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15 pages, 3415 KiB

Open AccessArticle

Virus-Like Particle Based Vaccines Elicit Neutralizing Antibodies against the HIV-1 Fusion Peptide

by Alemu Tekewe Mogus, Lihong Liu, Manxue Jia, Diane T. Ajayi, Kai Xu, Rui Kong, Jing Huang, Jian Yu, Peter D. Kwong, John R. Mascola, David D. Ho, Moriya Tsuji and Bryce Chackerian

Vaccines 2020, 8(4), 765; https://doi.org/10.3390/vaccines8040765 - 15 Dec 2020

Cited by 15 | Viewed by 5912

Abstract

Broadly neutralizing antibodies (bnAbs) isolated from HIV-infected individuals delineate vulnerable sites on the HIV envelope glycoprotein that are potential vaccine targets. A linear epitope within the N-terminal region of the HIV-1 fusion peptide (FP8) is the primary target of VRC34.01, a bnAb that [...] Read more.

Broadly neutralizing antibodies (bnAbs) isolated from HIV-infected individuals delineate vulnerable sites on the HIV envelope glycoprotein that are potential vaccine targets. A linear epitope within the N-terminal region of the HIV-1 fusion peptide (FP8) is the primary target of VRC34.01, a bnAb that neutralizes ~50% of primary HIV isolates. FP8 has attracted attention as a potential HIV vaccine target because it is a simple linear epitope. Here, platform technologies based on RNA bacteriophage virus-like particles (VLPs) were used to develop multivalent vaccines targeting the FP8 epitope. Both recombinant MS2 VLPs displaying the FP8 peptide and Qβ VLPs displaying chemically conjugated FP8 peptide induced high titers of FP8-specific antibodies in mice. Moreover, a heterologous prime-boost-boost regimen employing the two FP8-VLP vaccines and native envelope trimer was the most effective approach for eliciting HIV-1 neutralizing antibodies. Given the potent immunogenicity of VLP-based vaccines, this vaccination strategy—inspired by bnAb-guided epitope mapping, VLP bioengineering, and prime-boost immunization approaches—may be a useful strategy for eliciting bnAb responses against HIV. Full article

(This article belongs to the Special Issue HIV Vaccine)

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13 pages, 1341 KiB

Open AccessArticle

Frequent and Durable Anti-HIV Envelope VIV2 IgG Responses Induced by HIV-1 DNA Priming and HIV-MVA Boosting in Healthy Tanzanian Volunteers

by Agricola Joachim, Frank Msafiri, Sayali Onkar, Patricia Munseri, Said Aboud, Eligius F. Lyamuya, Muhammad Bakari, Erik Billings, Merlin L. Robb, Britta Wahren, Fred S. Mhalu, Eric Sandström, Mangala Rao, Charlotta Nilsson and Gunnel Biberfeld

Vaccines 2020, 8(4), 681; https://doi.org/10.3390/vaccines8040681 - 13 Nov 2020

Cited by 6 | Viewed by 2852

Abstract

We evaluated antibody responses to the human immunodeficiency virus (HIV) envelope variable regions 1 and 2 (V1V2) in 29 vaccinees who had received three HIV-1 DNA immunizations and two HIV-modified vaccinia virus Ankara (MVA) boosts in the phase I/II HIVIS03 vaccine trial. Twenty [...] Read more.

We evaluated antibody responses to the human immunodeficiency virus (HIV) envelope variable regions 1 and 2 (V1V2) in 29 vaccinees who had received three HIV-1 DNA immunizations and two HIV-modified vaccinia virus Ankara (MVA) boosts in the phase I/II HIVIS03 vaccine trial. Twenty vaccinees received a third HIV-MVA boost after three years in the HIVIS06 trial. IgG and IgG antibody subclasses to gp70V1V2 proteins of HIV-1 A244, CN54, Consensus C, and Case A2 were analysed using an enzyme-linked immunosorbent assay (ELISA). Cyclic V2 peptides of A244, Consensus C, and MN were used in a surface plasmon resonance (SPR) assay. Four weeks after the second HIV-MVA, anti-V1V2 IgG antibodies to A244 were detected in 97% of HIVIS03 vaccinees, in 75% three years later, and in 95% after the third HIV-MVA. Anti-CN54 V1V2 IgG was detectable in 48% four weeks after the second HIV-MVA. The SPR data supported the findings. The IgG response was predominantly IgG1. Four weeks after the second HIV-MVA, 85% of vaccinees had IgG1 antibodies to V1V2 A244, which persisted in 25% for three-years. IgG3 and IgG4 antibodies to V1V2 A244 were rare. In conclusion, the HIV-DNA/MVA vaccine regimen induced durable V1V2 IgG antibody responses in a high proportion of vaccinees. Full article

