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Nature Reviews. Immunology Mar 2023After nearly four decades of research, a safe and effective HIV-1 vaccine remains elusive. There are many reasons why the development of a potent and durable HIV-1... (Review)
Review
After nearly four decades of research, a safe and effective HIV-1 vaccine remains elusive. There are many reasons why the development of a potent and durable HIV-1 vaccine is challenging, including the extraordinary genetic diversity of HIV-1 and its complex mechanisms of immune evasion. HIV-1 envelope glycoproteins are poorly recognized by the immune system, which means that potent broadly neutralizing antibodies (bnAbs) are only infrequently induced in the setting of HIV-1 infection or through vaccination. Thus, the biology of HIV-1-host interactions necessitates novel strategies for vaccine development to be designed to activate and expand rare bnAb-producing B cell lineages and to select for the acquisition of critical improbable bnAb mutations. Here we discuss strategies for the induction of potent and broad HIV-1 bnAbs and outline the steps that may be necessary for ultimate success.
Topics: Humans; Broadly Neutralizing Antibodies; HIV Antibodies; HIV-1; Antibodies, Neutralizing; AIDS Vaccines; HIV Infections; Antigens, Viral
PubMed: 35962033
DOI: 10.1038/s41577-022-00753-w -
Cell Dec 2019B cell receptor (BCR) sequencing is a powerful tool for interrogating immune responses to infection and vaccination, but it provides limited information about the...
B cell receptor (BCR) sequencing is a powerful tool for interrogating immune responses to infection and vaccination, but it provides limited information about the antigen specificity of the sequenced BCRs. Here, we present LIBRA-seq (linking B cell receptor to antigen specificity through sequencing), a technology for high-throughput mapping of paired heavy- and light-chain BCR sequences to their cognate antigen specificities. B cells are mixed with a panel of DNA-barcoded antigens so that both the antigen barcode(s) and BCR sequence are recovered via single-cell next-generation sequencing. Using LIBRA-seq, we mapped the antigen specificity of thousands of B cells from two HIV-infected subjects. The predicted specificities were confirmed for a number of HIV- and influenza-specific antibodies, including known and novel broadly neutralizing antibodies. LIBRA-seq will be an integral tool for antibody discovery and vaccine development efforts against a wide range of antigen targets.
Topics: Antibodies, Neutralizing; Antigens; Cells, Cultured; Epitope Mapping; Epitopes; HEK293 Cells; HIV Antibodies; High-Throughput Nucleotide Sequencing; High-Throughput Screening Assays; Humans; Receptors, Antigen, B-Cell; Sequence Analysis, DNA; Single-Cell Analysis; THP-1 Cells
PubMed: 31787378
DOI: 10.1016/j.cell.2019.11.003 -
Seminars in Immunology Jan 2021HIV is a virus that remains a major health concern and results in an infection that has no cure even after over 30 years since its discovery. As such, HIV vaccine... (Review)
Review
HIV is a virus that remains a major health concern and results in an infection that has no cure even after over 30 years since its discovery. As such, HIV vaccine discovery continues to be an area of intensive research. In this review, we summarize the most recent HIV vaccine efficacy trials, clinical trials initiated within the last 3 years, and discuss prominent improvements that have been made in prophylactic HIV vaccine designs.
Topics: Antibodies, Neutralizing; HIV Antibodies; HIV Infections; HIV-1; Humans; Vaccinology
PubMed: 34272086
DOI: 10.1016/j.smim.2021.101470 -
Science (New York, N.Y.) Dec 2022Broadly neutralizing antibodies (bnAbs) can protect against HIV infection but have not been induced by human vaccination. A key barrier to bnAb induction is vaccine... (Randomized Controlled Trial)
Randomized Controlled Trial
Broadly neutralizing antibodies (bnAbs) can protect against HIV infection but have not been induced by human vaccination. A key barrier to bnAb induction is vaccine priming of rare bnAb-precursor B cells. In a randomized, double-blind, placebo-controlled phase 1 clinical trial, the HIV vaccine-priming candidate eOD-GT8 60mer adjuvanted with AS01 had a favorable safety profile and induced VRC01-class bnAb precursors in 97% of vaccine recipients with median frequencies reaching 0.1% among immunoglobulin G B cells in blood. bnAb precursors shared properties with bnAbs and gained somatic hypermutation and affinity with the boost. The results establish clinical proof of concept for germline-targeting vaccine priming, support development of boosting regimens to induce bnAbs, and encourage application of the germline-targeting strategy to other targets in HIV and other pathogens.
