Vaccines and Broadly Neutralizing Antibodies for HIV-1 Prevention

Development of improved approaches for HIV-1 prevention will likely be required for a durable end to the global AIDS pandemic. Recent advances in preclinical studies and early phase clinical trials offer renewed promise for immunologic strategies for blocking acquisition of HIV-1 infection. Clinical trials are currently underway to evaluate the efficacy of two vaccine candidates and a broadly neutralizing antibody (bNAb) to prevent HIV-1 infection in humans. However, the vast diversity of HIV-1 is a major challenge for both active and passive immunization. Here we review current immunologic strategies for HIV-1 prevention, with a focus on current and next-generation vaccines and bNAbs.

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The Neutralizing Antibody Response to the HIV-1 Env Protein

Current HIV Research ◽

10.2174/1570162x15666171124122044 ◽

2018 ◽

Vol 16 (1) ◽

pp. 21-28 ◽

Cited By ~ 13

Author(s):

Penny L. Moore

Keyword(s):

Neutralizing Antibodies ◽

Passive Immunization ◽

Neutralizing Antibody ◽

Developmental Pathways ◽

Broadly Neutralizing Antibodies ◽

Infected People ◽

B Cell Maturation ◽

Public Health Challenge ◽

Env Protein ◽

Hiv 1

Background: A vaccine able to elicit broadly neutralizing antibodies capable of blocking infection by global viruses has not been achieved, and remains a key public health challenge.Objective: During infection, a robust strain-specific neutralizing response develops in most people, but only a subset of infected people develop broadly neutralizing antibodies. Understanding how and why these broadly neutralizing antibodies develop has been a focus of the HIV-1 vaccine field for many years, and has generated extraordinary insights into the neutralizing response to HIV-1 infection.Results: This review describes the features, targets and developmental pathways of early strainspecific antibodies and later broadly neutralizing antibodies, and explores the reasons such broad antibodies are not more commonly elicited during infection.Conclusion: The insights from these studies have been harnessed for the development of pioneering new vaccine approaches that seek to drive B cell maturation towards breadth. Overall, this review describes how findings from infected donors have impacted on active and passive immunization approaches that seek to prevent HIV-1 infection.

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New Connections: Cell-to-Cell HIV-1 Transmission, Resistance to Broadly Neutralizing Antibodies, and an Envelope Sorting Motif

Journal of Virology ◽

10.1128/jvi.00149-17 ◽

2017 ◽

Vol 91 (9) ◽

Cited By ~ 2

Author(s):

S. Abigail Smith ◽

Cynthia A. Derdeyn

Keyword(s):

Neutralizing Antibodies ◽

Differential Susceptibility ◽

Neutralizing Antibody ◽

Dependent Manner ◽

Broadly Neutralizing Antibodies ◽

Cell Infection ◽

Viral Spread ◽

Broadly Neutralizing Antibody ◽

Hiv 1

ABSTRACT HIV-1 infection from cell-to-cell may provide an efficient mode of viral spread in vivo and could therefore present a significant challenge for preventative or therapeutic strategies based on broadly neutralizing antibodies. Indeed, Li et al. (H. Li, C. Zony, P. Chen, and B. K. Chen, J. Virol. 91:e02425-16, 2017, https://doi.org/10.1128/JVI.02425-16 ) showed that the potency and magnitude of multiple HIV-1 broadly neutralizing antibody classes are decreased during cell-to-cell infection in a context-dependent manner. A functional motif in gp41 appears to contribute to this differential susceptibility by modulating exposure of neutralization epitopes.

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Sensitivity to Broadly Neutralizing Antibodies of Recently Transmitted HIV-1 Clade CRF02_AG Viruses with a Focus on Evolution over Time

Journal of Virology ◽

10.1128/jvi.01492-18 ◽

2018 ◽

Vol 93 (2) ◽

Cited By ~ 5

Author(s):

Karl Stefic ◽

Mélanie Bouvin-Pley ◽

Asma Essat ◽

Clara Visdeloup ◽

Alain Moreau ◽

...

