scholarly journals Monocyte-derived transcriptome signature indicates antibody-dependent cellular phagocytosis as a potential mechanism of vaccine-induced protection against HIV-1

eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
Shida Shangguan ◽  
Philip K Ehrenberg ◽  
Aviva Geretz ◽  
Lauren Yum ◽  
Gautam Kundu ◽  
...  
Keyword(s):  
Single Cells ◽  
Vaccine Trial ◽  
Gene Signature ◽  
Potential Mechanism ◽  
Protein Vaccine ◽  
Vaccine Protection ◽  
Virus Challenge ◽  
Immunodeficiency Virus ◽  
Hiv 1 ◽  
Transcriptome Signature

A gene signature was previously found to be correlated with mosaic adenovirus 26 vaccine protection in simian immunodeficiency virus and simian-human immunodeficiency virus challenge models in non-human primates. In this report, we investigated the presence of this signature as a correlate of reduced risk in human clinical trials and potential mechanisms of protection. The absence of this gene signature in the DNA/rAd5 human vaccine trial, which did not show efficacy, strengthens our hypothesis that this signature is only enriched in studies that demonstrated protection. This gene signature was enriched in the partially effective RV144 human trial that administered the ALVAC/protein vaccine, and we find that the signature associates with both decreased risk of HIV-1 acquisition and increased vaccine efficacy (VE). Total RNA-seq in a clinical trial that used the same vaccine regimen as the RV144 HIV vaccine implicated antibody-dependent cellular phagocytosis (ADCP) as a potential mechanism of vaccine protection. CITE-seq profiling of 53 surface markers and transcriptomes of 53,777 single cells from the same trial showed that genes in this signature were primarily expressed in cells belonging to the myeloid lineage, including monocytes, which are major effector cells for ADCP. The consistent association of this transcriptome signature with VE represents a tool both to identify potential mechanisms, as with ADCP here, and to screen novel approaches to accelerate the development of new vaccine candidates.

scholarly journals Monocyte-derived transcriptome signature indicates antibody-dependent cellular 1 phagocytosis as the primary mechanism of vaccine-induced protection against HIV-1

2021 ◽  
Author(s):  
Shida Shangguan ◽  
Philip K Ehrenberg ◽  
Aviva Geretz ◽  
Lauren Yum ◽  
Gautam Kundu ◽  
...  
Keyword(s):  
Vaccine Efficacy ◽  
Single Cells ◽  
Vaccine Trial ◽  
Gene Signature ◽  
Potential Mechanism ◽  
Protein Vaccine ◽  
Vaccine Protection ◽  
Effector Cells ◽  
Hiv 1 ◽  
Transcriptome Signature

A gene signature previously correlated with mosaic adenovirus 26 vaccine protection in simian immunodeficiency virus (SIV) and SHIV challenge models in non-human primates (NHP). In this report we investigated presence of this signature as a correlate of reduced risk in human clinical trials and potential mechanism for protection. The absence of this gene signature in the DNA/rAd5 human vaccine trial which did not show efficacy, strengthens our hypothesis that this signature is only enriched in studies that demonstrated protection. This gene signature was enriched in the partially effective RV144 human trial that administered the ALVAC/protein vaccine, and we find that the signature associates with both decreased risk of HIV-1 acquisition and increased vaccine efficacy. Total RNA-seq in a clinical trial that used the same vaccine regimen as the RV144 HIV vaccine implicated antibody-dependent cellular phagocytosis (ADCP) as a potential mechanism of vaccine protection. CITE-seq profiling of 53 surface markers and transcriptomes of 53,777 single cells from the same trial, showed that genes in this signature were primarily expressed in cells belonging to the myeloid lineage including monocytes, which are major effector cells for ADCP. The consistent association of this transcriptome signature with vaccine efficacy represents a tool both to identify potential mechanisms, as with ADCP here, and to screen novel approaches to accelerate development of new vaccine candidates.

scholarly journals Biologic and Genetic Characterization of a Panel of 60 Human Immunodeficiency Virus Type 1 Isolates, Representing Clades A, B, C, D, CRF01_AE, and CRF02_AG, for the Development and Assessment of Candidate Vaccines

2005 ◽  
Vol 79 (10) ◽  
pp. 6089-6101 ◽  
Author(s):  
Bruce K. Brown ◽  
Janice M. Darden ◽  
Sodsai Tovanabutra ◽  
Tamara Oblander ◽  
Julie Frost ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Mononuclear Cells ◽  
Vaccine Development ◽  
Vaccine Trial ◽  
Viral Stock ◽  
Immunodeficiency Virus ◽  
Hiv 1