Topics: Humans; Adjuvants, Immunologic; AIDS Vaccines; Broadly Neutralizing Antibodies; HIV Infections; Vaccination; HIV Antibodies; Germ Cells; B-Lymphocytes; Mutation; Immunoglobulin Light Chains; Immunoglobulin Heavy Chains; Male; Female; Adult
PubMed: 36454825
DOI: 10.1126/science.add6502 -
International Journal of Antimicrobial... Jan 2021Long-acting and extended-release formulations represent one of the most important approaches to improving the treatment and prevention of chronic HIV infection.... (Review)
Review
Long-acting and extended-release formulations represent one of the most important approaches to improving the treatment and prevention of chronic HIV infection. Long-acting small molecules and monoclonal antibodies have demonstrated potent anti-HIV activity in early- and late-stage clinical trials. Strategies to manage toxicity and falling drug concentrations after missed doses, as well as primary and secondary resistance to current drugs and monoclonal antibodies are important considerations. Long-acting injectable nanoformulations of the integrase inhibitor cabotegravir and the non-nucleoside reverse transcriptase inhibitor rilpivirine were safe, well tolerated and efficacious in large randomised phase 3 studies. Regulatory approval for this two-drug combination for HIV maintenance therapy was granted in Canada in 2020 and is expected in the USA during 2021. 4'-Ethynyl-2-fluoro-2'-deoxyadenosine (islatravir) is a novel nucleoside reverse transcriptase inhibitor in clinical development as a long-acting oral drug and as a long-acting subcutaneous polymer implant. GS-6207 is a novel HIV capsid inhibitor that is injected subcutaneously every 3 months. Broadly-neutralising monoclonal antibodies have potent antiviral activity in early human trials, however there is substantial baseline resistance and rapid development of resistance to these antibodies if used as monotherapy. Limitations of these antiretroviral approaches include management of toxicities and prevention of drug resistance when these drugs are discontinued and drug concentrations are slowly reduced over time. These approaches appear to be especially attractive for patients complaining of pill fatigue and for those experiencing HIV-associated stigma. As these formulations are shown to be safe, well tolerated and economical, they are likely to gain broader appeal.
Topics: Anti-HIV Agents; Canada; Delayed-Action Preparations; Deoxyadenosines; Drug Combinations; Drug Delivery Systems; HIV Antibodies; HIV Infections; HIV-1; Humans; Pyridones; Rilpivirine
PubMed: 33166693
DOI: 10.1016/j.ijantimicag.2020.106220 -
Journal of the International AIDS... Nov 2021The development of an effective vaccine to protect against HIV is a longstanding global health need complicated by challenges inherent to HIV biology and to the... (Review)
Review
INTRODUCTION
The development of an effective vaccine to protect against HIV is a longstanding global health need complicated by challenges inherent to HIV biology and to the execution of vaccine efficacy testing in the context of evolving biomedical prevention interventions. This review describes lessons learnt from previous efficacy trials, highlights unanswered questions, and surveys new approaches in vaccine development addressing these gaps.
METHODS
We conducted a targeted peer-reviewed literature search of articles and conference abstracts from 1989 through 2021 for HIV vaccine studies and clinical trials. The US National Library of Medicine's Clinical Trials database was accessed to further identify clinical trials involving HIV vaccines. The content of the review was also informed by the authors' own experience and engagement with collaborators in HIV vaccine research.
DISCUSSION
The HIV vaccine field has successfully developed multiple vaccine platforms through advanced clinical studies; however, the modest efficacy signal of the RV144 Thai trial remains the only demonstration of HIV vaccine protection in humans. Current vaccine strategies include prime-boost strategies to improve elicitation of immune correlates derived from RV144, combination mosaic antigens, novel viral vectors, antigens designed to elicit broadly neutralizing antibody, new nucleic acid platforms and potent adjuvants to enhance immunogenicity across multiple classes of emerging vaccine candidates.
CONCLUSIONS
HIV vaccine developers have applied lessons learnt from previous successes and failures to innovative vaccine design approaches. These strategies have yielded novel mosaic antigen constructs now in efficacy testing, produced a diverse pipeline of early-stage immunogens and novel adjuvants, and advanced the field towards a globally effective HIV vaccine.
