Immunogenicity and Safety of a Booster Dose of an Investigational Adjuvanted Polyprotein HIV-1 Vaccine in Healthy Adults and Effect of Administration of Chloroquine

ABSTRACTThis phase II study evaluated the effect of chloroquine on the specific CD8+T-cell responses to and the safety of a booster dose of investigational human immunodeficiency virus type 1 (HIV-1) F4/AS01Bvaccine containing 10 μg of recombinant fusion protein (F4) adjuvanted with the AS01Badjuvant system. Healthy adults aged 21 to 41 years, primed 3 years before with two F4/AS01Bdoses containing 10 or 30 μg of F4 (ClinicalTrials.govregistration number NCT00434512), were randomized (1:1) to receive the F4/AS01Bbooster administered alone or 2 days after chloroquine (300 mg). F4-specific CD8+/CD4+T-cell responses were characterized by intracellular cytokine staining and lymphoproliferation assays and anti-F4 antibodies by enzyme-linked immunosorbent assays (ELISAs). No effect of chloroquine on CD4+/CD8+T-cell and antibody responses and no vaccine effect on CD8+T-cell responses (cytokine secretion or proliferation) were detected following F4/AS01Bbooster administration.In vitro, chloroquine had a direct inhibitory effect on AS01Badjuvant properties; AS01-induced cytokine production decreased upon coincubation of cells with chloroquine. In the pooled group of participants primed with F4/AS01Bcontaining 10 μg of F4, CD4+T-cell and antibody responses induced by primary vaccination persisted for at least 3 years. The F4/AS01Bbooster induced strong F4-specific CD4+T-cell responses, which persisted for at least 6 months with similar frequencies and polyfunctional phenotypes as following primary vaccination, and high anti-F4 antibody concentrations, reaching higher levels than those following primary vaccination. The F4/AS01Bbooster had a clinically acceptable safety and reactogenicity profile. An F4/AS01Bbooster dose, administered alone or after chloroquine, induced robust antibody and F4-specific CD4+T-cell responses but no significant CD8+T-cell responses (cytokine secretion or proliferation) in healthy adults. (This study has been registered atClinicalTrials.govunder registration number NCT00972725).

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Effects of neutralizing antibodies on escape from CD8 + T-cell responses in HIV-1 infection

Philosophical Transactions of the Royal Society B Biological Sciences ◽

10.1098/rstb.2014.0290 ◽

2015 ◽

Vol 370 (1675) ◽

pp. 20140290 ◽

Cited By ~ 6

Author(s):

Paul S. Wikramaratna ◽

José Lourenço ◽

Paul Klenerman ◽

Oliver G. Pybus ◽

Sunetra Gupta

Keyword(s):

T Cell ◽

Neutralizing Antibodies ◽

T Cell Responses ◽

Extended Period ◽

Antibody Responses ◽

Host Susceptibility ◽

Cell Responses ◽

Infection Dynamics ◽

Antibody Induction ◽

Hiv 1

Despite substantial advances in our knowledge of immune responses against HIV-1 and of its evolution within the host, it remains unclear why control of the virus eventually breaks down. Here, we present a new theoretical framework for the infection dynamics of HIV-1 that combines antibody and CD8 + T-cell responses, notably taking into account their different lifespans. Several apparent paradoxes in HIV pathogenesis and genetics of host susceptibility can be reconciled within this framework by assigning a crucial role to antibody responses in the control of viraemia. We argue that, although escape from or progressive loss of quality of CD8 + T-cell responses can accelerate disease progression, the underlying cause of the breakdown of virus control is the loss of antibody induction due to depletion of CD4 + T cells. Furthermore, strong antibody responses can prevent CD8 + T-cell escape from occurring for an extended period, even in the presence of highly efficacious CD8 + T-cell responses.

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Durability of immune responses to the BNT162b2 mRNA vaccine

10.1101/2021.09.30.462488 ◽

2021 ◽

Author(s):

Mehul Suthar ◽

Prabhu S Arunachalam ◽

Mengyun Hu ◽

Noah Reis ◽

Meera Trisal ◽

...

Keyword(s):

T Cell ◽

Immune Responses ◽

Significant Proportion ◽

T Cell Responses ◽

Primary Vaccination ◽

Antibody Responses ◽

Booster Immunization ◽

Cell Responses ◽

Cell Immunity ◽

Antibody Titers

The development of the highly efficacious mRNA vaccines in less than a year since the emergence of SARS-CoV-2 represents a landmark in vaccinology. However, reports of waning vaccine efficacy, coupled with the emergence of variants of concern that are resistant to antibody neutralization, have raised concerns about the potential lack of durability of immunity to vaccination. We recently reported findings from a comprehensive analysis of innate and adaptive immune responses in 56 healthy volunteers who received two doses of the BNT162b2 vaccination. Here, we analyzed antibody responses to the homologous Wu strain as well as several variants of concern, including the emerging Mu (B.1.621) variant, and T cell responses in a subset of these volunteers at six months (day 210 post-primary vaccination) after the second dose. Our data demonstrate a substantial waning of antibody responses and T cell immunity to SARS-CoV-2 and its variants, at 6 months following the second immunization with the BNT162b2 vaccine. Notably, a significant proportion of vaccinees have neutralizing titers below the detection limit, and suggest a 3rd booster immunization might be warranted to enhance the antibody titers and T cell responses.