Keyword(s):

Clinical Trials ◽

West Africa ◽

Neutralizing Antibodies ◽

Passive Immunization ◽

Broadly Neutralizing Antibodies ◽

Human Monoclonal Antibodies ◽

Large Panel ◽

Cd4 Binding Site ◽

Major Progress ◽

Hiv 1

ABSTRACT Broadly neutralizing antibodies (bnAbs) are promising agents for prevention and/or treatment of HIV-1 infection. However, the diversity among HIV-1 envelope (Env) glycoproteins impacts bnAb potency and breadth. Neutralization data on the CRF02_AG clade are scarce although it is highly prevalent in West Africa and Europe. We assessed the sensitivity to bnAbs of a panel of 33 early transmitted CRF02_AG viruses over a 15-year period of the French epidemic (1997 to 2012). Env pseudotyped CRF02_AG viruses were best neutralized by the CD4 binding site (CD4bs)-directed bnAbs (VRC01, 3BNC117, NIH45-46G54W, and N6) and the gp41 membrane-proximal external region (MPER)-directed bnAb 10E8 in terms of both potency and breadth. We observed a higher resistance to bnAbs targeting the V1V2-glycan region (PG9 and PGT145) and the V3-glycan region (PGT121 and 10-1074). Combinations were required to achieve full coverage across this subtype. We observed increased resistance to bnAbs targeting the CD4bs linked to the diversification of CRF02_AG Env over the course of the epidemic, a phenomenon which was previously described for subtypes B and C. These data on the sensitivity to bnAbs of CRF02_AG viruses, including only recently transmitted viruses, will inform future passive immunization studies. Considering the drift of the HIV-1 species toward higher resistance to neutralizing antibodies, it appears necessary to keep updating existing panels for evaluation of future vaccine and passive immunization studies. IMPORTANCE Major progress occurred during the last decade leading to the isolation of human monoclonal antibodies, termed broadly neutralizing antibodies (bnAbs) due to their capacity to neutralize various strains of HIV-1. Several clinical trials are under way in order to evaluate their efficacy in preventive or therapeutic strategies. However, no single bnAb is active against 100% of strains. It is important to gather data on the sensitivity to neutralizing antibodies of all genotypes, especially those more widespread in regions where the prevalence of HIV-1 infection is high. Here, we assembled a large panel of clade CRF02_AG viruses, the most frequent genotype circulating in West Africa and the second most frequent found in several European countries. We evaluated their sensitivities to bnAbs, including those most advanced in clinical trials, and looked for the best combinations. In addition, we observed a trend toward increased resistance to bnAbs over the course of the epidemic.

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Trimeric Glycosylphosphatidylinositol-Anchored HCDR3 of Broadly Neutralizing Antibody PG16 Is a Potent HIV-1 Entry Inhibitor

Journal of Virology ◽

10.1128/jvi.01038-12 ◽

2012 ◽

Vol 87 (3) ◽

pp. 1899-1905 ◽

Cited By ~ 8

Author(s):

Lihong Liu ◽

Weiming Wang ◽

Lifei Yang ◽

Huanhuan Ren ◽

Jason T. Kimata ◽

...

Keyword(s):

Plasma Membrane ◽

Lipid Rafts ◽

Neutralizing Antibodies ◽

Quaternary Structure ◽

Neutralizing Antibody ◽

Entry Inhibitor ◽

Broadly Neutralizing Antibodies ◽

Broadly Neutralizing Antibody ◽

Anti Hiv ◽

Hiv 1

ABSTRACTPG9 and PG16 are two quaternary-structure-specific broadly neutralizing antibodies with unique HCDR3 subdomains. Previously, we showed that glycosylphosphatidylinositol (GPI)-anchored HCDR3 subdomains (GPI-HCDR3) can be targeted to lipid rafts of the plasma membrane, bind to the epitope recognized by HCDR3 of PG16, and neutralize diverse HIV-1 isolates. In this study, we further developed trimeric GPI-HCDR3s and demonstrated that trimeric GPI-HCDR3 (PG16) dramatically improves anti-HIV-1 neutralization, suggesting that a stoichiometry of recognition of 3 or 2 HCDR3 molecules (PG16) to 1 viral spike is possible.