ABSTRACT A critical priority for human immunodeficiency virus type 1 (HIV-1) vaccine development is standardization of reagents and assays for evaluation of immune responses elicited by candidate vaccines. To provide a panel of viral reagents from multiple vaccine trial sites, 60 international HIV-1 isolates were expanded in peripheral blood mononuclear cells and characterized both genetically and biologically. Ten isolates each from clades A, B, C, and D and 10 isolates each from CRF01_AE and CRF02_AG were prepared from individuals whose HIV-1 infection was evaluated by complete genome sequencing. The main criterion for selection was that the candidate isolate was pure clade or pure circulating recombinant. After expansion in culture, the complete envelope (gp160) of each isolate was verified by sequencing. The 50% tissue culture infectious dose and p24 antigen concentration for each viral stock were determined; no correlation between these two biologic parameters was found. Syncytium formation in MT-2 cells and CCR5 or CXCR4 coreceptor usage were determined for all isolates. Isolates were also screened for neutralization by soluble CD4, a cocktail of monoclonal antibodies, and a pool of HIV-1-positive patient sera. The panel consists of 49 nonsyncytium-inducing isolates that use CCR5 as a major coreceptor and 11 syncytium-inducing isolates that use only CXCR4 or both coreceptors. Neutralization profiles suggest that the panel contains both neutralization-sensitive and -resistant isolates. This collection of HIV-1 isolates represents the six major globally prevalent strains, is exceptionally large and well characterized, and provides an important resource for standardization of immunogenicity assessment in HIV-1 vaccine trials.

scholarly journals Antibody Protects Macaques against Vaginal Challenge with a Pathogenic R5 Simian/Human Immunodeficiency Virus at Serum Levels Giving Complete Neutralization In Vitro

2001 ◽  
Vol 75 (17) ◽  
pp. 8340-8347 ◽  
Author(s):  
Paul W. H. I. Parren ◽  
Preston A. Marx ◽  
Ann J. Hessell ◽  
Amara Luckay ◽  
Janet Harouse ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Neutralizing Antibody ◽  
Serum Levels ◽  
Mucosal Transmission ◽  
Infected People ◽  
Virus Challenge ◽  
Immunodeficiency Virus ◽  
Antibody Titers ◽  
Hiv 1

ABSTRACT A major unknown in human immunodeficiency virus (HIV-1) vaccine design is the efficacy of antibodies in preventing mucosal transmission of R5 viruses. These viruses, which use CCR5 as a coreceptor, appear to have a selective advantage in transmission of HIV-1 in humans. Hence R5 viruses predominate during primary infection and persist throughout the course of disease in most infected people. Vaginal challenge of macaques with chimeric simian/human immunodeficiency viruses (SHIV) is perhaps one of the best available animal models for human HIV-1 infection. Passive transfer studies are widely used to establish the conditions for antibody protection against viral challenge. Here we show that passive intravenous transfer of the human neutralizing monoclonal antibody b12 provides dose-dependent protection to macaques vaginally challenged with the R5 virus SHIV162P4. Four of four monkeys given 25 mg of b12 per kg of body weight 6 h prior to challenge showed no evidence of viral infection (sterile protection). Two of four monkeys given 5 mg of b12/kg were similarly protected, whereas the other two showed significantly reduced and delayed plasma viremia compared to control animals. In contrast, all four monkeys treated with a dose of 1 mg/kg became infected with viremia levels close to those for control animals. Antibody b12 serum concentrations at the time of virus challenge corresponded to approximately 400 (25 mg/kg), 80 (5 mg/kg), and 16 (1 mg/kg) times the in vitro (90%) neutralization titers. Therefore, complete protection against mucosal challenge with an R5 SHIV required essentially complete neutralization of the infecting virus. This suggests that a vaccine based on antibody alone would need to sustain serum neutralizing antibody titers (90%) of the order of 1:400 to achieve sterile protection but that lower titers, around 1:100, could provide a significant benefit. The significance of such substerilizing neutralizing antibody titers in the context of a potent cellular immune response is an important area for further study.

scholarly journals Protection by Live, Attenuated Simian Immunodeficiency Virus against Heterologous Challenge

1999 ◽  
Vol 73 (10) ◽  
pp. 8356-8363 ◽  
Author(s):  
Michael S. Wyand ◽  
Kelledy Manson ◽  
David C. Montefiori ◽  
Jeffrey D. Lifson ◽  
R. Paul Johnson ◽  
...  
Keyword(s):  
Simian Immunodeficiency Virus ◽  
Intravenous Route ◽  
Envelope Gene ◽  
Structural Genes ◽  
Vaccine Protection ◽  
Live Attenuated Vaccine ◽  
Virus Challenge ◽  
Viral Loads ◽  
Cell Counts ◽  
Immunodeficiency Virus

