scholarly journals An Enhanced Synthetic Multiclade DNA Prime Induces Improved Cross-Clade-Reactive Functional Antibodies when Combined with an Adjuvanted Protein Boost in Nonhuman Primates

2015 ◽  
Vol 89 (18) ◽  
pp. 9154-9166 ◽  
Author(s):  
Megan C. Wise ◽  
Natalie A. Hutnick ◽  
Justin Pollara ◽  
Devin J. F. Myles ◽  
Constance Williams ◽  
...  
Keyword(s):  
T Cell ◽  
Neutralizing Antibodies ◽  
Vaccine Development ◽  
Consensus Sequence ◽  
Vaccine Trial ◽  
T Cell Responses ◽  
Antiretroviral Drugs ◽  
Cell Responses ◽  
Protein Boost ◽  
Hiv 1

ABSTRACTThe search for an efficacious human immunodeficiency virus type 1 (HIV-1) vaccine remains a pressing need. The moderate success of the RV144 Thai clinical vaccine trial suggested that vaccine-induced HIV-1-specific antibodies can reduce the risk of HIV-1 infection. We have made several improvements to the DNA platform and have previously shown that improved DNA vaccines alone are capable of inducing both binding and neutralizing antibodies in small-animal models. In this study, we explored how an improved DNA prime and recombinant protein boost would impact HIV-specific vaccine immunogenicity in rhesus macaques (RhM). After DNA immunization with either a single HIV Env consensus sequence or multiple constructs expressing HIV subtype-specific Env consensus sequences, we detected both CD4+and CD8+T-cell responses to all vaccine immunogens. These T-cell responses were further increased after protein boosting to levels exceeding those of DNA-only or protein-only immunization. In addition, we observed antibodies that exhibited robust cross-clade binding and neutralizing and antibody-dependent cellular cytotoxicity (ADCC) activity after immunization with the DNA prime-protein boost regimen, with the multiple-Env formulation inducing a more robust and broader response than the single-Env formulation. The magnitude and functionality of these responses emphasize the strong priming effect improved DNA immunogens can induce, which are further expanded upon protein boost. These results support further study of an improved synthetic DNA prime together with a protein boost for enhancing anti-HIV immune responses.IMPORTANCEEven with effective antiretroviral drugs, HIV remains an enormous global health burden. Vaccine development has been problematic in part due to the high degree of diversity and poor immunogenicity of the HIV Env protein. Studies suggest that a relevant HIV vaccine will likely need to induce broad cellular and humoral responses from a simple vaccine regimen due to the resource-limited setting in which the HIV pandemic is most rampant. DNA vaccination lends itself well to increasing the amount of diversity included in a vaccine due to the ease of manufacturing multiple plasmids and formulating them as a single immunization. By increasing the number of Envs within a formulation, we were able to show an increased breadth of responses as well as improved functionality induced in a nonhuman primate model. This increased breadth could be built upon, leading to better coverage against circulating strains with broader vaccine-induced protection.

scholarly journals Evaluation of antiviral T cell responses and TSCM cells in volunteers enrolled in a phase I HIV-1 subtype C prophylactic vaccine trial in India

PLoS ONE ◽  
2020 ◽  
Vol 15 (2) ◽  
pp. e0229461
Author(s):  
Sivasankaran Munusamy Ponnan ◽  
Peter Hayes ◽  
Natalia Fernandez ◽  
Kannan Thiruvengadam ◽  
Sathyamurthi Pattabiram ◽  
...  
Keyword(s):  
T Cell ◽  
Phase I ◽  
Vaccine Trial ◽  
T Cell Responses ◽  
Prophylactic Vaccine ◽  
Subtype C ◽  
Cell Responses ◽  
Hiv 1

scholarly journals Immunogenicity and Cross-Reactivity of Rhesus Adenoviral Vectors

2018 ◽  
Vol 92 (11) ◽  
Author(s):  
M. Justin Iampietro ◽  
Rafael A. Larocca ◽  
Nicholas M. Provine ◽  
Peter Abbink ◽  
Zi Han Kang ◽  
...  
Keyword(s):  
T Cell ◽  
Neutralizing Antibodies ◽  
Vaccine Development ◽  
T Cell Responses ◽  
Adenoviral Vectors ◽  
Cross Reactivity ◽  
Human Populations ◽  
Humoral Immune ◽  
Cell Responses ◽  
The Impact

