Designing optimal HIV-vaccine T-cell responses

ABSTRACTIn a follow-up to the modest efficacy observed in the RV144 trial, researchers in the HIV vaccine field seek to substantiate and extend the results by evaluating other poxvirus vectors and combinations with DNA and protein vaccines. Earlier clinical trials (EuroVacc trials 01 to 03) evaluated the immunogenicity of HIV-1 clade C GagPolNef and gp120 antigens delivered via the poxviral vector NYVAC. These showed that a vaccination regimen including DNA-C priming prior to a NYVAC-C boost considerably enhanced vaccine-elicited immune responses compared to those with NYVAC-C alone. Moreover, responses were improved by using three as opposed to two DNA-C primes. In the present study, we assessed in nonhuman primates whether such vaccination regimens can be streamlined further by using fewer and accelerated immunizations and employing a novel generation of improved DNA-C and NYVAC-C vaccine candidates designed for higher expression levels and more balanced immune responses. Three different DNA-C prime/NYVAC-C+ protein boost vaccination regimens were tested in rhesus macaques. All regimens elicited vigorous and well-balanced CD8+and CD4+T cell responses that were broad and polyfunctional. Very high IgG binding titers, substantial antibody-dependent cellular cytotoxicity (ADCC), and modest antibody-dependent cell-mediated virus inhibition (ADCVI), but very low neutralization activity, were measured after the final immunizations. Overall, immune responses elicited in all three groups were very similar and of greater magnitude, breadth, and quality than those of earlier EuroVacc vaccines. In conclusion, these findings indicate that vaccination schemes can be simplified by using improved antigens and regimens. This may offer a more practical and affordable means to elicit potentially protective immune responses upon vaccination, especially in resource-constrained settings.IMPORTANCEWithin the EuroVacc clinical trials, we previously assessed the immunogenicity of HIV clade C antigens delivered in a DNA prime/NYVAC boost regimen. The trials showed that the DNA prime crucially improved the responses, and three DNA primes with a NYVAC boost appeared to be optimal. Nevertheless, T cell responses were primarily directed toward Env, and humoral responses were modest. The aim of this study was to assess improved antigens for the capacity to elicit more potent and balanced responses in rhesus macaques, even with various simpler immunization regimens. Our results showed that the novel antigens in fact elicited larger numbers of T cells with a polyfunctional profile and a good Env-GagPolNef balance, as well as high-titer and Fc-functional antibody responses. Finally, comparison of the different schedules indicates that a simpler regimen of only two DNA primes and one NYVAC boost in combination with protein may be very efficient, thus showing that the novel antigens allow for easier immunization protocols.

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MTBVAC-Based TB-HIV Vaccine Is Safe, Elicits HIV-T Cell Responses, and Protects against Mycobacterium tuberculosis in Mice

Molecular Therapy — Methods & Clinical Development ◽

10.1016/j.omtm.2019.01.014 ◽

2019 ◽

Vol 13 ◽

pp. 253-264 ◽

Cited By ~ 5

Author(s):

Esther Broset ◽

Narcís Saubi ◽

Núria Guitart ◽

Nacho Aguilo ◽

Santiago Uranga ◽

...

Keyword(s):

Mycobacterium Tuberculosis ◽

T Cell ◽

T Cell Responses ◽

Hiv Vaccine ◽

Cell Responses

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A novel vaccine targeting the viral protease cleavage sites protects Mauritian cynomolgus macaques against vaginal SIVmac251 infection

10.1101/842955 ◽

2019 ◽

Author(s):

Hongzhao Li ◽

Robert W. Omange ◽

Binhua Liang ◽

Nikki Toledo ◽

Yan Hai ◽

...

