-
The New England Journal of Medicine Mar 2021Whether a broadly neutralizing antibody (bnAb) can be used to prevent human immunodeficiency virus type 1 (HIV-1) acquisition is unclear. (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Whether a broadly neutralizing antibody (bnAb) can be used to prevent human immunodeficiency virus type 1 (HIV-1) acquisition is unclear.
METHODS
We enrolled at-risk cisgender men and transgender persons in the Americas and Europe in the HVTN 704/HPTN 085 trial and at-risk women in sub-Saharan Africa in the HVTN 703/HPTN 081 trial. Participants were randomly assigned to receive, every 8 weeks, infusions of a bnAb (VRC01) at a dose of either 10 or 30 mg per kilogram (low-dose group and high-dose group, respectively) or placebo, for 10 infusions in total. HIV-1 testing was performed every 4 weeks. The VRC01 80% inhibitory concentration (IC) of acquired isolates was measured with the TZM-bl assay.
RESULTS
Adverse events were similar in number and severity among the treatment groups within each trial. Among the 2699 participants in HVTN 704/HPTN 085, HIV-1 infection occurred in 32 in the low-dose group, 28 in the high-dose group, and 38 in the placebo group. Among the 1924 participants in HVTN 703/HPTN 081, infection occurred in 28 in the low-dose group, 19 in the high-dose group, and 29 in the placebo group. The incidence of HIV-1 infection per 100 person-years in HVTN 704/HPTN 085 was 2.35 in the pooled VRC01 groups and 2.98 in the placebo group (estimated prevention efficacy, 26.6%; 95% confidence interval [CI], -11.7 to 51.8; P = 0.15), and the incidence per 100 person-years in HVTN 703/HPTN 081 was 2.49 in the pooled VRC01 groups and 3.10 in the placebo group (estimated prevention efficacy, 8.8%; 95% CI, -45.1 to 42.6; P = 0.70). In prespecified analyses pooling data across the trials, the incidence of infection with VRC01-sensitive isolates (IC <1 μg per milliliter) per 100 person-years was 0.20 among VRC01 recipients and 0.86 among placebo recipients (estimated prevention efficacy, 75.4%; 95% CI, 45.5 to 88.9). The prevention efficacy against sensitive isolates was similar for each VRC01 dose and trial; VRC01 did not prevent acquisition of other HIV-1 isolates.
CONCLUSIONS
VRC01 did not prevent overall HIV-1 acquisition more effectively than placebo, but analyses of VRC01-sensitive HIV-1 isolates provided proof-of-concept that bnAb prophylaxis can be effective. (Supported by the National Institute of Allergy and Infectious Diseases; HVTN 704/HPTN 085 and HVTN 703/HPTN 081 ClinicalTrials.gov numbers, NCT02716675 and NCT02568215.).
Topics: Adolescent; Adult; Africa South of the Sahara; Americas; Antibodies, Monoclonal; Broadly Neutralizing Antibodies; Double-Blind Method; Europe; Female; HIV Antibodies; HIV Infections; HIV-1; Humans; Incidence; Male; Proof of Concept Study; Young Adult
PubMed: 33730454
DOI: 10.1056/NEJMoa2031738 -
Cell Reports Nov 2022Non-neutralizing antibodies (nnAbs) can eliminate HIV-1-infected cells via antibody-dependent cellular cytotoxicity (ADCC) and were identified as a correlate of...
Non-neutralizing antibodies (nnAbs) can eliminate HIV-1-infected cells via antibody-dependent cellular cytotoxicity (ADCC) and were identified as a correlate of protection in the RV144 vaccine trial. Fc-mediated effector functions of nnAbs were recently shown to alter the course of HIV-1 infection in vivo using a vpu-defective virus. Since Vpu is known to downregulate cell-surface CD4, which triggers conformational changes in the viral envelope glycoprotein (Env), we ask whether the lack of Vpu expression was linked to the observed nnAbs activity. We find that restoring Vpu expression greatly reduces nnAb recognition of infected cells, rendering them resistant to ADCC. Moreover, administration of nnAbs in humanized mice reduces viral loads only in animals infected with a vpu-defective but not with a wild-type virus. CD4-mimetics administration, known to "open" Env and expose nnAb epitopes, renders wild-type viruses sensitive to nnAbs Fc-effector functions. This work highlights the importance of Vpu-mediated evasion of humoral responses.