ABSTRACT Adenovirus (Ad) vectors are being investigated as vaccine candidates, but baseline antivector immunity exists in human populations to both human Ad (HuAd) and chimpanzee Ad (ChAd) vectors. In this study, we investigated the immunogenicity and cross-reactivity of a panel of recently described rhesus adenoviral (RhAd) vectors. RhAd vectors elicited T cells with low exhaustion markers and robust anamnestic potential. Moreover, RhAd vector immunogenicity was unaffected by high levels of preexisting anti-HuAd immunity. Both HuAd/RhAd and RhAd/RhAd prime-boost vaccine regimens were highly immunogenic, despite a degree of cross-reactive neutralizing antibodies (NAbs) between phylogenetically related RhAd vectors. We observed extensive vector-specific cross-reactive CD4 T cell responses and more limited CD8 T cell responses between RhAd and HuAd vectors, but the impact of vector-specific cellular responses was far less than that of vector-specific NAbs. These data suggest the potential utility of RhAd vectors and define novel heterologous prime-boost strategies for vaccine development. IMPORTANCE To date, most adenoviral vectors developed for vaccination have been HuAds from species B, C, D, and E, and human populations display moderate to high levels of preexisting immunity. There is a clinical need for new adenoviral vectors that are not hindered by preexisting immunity. Moreover, the development of RhAd vector vaccines expands our ability to vaccinate against multiple pathogens in a population that may have received other HuAd or ChAd vectors. We evaluated the immunogenicity and cross-reactivity of RhAd vectors, which belong to the poorly described adenovirus species G. These vectors induced robust cellular and humoral immune responses and were not hampered by preexisting anti-HuAd vector immunity. Such properties make RhAd vectors attractive as potential vaccine vectors.

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

2015 ◽  
Vol 370 (1675) ◽  
pp. 20140290 ◽  
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.

scholarly journals A strongly selected mutation in the HIV-1 genome is independent of T cell responses and neutralizing antibodies

Retrovirology ◽  
2017 ◽  
Vol 14 (1) ◽  
Author(s):  
Donglai Liu ◽  
Chu Wang ◽  
Bhavna Hora ◽  
Tao Zuo ◽  
Nilu Goonetilleke ◽  
...  
Keyword(s):  
T Cell ◽  
Neutralizing Antibodies ◽  
T Cell Responses ◽  
Cell Responses ◽  
Hiv 1

scholarly journals Immunization of BLT Humanized Mice Redirects T Cell Responses to Gag and Reduces Acute HIV-1 Viremia

2019 ◽  
Vol 93 (20) ◽  
Author(s):  
Daniel T. Claiborne ◽  
Timothy E. Dudek ◽  
Colby R. Maldini ◽  
Karen A. Power ◽  
Musie Ghebremichael ◽  
...  
Keyword(s):  
T Cell ◽  
Vaccine Development ◽  
Plasma Concentrations ◽  
T Cell Responses ◽  
Humanized Mice ◽  
Gag Protein ◽  
Cell Responses ◽  
Acute Hiv ◽  
Blt Mice ◽  
Hiv 1

ABSTRACT BLT (bone marrow-liver-thymus) humanized mice, which reconstitute a functional human immune system, develop prototypic human virus-specific CD8+ T cell responses following infection with human immunodeficiency virus type 1 (HIV-1). We explored the utility of the BLT model for HIV-1 vaccine development by immunizing BLT mice against the conserved viral Gag protein, utilizing a rapid prime-boost protocol of poly(lactic-co-glycolic) acid microparticles and a replication-defective herpes simplex virus (HSV) recombinant vector. After HIV-1 challenge, the mice developed broad, proteome-wide gamma interferon-positive (IFN-γ+) T cell responses against HIV-1 that reached magnitudes equivalent to what is observed in HIV-1-infected individuals. The functionality of these responses was underscored by the consistent emergence of escape mutations in multiple CD8+ T cell epitopes during the course of infection. Although prechallenge vaccine-induced responses were largely undetectable, the Gag immunization increased both the magnitude and the kinetics of anamnestic Gag-specific T cell responses following HIV-1 infection, and the magnitude of these postchallenge Gag-specific responses was inversely correlated with acute HIV-1 viremia. Indeed, Gag immunization was associated with a modest but significant 0.5-log reduction in HIV-1 viral load when analyzed across four experimental groups of BLT mice. Notably, the HSV vector induced elevated plasma concentrations of polarizing cytokines and chemotactic factors, including interleukin-12p70 (IL-12p70) and MIP-1α, which were positively correlated with the magnitude of Gag-specific responses. Overall, these results support the ability of BLT mice to recapitulate human pathogen-specific T cell responses and to respond to immunization; however, additional improvements to the model are required to develop a robust system for testing HIV-1 vaccine efficacy. IMPORTANCE Advances in the development of humanized mice have raised the possibility of a small-animal model for preclinical testing of an HIV-1 vaccine. Here, we describe the capacity of BLT humanized mice to mount broadly directed HIV-1-specific human T cell responses that are functionally active, as indicated by the rapid emergence of viral escape mutations. Although immunization of BLT mice with the conserved viral Gag protein did not result in detectable prechallenge responses, it did increase the magnitude and kinetics of postchallenge Gag-specific T cell responses, which was associated with a modest but significant reduction in acute HIV-1 viremia. Additionally, the BLT model revealed immunization-associated increases in the plasma concentrations of immunomodulatory cytokines and chemokines that correlated with more robust T cell responses. These data support the potential utility of the BLT humanized mouse for HIV-1 vaccine development but suggest that additional improvements to the model are warranted.

