Special Issue "Advances in Antibody-based HIV-1 Vaccine Development"

A special issue of Vaccines (ISSN 2076-393X).

Deadline for manuscript submissions: closed (30 June 2019).

Special Issue Editor

Dr. Ursula Dietrich
E-Mail Website
Guest Editor
Department of Experimental Therapy, Georg-Speyer-Haus, Paul-Ehrlich-Str. 42-44, 60596 Frankfurt, Germany
Interests: HIV-1; broadly neutralizing antibodies; nanobodies; vaccine development; phage display

Special Issue Information

Dear Colleagues,

Despite the great success of antiretroviral therapy, both in the treatment and prevention of HIV-1 infection, a vaccine is still urgently needed to end the epidemic. Intensive collaborative work in the last decade resulted in the isolation of antibodies from a subset of HIV-positive patients, that can potently neutralize a broad spectrum of primary HIV-1 isolates in vitro and protect from infection in animal models, advancing these broadly neutralizing antibodies (bnAbs) to clinical trials in recent years. In parallel, detailed structural characterizations of bnAbs in complex with HIV-1 envelope proteins (Env) gave structural insights into particular features of these antibodies and their epitopes. Unfortunately, HIV-1 Env immunogens derived from this knowledge were not able to date to induce bnAbs upon vaccination of humans or non-human primates. However, they can do so in certain species like camelids or cows, which naturally generate antibodies with special characteristics of bnAbs. Detailed immunological studies are being performed to understand the generation of bnAbs in patients with the aim to recapitulate the underlying mechanisms in vaccination approaches. A continous coevolution of virus and antibodies driven by immunological escape mutants seems to be essential and serves as the basis for the generation of a series of Env immunogens for the next vaccine trials. Besides neutralization, Fc-mediated effector functions of antibodies are also important to control viremia by targeting cytotoxic immune activities to HIV-1 infected cells, thus potentially eliminating viral reservoirs in the body. In view of future therapeutic vaccine trials, the focus will be on choosing the right combinations of antibodies as well as delivery modes in order to achieve persisting and highly effective antibody concentrations. For prophylactic passive vaccine trials, bnAbs or derivatives may be particularly interesting to prevent infection in high risk cohorts. For classical active vaccination programs it has to be shown whether suitable Env immunogens can be identified that are able to stimulate naive B cell precursors in large populations to generate bnAbs.

Dr. Ursula Dietrich
Guest Editor

Manuscript Submission Information

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Keywords

  • HIV-1 vaccine development
  • broadly neutralizing antibodies
  • natural vs. vaccine-induced antibody response
  • effector functions of antibodies
  • structure-based immunogen design
  • vectors for vaccine delivery
  • perspectives for clinical applications

Published Papers (11 papers)

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Editorial

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Editorial
Advances in Antibody-Based HIV-1 Vaccines Development
Vaccines 2020, 8(1), 44; https://doi.org/10.3390/vaccines8010044 - 25 Jan 2020
Viewed by 1256
Abstract
Despite the great success of antiretroviral therapy, both in the treatment and prevention of HIV-1 infection, a vaccine is still urgently needed to end the epidemic [...] Full article
(This article belongs to the Special Issue Advances in Antibody-based HIV-1 Vaccine Development)