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Behavioral and social science research to support development of educational materials for clinical trials of broadly neutralizing antibodies for HIV treatment and prevention

Clinical Trials ◽

10.1177/1740774520948042 ◽

2020 ◽

pp. 174077452094804

Author(s):

Pablo K Valente ◽

Yumeng Wu ◽

Yehuda Z Cohen ◽

Marina Caskey ◽

Kathrine Meyers

Keyword(s):

Clinical Trials ◽

Neutralizing Antibodies ◽

Neutralizing Antibody ◽

Trial Participation ◽

Broadly Neutralizing Antibodies ◽

Educational Materials ◽

Key Informants ◽

Trial Staff ◽

Broadly Neutralizing Antibody ◽

Trial Participants

Background/Aims Early integration of behavioral and social sciences research into clinical trials can improve trial conduct and facilitate future implementation of biomedical interventions. We sought to examine participants’ experiences in clinical trials with broadly neutralizing antibodies and describe the development of educational materials for use in future broadly neutralizing antibody research. Methods We conducted semi-structured interviews with trial participants in phase 1 trials evaluating safety and efficacy of broadly neutralizing antibodies for HIV prevention and treatment and key informants (i.e. trial staff involved in broadly neutralizing antibody research). Semi-structured interviews were transcribed and analyzed thematically. Based on findings from the interviews, we developed educational materials addressing concerns and misconceptions identified among trial participants with input from community and research stakeholders. Educational materials were used in subsequent clinical trials with broadly neutralizing antibodies. We evaluated trial staff’s experiences with newly developed educational materials in follow-up key informant interviews. Results Although most participants were concerned about long-term harms related to the investigational product upon enrollment, absence of severe side effects in the trial led to an underestimation of risks related to the study during trial participation. Participants showed a poor understanding of what broadly neutralizing antibodies are and the differences between broadly neutralizing antibodies and other HIV prevention and treatment products, such as antiretrovirals. Many trial participants overestimated the possible public health impact of the broadly neutralizing antibody trials in which they were enrolled, associating broadly neutralizing antibody research with the development of vaccine or cure for HIV in the near future. Based on these concerns and misconceptions among trial participants, we developed a frequently asked questions document and adapted an existing educational video about broadly neutralizing antibodies. In follow-up interviews, key informants reported that materials helped address trial participants’ concerns and questions related to the trial. Key informants reported using the educational materials not only during informed consent but also throughout trial participation, which contributed to making informed consent an “ongoing” process. Conclusion Integration of behavioral research into clinical trials with broadly neutralizing antibodies is key to identify and address key concerns among trial participants. Behavioral and social sciences research promotes communication between trial participants and biomedical researchers, facilitates engagement of participants and trial staff, and strengthens trial conduct. Development of educational materials collaboratively by behavioral and clinical scientists, trial staff, and community stakeholders is feasible and may help to address trial participants’ concerns and misconceptions. Future research should evaluate the impact of educational materials in recruitment and retention of trial participants.

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Validation of a Triplex Pharmacokinetic Assay for Simultaneous Quantitation of HIV-1 Broadly Neutralizing Antibodies PGT121, PGDM1400, and VRC07-523-LS

Frontiers in Immunology ◽

10.3389/fimmu.2021.709994 ◽

2021 ◽

Vol 12 ◽

Author(s):

Martina S. Wesley ◽

Kelvin T. Chiong ◽

Kelly E. Seaton ◽

Christine A. Arocena ◽

Sheetal Sawant ◽

...

