A phase I double blind, placebo-controlled, randomized study of the safety and immunogenicity of an adjuvanted HIV-1 Gag-Pol-Nef fusion protein and adenovirus 35 Gag-RT-Int-Nef vaccine in healthy HIV-uninfected African adults
Omosa-Manyonyi G.,University of Nairobi |
Mpendo J.,Uganda Virus Research Institute IAVI |
Ruzagira E.,Medical Research Council MRC Uganda Virus Research Institute UVRI |
Ruzagira E.,Research Unit on AIDS |
And 24 more authors.
PLoS ONE | Year: 2015
Background: Sequential prime-boost or co-administration of HIV vaccine candidates based on an adjuvanted clade B p24, RT, Nef, p17 fusion protein (F4/AS01) plus a non-replicating adenovirus 35 expressing clade A Gag, RT, Int and Nef (Ad35-GRIN) may lead to a unique immune profile, inducing both strong T-cell and antibody responses. Methods: In a phase 1, double-blind, placebo-controlled trial, 146 healthy adult volunteers were randomized to one of four regimens: heterologous prime-boost with two doses of F4/AS01E or F4/AS01B followed by Ad35-GRIN; Ad35-GRIN followed by two doses of F4/AS01B; or three co-administrations of Ad35-GRIN and F4/AS01B. T cell and antibody responses were measured. Results: The vaccines were generally well-tolerated, and did not cause serious adverse events. The response rate, by IFN-γ ELISPOT, was greater when Ad35-GRIN was the priming vaccine and in the co-administration groups. F4/AS01 induced CD4+ T-cells expressing primarily CD40L and IL2 +/- TNF-α, while Ad35-GRIN induced predominantly CD8+ T-cells expressing IFN-γ +/- IL2 or TNF-α. Viral inhibition was induced after Ad35-GRIN vaccination, regardless of the regimen. Strong F4-specific antibody responses were induced. Immune responses persisted at least a year after the last vaccination. The complementary response profiles, characteristic of each vaccine, were both expressed after co-administration. Conclusion: Co-administration of an adjuvanted protein and an adenovirus vector showed an acceptable safety and reactogenicity profile and resulted in strong, multifunctional and complementary HIV-specific immune responses. Trial Registration: ClinicalTrials.gov NCT01264445. © 2015 Omosa-Manyonyi et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Amin M.N.,University of Maryland, Baltimore |
Mclellan J.S.,National Institute of Allergy and Infectious Diseases |
Huang W.,University of Maryland, Baltimore |
Orwenyo J.,University of Maryland, Baltimore |
And 5 more authors.
Nature Chemical Biology | Year: 2013
A new class of glycan-reactive HIV-neutralizing antibodies, including PG9 and PG16, has been recently discovered that seem to recognize previously uncharacterized glycopeptide epitopes on HIV-1 gp120. However, further characterization and reconstitution of the precise neutralizing epitopes are complicated by the heterogeneity of glycosylation. We report here the design, synthesis and antigenic evaluation of new cyclic V1V2 glycopeptides carrying defined N-linked glycans at the conserved glycosylation sites (Asn160 and Asn156 or Asn173) derived from gp120 of two HIV-1 isolates. Antibody binding studies confirmed the necessity of a Man 5 GlcNAc 2 glycan at Asn160 for recognition by PG9 and PG16 and further revealed a critical role of a sialylated N-glycan at the secondary site (Asn156 or Asn173) in the context of glycopeptides for antibody binding. In addition to defining the glycan specificities of PG9 and PG16, the identified synthetic glycopeptides provide a valuable template for HIV-1 vaccine design. © 2013 Nature America, Inc. All rights reserved.
Kopycinski J.,Imperial College London |
Hayes P.,Imperial College London |
Ashraf A.,Imperial College London |
Cheeseman H.,Imperial College London |
And 9 more authors.
PLoS ONE | Year: 2014
A correlation between in vivo and in vitro virus control mediated by CD8+ T-cell populations has been demonstrated by CD8 T-cell-mediated inhibition of HIV-1 and SIV replication in vitro in peripheral blood mononuclear cells (PBMCs) from infected humans and non-human primates (NHPs), respectively. Here, the breadth and specificity of T-cell responses induced following vaccination with replication-defective adenovirus serotype 35 (Ad35) vectors containing a fusion protein of Gag, reverse transcriptase (RT), Integrase (Int) and Nef (Ad35-GRIN) and Env (Ad35-ENV), derived from HIV-1 subtype A isolates, was assessed in 25 individuals. The vaccine induced responses to a median of 4 epitopes per vaccinee. We correlated the CD8 responses to conserved vs. variable regions with the ability to inhibit a panel of 7 HIV-1 isolates representing multiple clades in a virus inhibition assay (VIA). The results indicate that targeting immunodominant responses to highly conserved regions of the HIV-1 proteome may result in an increased ability to inhibit multiple clades of HIV-1 in vitro. The data further validate the use of the VIA to screen and select future HIV vaccine candidates. Moreover, our data suggest that future T cellfocused vaccine design should aim to induce immunodominant responses to highly conserved regions of the virus. © 2014 Kopycinski et al.