Keyword(s):

T Cell ◽

Vaccine Efficacy ◽

T Cell Responses ◽

Hiv Vaccine ◽

Cleavage Sites ◽

Viral Protease ◽

Cell Responses ◽

Protease Cleavage ◽

Cynomolgus Macaques ◽

Protease Cleavage Sites

AbstractAfter over three decades of research, an effective anti-HIV vaccine remains elusive. Unconventional and novel vaccine strategies are needed. Here, we report that a vaccine focusing the immune response on the sequences surrounding the 12 viral protease cleavage sites (PCSs) provides greater than 80% protection of Mauritian cynomolgus macaques (MCMs) against repeated intravaginal SIVmac251 challenges. The PCS-specific T cell responses are correlated with vaccine efficacy. The PCS vaccine does not induce immune activation and inflammation known to be associated with increased susceptibility to HIV infection. Machine learning analyses revealed that the immune environment generated by the PCS vaccine predicts vaccine efficacy. Our study demonstrates for the first time that a novel vaccine which targets viral maturation, but lacks full Env and Gag proteins as immunogens, can prevent intravaginal infection in a highly stringent NHP/SIV challenge model. Targeting HIV maturation thus offers a novel approach to developing an effective HIV vaccine.One Sentence SummaryThe anti-PCS T cell responses and the immune environment induced by the novel PCS vaccine are key correlates of vaccine efficacy

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Balance of cellular and humoral immunity determines the level of protection by HIV vaccines in rhesus macaque models of HIV infection

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1423669112 ◽

2015 ◽

Vol 112 (9) ◽

pp. E992-E999 ◽

Cited By ~ 86

Author(s):

Timothy R. Fouts ◽

Kenneth Bagley ◽

Ilia J. Prado ◽

Kathryn L. Bobb ◽

Jennifer A. Schwartz ◽

...

Keyword(s):

T Cell ◽

Rhesus Macaque ◽

Humoral Immunity ◽

T Cell Responses ◽

Hiv Vaccine ◽

Single Chain ◽

Hiv Vaccines ◽

Cell Responses ◽

Immunodeficiency Virus ◽

Cellular And Humoral Immunity

A guiding principle for HIV vaccine design has been that cellular and humoral immunity work together to provide the strongest degree of efficacy. However, three efficacy trials of Ad5-vectored HIV vaccines showed no protection. Transmission was increased in two of the trials, suggesting that this vaccine strategy elicited CD4+ T-cell responses that provide more targets for infection, attenuating protection or increasing transmission. The degree to which this problem extends to other HIV vaccine candidates is not known. Here, we show that a gp120-CD4 chimeric subunit protein vaccine (full-length single chain) elicits heterologous protection against simian-human immunodeficiency virus (SHIV) or simian immunodeficiency virus (SIV) acquisition in three independent rhesus macaque repeated low-dose rectal challenge studies with SHIV162P3 or SIVmac251. Protection against acquisition was observed with multiple formulations and challenges. In each study, protection correlated with antibody-dependent cellular cytotoxicity specific for CD4-induced epitopes, provided that the concurrent antivaccine T-cell responses were minimal. Protection was lost in instances when T-cell responses were high or when the requisite antibody titers had declined. Our studies suggest that balance between a protective antibody response and antigen-specific T-cell activation is the critical element to vaccine-mediated protection against HIV. Achieving and sustaining such a balance, while enhancing antibody durability, is the major challenge for HIV vaccine development, regardless of the immunogen or vaccine formulation.

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HIV-1 gp120 and Modified Vaccinia Virus Ankara (MVA) gp140 Boost Immunogens Increase Immunogenicity of a DNA/MVA HIV-1 Vaccine

Journal of Virology ◽

10.1128/jvi.01077-17 ◽

2017 ◽

Vol 91 (24) ◽

Cited By ~ 14

Author(s):

Xiaoying Shen ◽

Rahul Basu ◽

Sheetal Sawant ◽

David Beaumont ◽

Sue Fen Kwa ◽

...