ABSTRACT We examined the ability of a live, attenuated deletion mutant of simian immunodeficiency virus (SIV), SIVmac239Δ3, which is missingnef and vpr genes, to protect against challenge by heterologous strains SHIV89.6p and SIVsmE660. SHIV89.6p is a pathogenic, recombinant SIV in which the envelope gene has been replaced by a human immunodeficiency virus type 1 envelope gene; other structural genes of SHIV89.6p are derived from SIVmac239. SIVsmE660 is an uncloned, pathogenic, independent isolate from the same primate lentivirus subgrouping as SIVmac but with natural sequence variation in all structural genes. The challenge with SHIV89.6p was performed by the intravenous route 37 months after the time of vaccination. By the criteria of CD4+ cell counts and disease, strong protection against the SHIV89.6p challenge was observed in four of four vaccinated monkeys despite the complete mismatch of env sequences. However, SHIV89.6p infection was established in all four previously vaccinated monkeys and three of the four developed fluctuating viral loads between 300 and 10,000 RNA copy equivalents per ml of plasma 30 to 72 weeks postchallenge. When other vaccinated monkeys were challenged with SIVsmE660 at 28 months after the time of vaccination, SIV loads were lower than those observed in unvaccinated controls but the level of protection was less than what was observed against SHIV89.6p in these experiments and considerably less than the level of protection against SIVmac251 observed in previous experiments. These results demonstrate a variable level of vaccine protection by live, attenuated SIVmac239Δ3 against heterologous virus challenge and suggest that even live, attenuated vaccine approaches for AIDS will face significant hurdles in providing protection against the natural variation present in field strains of virus. The results further suggest that factors other than anti-Env immune responses can be principally responsible for the vaccine protection by live, attenuated SIV.

scholarly journals Vaccine Protection against a Heterologous, Non-Syncytium-Inducing, Primary Human Immunodeficiency Virus

1998 ◽  
Vol 72 (12) ◽  
pp. 10275-10280 ◽  
Author(s):  
Marjorie Robert-Guroff ◽  
Harvinder Kaur ◽  
L. Jean Patterson ◽  
Michel Leno ◽  
Anthony J. Conley ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Neutralizing Antibody ◽  
High Dose ◽  
Antibody Activity ◽  
Complete Protection ◽  
Vaccine Strategy ◽  
Vaccine Protection ◽  
Immunodeficiency Virus ◽  
Hiv 1

ABSTRACT Vaccine-induced protection of chimpanzees against laboratory-adapted and syncytium-inducing, multiply passaged primary human immunodeficiency virus type 1 (HIV-1) isolates, but not against non-syncytium-inducing, minimally passaged ones, has been demonstrated. Following challenge with such an isolate, HIV-15016, we obtained complete protection in one of three chimpanzees previously protected against low- and high-dose HIV-1SF2 exposures after immunization with an adenovirus-HIV-1MN gp160 priming–HIV-1SF2gp120 boosting regimen. At challenge, the protected chimpanzee exhibited broad humoral immunity, including neutralizing antibody activity. These results demonstrate the potential of this combination vaccine strategy and suggest that vaccine protection against an HIV isolate relevant to infection of people is feasible.

scholarly journals A vaccine-induced gene expression signature correlates with protection against SIV and HIV in multiple trials

2019 ◽  
Vol 11 (507) ◽  
pp. eaaw4236 ◽  
Author(s):  
Philip K. Ehrenberg ◽  
Shida Shangguan ◽  
Biju Issac ◽  
Galit Alter ◽  
Aviva Geretz ◽  
...  
Keyword(s):  
Gene Expression ◽  
B Cells ◽  
Vaccine Trial ◽  
Gene Expression Signature ◽  
Gene Signature ◽  
Antibody Responses ◽  
Expression Signature ◽  
Transcriptional Signature ◽  
Correlates Of Protection ◽  
Immunodeficiency Virus

