Subtype C gp140 Vaccine Boosts Immune Responses Primed by the South African AIDS Vaccine Initiative DNA-C2 and MVA-C HIV Vaccines after More than a 2-Year Gap

Gray, Glenda; Mayer, Kenneth H.; Elizaga, Marnie; Bekker, Linda‐Gail; Allen, Mary; Morris, Lynn; Montefiori, David C.; Rosa, Stephen C. De; Sato, Alicia; Gu, Niya; Tomaras, Georgia D.; Tucker, Timothy J.; Barnett, Susan W.; Mkhize, Nonhlanhla N.; Shen, Xiaoying; Downing, Katrina; Williamson, Carolyn; Pensiero, Michael; Corey, Lawrence; Williamson, Anna‐Lise

doi:10.1128/cvi.00717-15

Cited by 26 publications

(43 citation statements)

References 25 publications

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“…[57] In collaboration with community, local and international stakeholders, the SA Medical Research Council (SAMRC), through the SA AIDS Vaccine Initiative (SAAVI), has pioneered studies of vaccines against the clade C HIV subtype responsible for the highest number of global HIV infections, such as the SAAVI-developed DNA.C and recombinant MVA vaccines. [60,61] The SAMRC-led SAAVI programme was a public-private partnership funded by the NDoH, Department of Science and Technology and Eskom, which, after a 9-year development period, created a pipeline of candidate HIV-1 subtype C vaccines. These included virus-like particles, novel DNA plasmid vaccines, capripoxvirus and Bacillus Calmette-Guérin (BCG)-vectored vaccines.…”

Section: Sa Contributions To the Search For A Preventive Hiv-1 Vaccinementioning

confidence: 99%

HIV research in South Africa: Advancing life

Gray¹,

Doherty²,

Mohapi³

et al. 2019

S Afr Med J

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This open-access article is distributed under Creative Commons licence CC-BY-NC 4.0. South African (SA) researchers have made both national and global contributions to HIV prevention and treatment. Research conducted in SA has contributed markedly to improved survival in HIV-infected infants, children and adults. The translation of clinical research into practice has enabled the curtailment of paediatric HIV in SA. Along with international collaborators, SA has made pivotal contributions to biomedical prevention modalities including medical male circumcision and oral and topical microbicides, and is undertaking pivotal HIV vaccine research. Research into the structural and psychosocial drivers of HIV infection will be critical for sustaining biomedical interventions, and necessary to end AIDS.

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Section: Sa Contributions To the Search For A Preventive Hiv-1 Vaccinementioning

confidence: 99%

HIV research in South Africa: Advancing life

Gray¹,

Doherty²,

Mohapi³

et al. 2019

S Afr Med J

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“…It relies on the human cytomegalovirus immediate/early promoter/enhancer element (CMV I/E) constituting the promoter Pcmv [7], one of the strongest known promoters in mammalian expression systems, driving in vivo antigen expression with the help of the CMV intron A and the bovine growth hormone polyadenylation signal. It has been used to vector the synthetic HIV-1 subtype C vaccine antigen GrttnC, a polyprotein incorporating Gag, reverse transcriptase (RT), Tat and Nef sequences, in studies in mice, guinea pigs, monkeys and humans [8][9][10][11][12].…”

Section: A Novel Enhancer Sequence For Dna Vaccine Antigen Expressionmentioning

confidence: 99%

“…In 2000, a UCT-based consortium headed by Prof Anna-Lise Williamson was awarded funds by the South African AIDS Vaccine Initiative (SAAVI) for the development of HIV-1C vaccines for South Africa. Two vaccines -designated SAAVI DNA-C2 and SAAVI MVA-C -were deemed suitable for human clinical trials [9,10]. The vaccines expressed a HIV-1 subtype C truncated envelope protein Du151 (gp150) and the polyprotein designated Grttn described above, consisting of translational fusions of HIV-1 subtype C Gag Du422, and modified reverse transcriptase (RT), Tat and Nefencoding ORFs.…”

Section: Comparison Of Dna Vaccines Between Two Initiatives In South mentioning

confidence: 99%

Use of a Novel Enhanced DNA Vaccine Vector for Preclinical Virus Vaccine Investigation

Chapman

Rybicki

2019

Preprint

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DNA vaccines are stable, safe, cost effective to produce and relatively quick and easy to manufacture. However, to date DNA vaccines have shown relatively poor immunogenicity in humans despite promising preclinical results. Consequently, a number of different approaches have been investigated to improve the immunogenicity of DNA vaccines. These include the use of improved delivery methods, adjuvants, stronger promoters and enhancer elements to increase antigen expression, and codon optimization of the gene of interest. This review describes the creation and use of a DNA vaccine vector containing a porcine circovirus (PCV-1) enhancer element that significantly increases recombinant antigen expression and immunogenicity and allows for dose sparing. A 172bp region containing the PCV-1 capsid protein promoter (Pcap) and a smaller element (PC; 70 bp) within this were found to be equally effective. DNA vaccines containing the Pcap region expressing various HIV-1 antigens were found to be highly immunogenic in mice, rabbits and macaques, at 4 to 10-fold lower doses than normally used and to be highly effective in heterologous prime-boost regimens. By lowering the amount of DNA used for immunization, safety concerns over injecting large amounts of DNA into humans can be overcome.