Review

Jump to: Editorial

Review
Exploiting B Cell Receptor Analyses to Inform on HIV-1 Vaccination Strategies
Vaccines 2020, 8(1), 13; https://doi.org/10.3390/vaccines8010013 - 01 Jan 2020
Cited by 8 | Viewed by 2559
Abstract
The human antibody repertoire is generated by the recombination of different gene segments as well as by processes of somatic mutation. Together these mechanisms result in a tremendous diversity of antibodies that are able to combat various pathogens including viruses and bacteria, or [...] Read more.
The human antibody repertoire is generated by the recombination of different gene segments as well as by processes of somatic mutation. Together these mechanisms result in a tremendous diversity of antibodies that are able to combat various pathogens including viruses and bacteria, or malignant cells. In this review, we summarize the opportunities and challenges that are associated with the analyses of the B cell receptor repertoire and the antigen-specific B cell response. We will discuss how recent advances have increased our understanding of the antibody response and how repertoire analyses can be exploited to inform on vaccine strategies, particularly against HIV-1. Full article
(This article belongs to the Special Issue Advances in Antibody-based HIV-1 Vaccine Development)
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Review
Mucosal Antibodies: Defending Epithelial Barriers against HIV-1 Invasion
Vaccines 2019, 7(4), 194; https://doi.org/10.3390/vaccines7040194 - 23 Nov 2019
Cited by 10 | Viewed by 1907
Abstract
The power of mucosal anti-HIV-1 envelope immunoglobulins (Igs) to block virus transmission is underappreciated. We used passive immunization, a classical tool to unequivocally prove whether antibodies are protective. We mucosally instilled recombinant neutralizing monoclonal antibodies (nmAbs) of different Ig classes in rhesus macaques [...] Read more.
The power of mucosal anti-HIV-1 envelope immunoglobulins (Igs) to block virus transmission is underappreciated. We used passive immunization, a classical tool to unequivocally prove whether antibodies are protective. We mucosally instilled recombinant neutralizing monoclonal antibodies (nmAbs) of different Ig classes in rhesus macaques (RMs) followed by mucosal simian–human immunodeficiency virus (SHIV) challenge. We gave anti-HIV-1 IgM, IgG, and dimeric IgA (dIgA) versions of the same human nmAb, HGN194 that targets the conserved V3 loop crown. Surprisingly, dIgA1 with its wide-open, flat hinge protected 83% of the RMs against intrarectal R5-tropic SHIV-1157ipEL-p challenge, whereas dIgA2, with its narrow hinge, only protected 17% of the animals—despite identical epitope specificities and in vitro neutralization curves of the two dIgA isotypes (Watkins et al., AIDS 2013 27(9):F13-20). These data imply that factors in addition to neutralization determine in vivo protection. We propose that this underlying protective mechanism is immune exclusion, which involves large nmAb/virion aggregates that prevent virus penetration of mucosal barriers. Future studies need to find biomarkers that predict effective immune exclusion in vivo. Vaccine development strategies against HIV-1 and/or other mucosally transmissible pathogens should include induction of strong mucosal Abs of different Ig classes to defend epithelial barriers against pathogen invasion. Full article
(This article belongs to the Special Issue Advances in Antibody-based HIV-1 Vaccine Development)
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Review
Viral Vectors for the Induction of Broadly Neutralizing Antibodies against HIV
Vaccines 2019, 7(3), 119; https://doi.org/10.3390/vaccines7030119 - 19 Sep 2019
Cited by 5 | Viewed by 1336
Abstract
Extensive research on generating an efficient HIV vaccine is ongoing. A major aim of HIV vaccines is the induction of long-lasting, broadly neutralizing antibodies (bnAbs) that can confer sterile immunity for a prolonged period of time. Several strategies have been explored to reach [...] Read more.
Extensive research on generating an efficient HIV vaccine is ongoing. A major aim of HIV vaccines is the induction of long-lasting, broadly neutralizing antibodies (bnAbs) that can confer sterile immunity for a prolonged period of time. Several strategies have been explored to reach this goal, i.e. protein immunization, DNA, or viral vectors, or a combination thereof. In this review, we give an overview of approaches using viral vectors for the induction of HIV-specific bnAbs. Many pre-clinical studies were performed using various replication-competent and -incompetent vectors. Amongst them, poxviral and adenoviral vectors were the most prevalent ones. In many studies, viral vectors were combined with a DNA prime or a protein boost. However, neutralizing antibodies were mainly induced against the homologous HIV-1 vaccine strain or tier 1 viruses, and in rare cases, against tier 2 viruses, indicating the need for improved antigens and vaccination strategies. Furthermore, we also review next generation Env antigens that are currently being used in protein vaccination approaches and point out how they could be utilized in viral vectors. Full article
(This article belongs to the Special Issue Advances in Antibody-based HIV-1 Vaccine Development)
Review
Peptide-Based Vaccination for Antibody Responses Against HIV
Vaccines 2019, 7(3), 105; https://doi.org/10.3390/vaccines7030105 - 02 Sep 2019
Cited by 8 | Viewed by 1993
Abstract
HIV-1 is responsible for a global pandemic of 35 million people and continues to spread at a rate of >2 million new infections/year. It is widely acknowledged that a protective vaccine would be the most effective means to reduce HIV-1 spread and ultimately [...] Read more.