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HIV-1 gp120 and Modified Vaccinia Virus Ankara (MVA) gp140 Boost Immunogens Increase Immunogenicity of a DNA/MVA HIV-1 Vaccine

Journal of Virology ◽

10.1128/jvi.01077-17 ◽

2017 ◽

Vol 91 (24) ◽

Cited By ~ 14

Author(s):

Xiaoying Shen ◽

Rahul Basu ◽

Sheetal Sawant ◽

David Beaumont ◽

Sue Fen Kwa ◽

...

Keyword(s):

T Cell ◽

Vaccinia Virus ◽

T Cell Responses ◽

Hiv Vaccine ◽

Antibody Responses ◽

Cell Responses ◽

Modified Vaccinia Virus Ankara ◽

Gp120 Protein ◽

Boost Vaccine ◽

Hiv 1

ABSTRACT An important goal of human immunodeficiency virus (HIV) vaccine design is identification of strategies that elicit effective antiviral humoral immunity. One novel approach comprises priming with DNA and boosting with modified vaccinia virus Ankara (MVA) expressing HIV-1 Env on virus-like particles. In this study, we evaluated whether the addition of a gp120 protein in alum or MVA-expressed secreted gp140 (MVAgp140) could improve immunogenicity of a DNA prime-MVA boost vaccine. Five rhesus macaques per group received two DNA primes at weeks 0 and 8 followed by three MVA boosts (with or without additional protein or MVAgp140) at weeks 18, 26, and 40. Both boost immunogens enhanced the breadth of HIV-1 gp120 and V1V2 responses, antibody-dependent cellular cytotoxicity (ADCC), and low-titer tier 1B and tier 2 neutralizing antibody responses. However, there were differences in antibody kinetics, linear epitope specificity, and CD4 T cell responses between the groups. The gp120 protein boost elicited earlier and higher peak responses, whereas the MVAgp140 boost resulted in improved antibody durability and comparable peak responses after the final immunization. Linear V3 specific IgG responses were particularly enhanced by the gp120 boost, whereas the MVAgp140 boost also enhanced responses to linear C5 and C2.2 epitopes. Interestingly, gp120, but not the MVAgp140 boost, increased peak CD4+ T cell responses. Thus, both gp120 and MVAgp140 can augment potential protection of a DNA/MVA vaccine by enhancing gp120 and V1/V2 antibody responses, whereas potential protection by gp120, but not MVAgp140 boosts, may be further impacted by increased CD4+ T cell responses. IMPORTANCE Prior immune correlate analyses with humans and nonhuman primates revealed the importance of antibody responses in preventing HIV-1 infection. A DNA prime-modified vaccinia virus Ankara (MVA) boost vaccine has proven to be potent in eliciting antibody responses. Here we explore the ability of boosts with recombinant gp120 protein or MVA-expressed gp140 to enhance antibody responses elicited by the GOVX-B11 DNA prime-MVA boost vaccine. We found that both types of immunogen boosts enhanced potentially protective antibody responses, whereas the gp120 protein boosts also increased CD4+ T cell responses. Our data provide important information for HIV vaccine designs that aim for effective and balanced humoral and T cell responses.

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Superiority in Rhesus Macaques of Targeting HIV-1 Env gp140 to CD40 versus LOX-1 in Combination with Replication-Competent NYVAC-KC for Induction of Env-Specific Antibody and T Cell Responses

Journal of Virology ◽

10.1128/jvi.01596-16 ◽

2017 ◽

Vol 91 (9) ◽

Cited By ~ 12

Author(s):

Gerard Zurawski ◽

Xiaoying Shen ◽

Sandra Zurawski ◽

Georgia D. Tomaras ◽

David C. Montefiori ◽

...

Keyword(s):