Keyword(s):

T Cell ◽

Vaccinia Virus ◽

T Cell Responses ◽

Hiv Vaccine ◽

Antibody Responses ◽

Cell Responses ◽

Modified Vaccinia Virus Ankara ◽

Gp120 Protein ◽

Boost Vaccine ◽

Hiv 1

ABSTRACT An important goal of human immunodeficiency virus (HIV) vaccine design is identification of strategies that elicit effective antiviral humoral immunity. One novel approach comprises priming with DNA and boosting with modified vaccinia virus Ankara (MVA) expressing HIV-1 Env on virus-like particles. In this study, we evaluated whether the addition of a gp120 protein in alum or MVA-expressed secreted gp140 (MVAgp140) could improve immunogenicity of a DNA prime-MVA boost vaccine. Five rhesus macaques per group received two DNA primes at weeks 0 and 8 followed by three MVA boosts (with or without additional protein or MVAgp140) at weeks 18, 26, and 40. Both boost immunogens enhanced the breadth of HIV-1 gp120 and V1V2 responses, antibody-dependent cellular cytotoxicity (ADCC), and low-titer tier 1B and tier 2 neutralizing antibody responses. However, there were differences in antibody kinetics, linear epitope specificity, and CD4 T cell responses between the groups. The gp120 protein boost elicited earlier and higher peak responses, whereas the MVAgp140 boost resulted in improved antibody durability and comparable peak responses after the final immunization. Linear V3 specific IgG responses were particularly enhanced by the gp120 boost, whereas the MVAgp140 boost also enhanced responses to linear C5 and C2.2 epitopes. Interestingly, gp120, but not the MVAgp140 boost, increased peak CD4+ T cell responses. Thus, both gp120 and MVAgp140 can augment potential protection of a DNA/MVA vaccine by enhancing gp120 and V1/V2 antibody responses, whereas potential protection by gp120, but not MVAgp140 boosts, may be further impacted by increased CD4+ T cell responses. IMPORTANCE Prior immune correlate analyses with humans and nonhuman primates revealed the importance of antibody responses in preventing HIV-1 infection. A DNA prime-modified vaccinia virus Ankara (MVA) boost vaccine has proven to be potent in eliciting antibody responses. Here we explore the ability of boosts with recombinant gp120 protein or MVA-expressed gp140 to enhance antibody responses elicited by the GOVX-B11 DNA prime-MVA boost vaccine. We found that both types of immunogen boosts enhanced potentially protective antibody responses, whereas the gp120 protein boosts also increased CD4+ T cell responses. Our data provide important information for HIV vaccine designs that aim for effective and balanced humoral and T cell responses.

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HLA-I Associated Adaptation Dampens CD8 T-Cell Responses in HIV Ad5-Vectored Vaccine Recipients

The Journal of Infectious Diseases ◽

10.1093/infdis/jiz368 ◽

2019 ◽

Vol 220 (10) ◽

pp. 1620-1628 ◽

Cited By ~ 1

Author(s):

Sushma Boppana ◽

Sarah Sterrett ◽

Jacob Files ◽

Kai Qin ◽

Andrew Fiore-Gartland ◽

...

Keyword(s):

Human Immunodeficiency Virus ◽

T Cell ◽

T Cell Responses ◽

Cd8 T Cell ◽

Hiv Vaccine ◽

Viral Control ◽

Cell Responses ◽

Efficacy Trials ◽

Immunodeficiency Virus ◽

Vectored Vaccine

Abstract HLA-I–associated human immunodeficiency virus (HIV) adaptation is known to negatively affect disease progression and CD8 T-cell responses. We aimed to assess how HLA-I–associated adaptation affects HIV vaccine–induced CD8 T-cell responses in 2 past vaccine efficacy trials. We found that vaccine-encoded adapted epitopes were less immunogenic than vaccine-encoded nonadapted epitopes, and adapted epitope-specific responses were less polyfunctional than nonadapted epitope-specific responses. Along those lines, vaccine recipients with higher HLA-I adaptation to the Gag vaccine insert mounted less polyfunctional CD8 T-cell responses at the protein level. Breadth of response, which correlated with viral control in recipients who became infected, is also dampened by HLA-I adaptation. These findings suggest that HLA-I–associated adaptation is an important consideration for strategies aiming to induce robust CD8 T-cell responses.

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