Adenovirus-based HIV-1 vaccine candidates tested in efficacy trials elicit CD8+ T cells with limited breadth of HIV-1 inhibition

Hayes, Peter; Cox, Josephine H.; Coleman, Andrew; Fernández, Natalia; Bergin, Philip; Kopycinski, Jakub; Nitayaphan, Sorachai; Pitisuttihum, Punnee; Souza, Mark de; Duerr, Ann; Morgan, Cecilia; Gilmour, Jill

doi:10.1097/qad.0000000000001122

Cited by 23 publications

(24 citation statements)

References 62 publications

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“…Polyfunctional CD8 + T‐cell responses significantly correlated with decreased HIV‐1 risk [Frahm, McElrath et al. HIV Research for Prevention (R4P) meeting, Chicago, Illinois 2016] and efforts are underway to examine the capacity of these CD8 + T cells to mediate virus inhibition as previously reported for this vaccine regimen . A genetic sequence analysis of the viruses transmitted in the vaccinees compared to the placebos (ie virus sieve analysis) examined if there were significant differences in virus sequences that could have resulted from vaccine‐induced immune responses able to partially block HIV‐1 acquisition or alter HIV evolution postacquisition.…”

Section: Hiv‐1 Vaccine Efficacy Trialsmentioning

confidence: 99%

Complex immune correlates of protection in HIV‐1 vaccine efficacy trials

Tomaras¹,

Plotkin

2017

Immunological Reviews

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Summary Development of an efficacious HIV-1 vaccine is a major priority for improving human health worldwide. Vaccine mediated protection against human pathogens can be achieved through elicitation of protective innate, humoral, and cellular responses. Identification of specific immune responses responsible for pathogen protection enables vaccine development and provides insights into host defenses against pathogens and the immunological mechanisms that most effectively fight infection. Defining immunological correlates of transmission risk in preclinical and clinical HIV-1 vaccine trials has moved the HIV-1 vaccine development field forward and directed new candidate vaccine development. Immune correlate studies are providing novel hypotheses about immunological mechanisms that may be responsible for preventing HIV-1 acquisition. Recent results from HIV-1 immune correlates work has demonstrated that there are multiple types of immune responses that together, comprise an immune correlate—thus implicating polyfunctional immune control of HIV-1 transmission. An in depth understanding of these complex immunological mechanisms of protection against HIV-1 will accelerate the development of an efficacious HIV-1 vaccine.

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Section: Hiv‐1 Vaccine Efficacy Trialsmentioning

confidence: 99%

Complex immune correlates of protection in HIV‐1 vaccine efficacy trials

Tomaras¹,

Plotkin

2017

Immunological Reviews

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“…The strongest Gag-specific T-cell responses were detected by ELISPOT and ICS assays after the SeV-Gag prime and Ad35-GRIN boost, with no clear effect of the SeV-Gag dose. Functional viral inhibition responses mediated by T cells [41] with greater breadth, magnitude, and frequency were also seen in groups S L A and S H A after the Ad35-GRIN boost. The frequency and magnitude of Gag ELISPOT responses in the S L A and S H A groups combined were equivalent to those of Ad35-GRIN given twice intramuscularly, indicating that SeV-Gag given intranasally provides as strong a prime as an Ad vector given intramuscularly [31].…”

Section: Discussionmentioning

confidence: 99%

“…Colorectal biopsy specimens were pooled and disaggregated by collagenase digestion to isolate mucosal mononuclear cells within 6 hours of collection, and intracellular cytokine staining (ICS) assays were performed after an overnight rest as described elsewhere [38, 39]. T-cell responses were assessed by qualified interferon-γ (IFN-γ) enzyme-linked immunospot (ELISPOT) and ICS assays, using peptides matched to Gag, and by a functional viral inhibition assay, using a panel of 8 HIV-1 strains from subtypes A, B, C, and D [7, 8, 31, 40, 41]. …”

Section: Methodsmentioning

confidence: 99%

First-in-Human Evaluation of the Safety and Immunogenicity of an Intranasally Administered Replication-Competent Sendai Virus–Vectored HIV Type 1 Gag Vaccine: Induction of Potent T-Cell or Antibody Responses in Prime-Boost Regimens

