureus clinical isolates. The isolated 11-amino-acid peptide probe was predicted to retain the native three-dimensional (3D) conformation seen within the Luk holotoxin. Indeed, this peptide was recognized by the selecting anti-Luk MAb, and, using mutated peptides, we showed that a particular amino acid side chain was essential for these interactions. Furthermore, murine immunization with this peptide elicited IgG responses that were highly reactive with both the autologous synthetic peptide and the full-length Luk toxin homologues. Thus, using a gene fragment- and phage display-based pipeline, we have identified and validated immunogenic B-cell epitopes that are cross-reactive between members of the pore-forming leukocidin family. This approach could be harnessed to identify novel epitopes for a much-needed S. aureus-protective subunit vaccine.

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Vaccine focusing to cross-subtype HIV-1 gp120 variable loop epitopes

Cited by 9 publications

References 61 publications

Antibodies Targeting the Envelope of HIV-1

Antibodies Targeting the Envelope of HIV-1

Comprehensive Bioinformatic Assessments of the Variability of Neisseria gonorrhoeae Vaccine Candidates

Unbiased Identification of Immunogenic Staphylococcus aureus Leukotoxin B-Cell Epitopes

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