(This article belongs to the Special Issue HIV Vaccine)

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20 pages, 5422 KiB

Open AccessArticle

CD4⁺ T Cells Induced by Tuberculosis Subunit Vaccine H1 Can Improve the HIV-1 Env Humoral Response by Intrastructural Help

by Stephan Klessing, Vladimir Temchura, Pierre Tannig, Antonia Sophia Peter, Dennis Christensen, Roland Lang and Klaus Überla

Vaccines 2020, 8(4), 604; https://doi.org/10.3390/vaccines8040604 - 13 Oct 2020

Cited by 10 | Viewed by 4277

Abstract

The induction of a potent and long-lasting, broadly neutralizing antibody response is one of the most promising approaches in HIV-1 vaccination. Recently, we demonstrated that Gag-specific T helper cells induced by DNA priming can enhance and modulate the HIV Env-specific B cell response [...] Read more.

The induction of a potent and long-lasting, broadly neutralizing antibody response is one of the most promising approaches in HIV-1 vaccination. Recently, we demonstrated that Gag-specific T helper cells induced by DNA priming can enhance and modulate the HIV Env-specific B cell response upon virus-like particle (VLP) boost by intrastructural help (ISH). In order to minimize the induction of potentially harmful HIV specific T_H cells, we explored the possibility to harness the heterologous T_H cells induced by a recombinant tuberculosis subunit vaccine H1, which contains a fusion protein of Ag85B and ESAT-6 antigens in combination with the liposomal adjuvant CAF01. To provide ISH, immunodominant MHC-II restricted peptides from the H1 vaccine were genetically incorporated into the HIV 1 Gag protein and used for HIV VLP production. ISH effects on Env-specific antibody levels and B cell differentiation were analyzed in mice primed against H1 and boosted with VLPs. In contrast to non-primed mice, a significant increase of Env-specific IgG levels for up to 26 weeks after the last immunization was observed. This increase was largely caused by elevated IgG2b and IgG2c levels in mice that received H1 priming. Additionally, ISH enhanced the frequency of Env-specific long-lived plasma cells in the bone marrow. In this study, we were able to demonstrate that a heterologous prime-boost regimen consisting of the H1 tuberculosis subunit vaccine and T helper epitope modified HIV-1 VLPs resulted in enhanced HIV Env antibody and B cell responses, mediated by intrastructural help. Full article

(This article belongs to the Special Issue HIV Vaccine)

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30 pages, 5680 KiB

Open AccessArticle

Deletion of Vaccinia Virus A40R Gene Improves the Immunogenicity of the HIV-1 Vaccine Candidate MVA-B

by Patricia Pérez, María Q. Marín, Adrián Lázaro-Frías, Carlos Óscar S. Sorzano, Carmen E. Gómez, Mariano Esteban and Juan García-Arriaza

Vaccines 2020, 8(1), 70; https://doi.org/10.3390/vaccines8010070 - 6 Feb 2020

Cited by 12 | Viewed by 5230

Abstract

Development of a safe and efficacious vaccine against the HIV/AIDS pandemic remains a major scientific goal. We previously described an HIV/AIDS vaccine based on the modified vaccinia virus Ankara (MVA) expressing HIV-1 gp120 and Gag-Pol-Nef (GPN) of clade B (termed MVA-B), which showed [...] Read more.

Development of a safe and efficacious vaccine against the HIV/AIDS pandemic remains a major scientific goal. We previously described an HIV/AIDS vaccine based on the modified vaccinia virus Ankara (MVA) expressing HIV-1 gp120 and Gag-Pol-Nef (GPN) of clade B (termed MVA-B), which showed moderate immunogenicity in phase I prophylactic and therapeutic clinical trials. Here, to improve the immunogenicity of MVA-B, we generated a novel recombinant virus, MVA-B ΔA40R, by deleting in the MVA-B genome the vaccinia virus (VACV) A40R gene, which encodes a protein with unknown immune function. The innate immune responses triggered by MVA-B ΔA40R in infected human macrophages, in comparison to parental MVA-B, revealed an increase in the mRNA expression levels of interferon (IFN)-β, IFN-induced genes, and chemokines. Compared to priming with DNA-B (a mixture of DNA-gp120 plus DNA-GPN) and boosting with MVA-B, mice immunized with a DNA-B/MVA-B ΔA40R regimen induced higher magnitude of adaptive and memory HIV-1-specific CD4+ and CD8+ T-cell immune responses that were highly polyfunctional, mainly directed against Env. and of an effector memory phenotype, together with enhanced levels of antibodies against HIV-1 gp120. Reintroduction of the A40R gene into the MVA-B ΔA40R genome (virus termed MVA-B ΔA40R-rev) promoted in infected cells high mRNA and protein A40 levels, with A40 protein localized in the cell membrane. MVA-B ΔA40R-rev significantly reduced mRNA levels of IFN-β and of several other innate immune-related genes in infected human macrophages. In immunized mice, MVA-B ΔA40R-rev reduced the magnitude of the HIV-1-specific CD4+ and CD8+ T cell responses compared to MVA-B ΔA40R. These results revealed an immunosuppressive role of the A40 protein, findings relevant for the optimization of poxvirus vectors as vaccines. Full article