Topics: Animals; Humans; Mice; Antibodies, Neutralizing; Antibody-Dependent Cell Cytotoxicity; HIV Antibodies; HIV Infections; HIV Seropositivity; HIV-1
PubMed: 36351384
DOI: 10.1016/j.celrep.2022.111624 -
Current Opinion in HIV and AIDS Jul 2023To discuss progress and challenges in the development of antiretroviral regimens that combine broadly neutralizing antibodies (bNAbs) and long-acting (LA) small-molecule... (Review)
Review
PURPOSE OF REVIEW
To discuss progress and challenges in the development of antiretroviral regimens that combine broadly neutralizing antibodies (bNAbs) and long-acting (LA) small-molecule antiretroviral drugs (ARVs).
RECENT FINDINGS
Data are extremely limited, with results from only a single phase 1a clinical trial reported to date. That study, a combination of lenacapavir plus the bNAbs teropavimab and zinlirvimab, maintained viral suppression over 26 weeks in 18 of 20 participants. A second pilot study, ACTG A5357, which tests the safety and virologic efficacy of the combination of LA injectable cabotegravir with the bNAb VRC07-523LS is fully enrolled; results are expected in the second half of 2023.
SUMMARY
The development of regimens that combine bNAbs and LA ARVs has been challenging. Both agents need similar half-lives in order to harmonize dosing schedules. In addition, the need to perform bNAb susceptibility testing to assure activity of the bNAb in order to protect against the risk of developing resistance to the LA ARV has slowed enrollment into trials and poses substantial logistical challenges to widespread adoption of these combinations should they prove safe and effective. Improvements in manufacture that reduce the cost of goods and advances in delivery systems are needed to ensure equitable access to these regimens.
Topics: Humans; HIV Infections; Broadly Neutralizing Antibodies; Pharmaceutical Preparations; Pilot Projects; Antibodies, Neutralizing; HIV-1; Anti-Retroviral Agents; HIV Antibodies
PubMed: 37265259
DOI: 10.1097/COH.0000000000000801 -
Cell Reports Jul 2023Broadly neutralizing antibodies (bNAbs) against HIV can reduce viral transmission in humans, but an effective therapeutic will require unusually high breadth and potency...
Broadly neutralizing antibodies (bNAbs) against HIV can reduce viral transmission in humans, but an effective therapeutic will require unusually high breadth and potency of neutralization. We employ the OSPREY computational protein design software to engineer variants of two apex-directed bNAbs, PGT145 and PG9RSH, resulting in increases in potency of over 100-fold against some viruses. The top designed variants improve neutralization breadth from 39% to 54% at clinically relevant concentrations (IC < 1 μg/mL) and improve median potency (IC) by up to 4-fold over a cross-clade panel of 208 strains. To investigate the mechanisms of improvement, we determine cryoelectron microscopy structures of each variant in complex with the HIV envelope trimer. Surprisingly, we find the largest increases in breadth to be a result of optimizing side-chain interactions with highly variable epitope residues. These results provide insight into mechanisms of neutralization breadth and inform strategies for antibody design and improvement.
Topics: Humans; HIV Infections; HIV Antibodies; Antibodies, Neutralizing; HIV-1; Broadly Neutralizing Antibodies; Cryoelectron Microscopy; HIV Seropositivity; Neutralization Tests
PubMed: 37436900
DOI: 10.1016/j.celrep.2023.112711 -
HIV-1 neutralizing antibodies provide sterilizing immunity by blocking infection of the first cells.Cell Reports. Medicine Oct 2023Neutralizing antibodies targeting HIV-1 Env have been shown to protect from systemic infection. To explore whether these antibodies can inhibit infection of the first...