Keyword(s):

Neutralizing Antibodies ◽

Neutralizing Antibody ◽

Broadly Neutralizing Antibodies ◽

Testing Method ◽

Cd4 Binding Site ◽

Broadly Neutralizing Antibody ◽

Effective Doses ◽

Pharmacokinetic Assay ◽

Hiv 1

The outcome of the recent Antibody Mediated Prevention (AMP) trials that tested infusion of the broadly neutralizing antibody (bnAb) VRC01 provides proof of concept for blocking infection from sensitive HIV-1 strains. These results also open up the possibility that triple combinations of bnAbs such as PGT121, PGDM1400, as well as long-lasting LS variants such as VRC07-523 LS, have immunoprophylactic potential. PGT121 and PGDM1400 target the HIV-1 V3 and V2 glycan regions of the gp120 envelope protein, respectively, while VRC07-523LS targets the HIV-1 CD4 binding site. These bnAbs demonstrate neutralization potency and complementary breadth of HIV-1 strain coverage. An important clinical trial outcome is the accurate measurement of in vivo concentrations of passively infused bnAbs to determine effective doses for therapy and/or prevention. Standardization and validation of this testing method is a key element for clinical studies as is the ability to simultaneously detect multiple bnAbs in a specific manner. Here we report the development of a sensitive, specific, accurate, and precise multiplexed microsphere-based assay that simultaneously quantifies the respective physiological concentrations of passively infused bnAbs in human serum to ultimately define the threshold needed for protection from HIV-1 infection.

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Functional development of a V3/glycan-specific broadly neutralizing antibody isolated from a case of HIV superinfection

eLife ◽

10.7554/elife.68110 ◽

2021 ◽

Vol 10 ◽

Author(s):

Mackenzie M Shipley ◽

Vidya Mangala Prasad ◽

Laura E Doepker ◽

Adam S Dingens ◽

Duncan K Ralph ◽

...

Keyword(s):

Neutralizing Antibodies ◽

Neutralizing Antibody ◽

Viral Escape ◽

Single Infection ◽

Structural Studies ◽

Broadly Neutralizing Antibodies ◽

Hiv Vaccines ◽

Functional Development ◽

Broadly Neutralizing Antibody

Stimulating broadly neutralizing antibodies (bnAbs) directly from germline remains a barrier for HIV vaccines. HIV superinfection elicits bnAbs more frequently than single infection, providing clues of how to elicit such responses. We used longitudinal antibody sequencing and structural studies to characterize bnAb development from a superinfection case. BnAb QA013.2 bound initial and superinfecting viral Env, despite its probable naïve progenitor only recognizing the superinfecting strain, suggesting both viruses influenced this lineage. A 4.15 Å cryo-EM structure of QA013.2 bound to native-like trimer showed recognition of V3 signatures (N301/N332 and GDIR). QA013.2 relies less on CDRH3 and more on framework and CDRH1 for affinity and breadth compared to other V3/glycan-specific bnAbs. Antigenic profiling revealed that viral escape was achieved by changes in the structurally-defined epitope and by mutations in V1. These results highlight shared and novel properties of QA013.2 relative to other V3/glycan-specific bnAbs in the setting of sequential, diverse antigens.

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Nanoparticle Vaccines for Inducing HIV-1 Neutralizing Antibodies

Vaccines ◽

10.3390/vaccines7030076 ◽

2019 ◽

Vol 7 (3) ◽

pp. 76 ◽

Cited By ~ 15

Author(s):

Mitch Brinkkemper ◽

Kwinten Sliepen

Keyword(s):

Envelope Glycoprotein ◽

Neutralizing Antibodies ◽

Critical Role ◽

Neutralizing Antibody ◽

Antibody Responses ◽

Broadly Neutralizing Antibodies ◽

Viral Membrane ◽

Immunodeficiency Virus ◽

Hiv 1

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.