Scientists at The Scripps Research Institute (TSRI) have new weapons in the fight against HIV. Their new study, published today as the cover article of the November issue of Immunity, describes four prototype antibodies that target a specific weak spot on the virus. Guided by these antibodies, the researchers then mimicked the molecular structure of a protein on HIV when designing their own potential HIV vaccine candidate. “This study is an example of how we can learn from natural infection and translate that information into vaccine development,” said TSRI Research Associate Raiees Andrabi. “This is an important advance in the field of antibody-based HIV vaccine development.” Andrabi served as first author of the study, working in the lab of senior author TSRI Professor Dennis R. Burton, who is also scientific director of the International AIDS Vaccine Initiative (IAVI) Neutralizing Antibody Center and of the National Institutes of Health’s Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery (CHAVI-ID) at TSRI. The findings build on the success of several recent TSRI studies showing that, with prompting, the immune system can develop antibodies to neutralize many strains of HIV. In the new study, the researchers carried out a series of experiments involving virus modifications, protein and antibody engineering. They found that four antibodies targeted a single spot on HIV’s surface called the V2 apex. This was significant because the V2 apex could be recognized by these antibodies on about 90 percent of known HIV strains—and even related strains that infect other species. A vaccine targeting this region could protect against many forms of the virus. “This region helps stabilize the virus, so it’s an important area to target if you want to neutralize HIV,” said Andrabi. Investigating further, the researchers noticed that two of the four antibodies had an unusual feature that could prove important in vaccine design. The immune system usually begins its fight against infection by activating immune B cells that express “germline” forms of antibodies, on their surface, to bind invading pathogens. Germline antibodies rarely bind viruses very effectively themselves; instead, they are precursors for more developed antibodies, which mutate and hone their response to the invader. Yet in the new study, two of the antibodies did not need to mutate to bind with the V2 apex; instead, these antibodies used part of their basic germline structure, encoded by non-mutated genes. This means any patient with HIV should, in theory, have the ability to kick-start the right immune response. Unfortunately, the immune system seems to naturally produce only a small number of these HIV-neutralizing germline antibodies. To generate an immune response that would favor these antibodies, it was critical for the scientists to find the right proteins in HIV that the antibodies could recognize and bind to. In the new study, the researchers succeeded in mimicking a structure on HIV called the native HIV coat protein. This let them design proteins that do indeed bind well to the germline antibodies and hopefully start a useful immune response. The next step will be to test the vaccine candidates in animal models. HAVI-ID; Pascal Poignard of TSRI and IAVI; and Chung-Yi Wu and Chi-Huey Wong of the Genomics Research Center, Academia Sinica and TSRI. This study was supported by the National Institute of Allergy and Infectious Diseases (NIAID), the Bill and Melinda Gates Foundation Collaboration for AIDS Vaccine Discovery (CAVD), the International AIDS Vaccine Initiative (IAVI) and the United States Agency for International Development (USAID).
Kamali A.,Medical Research Council Uganda Virus Research Institute |
Kamali A.,Uganda Virus Research Institute UVRI |
Price M.A.,International AIDS Vaccine Initiative IAVI |
Price M.A.,University of California at San Francisco |
And 46 more authors.
PLoS ONE | Year: 2015
HIV epidemiology informs prevention trial design and program planning. Nine clinical research centers (CRC) in sub-Saharan Africa conducted HIV observational epidemiology studies in populations at risk for HIV infection as part of an HIV prevention and vaccine trial network. Annual HIV incidence ranged from below 2% to above 10% and varied by CRC and risk group, with rates above 5% observed in Zambian men in an HIV-discordant relationship, Ugandan men from Lake Victoria fishing communities, men who have sex with men, and several cohorts of women. HIV incidence tended to fall after the first three months in the study and over calendar time. Among suspected transmission pairs, 28% of HIV infections were not from the reported partner. Volunteers with high incidence were successfully identified and enrolled into large scale cohort studies. Over a quarter of new cases in couples acquired infection from persons other than the suspected transmitting partner. © 2015 Kamali et al.