Neutralizing antibodies targeting HIV-1 Env have been shown to protect from systemic infection. To explore whether these antibodies can inhibit infection of the first cells, challenge viruses based on simian immunodeficiency virus (SIV) were developed that use HIV-1 Env for entry into target cells during the first replication cycle, but then switch to SIV Env usage. Antibodies binding to Env of HIV-1, but not SIV, block HIV-1 Env-mediated infection events after rectal exposure of non-human primates to the switching challenge virus. After natural exposure to HIV-1, such a reduction of the number of first infection events should be sufficient to provide sterilizing immunity in the strictest sense in most of the exposed individuals. Since blocking infection of the first cells avoids the formation of latently infected cells and reduces the risk of emergence of antibody-resistant mutants, it may be the best mode of protection.
Topics: Animals; Simian Acquired Immunodeficiency Syndrome; Antibodies, Viral; HIV-1; Macaca mulatta; Antibodies, Neutralizing; Simian Immunodeficiency Virus; HIV Infections; HIV Antibodies
PubMed: 37804829
DOI: 10.1016/j.xcrm.2023.101201 -
Nature Jun 2022HIV-1 infection remains a public health problem with no cure. Anti-retroviral therapy (ART) is effective but requires lifelong drug administration owing to a stable...
HIV-1 infection remains a public health problem with no cure. Anti-retroviral therapy (ART) is effective but requires lifelong drug administration owing to a stable reservoir of latent proviruses integrated into the genome of CD4 T cells. Immunotherapy with anti-HIV-1 antibodies has the potential to suppress infection and increase the rate of clearance of infected cells. Here we report on a clinical study in which people living with HIV received seven doses of a combination of two broadly neutralizing antibodies over 20 weeks in the presence or absence of ART. Without pre-screening for antibody sensitivity, 76% (13 out of 17) of the volunteers maintained virologic suppression for at least 20 weeks off ART. Post hoc sensitivity analyses were not predictive of the time to viral rebound. Individuals in whom virus remained suppressed for more than 20 weeks showed rebound viraemia after one of the antibodies reached serum concentrations below 10 µg ml. Two of the individuals who received all seven antibody doses maintained suppression after one year. Reservoir analysis performed after six months of antibody therapy revealed changes in the size and composition of the intact proviral reservoir. By contrast, there was no measurable decrease in the defective reservoir in the same individuals. These data suggest that antibody administration affects the HIV-1 reservoir, but additional larger and longer studies will be required to define the precise effect of antibody immunotherapy on the reservoir.
Topics: Anti-Retroviral Agents; CD4-Positive T-Lymphocytes; HIV Antibodies; HIV Infections; HIV-1; Humans; Proviruses; Viral Load; Viremia; Virus Latency
PubMed: 35418681
DOI: 10.1038/s41586-022-04597-1 -
Current Opinion in HIV and AIDS Jul 2023Anti-human immunodeficiency virus (HIV) antibody-based therapeutics offer an alternative treatment option to current antiretroviral drugs. This review aims to provide an... (Review)
Review
PURPOSE OF REVIEW
Anti-human immunodeficiency virus (HIV) antibody-based therapeutics offer an alternative treatment option to current antiretroviral drugs. This review aims to provide an overview of the Fc- and Fab-engineering strategies that have been developed to optimize broadly neutralizing antibodies and discuss recent findings from preclinical and clinical studies.
RECENT FINDINGS
Multispecific antibodies, including bispecific and trispecific antibodies, DART molecules, and BiTEs, as well as Fc-optimized antibodies, have emerged as promising therapeutic candidates for the treatment of HIV. These engineered antibodies engage multiple epitopes on the HIV envelope protein and human receptors, resulting in increased potency and breadth of activity. Additionally, Fc-enhanced antibodies have demonstrated extended half-life and improved effector function.
SUMMARY
The development of Fc and Fab-engineered antibodies for the treatment of HIV continues to show promising progress. These novel therapies have the potential to overcome the limitations of current antiretroviral pharmacologic agents by more effectively suppressing viral load and targeting latent reservoirs in individuals living with HIV. Further studies are needed to fully understand the safety and efficacy of these therapies, but the growing body of evidence supports their potential as a new class of therapeutics for the treatment of HIV.