Current HIV vaccines are only partially efficacious, presenting an opportunity to identify correlates of protection and, thereby, potential insight into mechanisms that prevent HIV acquisition. Two independent preclinical challenge studies in nonhuman primates (NHPs) previously showed partial efficacy of a mosaic adenovirus 26 (Ad26)–based HIV-1 vaccine candidate. To investigate the basis of this protection, we performed whole transcriptomics profiling by RNA sequencing (RNA-seq) in sorted lymphocytes from peripheral blood samples taken during these studies at different time points after vaccination but before challenge. We observed a transcriptional signature in B cells that associated with protection from acquisition of simian immunodeficiency virus (SIV) or the simian-human immunodeficiency virus (SHIV) in both studies. Strong antibody responses were elicited, and genes from the signature for which expression was enriched specifically associated with higher magnitude of functional antibody responses. The same gene expression signature also associated with protection in RV144 in the only human HIV vaccine trial to date that has shown efficacy and in two additional NHP studies that evaluated similar canarypox-based vaccine regimens. A composite gene expression score derived from the gene signature was one of the top-ranked correlates of protection in the NHP vaccine studies. This study aims to bridge preclinical and clinical data with the identification of a gene signature in B cells that is associated with protection from SIV and HIV infection by providing a new approach for evaluating future vaccine candidates.

scholarly journals Pentavalent HIV-1 vaccine protects against simian-human immunodeficiency virus challenge

2017 ◽  
Vol 8 (1) ◽  
Author(s):  
Todd Bradley ◽  
Justin Pollara ◽  
Sampa Santra ◽  
Nathan Vandergrift ◽  
Srivamshi Pittala ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Virus Challenge ◽  
Immunodeficiency Virus ◽  
Hiv 1

scholarly journals Anti-V3 Humanized Antibody KD-247 Effectively Suppresses Ex Vivo Generation of Human Immunodeficiency Virus Type 1 and Affords Sterile Protection of Monkeys against a Heterologous Simian/Human Immunodeficiency Virus Infection

2006 ◽  
Vol 80 (11) ◽  
pp. 5563-5570 ◽  
Author(s):  
Yasuyuki Eda ◽  
Toshio Murakami ◽  
Yasushi Ami ◽  
Tadashi Nakasone ◽  
Mari Takizawa ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Ex Vivo ◽  
High Dose ◽  
Virus Challenge ◽  
Clade B ◽  
Immunodeficiency Virus ◽  
Hiv 1

ABSTRACT In an accompanying report (Y. Eda, M. Takizawa, T. Murakami, H. Maeda, K. Kimachi, H. Yonemura, S. Koyanagi, K. Shiosaki, H. Higuchi, K. Makizumi, T. Nakashima, K. Osatomi, S. Tokiyoshi, S. Matsushita, N. Yamamoto, and M. Honda, J. Virol. 80:5552-5562, 2006), we discuss our production of a high-affinity humanized monoclonal antibody, KD-247, by sequential immunization with V3 peptides derived from human immunodeficiency virus type 1 (HIV-1) clade B primary isolates. Epitope mapping revealed that KD-247 recognized the Pro-Gly-Arg V3 tip sequence conserved in HIV-1 clade B isolates. In this study, we further demonstrate that in vitro, KD-247 efficiently neutralizes CXCR4- and CCR5-tropic primary HIV-1 clade B and clade B′ with matching neutralization sequence motifs but does not neutralize sequence-mismatched clade B and clade E isolates. Monkeys were provided sterile protection against heterologous simian/human immunodeficiency virus challenge by the passive transfer of a single high dose (45 mg per kg of body weight) of KD-247 and afforded partial protection by lower antibody doses (30 and 15 mg per kg). Protective neutralization endpoint titers in plasma at the time of virus challenge were 1:160 in animals passively transferred with a high dose of the antibody. The antiviral efficacy of the antibody was further confirmed by its suppression of the ex vivo generation of primary HIV-1 quasispecies in peripheral blood mononuclear cell cultures from HIV-infected individuals. Therefore, KD-247 promises to be a valuable tool not only as a passive immunization antibody for the prevention of HIV infection but also as an immunotherapy for the suppression of HIV in phenotype-matched HIV-infected individuals.

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

Vaccines ◽  
2020 ◽  
Vol 8 (4) ◽  
pp. 681
Author(s):  
Agricola Joachim ◽  
Frank Msafiri ◽  
Sayali Onkar ◽  
Patricia Munseri ◽  
Said Aboud ◽  
...  
Keyword(s):  
Vaccine Trial ◽  
Antibody Responses ◽  
Enzyme Linked Immunosorbent Assay ◽  
Igg Antibody ◽  
Variable Regions ◽  
Modified Vaccinia Virus Ankara ◽  
Immunodeficiency Virus ◽  
Hiv Envelope ◽  
Anti Hiv ◽  
Hiv 1

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.

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