HIV-1 is responsible for a global pandemic of 35 million people and continues to spread at a rate of >2 million new infections/year. It is widely acknowledged that a protective vaccine would be the most effective means to reduce HIV-1 spread and ultimately eliminate the pandemic, whereas a therapeutic vaccine might help to mitigate the clinical course of the disease and to contribute to virus eradication strategies. However, despite more than 30 years of research, we do not have a vaccine capable of protecting against HIV-1 infection or impacting on disease progression. This, in part, denotes the challenge of identifying immunogens and vaccine modalities with a reduced risk of failure in late stage development. However, progress has been made in epitope identification for the induction of broadly neutralizing antibodies. Thus, peptide-based vaccination has become one of the challenges of this decade. While some researchers reconstitute envelope protein conformation and stabilization to conserve the epitope targeted by neutralizing antibodies, others have developed strategies based on peptide-carrier vaccines with a similar goal. Here, we will review the major peptide-carrier based approaches in the vaccine field and their application and recent development in the HIV-1 field. Full article
(This article belongs to the Special Issue Advances in Antibody-based HIV-1 Vaccine Development)
Review
Understudied Factors Influencing Fc-Mediated Immune Responses against Viral Infections
Vaccines 2019, 7(3), 103; https://doi.org/10.3390/vaccines7030103 - 30 Aug 2019
Cited by 7 | Viewed by 1789
Abstract
Antibodies play a crucial role in host defense against viruses, both by preventing infection and by controlling viral replication. Besides their capacity to neutralize viruses, antibodies also exert their antiviral effects by crystallizable fragment (Fc)-mediated effector mechanisms. This involves a bridge between innate [...] Read more.
Antibodies play a crucial role in host defense against viruses, both by preventing infection and by controlling viral replication. Besides their capacity to neutralize viruses, antibodies also exert their antiviral effects by crystallizable fragment (Fc)-mediated effector mechanisms. This involves a bridge between innate and adaptive immune systems, wherein antibodies form immune complexes that drive numerous innate immune effector functions, including antibody-dependent cellular cytotoxicity, antibody-dependent complement-mediated lysis, and antibody-dependent phagocytosis. Here, we review certain mechanisms that modulate these antibody-mediated effector functions against virally infected cells, such as viral glycoprotein shedding, viral glycoprotein internalization, antibody cooperativity, and antibody glycosylation. These mechanisms can either protect viral replication or enhance infected cell clearance. Here we discuss the importance of these understudied factors in modulating Fc-mediated effector functions. Full article
(This article belongs to the Special Issue Advances in Antibody-based HIV-1 Vaccine Development)
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Review
Anti-Tat Immunity in HIV-1 Infection: Effects of Naturally Occurring and Vaccine-Induced Antibodies Against Tat on the Course of the Disease
Vaccines 2019, 7(3), 99; https://doi.org/10.3390/vaccines7030099 - 26 Aug 2019
Cited by 10 | Viewed by 2069
Abstract
HIV-1 Tat is an essential protein in the virus life cycle, which is required for virus gene expression and replication. Most Tat that is produced during infection is released extracellularly and it plays a key role in HIV pathogenesis, including residual disease upon [...] Read more.
HIV-1 Tat is an essential protein in the virus life cycle, which is required for virus gene expression and replication. Most Tat that is produced during infection is released extracellularly and it plays a key role in HIV pathogenesis, including residual disease upon combination antiretroviral therapy (cART). Here, we review epidemiological and experimental evidence showing that antibodies against HIV-1 Tat, infrequently occurring in natural infection, play a protective role against disease progression, and that vaccine targeting Tat can intensify cART. In fact, Tat vaccination of subjects on suppressive cART in Italy and South Africa promoted immune restoration, including CD4+ T-cell increase in low immunological responders, and a reduction of proviral DNA even after six years of cART, when both CD4+ T-cell gain and DNA decay have reached a plateau. Of note, DNA decay was predicted by the neutralization of Tat-mediated entry of Env into dendritic cells by anti-Tat antibodies, which were cross-clade binding and neutralizing. Anti-Tat cellular immunity also contributed to the DNA decay. Based on these data, we propose the Tat therapeutic vaccine as a pathogenesis-driven intervention that effectively intensifies cART and it may lead to a functional cure, providing new perspectives and opportunities also for prevention and virus eradication strategies. Full article
(This article belongs to the Special Issue Advances in Antibody-based HIV-1 Vaccine Development)
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Review
V2-Specific Antibodies in HIV-1 Vaccine Research and Natural Infection: Controllers or Surrogate Markers
Vaccines 2019, 7(3), 82; https://doi.org/10.3390/vaccines7030082 - 06 Aug 2019
Cited by 6 | Viewed by 1924
Abstract
Most human immunodeficiency virus (HIV) vaccine trials have lacked efficacy and empirical vaccine lead targets are scarce. Thus far, the only independent correlate of reduced risk of HIV-1 acquisition in humans is elevated levels of V2-specific antibodies identified in the modestly protective RV144 [...] Read more.