scholarly journals The Case for S2: The Potential Benefits of the S2 Subunit of the SARS-CoV-2 Spike Protein as an Immunogen in Fighting the COVID-19 Pandemic

2021 ◽  
Vol 12 ◽  
Author(s):  
Priyanka Shah ◽  
Gabriela A. Canziani ◽  
Erik P. Carter ◽  
Irwin Chaiken
Keyword(s):  
T Cell ◽  
Neutralizing Antibodies ◽  
Rapid Development ◽  
T Cell Responses ◽  
Receptor Binding Domain ◽  
Vaccine Research ◽  
Neutralization Potential ◽  
Cell Responses ◽  
Potential Benefits ◽  
Hiv 1

As COVID-19 cases continue to rise, it is imperative to learn more about antibodies and T-cells produced against the causative virus, SARS-CoV-2, in order to guide the rapid development of therapies and vaccines. While much of the current antibody and vaccine research focuses on the receptor-binding domain of S1, a less-recognized opportunity is to harness the potential benefits of the more conserved S2 subunit. Similarities between the spike proteins of both SARS-CoV-2 and HIV-1 warrant exploring S2. Possible benefits of employing S2 in therapies and vaccines include the structural conservation of S2, extant cross-reactive neutralizing antibodies in populations (due to prior exposure to common cold coronaviruses), the steric neutralization potential of antibodies against S2, and the stronger memory B-cell and T-cell responses. More research is necessary on the effect of glycans on the accessibility and stability of S2, SARS-CoV-2 mutants that may affect infectivity, the neutralization potential of antibodies produced by memory B-cells, cross-reactive T-cell responses, antibody-dependent enhancement, and antigen competition. This perspective aims to highlight the evidence for the potential advantages of using S2 as a target of therapy or vaccine design.

scholarly journals HIV-1 Env DNA Vaccine plus Protein Boost Delivered by EP Expands B- and T-Cell Responses and Neutralizing Phenotype In Vivo

PLoS ONE ◽  
2013 ◽  
Vol 8 (12) ◽  
pp. e84234 ◽  
Author(s):  
Kar Muthumani ◽  
Megan C. Wise ◽  
Kate E. Broderick ◽  
Natalie Hutnick ◽  
Jonathan Goodman ◽  
...  
Keyword(s):  
T Cell ◽  
Dna Vaccine ◽  
T Cell Responses ◽  
Cell Responses ◽  
Protein Boost ◽  
Hiv 1

scholarly journals HIV-1-Based Virus-like Particles that Morphologically Resemble Mature, Infectious HIV-1 Virions

Viruses ◽  
2019 ◽  
Vol 11 (6) ◽  
pp. 507 ◽  
Author(s):  
Christopher A. Gonelli ◽  
Georges Khoury ◽  
Rob J. Center ◽  
Damian F.J. Purcell
Keyword(s):  
T Cell ◽  
Dna Vaccine ◽  
Neutralizing Antibodies ◽  
T Cell Responses ◽  
Expression Vectors ◽  
Virus Like Particles ◽  
Cell Responses ◽  
Hiv 1

A prophylactic vaccine eliciting both broad neutralizing antibodies (bNAbs) to the HIV-1 envelope glycoprotein (Env) and strong T cell responses would be optimal for preventing HIV-1 transmissions. Replication incompetent HIV-1 virus-like particles (VLPs) offer the opportunity to present authentic-structured, virion-associated Env to elicit bNAbs, and also stimulate T cell responses. Here, we optimize our DNA vaccine plasmids as VLP expression vectors for efficient Env incorporation and budding. The original vector that was used in human trials inefficiently produced VLPs, but maximized safety by inactivating RNA genome packaging, enzyme functions that are required for integration into the host genome, and deleting accessory proteins Vif, Vpr, and Nef. These original DNA vaccine vectors generated VLPs with incomplete protease-mediated cleavage of Gag and were irregularly sized. Mutations to restore function within the defective genes revealed that several of the reverse transcriptase (RT) deletions mediated this immature phenotype. Here, we made efficient budding, protease-processed, and mature-form VLPs that resembled infectious virions by introducing alternative mutations that completely removed the RT domain, but preserved most other safety mutations. These VLPs, either expressed from DNA vectors in vivo or purified after expression in vitro, are potentially useful immunogens that can be used to elicit antibody responses that target Env on fully infectious HIV-1 virions.