(This article belongs to the Special Issue HIV Vaccine)

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22 pages, 3196 KiB

Open AccessArticle

An MVA Vector Expressing HIV-1 Envelope under the Control of a Potent Vaccinia Virus Promoter as a Promising Strategy in HIV/AIDS Vaccine Design

by Patricia Pérez, María Q. Marín, Adrián Lázaro-Frías, Carlos Óscar S. Sorzano, Mauro Di Pilato, Carmen E. Gómez, Mariano Esteban and Juan García-Arriaza

Vaccines 2019, 7(4), 208; https://doi.org/10.3390/vaccines7040208 - 6 Dec 2019

Cited by 5 | Viewed by 5169

Abstract

Highly attenuated poxviral vectors, such as modified vaccinia virus ankara (MVA), are promising vaccine candidates against several infectious diseases. One of the approaches developed to enhance the immunogenicity of poxvirus vectors is increasing the promoter strength and accelerating during infection production levels of [...] Read more.

Highly attenuated poxviral vectors, such as modified vaccinia virus ankara (MVA), are promising vaccine candidates against several infectious diseases. One of the approaches developed to enhance the immunogenicity of poxvirus vectors is increasing the promoter strength and accelerating during infection production levels of heterologous antigens. Here, we have generated and characterized the biology and immunogenicity of an optimized MVA-based vaccine candidate against HIV/AIDS expressing HIV-1 clade B gp120 protein under the control of a novel synthetic late/early optimized (LEO) promoter (LEO160 promoter; with a spacer length of 160 nucleotides), termed MVA-LEO160-gp120. In infected cells, MVA-LEO160-gp120 significantly increased the expression levels of HIV-1 gp120 mRNA and protein, compared to the clinical vaccine MVA-B vector expressing HIV-1 gp120 under the control of the commonly used synthetic early/late promoter. When mice were immunized with a heterologous DNA-prime/MVA-boost protocol, the immunization group DNA-gp120/MVA-LEO160-gp120 induced an enhancement in the magnitude of gp120-specific CD4⁺ and CD8⁺ T-cell responses, compared to DNA-gp120/MVA-B; with most of the responses being mediated by the CD8⁺ T-cell compartment, with a T effector memory phenotype. DNA-gp120/MVA-LEO160-gp120 also elicited a trend to a higher magnitude of gp120-specific CD4⁺ T follicular helper cells, and modest enhanced levels of antibodies against HIV-1 gp120. These findings revealed that this new optimized vaccinia virus promoter could be considered a promising strategy in HIV/AIDS vaccine design, confirming the importance of early expression of heterologous antigen and its impact on the antigen-specific immunogenicity elicited by poxvirus-based vectors. Full article

(This article belongs to the Special Issue HIV Vaccine)

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Review

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18 pages, 1678 KiB

Open AccessReview

HIV-1 Envelope Glycosylation and the Signal Peptide

by Gregory S. Lambert and Chitra Upadhyay

Vaccines 2021, 9(2), 176; https://doi.org/10.3390/vaccines9020176 - 19 Feb 2021

Cited by 7 | Viewed by 3875

Abstract

The RV144 trial represents the only vaccine trial to demonstrate any protective effect against HIV-1 infection. While the reason(s) for this protection are still being evaluated, it serves as justification for widespread efforts aimed at developing new, more effective HIV-1 vaccines. Advances in [...] Read more.