Most human immunodeficiency virus (HIV) vaccine trials have lacked efficacy and empirical vaccine lead targets are scarce. Thus far, the only independent correlate of reduced risk of HIV-1 acquisition in humans is elevated levels of V2-specific antibodies identified in the modestly protective RV144 vaccine trial. Ten years after RV144, human and non-human primate vaccine studies have reassessed the potential contribution of V2-specific antibodies to vaccine efficacy. In addition, studies of natural HIV-1 infection in humans have provided insight into the development of V1V2-directed antibody responses and their impact on clinical parameters and disease progression. Functionally diverse anti-V2 monoclonal antibodies were isolated and their structurally distinct V2 epitope regions characterized. After RV144, a plethora of research studies were performed using different model systems, immunogens, protocols, and challenge viruses. These diverse studies failed to provide a clear picture regarding the contribution of V2 antibodies to vaccine efficacy. Here, we summarize the biological functions and clinical findings associated with V2-specific antibodies and discuss their impact on HIV vaccine research. Full article
(This article belongs to the Special Issue Advances in Antibody-based HIV-1 Vaccine Development)
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Review
Nanobodies that Neutralize HIV
Vaccines 2019, 7(3), 77; https://doi.org/10.3390/vaccines7030077 - 31 Jul 2019
Cited by 12 | Viewed by 2736
Abstract
Nanobodies or VHH (variable domains of heavy-chain only antibodies) are derived from camelid species such as llamas and camels. Nanobodies isolated and selected through phage display can neutralize a broad range of human immunodeficiency virus type 1 (HIV-1) strains. Nanobodies fit into canyons [...] Read more.
Nanobodies or VHH (variable domains of heavy-chain only antibodies) are derived from camelid species such as llamas and camels. Nanobodies isolated and selected through phage display can neutralize a broad range of human immunodeficiency virus type 1 (HIV-1) strains. Nanobodies fit into canyons on the HIV envelope that may not be accessible to IgG (immunoglobulin G) containing both heavy and light chains, and they tend to have long CDR3 (complementarity-determining region 3) loops that further enhance recognition of otherwise cryptic epitopes. Nanobodies are readily expressed at high levels in bacteria and yeast, as well as by viral vectors, and they form relatively stable, heat-resistant molecules. Nanobodies can be linked to human Fc chains to gain immune effector functions. Bivalent and trivalent nanobodies recognizing the same or distinct epitopes on the envelope glycoproteins, gp120 and gp41, greatly increase the potency of HIV-1 neutralization. Nanobodies have potential applications for HIV-1 diagnostics, vaccine design, microbicides, immunoprophylaxis, and immunotherapy. Full article
(This article belongs to the Special Issue Advances in Antibody-based HIV-1 Vaccine Development)
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Review
Nanoparticle Vaccines for Inducing HIV-1 Neutralizing Antibodies
Vaccines 2019, 7(3), 76; https://doi.org/10.3390/vaccines7030076 - 29 Jul 2019
Cited by 20 | Viewed by 2401
Abstract
The enormous sequence diversity between human immunodeficiency virus type 1 (HIV-1) strains poses a major roadblock for generating a broadly protective vaccine. Many experimental HIV-1 vaccine efforts are therefore aimed at eliciting broadly neutralizing antibodies (bNAbs) that are capable of neutralizing the majority [...] Read more.
The enormous sequence diversity between human immunodeficiency virus type 1 (HIV-1) strains poses a major roadblock for generating a broadly protective vaccine. Many experimental HIV-1 vaccine efforts are therefore aimed at eliciting broadly neutralizing antibodies (bNAbs) that are capable of neutralizing the majority of circulating HIV-1 strains. The envelope glycoprotein (Env) trimer on the viral membrane is the sole target of bNAbs and the key component of vaccination approaches aimed at eliciting bNAbs. Multimeric presentation of Env on nanoparticles often plays a critical role in these strategies. Here, we will discuss the different aspects of nanoparticles in Env vaccination, including recent insights in immunological processes underlying their perceived advantages, the different nanoparticle platforms and the various immunogenicity studies that employed nanoparticles to improve (neutralizing) antibody responses against Env. Full article
(This article belongs to the Special Issue Advances in Antibody-based HIV-1 Vaccine Development)
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Review
Impact of HIV-1 Diversity on Its Sensitivity to Neutralization
Vaccines 2019, 7(3), 74; https://doi.org/10.3390/vaccines7030074 - 25 Jul 2019
Cited by 9 | Viewed by 2004
Abstract
The HIV-1 pandemic remains a major burden on global public health and a vaccine to prevent HIV-1 infection is highly desirable but has not yet been developed. Among the many roadblocks to achieve this goal, the high antigenic diversity of the HIV-1 envelope [...] Read more.
The HIV-1 pandemic remains a major burden on global public health and a vaccine to prevent HIV-1 infection is highly desirable but has not yet been developed. Among the many roadblocks to achieve this goal, the high antigenic diversity of the HIV-1 envelope protein (Env) is one of the most important and challenging to overcome. The recent development of broadly neutralizing antibodies has considerably improved our knowledge on Env structure and its interplay with neutralizing antibodies. This review aims at highlighting how the genetic diversity of HIV-1 thwarts current, and possibly future, vaccine developments. We will focus on the impact of HIV-1 Env diversification on the sensitivity to neutralizing antibodies and the repercussions of this continuous process at a population level. Full article
(This article belongs to the Special Issue Advances in Antibody-based HIV-1 Vaccine Development)
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