Acceptability and tolerability of repeated intramuscular electroporation of Multi-antigenic HIV (HIVMAG) DNA vaccine among healthy African participants in a phase 1 randomized controlled trial

Mpendo, Juliet; Mutua, Gaudensia; Nanvubya, Annet; Anzala, Omu; Nyombayire, Julien; Karita, Etienne; Dally, Len; Hannaman, Drew; Price, Matt A.; Fast, Patricia E.; Priddy, Frances; Gelderblom, Huub C.; Hills, Nancy K.

doi:10.1371/journal.pone.0233151

Cited by 16 publications

(10 citation statements)

References 15 publications

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“…Intramuscular vaccination with DNA followed by electroporation has been studied extensively in patients targeted a variety of pathogen-derived [ 39 – 42 ] and self-antigens [ 43 ] and has been well tolerated. Nevertheless, it is complicated by the need for the electroporation device and the electrical stimulation can be more painful [ 44 ] than conventional protein-based vaccination. A more robust antibody response to MUC16 might be achieved by combining L1-VLP (purified from yeast or Sf9 insect cells, for example) that display MUC16 epitopes with adjuvants like alum and monophosphoryl lipid A, as utilized in the licensed Gardasil and Cervarix vaccines.…”

Section: Discussionmentioning

confidence: 99%

Virus-like particle vaccine displaying an external, membrane adjacent MUC16 epitope elicits ovarian cancer-reactive antibodies

Tu,

Wong,

Tseng

et al. 2024

J Ovarian Res

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Background MUC16 is a heavily glycosylated cell surface mucin cleaved in the tumor microenvironment to shed CA125. CA125 is a serum biomarker expressed by > 95% of non-mucinous advanced stage epithelial ovarian cancers. MUC16/CA125 contributes to the evasion of anti-tumor immunity, peritoneal spread and promotes carcinogenesis; consequently, it has been targeted with antibody-based passive and active immunotherapy. However, vaccination against this self-antigen likely requires breaking B cell tolerance and may trigger autoimmune disease. Display of self-antigens on virus-like particles (VLPs), including those produced with human papillomavirus (HPV) L1, can efficiently break B cell tolerance. Results A 20 aa juxta-membrane peptide of the murine MUC16 (mMUC16) or human MUC16 (hMUC16) ectodomain was displayed either via genetic insertion into an immunodominant loop of HPV16 L1-VLPs between residues 136/137, or by chemical coupling using malemide to cysteine sulfhydryl groups on their surface. Female mice were vaccinated intramuscularly three times with either DNA expressing L1-MUC16 fusions via electroporation, or with alum-formulated VLP chemically-coupled to MUC16 peptides. Both regimens were well tolerated, and elicited MUC16-specific serum IgG, although titers were higher in mice vaccinated with MUC16-coupled VLP on alum as compared to L1-MUC16 DNA vaccination. Antibody responses to mMUC16-targeted vaccination cross-reacted with hMUC16 peptide, and vice versa; both were reactive with the surface of CA125+ OVCAR3 cells, but not SKOV3 that lack detectable CA125 expression. Interestingly, vaccination of mice with mMUC16 peptide mixed with VLP and alum elicited mMUC16-specific IgG, implying VLPs provide robust T help and that coupling may not be required to break tolerance to this epitope. Conclusion Vaccination with VLP displaying the 20 aa juxta-membrane MUC16 ectodomain, which includes the membrane proximal cleavage site, is likely to be well tolerated and induce IgG targeting ovarian cancer cells, even after CA125 is shed.

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Section: Discussionmentioning

confidence: 99%

Virus-like particle vaccine displaying an external, membrane adjacent MUC16 epitope elicits ovarian cancer-reactive antibodies

Tu,

Wong,

Tseng

et al. 2024

J Ovarian Res

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“…Previous clinical studies demonstrated that electroporation-mediated intramuscular injection of DNA encoding HIVantigens can dramatically enhance the magnitude, frequency and breadth of immune response compared with conventional methods of injection [13,14]. The vaccines and placebo were administered using the investigational TriGrid Delivery System (TDS-IM v2.0) for electroporation-based intramuscular administration (ICHOR Medical Systems, San Diego, California, USA) [13][14][15][16].…”

Section: Methodsmentioning

confidence: 99%

The immunogenicity of an HIV-1 Gag conserved element DNA vaccine in people with HIV and receiving antiretroviral therapy