et al. 2016

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Background. We report the first-in-human safety and immunogenicity assessment of a prototype intranasally administered, replication-competent Sendai virus (SeV)–vectored, human immunodeficiency virus type 1 (HIV-1) vaccine.Methods. Sixty-five HIV-1–uninfected adults in Kenya, Rwanda, and the United Kingdom were assigned to receive 1 of 4 prime-boost regimens (administered at 0 and 4 months, respectively; ratio of vaccine to placebo recipients, 12:4): priming with a lower-dose SeV-Gag given intranasally, followed by boosting with an adenovirus 35–vectored vaccine encoding HIV-1 Gag, reverse transcriptase, integrase, and Nef (Ad35-GRIN) given intramuscularly (SLA); priming with a higher-dose SeV-Gag given intranasally, followed by boosting with Ad35-GRIN given intramuscularly (SHA); priming with Ad35-GRIN given intramuscularly, followed by boosting with a higher-dose SeV-Gag given intranasally (ASH); and priming and boosting with a higher-dose SeV-Gag given intranasally (SHSH).Results. All vaccine regimens were well tolerated. Gag-specific IFN-γ enzyme-linked immunospot–determined response rates and geometric mean responses were higher (96% and 248 spot-forming units, respectively) in groups primed with SeV-Gag and boosted with Ad35-GRIN (SLA and SHA) than those after a single dose of Ad35-GRIN (56% and 54 spot-forming units, respectively) or SeV-Gag (55% and 59 spot-forming units, respectively); responses persisted for ≥8 months after completion of the prime-boost regimen. Functional CD8+ T-cell responses with greater breadth, magnitude, and frequency in a viral inhibition assay were also seen in the SLA and SHA groups after Ad35-GRIN boost, compared with those who received either vaccine alone. SeV-Gag did not boost T-cell counts in the ASH group. In contrast, the highest Gag-specific antibody titers were seen in the ASH group. Mucosal antibody responses were sporadic.Conclusions. SeV-Gag primed functional, durable HIV-specific T-cell responses and boosted antibody responses. The prime-boost sequence appears to determine which arm of the immune response is stimulated.Clinical Trials Registration. NCT01705990.

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“…40,41 Hanke HIVconsv 2007: 14 concatenated peptide fragments derived from different subtype consensus sequences (median length 40, range 27-130 amino acids (aa)); 17 Mothe HTI 2015: 16 fragments (median length 22.5, range 11-78 aa), concatenated with three joining alanine residues, based on regions that were preferentially targeted by individuals with low viral loads, published as European Patent EP2620446A1; 25 Korber Ultra CE: 40 highly conserved peptides (median length 18, range 14-22 aa), selected based on contiguous HIV-1 M group 9-mer coverage >80%, designed using the Epigraph tools, 42 currently under study, and first published here; Mullins p24 CE: Two variants each, of 7 regions of Gag (median 18, range 12-24 aa), concatenated with 2-4 aa alanine-rich linkers. 43. responses, 44,45 many of the observed CD8+ T-cell responses would have been immunologically silent against circulating viruses in the study population.…”

Section: Vaccine-induced Cd8+ T-cells Responses Associated With Protementioning

confidence: 96%

T cell-based strategies for HIV-1 vaccines

Korber

Fischer

2019

Human Vaccines & Immunotherapeutics

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Despite 30 years of effort, we do not have an effective HIV-1 vaccine. Over the past decade, the HIV-1 vaccine field has shifted emphasis toward antibody-based vaccine strategies, following a lack of efficacy in CD8+ T-cell-based vaccine trials. Several lines of evidence, however, suggest that improved CD8+ T-cell-directed strategies could benefit an HIV-1 vaccine. First, T-cell responses often correlate with good outcomes in non-human primate (NHP) challenge models. Second, subgroup studies of two no-efficacy human clinical vaccine trials found associations between CD8+ T-cell responses and protective effects. Finally, improved strategies can increase the breadth and potency of CD8+ T-cell responses, direct them toward preferred epitopes (that are highly conserved and/or associated with viral control), or both. Optimized CD8+ T-cell vaccine strategies are promising in both prophylactic and therapeutic settings. This commentary briefly outlines some encouraging findings from T-cell vaccine studies, and then directly compares key features of some T-cell vaccine candidates currently in the clinical pipeline.

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Adenovirus-based HIV-1 vaccine candidates tested in efficacy trials elicit CD8+ T cells with limited breadth of HIV-1 inhibition

Cited by 23 publications

References 62 publications

Complex immune correlates of protection in HIV‐1 vaccine efficacy trials

Complex immune correlates of protection in HIV‐1 vaccine efficacy trials

First-in-Human Evaluation of the Safety and Immunogenicity of an Intranasally Administered Replication-Competent Sendai Virus–Vectored HIV Type 1 Gag Vaccine: Induction of Potent T-Cell or Antibody Responses in Prime-Boost Regimens

T cell-based strategies for HIV-1 vaccines

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