scholarly journals 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

2016 ◽  
Vol 23 (6) ◽  
pp. 496-506 ◽  
Author(s):  
Glenda E. Gray ◽  
Kenneth H. Mayer ◽  
Marnie L. Elizaga ◽  
Linda-Gail Bekker ◽  
Mary Allen ◽  
...  
Keyword(s):  
T Cell ◽  
South African ◽  
T Cell Responses ◽  
Subtype C ◽  
Vaccine Regimen ◽  
Aids Vaccine ◽  
Cell Responses ◽  
Protein Boost ◽  
To Receive ◽  
Hiv 1

ABSTRACTA phase I safety and immunogenicity study investigated South African AIDS Vaccine Initiative (SAAVI) HIV-1 subtype C (HIV-1C) DNA vaccine encoding Gag-RT-Tat-Nef and gp150, boosted with modified vaccinia Ankara (MVA) expressing matched antigens. Following the finding of partial protective efficacy in the RV144 HIV vaccine efficacy trial, a protein boost with HIV-1 subtype C V2-deleted gp140 with MF59 was added to the regimen. A total of 48 participants (12 U.S. participants and 36 Republic of South Africa [RSA] participants) were randomized to receive 3 intramuscular (i.m.) doses of SAAVI DNA-C2 of 4 mg (months 0, 1, and 2) and 2 i.m. doses of SAAVI MVA-C of 1.45 × 109PFU (months 4 and 5) (n= 40) or of a placebo (n= 8). Approximately 2 years after vaccination, 27 participants were rerandomized to receive gp140/MF59 at 100 μg or placebo, as 2 i.m. injections, 3 months apart. The vaccine regimen was safe and well tolerated. After the DNA-MVA regimen, CD4+T-cell and CD8+T-cell responses occurred in 74% and 32% of the participants, respectively. The protein boost increased CD4+T-cell responses to 87% of the subjects. All participants developed tier 1 HIV-1C neutralizing antibody responses as well as durable Env binding antibodies that recognized linear V3 and C5 peptides. The HIV-1 subtype C DNA-MVA vaccine regimen showed promising cellular immunogenicity. Boosting with gp140/MF59 enhanced levels of binding and neutralizing antibodies as well as CD4+T-cell responses to HIV-1 envelope. (This study has been registered at ClinicalTrials.gov under registration no. NCT00574600 and NCT01423825.)

scholarly journals Antibodies with High Avidity to the gp120 Envelope Protein in Protection from Simian Immunodeficiency Virus SIVmac251Acquisition in an Immunization Regimen That Mimics the RV-144 Thai Trial

2012 ◽  
Vol 87 (3) ◽  
pp. 1708-1719 ◽  
Author(s):  
Poonam Pegu ◽  
Monica Vaccari ◽  
Shari Gordon ◽  
Brandon F. Keele ◽  
Melvin Doster ◽  
...  
Keyword(s):  
T Cell ◽  
Simian Immunodeficiency Virus ◽  
Neutralizing Antibodies ◽  
Hiv Transmission ◽  
Vaccine Trial ◽  
T Cell Responses ◽  
High Avidity ◽  
Cell Responses ◽  
Gp120 Envelope ◽  
Immunodeficiency Virus

ABSTRACTThe recombinant canarypox vector, ALVAC-HIV, together with human immunodeficiency virus (HIV) gp120 envelope glycoprotein, has protected 31.2% of Thai individuals from HIV acquisition in the RV144 HIV vaccine trial. This outcome was unexpected, given the limited ability of the vaccine components to induce CD8+T-cell responses or broadly neutralizing antibodies. We vaccinated macaques with an immunization regimen intended to mimic the RV144 trial and exposed them intrarectally to a dose of the simian immunodeficiency virus SIVmac251that transmits few virus variants, similar to HIV transmission to humans. Vaccination induced anti-envelope antibodies in all vaccinees and CD4+and CD8+T-cell responses. Three of the 11 macaques vaccinated with ALVAC-SIV/gp120 were protected from SIVmac251acquisition, but the result was not significant. The remaining vaccinees were infected and progressed to disease. The magnitudes of vaccine-induced SIVmac251-specific T-cell responses and binding antibodies were not significantly different between protected and infected animals. However, sera from protected animals had higher avidity antibodies to gp120, recognized the variable envelope regions V1/V2, and reduced SIVmac251infectivity in cells that express high levels of α4β7integrins, suggesting a functional role of antibodies to V2. The current results emphasize the utility of determining the titer of repeated mucosal challenge in the preclinical evaluation of HIV vaccines.

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