Jacobson,

Felber,

Chen

et al. 2023

Aids

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Objective: The primary objective of the study was to assess the immunogenicity of an HIV-1 Gag conserved element DNA vaccine (p24CE DNA) in people with HIV (PWH) receiving suppressive antiretroviral therapy (ART). Design: AIDS Clinical Trials Group A5369 was a phase I/IIa, randomized, double-blind, placebo-controlled study of PWH receiving ART with plasma HIV-1 RNA less than 50 copies/ml, current CD4+ T-cell counts greater than 500 cells/μl, and nadir CD4+ T-cell counts greater than 350 cells/μl. Methods: The study enrolled 45 participants randomized 2 : 1 : 1 to receive p24CE DNA vaccine at weeks 0 and 4, followed by p24CE DNA admixed with full-length p55Gag DNA vaccine at weeks 12 and 24 (arm A); full-length p55Gag DNA vaccine at weeks 0, 4, 12, and 24 (arm B); or placebo at weeks 0, 4, 12, and 24 (arm c). The active and placebo vaccines were administered by intramuscular electroporation. Results: There was a modest, but significantly greater increase in the number of conserved elements recognized by CD4+ and/or CD8+ T cells in arm A compared with arm C (P = 0.014). The percentage of participants with an increased number of conserved elements recognized by T cells was also highest in arm A (8/18, 44.4%) vs. arm C (0/10, 0.0%) (P = 0.025). There were no significant differences between treatment groups in the change in magnitude of responses to total conserved elements. Conclusion: A DNA-delivered HIV-1 Gag conserved element vaccine boosted by a combination of this vaccine with a full-length p55Gag DNA vaccine induced a new conserved element-directed cellular immune response in approximately half the treated PWH on ART.

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“…One approach is to increase the efficiency of plasmid-based DNA vaccination by electroporation (EP). In vivo EP is an efficient vaccine strategy that enhances cell permeability, local tissue inflammation, and immunogenicity in experimental animals [ 22 , 23 , 24 , 25 , 26 , 27 ] and in humans [ 28 , 29 , 30 , 31 ]. When EP is applied to the target organism, the encoded antigens are expressed and elicit the corresponding immune response, with the potential to induce antibody-mediated, helper T cell-mediated, and cytotoxic T cell-mediated immune responses [ 32 ].…”

Section: Introductionmentioning

confidence: 99%

Safety and Immunogenicity of an In Vivo Muscle Electroporation Delivery System for DNA-hsp65 Tuberculosis Vaccine in Cynomolgus Monkeys

de Lima,

Leandro,

de Souza

et al. 2023

Vaccines

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A Bacille Calmette–Guérin (BCG) is still the only licensed vaccine for the prevention of tuberculosis, providing limited protection against Mycobacterium tuberculosis infection in adulthood. New advances in the delivery of DNA vaccines by electroporation have been made in the past decade. We evaluated the safety and immunogenicity of the DNA-hsp65 vaccine administered by intramuscular electroporation (EP) in cynomolgus macaques. Animals received three doses of DNA-hsp65 at 30-day intervals. We demonstrated that intramuscular electroporated DNA-hsp65 vaccine immunization of cynomolgus macaques was safe, and there were no vaccine-related effects on hematological, renal, or hepatic profiles, compared to the pre-vaccination parameters. No tuberculin skin test conversion nor lung X-ray alteration was identified. Further, low and transient peripheral cellular immune response and cytokine expression were observed, primarily after the third dose of the DNA-hsp65 vaccine. Electroporated DNA-hsp65 vaccination is safe but provides limited enhancement of peripheral cellular immune responses. Preclinical vaccine trials with DNA-hsp65 delivered via EP may include a combination of plasmid cytokine adjuvant and/or protein prime–boost regimen, to help the induction of a stronger cellular immune response.

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Acceptability and tolerability of repeated intramuscular electroporation of Multi-antigenic HIV (HIVMAG) DNA vaccine among healthy African participants in a phase 1 randomized controlled trial

Abstract: Acceptability and tolerability of repeated intramuscular electroporation of Multi-antigenic HIV (HIVMAG) DNA vaccine among healthy African participants in a phase 1 randomized controlled trial. PLoS ONE 15(5): e0233151.

Cited by 16 publications

References 15 publications

Virus-like particle vaccine displaying an external, membrane adjacent MUC16 epitope elicits ovarian cancer-reactive antibodies

Virus-like particle vaccine displaying an external, membrane adjacent MUC16 epitope elicits ovarian cancer-reactive antibodies

The immunogenicity of an HIV-1 Gag conserved element DNA vaccine in people with HIV and receiving antiretroviral therapy

Safety and Immunogenicity of an In Vivo Muscle Electroporation Delivery System for DNA-hsp65 Tuberculosis Vaccine in Cynomolgus Monkeys

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