Breadth Of Cellular Immune Responses Research Articles

Ad26/MVA therapeutic vaccination with TLR7 stimulation in SIV-infected rhesus monkeys.

The development of immunologic interventions that can target the viral reservoir in HIV-1-infected individuals is a major goal of the HIV-1 cure field1,2. However, little evidence exists that the viral reservoir can be sufficiently targeted to improve virologic control following discontinuation of antiretroviral therapy (ART). Here we show that Ad26/MVA3,4 therapeutic vaccination with toll-like receptor 7 (TLR7) stimulation improves virologic control and delays viral rebound following ART discontinuation in SIV-infected rhesus monkeys that initiated ART during acute infection. Ad26/MVA therapeutic vaccination resulted in a dramatic increase in the magnitude and breadth of SIV-specific cellular immune responses in virologically suppressed, SIV-infected monkeys. TLR7 agonist administration led to innate immune stimulation and cellular immune activation. The combination of Ad26/MVA vaccination and TLR7 stimulation resulted in decreased levels of viral DNA in lymph nodes and peripheral blood, as well as improved virologic control and delayed viral rebound following ART discontinuation. Cellular immune breadth correlated inversely with setpoint viral loads and correlated directly with time to viral rebound. These data demonstrate the potential of therapeutic vaccination with innate immune stimulation as a strategy aimed at an HIV-1 functional cure.

Full-Length HIV-1 Immunogens Induce Greater Magnitude and Comparable Breadth of T Lymphocyte Responses to Conserved HIV-1 Regions Compared with Conserved-Region-Only HIV-1 Immunogens in Rhesus Monkeys

A global HIV-1 vaccine will likely need to induce immune responses against conserved HIV-1 regions to contend with the profound genetic diversity of HIV-1. Here we evaluated the capacity of immunogens consisting of only highly conserved HIV-1 sequences that are aimed at focusing cellular immune responses on these potentially critical regions. We assessed in rhesus monkeys the breadth and magnitude of T lymphocyte responses elicited by adenovirus vectors expressing either full-length HIV-1 Gag/Pol/Env immunogens or concatenated immunogens consisting of only highly conserved HIV-1 sequences. Surprisingly, we found that the full-length immunogens induced comparable breadth (P = 1.0) and greater magnitude (P = 0.01) of CD8(+) T lymphocyte responses against conserved HIV-1 regions compared with the conserved-region-only immunogens. Moreover, the full-length immunogens induced a 5-fold increased total breadth of HIV-1-specific T lymphocyte responses compared with the conserved-region-only immunogens (P = 0.007). These results suggest that full-length HIV-1 immunogens elicit a substantially increased magnitude and breadth of cellular immune responses compared with conserved-region-only HIV-1 immunogens, including greater magnitude and comparable breadth of responses against conserved sequences.

Focus and breadth of cellular immune responses elicited by a heterologous insert prime-boost vaccine regimen in rhesus monkeys

The global sequence diversity of HIV-1 presents a daunting challenge for vaccine development. We investigated whether a heterologous insert prime-boost regimen could expand global coverage by selectively boosting cellular immune responses to conserved epitopes. Rhesus monkeys were primed and boosted with recombinant adenovirus vectors expressing homologous or heterologous HIV-1 Gag sequences that were optimized to focus responses on highly conserved epitopes. We observed comparable responses directed to specific regions of the Gag protein in all experimental groups without evidence of improved coverage or expanded breadth in the heterologous insert group. These data suggest that antigen-independent factors contribute to the immunodominance patterns of vaccine-elicited cellular immune responses.

Evaluation of cellular immune responses in mice elicited by Chinese AIDS candidate vaccines

Objective To compare cellular immune responses in mice elicited by Chinese different AIDS candidate vaccines.Methods According to their different immunization procedures,BALB/c mice were immunized with 6 AIDS candidate vaccines,separately.Spleen cells were isolated for the detection of cellular immune response to HIV-specific peptides using enzyme-linked immunosorbent spot(ELISPOT)assay and intracellular cytokine staining(ICS)method.Results AIDS vaccines were evaluated by using potential T-cell epitopes(PTE)Gag,Env and Pol peptides pool and ELISPOT.The positive conversion rates for cellular immune response of 1#-6# vaccines fluctuated from 70% to 100%.The vaccine-induced cellular immune responses to specific peptides pool are different not only in magnitude but also in breadth.The Th1type cytokines,IFN-γand IL-2,were detected with ELISPOT in 1# and 2# vaccines.The productions of IFN-γand IL-2 induced by both of the two vaccines showed a moderate correlation(r1 =0.62,P1 ＜0.01 ;r2=0.79,P2 ＜ 0.01).The positive conversion rate of IFN-γ secreting cells of 1 # vaccine was 66.7%(10/15)mice detected with both ELISPOT and ICS.And the results tested by ELISPOT and ICS showed moderate correlation(r = 0.55,P ＜ 0.05).Conclusion The magnitude and breadth of cellular immune responses induced by different AIDS candidate vaccines are different.Being induced by different AIDS candidate vaccines,the IFN-γand other Th1 type cytokines detected by ELISPOT or ICS could be used to evaluate the cellular immune responses in mice. Key words: AIDS; Vaccine; Cellular immune responses

Mosaic HIV-1 vaccines expand the breadth and depth of cellular immune responses in rhesus monkeys

The worldwide diversity of HIV-1 presents an unprecedented challenge for vaccine development 1-2. Antigens derived from natural HIV-1 sequences have elicited only limited breadth of cellular immune responses in nonhuman primate studies and clinical trials to date. Polyvalent “mosaic” antigens, in contrast, are designed to optimize cellular immunologic coverage of global HIV-1 sequence diversity 3. Here we show that mosaic HIV-1 Gag, Pol, and Env antigens expressed by recombinant, replication-incompetent adenovirus serotype 26 vectors markedly augmented both the breadth and depth without compromising the magnitude of antigen-specific T lymphocyte responses as compared with consensus or natural sequence HIV-1 antigens in rhesus monkeys. Polyvalent mosaic antigens therefore represent a promising strategy to expand cellular immunologic vaccine coverage for genetically diverse pathogens such as HIV-1.