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“…HVTN 073 was the first trial to assess the safety and immunogenicity of this DNA/MVA prime-boost regimen. This regimen induced a high frequency of T-cell immune responses but low levels of binding responses to HIV antigens and no neutralizing responses (15). This DNA/MVA regimen, when boosted with a gp140 protein (also tested in HVTN 086), induced binding and tier 1A virus-neutralizing responses but no broadly neutralizing antibody activity (14).…”

mentioning

confidence: 99%

“…In South Africa, the country with the highest HIV infection burden, researchers have been pursuing vaccines against the dominant subtype in the region: HIV-1 subtype C. HVTN 073/SAAVI 102 and HVTN 086/SAAVI 103 were early-phase trials of immunogens, based on the subtype C TV1.21 strain, developed in South Africa (14,15). HVTN 073 was the first trial to assess the safety and immunogenicity of this DNA/MVA prime-boost regimen.…”

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confidence: 99%

Effect of HIV Envelope Vaccination on the Subsequent Antibody Response to HIV Infection

Ditse

Mkhize

Yin

et al. 2020

mSphere

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Analysis of breakthrough HIV-1 infections could elucidate whether prior vaccination primes relevant immune responses. Here, we measured HIV-specific antibody responses in 14 South African volunteers who acquired HIV infection after participating in phase 1/2 trials of envelope-containing immunogens. Serum samples were collected annually following HIV-1 infection from participants in trials HVTN 073 (subtype C, DNA/MVA, phase 1 trial, n = 1), HVTN 086 (subtype C, DNA/MVA/gp140 protein, phase 1 trial, n = 2), and HVTN 204 (multisubtype, DNA/adenovirus serotype 5 [Ad5], phase 2 trial, n = 7) and 4 placebo recipients. Binding and neutralizing antibody responses to Env proteins and peptides were determined pre- and post-HIV infection using an enzyme-linked immunosorbent assay and the TZM-bl cell neutralization assay, respectively. HIV-infected South African individuals served as unvaccinated controls. Binding antibodies to gp41, V3, V2, the membrane-proximal external region (MPER), and the CD4 binding site were detected from the first year of HIV-1 subtype C infection, and the levels were similar in vaccinated and placebo recipients. Neutralizing antibody responses against tier 1A viruses were detected in all participants, with the highest titers being to a subtype C virus, MW965.26. No responses were observed just prior to infection, indicating that vaccine-primed HIV-specific antibodies had waned. Sporadic neutralization activity against tier 2 isolates was observed after 2 to 3 years of HIV infection, but these responses were similar in the vaccinated and placebo groups as well as the unvaccinated controls. Our data suggest that prior vaccination with these immunogens did not alter the antibody responses to HIV-1 infection, nor did it accelerate the development of HIV neutralization breadth. IMPORTANCE There is a wealth of information on HIV-specific vaccine-induced immune responses among HIV-uninfected participants; however, data on immune responses among participants who acquire HIV after vaccination are limited. Here we show that HIV-specific binding antibody responses in individuals with breakthrough HIV infections were not affected by prior vaccination with HIV envelope-containing immunogens. We also found that these vectored vaccines did not prime tier 2 virus-neutralizing antibody responses, which are thought to be required for prevention against HIV acquisition, or accelerate the development of neutralization breadth. Although this study is limited, such studies can provide insights into whether vaccine-elicited antibody responses are boosted by HIV infection to acquire broader neutralizing activity, which may help to identify antigens relevant to the design of more effective vaccines.

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Subtype C gp140 Vaccine Boosts Immune Responses Primed by the South African AIDS Vaccine Initiative DNA-C2 and MVA-C HIV Vaccines after More than a 2-Year Gap

Cited by 26 publications

References 25 publications

HIV research in South Africa: Advancing life

HIV research in South Africa: Advancing life

Use of a Novel Enhanced DNA Vaccine Vector for Preclinical Virus Vaccine Investigation

Effect of HIV Envelope Vaccination on the Subsequent Antibody Response to HIV Infection

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