Topics: Humans; HIV Infections; Antibodies, Neutralizing; HIV-1; Antibodies, Bispecific; HIV Antibodies
PubMed: 37144557
DOI: 10.1097/COH.0000000000000796 -
Frontiers in Immunology 2023Glycan masking is a novel technique in reverse vaccinology in which sugar chains (glycans) are added on the surface of immunogen candidates to hide regions of low... (Review)
Review
Glycan masking is a novel technique in reverse vaccinology in which sugar chains (glycans) are added on the surface of immunogen candidates to hide regions of low interest and thus focus the immune system on highly therapeutic epitopes. This shielding strategy is inspired by viruses such as influenza and HIV, which are able to escape the immune system by incorporating additional glycosylation and preventing the binding of therapeutic antibodies. Interestingly, the glycan masking technique is mainly used in vaccine design to fight the same viruses that naturally use glycans to evade the immune system. In this review we report the major successes obtained with the glycan masking technique in epitope-focused vaccine design. We focus on the choice of the target antigen, the strategy for immunogen design and the relevance of the carrier vector to induce a strong immune response. Moreover, we will elucidate the different applications that can be accomplished with glycan masking, such as shifting the immune response from hyper-variable epitopes to more conserved ones, focusing the response on known therapeutic epitopes, broadening the response to different viral strains/sub-types and altering the antigen immunogenicity to elicit higher or lower immune response, as desired.
Topics: HIV Antibodies; Antibodies, Neutralizing; Epitopes; Polysaccharides; HIV-1
PubMed: 37033915
DOI: 10.3389/fimmu.2023.1126034 -
Immunity Oct 2023V2-glycan/apex broadly neutralizing antibodies (bnAbs) recognize a closed quaternary epitope of the HIV-1 envelope glycoprotein (Env). This closed structure is necessary...
V2-glycan/apex broadly neutralizing antibodies (bnAbs) recognize a closed quaternary epitope of the HIV-1 envelope glycoprotein (Env). This closed structure is necessary to elicit apex antibodies and useful to guide the maturation of other bnAb classes. To compare antigens designed to maintain this conformation, we evaluated apex-specific responses in mice engrafted with a diverse repertoire of B cells expressing the HCDR3 of the apex bnAb VRC26.25. Engineered B cells affinity matured, guiding the improvement of VRC26.25 itself. We found that soluble Env (SOSIP) variants differed significantly in their ability to raise anti-apex responses. A transmembrane SOSIP (SOSIP-TM) delivered as an mRNA-lipid nanoparticle elicited more potent neutralizing responses than multimerized SOSIP proteins. Importantly, SOSIP-TM elicited neutralizing sera from B cells engineered with the predicted VRC26.25-HCDR3 progenitor, which also affinity matured. Our data show that HCDR3-edited B cells facilitate efficient in vivo comparisons of Env antigens and highlight the potential of an HCDR3-focused vaccine approach.
Topics: Animals; Mice; HIV Antibodies; Antibodies, Neutralizing; Broadly Neutralizing Antibodies; HIV-1; Antigens, Viral; Vaccines; env Gene Products, Human Immunodeficiency Virus; HIV Infections; AIDS Vaccines
PubMed: 37531955
DOI: 10.1016/j.immuni.2023.07.003 -
Frontiers in Immunology 2021Many broadly neutralizing antibodies (bnAbs) targeting the HIV-1 envelope glycoprotein are being assessed in clinical trials as strategies for HIV-1 prevention,... (Review)
Review
Many broadly neutralizing antibodies (bnAbs) targeting the HIV-1 envelope glycoprotein are being assessed in clinical trials as strategies for HIV-1 prevention, treatment, and antiretroviral-free remission. BnAbs can neutralize HIV-1 and target infected cells for elimination. Concerns about HIV-1 resistance to single bnAbs have led to studies of bnAb combinations with non-overlapping resistance profiles. This review focuses on the potential for bnAbs to induce HIV-1 remission, either alone or in combination with latency reversing agents, therapeutic vaccines or other novel therapeutics. Key topics include preliminary activity of bnAbs in preclinical models and in human studies of HIV-1 remission, clinical trial designs, and antibody design strategies to optimize pharmacokinetics, coverage of rebound-competent virus, and enhancement of cellular immune functions.
Topics: Anti-Retroviral Agents; Broadly Neutralizing Antibodies; Clinical Trials as Topic; HIV Antibodies; HIV Infections; Humans; Vaccination; Virus Replication
PubMed: 34322136
DOI: 10.3389/fimmu.2021.710044