Dendritic Cells ◽

T Cell ◽

Rhesus Macaques ◽

Serum Antibody ◽

T Cell Responses ◽

Antibody Responses ◽

Effective Vaccine ◽

Protective Antibody ◽

Cell Responses ◽

Hiv 1

ABSTRACT We compared the HIV-1-specific immune responses generated by targeting HIV-1 envelope protein (Env gp140) to either CD40 or LOX-1, two endocytic receptors on dendritic cells (DCs), in rhesus macaques primed with a poxvirus vector (NYVAC-KC) expressing Env gp140. The DC-targeting vaccines, humanized recombinant monoclonal antibodies fused to Env gp140, were administered as a boost with poly-ICLC adjuvant either alone or coadministered with the NYVAC-KC vector. All the DC-targeting vaccine administrations with poly-ICLC increased the low-level serum anti-Env IgG responses elicited by NYVAC-KC priming significantly more (up to a P value of 0.01) than in a group without poly-ICLC. The responses were robust and cross-reactive and contained antibodies specific to multiple epitopes within gp140, including the C1, C2, V1, V2, and V3, C4, C5, and gp41 immunodominant regions. The DC-targeting vaccines also elicited modest serum Env-specific IgA responses. All groups gave serum neutralization activity limited to tier 1 viruses and antibody-dependent cytotoxicity responses (ADCC) after DC-targeting boosts. Furthermore, CD4+ and CD8+ T cell responses specific to multiple Env epitopes were strongly boosted by the DC-targeting vaccines plus poly-ICLC. Together, these results indicate that prime-boost immunization via NYVAC-KC and either anti-CD40.Env gp140/poly-ICLC or anti-LOX-1.Env gp140/poly-ICLC induced balanced antibody and T cell responses against HIV-1 Env. Coadministration of NYVAC-KC with the DC-targeting vaccines increased T cell responses but had minimal effects on antibody responses except for suppressing serum IgA responses. Overall, targeting Env to CD40 gave more robust T cell and serum antibody responses with broader epitope representation and greater durability than with LOX-1. IMPORTANCE An effective vaccine to prevent HIV-1 infection does not yet exist. An approach to elicit strong protective antibody development is to direct virus protein antigens specifically to dendritic cells, which are now known to be the key cell type for controlling immunity. In this study, we have tested in nonhuman primates two prototype vaccines engineered to direct the HIV-1 coat protein Env to dendritic cells. These vaccines bind to either CD40 or LOX-1, two dendritic cell surface receptors with different functions and tissue distributions. We tested the vaccines described above in combination with attenuated virus vectors that express Env. Both vaccines, but especially that delivered via CD40, raised robust immunity against HIV-1 as measured by monitoring potentially protective antibody and T cell responses in the blood. The safety and efficacy of the CD40-targeted vaccine justify further development for future human clinical trials.

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Amplification of T-cell responses in DNA-based immunization with HIV-1 Nef by coinjection with a GM-CSF expression vector

Immunology Letters ◽

10.1016/s0165-2478(97)88025-x ◽

1997 ◽

Vol 56 (1-3) ◽

pp. 294-295

Author(s):

C Svanholm

Keyword(s):

T Cell ◽

Expression Vector ◽

T Cell Responses ◽

Gm Csf ◽

Cell Responses ◽

Hiv 1

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Faculty Opinions recommendation of A dendritic cell-based vaccine elicits T cell responses associated with control of HIV-1 replication.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.717972955.793495235 ◽

2014 ◽

Author(s):

Angus Dalgleish

Keyword(s):

T Cell ◽

Dendritic Cell ◽

T Cell Responses ◽

Cell Responses ◽

Hiv 1 ◽

Dendritic Cell Based Vaccine

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Polyfunctional CD8+ T-Cell Response to Autologous Peptides from Protease and Reverse Transcriptase of HIV-1 Clade B

Current HIV Research ◽

10.2174/1570162x17666191017105910 ◽

2019 ◽

Vol 17 (5) ◽

pp. 350-359

Author(s):

Liliana Acevedo-Saenz ◽

Federico Perdomo-Celis ◽

Carlos J. Montoya ◽

Paula A. Velilla

Keyword(s):

T Cell ◽

Reverse Transcriptase ◽

Cellular Response ◽

T Cell Responses ◽

Cd8 T Cell ◽

T Cell Response ◽

Effective Vaccine ◽

Cell Responses ◽

Clade B ◽

Hiv 1

Background: : The diversity of the HIV proteome influences the cellular response and development of an effective vaccine, particularly due to the generation of viral variants with mutations located within CD8+ T-cell epitopes. These mutations can affect the recognition of the epitopes, that may result in the selection of HIV variants with mutated epitopes (autologous epitopes) and different CD8+ T-cell functional profiles. Objective:: To determine the phenotype and functionality of CD8+ T-cell from HIV-infected Colombian patients in response to autologous and consensus peptides derived from HIV-1 clade B protease and reverse transcriptase (RT). Methods:: By flow cytometry, we compared the ex vivo CD8+ T-cell responses from HIV-infected patients to autologous and consensus peptides derived from HIV-1 clade B protease and RT, restricted by HLA-B*35, HLA-B*44 and HLA-B*51 alleles. Results:: Although autologous peptides restricted by HLA-B*35 and HLA-B*44 did not show any differences compared with consensus peptides, we observed the induction of a higher polyfunctional profile of CD8+ T-cells by autologous peptides restricted by HLA-B*51, particularly by the production of interferon-γ and macrophage inflammatory protein-1β. The response by different memory CD8+ T-cell populations was comparable between autologous vs. consensus peptides. In addition, the magnitude of the polyfunctional response induced by the HLA-B*51-restricted QRPLVTIRI autologous epitope correlated with low viremia. Conclusion:: Autologous peptides should be considered for the evaluation of HIV-specific CD8+ Tcell responses and to reveal some relevant epitopes that could be useful for therapeutic strategies aiming to promote polyfunctional CD8+ T-cell responses in a specific population of HIV-infected patients.

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