The RV144 trial represents the only vaccine trial to demonstrate any protective effect against HIV-1 infection. While the reason(s) for this protection are still being evaluated, it serves as justification for widespread efforts aimed at developing new, more effective HIV-1 vaccines. Advances in our knowledge of HIV-1 immunogens and host antibody responses to these immunogens are crucial to informing vaccine design. While the envelope (Env) protein is the only viral protein present on the surface of virions, it exists in a complex trimeric conformation and is decorated with an array of variable N-linked glycans, making it an important but difficult target for vaccine design. Thus far, efforts to elicit a protective humoral immune response using structural mimics of native Env trimers have been unsuccessful. Notably, the aforementioned N-linked glycans serve as a component of many of the epitopes crucial for the induction of potentially protective broadly neutralizing antibodies (bnAbs). Thus, a greater understanding of Env structural determinants, most critically Env glycosylation, will no doubt be of importance in generating effective immunogens. Recent studies have identified the HIV-1 Env signal peptide (SP) as an important contributor to Env glycosylation. Further investigation into the mechanisms by which the SP directs glycosylation will be important, both in the context of understanding HIV-1 biology and in order to inform HIV-1 vaccine design. Full article

(This article belongs to the Special Issue HIV Vaccine)

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21 pages, 1339 KiB

Open AccessReview

Immune Complex Vaccine Strategies to Combat HIV-1 and Other Infectious Diseases

by Alex F. Tang, Gospel Enyindah-Asonye and Catarina E. Hioe

Vaccines 2021, 9(2), 112; https://doi.org/10.3390/vaccines9020112 - 2 Feb 2021

Cited by 5 | Viewed by 5953

Abstract

Immune complexes (ICs) made of antibody-bound antigens exhibit immunomodulatory activities exploitable in a vaccination strategy to optimize vaccine efficacy. The modulatory effects of ICs are typically attributed to the Fc fragments of the antibody components, which engage Fc receptors, complement and complement receptors [...] Read more.

Immune complexes (ICs) made of antibody-bound antigens exhibit immunomodulatory activities exploitable in a vaccination strategy to optimize vaccine efficacy. The modulatory effects of ICs are typically attributed to the Fc fragments of the antibody components, which engage Fc receptors, complement and complement receptors on various immune cells. These Fc-mediated functions facilitate the critical interplay between innate and adaptive immune systems to impact the quality and quantity of the elicited adaptive responses. In addition to the Fc contribution, the Fab fragment also plays an immunoregulation role. The antigen-binding domains of the Fab fragment can bind their specific epitopes at high affinity to sterically occlude these antigenic sites from recognition by other antibodies. Moreover, the Fab-mediated binding has been demonstrated to induce allosteric alterations at nearby or distant antigenic sites. In this review article, we survey published studies to illuminate how the immunomodulatory functions of ICs have been investigated or utilized in a vaccination strategy to fight against an array of infectious pathogens, culminating with IC vaccine designs aimed at preventing HIV-1 infection. In particular, we highlight IC vaccine candidates that exploit Fab-mediated steric and allosteric effects to direct antibody responses away or toward the V1V2 domain, the V3 loop, and other antigenic sites on the HIV-1 envelope gp120 glycoprotein. Like other HIV-1 vaccine approaches, the path for IC-based vaccines to reach the clinic faces major hurdles yet to be overcome; however, investigations into this vaccine strategy have provided insights into the multifaceted activities of antibodies beyond their conventional roles in the host defense against HIV-1 and other microbial pathogens. Full article

(This article belongs to the Special Issue HIV Vaccine)

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20 pages, 1757 KiB

Open AccessReview

SLAM Family Receptor Signaling in Viral Infections: HIV and Beyond

by Patrick O’Connell, Andrea Amalfitano and Yasser A. Aldhamen

Vaccines 2019, 7(4), 184; https://doi.org/10.3390/vaccines7040184 - 16 Nov 2019

Cited by 11 | Viewed by 5442

Abstract

The signaling lymphocytic activation molecule (SLAM) family of receptors are expressed on the majority of immune cells. These receptors often serve as self-ligands, and play important roles in cellular communication and adhesion, thus modulating immune responses. SLAM family receptor signaling is differentially regulated [...] Read more.

The signaling lymphocytic activation molecule (SLAM) family of receptors are expressed on the majority of immune cells. These receptors often serve as self-ligands, and play important roles in cellular communication and adhesion, thus modulating immune responses. SLAM family receptor signaling is differentially regulated in various immune cell types, with responses generally being determined by the presence or absence of two SLAM family adaptor proteins—Ewing’s sarcoma-associated transcript 2 (EAT-2) and SLAM-associated adaptor protein (SAP). In addition to serving as direct regulators of the immune system, certain SLAM family members have also been identified as direct targets for specific microbes and viruses. Here, we will discuss the known roles for these receptors in the setting of viral infection, with special emphasis placed on HIV infection. Because HIV causes such complex dysregulation of the immune system, studies of the roles for SLAM family receptors in this context are particularly exciting. Full article

(This article belongs to the Special Issue HIV Vaccine)

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