Topics: AIDS Vaccines; Adjuvants, Immunologic; Antibodies, Neutralizing; HIV Antibodies; HIV Infections; Humans; Thailand
PubMed: 34806296
DOI: 10.1002/jia2.25793 -
Nature Jun 2022Antiretroviral therapy is highly effective in suppressing human immunodeficiency virus (HIV). However, eradication of the virus in individuals with HIV has not been... (Randomized Controlled Trial)
Randomized Controlled Trial
Antiretroviral therapy is highly effective in suppressing human immunodeficiency virus (HIV). However, eradication of the virus in individuals with HIV has not been possible to date. Given that HIV suppression requires life-long antiretroviral therapy, predominantly on a daily basis, there is a need to develop clinically effective alternatives that use long-acting antiviral agents to inhibit viral replication. Here we report the results of a two-component clinical trial involving the passive transfer of two HIV-specific broadly neutralizing monoclonal antibodies, 3BNC117 and 10-1074. The first component was a randomized, double-blind, placebo-controlled trial that enrolled participants who initiated antiretroviral therapy during the acute/early phase of HIV infection. The second component was an open-label single-arm trial that enrolled individuals with viraemic control who were naive to antiretroviral therapy. Up to 8 infusions of 3BNC117 and 10-1074, administered over a period of 24 weeks, were well tolerated without any serious adverse events related to the infusions. Compared with the placebo, the combination broadly neutralizing monoclonal antibodies maintained complete suppression of plasma viraemia (for up to 43 weeks) after analytical treatment interruption, provided that no antibody-resistant HIV was detected at the baseline in the study participants. Similarly, potent HIV suppression was seen in the antiretroviral-therapy-naive study participants with viraemia carrying sensitive virus at the baseline. Our data demonstrate that combination therapy with broadly neutralizing monoclonal antibodies can provide long-term virological suppression without antiretroviral therapy in individuals with HIV, and our experience offers guidance for future clinical trials involving next-generation antibodies with long half-lives.
Topics: Anti-HIV Agents; Antibodies, Monoclonal; Antibodies, Neutralizing; Broadly Neutralizing Antibodies; Double-Blind Method; HIV Antibodies; HIV Infections; HIV-1; Humans; Viral Load; Viremia
PubMed: 35650437
DOI: 10.1038/s41586-022-04797-9 -
Nature Biotechnology Aug 2022Transplantation of B cells engineered ex vivo to secrete broadly neutralizing antibodies (bNAbs) has shown efficacy in disease models. However, clinical translation of...
Transplantation of B cells engineered ex vivo to secrete broadly neutralizing antibodies (bNAbs) has shown efficacy in disease models. However, clinical translation of this approach would require specialized medical centers, technically demanding protocols and major histocompatibility complex compatibility of donor cells and recipients. Here we report in vivo B cell engineering using two adeno-associated viral vectors, with one coding for Staphylococcus aureus Cas9 (saCas9) and the other for 3BNC117, an anti-HIV bNAb. After intravenously injecting the vectors into mice, we observe successful editing of B cells leading to memory retention and bNAb secretion at neutralizing titers of up to 6.8 µg ml. We observed minimal clustered regularly interspaced palindromic repeats (CRISPR)-Cas9 off-target cleavage as detected by unbiased CHANGE-sequencing analysis, whereas on-target cleavage in undesired tissues is reduced by expressing saCas9 from a B cell-specific promoter. In vivo B cell engineering to express therapeutic antibodies is a safe, potent and scalable method, which may be applicable not only to infectious diseases but also in the treatment of noncommunicable conditions, such as cancer and autoimmune disease.
Topics: Animals; Antibodies, Neutralizing; B-Lymphocytes; Broadly Neutralizing Antibodies; HIV Antibodies; HIV Infections; HIV-1; Mice; Staphylococcus aureus
PubMed: 35681059
DOI: 10.1038/s41587-022-01328-9 -
Journal of the International AIDS... Nov 2021
Topics: AIDS Vaccines; Antibodies, Neutralizing; HIV Antibodies; HIV Infections; HIV-1; Humans
PubMed: 34806319
DOI: 10.1002/jia2.25828 -
PLoS Pathogens Oct 2023Antibodies that can bind to viruses but are unable to block infection in cell culture are known as "nonneutralizing antibodies." Such antibodies are nearly universally... (Review)
Review
Antibodies that can bind to viruses but are unable to block infection in cell culture are known as "nonneutralizing antibodies." Such antibodies are nearly universally elicited following viral infection and have been characterized in viral infections such as influenza, rotavirus, cytomegalovirus, HIV, and SARS-CoV-2. It has been widely assumed that these nonneutralizing antibodies do not function in a protective way in vivo and therefore are not desirable targets of antiviral interventions; however, increasing evidence now shows this not to be true. Several virus-specific nonneutralizing antibody responses have been correlated with protection in human studies and also shown to significantly reduce virus replication in animal models. The mechanisms by which many of these antibodies function is only now coming to light. While nonneutralizing antibodies cannot prevent viruses entering their host cell, nonneutralizing antibodies work in the extracellular space to recruit effector proteins or cells that can destroy the antibody-virus complex. Other nonneutralizing antibodies exert their effects inside cells, either by blocking the virus life cycle directly or by recruiting the intracellular Fc receptor TRIM21. In this review, we will discuss the multitude of ways in which nonneutralizing antibodies function against a range of viral infections.
Topics: Animals; Humans; Antibodies, Viral; Virus Diseases; Influenza, Human; Receptors, Fc; Antiviral Agents; Antibodies, Neutralizing; HIV Antibodies
PubMed: 37796829
DOI: 10.1371/journal.ppat.1011670