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Immunogenicity, safety and efficacy of sequential immunizations with an SIV-based IDLV expressing CH505 Envs

10.1101/2020.03.06.980680 ◽

2020 ◽

Author(s):

Blasi Maria ◽

Negri Donatella ◽

Saunders O Kevin ◽

Baker J Erich ◽

Stadtler Hannah ◽

...

Keyword(s):

Neutralizing Antibodies ◽

Lentiviral Vector ◽

Rhesus Macaques ◽

Infected Individual ◽

Neutralizing Antibody ◽

Antibody Responses ◽

Safety And Efficacy ◽

Broadly Neutralizing Antibody ◽

Env Protein ◽

Hiv 1

AbstractA preventative HIV-1 vaccine is an essential intervention needed to halt the HIV-1 pandemic. Neutralizing antibodies protect against HIV-1 infection in animal models, and thus an approach toward a protective HIV-1 vaccine is to induce broadly cross-reactive neutralizing antibodies (bnAbs). One strategy to achieve this goal is to define envelope (Env) evolution that drives bnAb development in infection and to recreate those events by vaccination. In this study we report the immunogenicity, safety and efficacy in rhesus macaques of an SIV-based integrase defective lentiviral vector (IDLV) expressing sequential gp140 Env immunogens derived from the CH505 HIV-1-infected individual who made the CH103 and CH235 bnAb lineages. Immunization with IDLV expressing sequential CH505 Env induced higher magnitude and more durable binding and neutralizing antibody responses compared to protein or DNA +/- protein immunizations using the same sequential envelopes. Compared to monkeys immunized with vector expressing Envs alone, those immunized with the combination of IDLV expressing Env and CH505 Env protein demonstrated improved durability of antibody responses at six month after the last immunization as well as lower peak viremia and better virus control following autologous SHIV-CH505 challenge. There was no evidence of vector mobilization or recombination in the immunized and challenged monkeys. Our results show that while IDLV proved safe and successful at inducing higher titer and more durable immune responses compared to other vaccine platforms, the use of non-stabilized sequential envelope trimers did not induce broadly neutralizing antibody responses.

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Design of an optimal combination therapy with broadly neutralizing antibodies to suppress HIV-1

10.1101/2021.12.03.21267269 ◽

2021 ◽

Author(s):

Colin LaMont ◽

Jakub Otwinowski ◽

Kanika Vanshylla ◽

Henning Gruell ◽

Florian Klein ◽

...

Keyword(s):

Clinical Trials ◽

Neutralizing Antibodies ◽

Rational Design ◽

Sequence Data ◽

Viral Escape ◽

Broadly Neutralizing Antibodies ◽

Standing Variation ◽

Potential Alternative ◽

Pre Treatment ◽

Hiv 1

Broadly neutralizing antibodies (bNAbs) are promising targets for vaccination and therapy against HIV. Passive infusions of bNAbs have shown promise in clinical trials as a potential alternative for anti-retroviral therapy. A key challenge for the potential clinical application of bnAbs is the suppression of viral escape, which is more effectively achieved with a combination of bNAbs. However, identifying an optimal bNAb cocktail is combinatorially complex. Here, we propose a computational approach to predict the efficacy of a bNAb therapy trial based on the population genetics of HIV escape, which we parametrize using high-throughput HIV sequence data from a cohort of untreated bNAb-naive patients. By quantifying the mutational target size and the fitness cost of HIV-1 escape from bNAbs, we reliably predict the distribution of rebound times in three clinical trials. Importantly, we show that early rebounds are dominated by the pre-treatment standing variation of HIV-1 populations, rather than spontaneous mutations during treatment. Lastly, we show that a cocktail of three bNAbs is necessary to suppress the chances of viral escape below 1%, and we predict the optimal composition of such a bNAb cocktail. Our results offer a rational design for bNAb therapy against HIV-1, and more generally show how genetic data could be used to predict treatment outcomes and design new approaches to pathogenic control.

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