RESUMO
While antibody titers and neutralization are considered the gold standard for the selection of successful vaccines, these parameters are often inadequate predictors of protective immunity. As antibodies mediate an array of extra-neutralizing Fc functions, when neutralization fails to predict protection, investigating Fc-mediated activity may help identify immunological correlates and mechanism(s) of humoral protection. Here, we used an integrative approach termed Systems Serology to analyze relationships among humoral responses elicited in four HIV vaccine trials. Each vaccine regimen induced a unique humoral "Fc fingerprint." Moreover, analysis of case:control data from the first moderately protective HIV vaccine trial, RV144, pointed to mechanistic insights into immune complex composition that may underlie protective immunity to HIV. Thus, multi-dimensional relational comparisons of vaccine humoral fingerprints offer a unique approach for the evaluation and design of novel vaccines against pathogens for which correlates of protection remain elusive.
Assuntos
Vacinas contra a AIDS/imunologia , Anticorpos Antivirais/imunologia , Imunoglobulina G/imunologia , Animais , Anticorpos Antivirais/sangue , Citotoxicidade Celular Dependente de Anticorpos , Complexo Antígeno-Anticorpo/imunologia , Ensaios Clínicos como Assunto , Desenho de Fármacos , Infecções por HIV/imunologia , Humanos , Imunoglobulina G/sangue , Receptores Fc/imunologiaRESUMO
The global diversity of HIV-1 represents a critical challenge facing HIV-1 vaccine development. HIV-1 mosaic antigens are bioinformatically optimized immunogens designed for improved coverage of HIV-1 diversity. However, the protective efficacy of such global HIV-1 vaccine antigens has not previously been evaluated. Here, we demonstrate the capacity of bivalent HIV-1 mosaic antigens to protect rhesus monkeys against acquisition of infection following heterologous challenges with the difficult-to-neutralize simian-human immunodeficiency virus SHIV-SF162P3. Adenovirus/poxvirus and adenovirus/adenovirus vector-based vaccines expressing HIV-1 mosaic Env, Gag, and Pol afforded a significant reduction in the per-exposure acquisition risk following repetitive, intrarectal SHIV-SF162P3 challenges. Protection against acquisition of infection correlated with vaccine-elicited binding, neutralizing, and functional nonneutralizing antibodies, suggesting that the coordinated activity of multiple antibody functions may contribute to protection against difficult-to-neutralize viruses. These data demonstrate the protective efficacy of HIV-1 mosaic antigens and suggest a potential strategy for the development of a global HIV-1 vaccine. PAPERCLIP:
Assuntos
Vacinas contra a AIDS/imunologia , HIV-1 , Animais , Formação de Anticorpos , Feminino , Antígenos HIV/imunologia , Proteínas do Vírus da Imunodeficiência Humana/imunologia , Imunidade Celular , Macaca mulatta , Masculino , Dados de Sequência Molecular , Organismos Livres de Patógenos EspecíficosRESUMO
HLA class I variation has the strongest effect genome-wide on outcome after HIV infection, and as such, an understanding of the impact of HLA polymorphism on response to HIV vaccination may inform vaccine design. We sought HLA associations with HIV-directed immunogenicity in the phase 1/2a APPROACH vaccine trial, which tested vaccine regimens containing mosaic inserts in Ad26 and MVA vectors, with or without a trimeric gp140 protein. While there were no HLA allelic associations with the overall cellular immune response to the vaccine assessed by ELISpot (Gag, Pol, and Env combined), significant associations with differential response to Gag compared to Env antigens were observed. Notably, HLA class I alleles known to associate with disease susceptibility in HIV natural history cohorts are associated with stronger Env-directed responses, whereas protective alleles are associated with stronger Gag-directed responses. Mean viral loads determined for each HLA allele in untreated individuals correlated negatively with the strength of the Gag response minus the Env response in Black vaccinees based on both ELISpot and CD8+ T cell ICS responses. As the association of T cell responses to conserved Gag epitopes with lower viral load in untreated individuals is well established, our data raise the possibility that the Ad26.Mos.HIV vaccine may induce more effective cellular responses in those with HLA alleles that confer improved virologic control in untreated HIV infection.IMPORTANCENo vaccine tested to date has shown sufficient efficacy against HIV infection. A vaccine that induces robust responses in one individual may fail to do so in another individual due to variation in HLA class I genes, loci central to the immune response. Extensive data have shown the strong effect of HLA variation on outcome after HIV infection, but very little is known about the effect of such variation on HIV vaccine success. Here, we identify a link between the effect of HLA variation on HIV disease outcome and immune responses to an HIV vaccine. HLA variants associated with better HIV control after infection also induce stronger responses against the HIV Gag protein relative to the Env protein after vaccination. Given the virologic control conferred by responses to Gag in natural history of HIV infection, these data suggest that HLA alleles conferring protection after HIV infection may also support a more effective cellular response to HIV vaccination.
Assuntos
Vacinas contra a AIDS , Alelos , Infecções por HIV , HIV-1 , Produtos do Gene env do Vírus da Imunodeficiência Humana , Produtos do Gene gag do Vírus da Imunodeficiência Humana , Humanos , Vacinas contra a AIDS/imunologia , Vacinas contra a AIDS/administração & dosagem , HIV-1/imunologia , HIV-1/genética , Infecções por HIV/imunologia , Infecções por HIV/virologia , Infecções por HIV/genética , Infecções por HIV/prevenção & controle , Produtos do Gene gag do Vírus da Imunodeficiência Humana/imunologia , Produtos do Gene gag do Vírus da Imunodeficiência Humana/genética , Produtos do Gene env do Vírus da Imunodeficiência Humana/imunologia , Produtos do Gene env do Vírus da Imunodeficiência Humana/genética , Antígenos de Histocompatibilidade Classe I/imunologia , Antígenos de Histocompatibilidade Classe I/genética , Masculino , Carga Viral , Adulto , Feminino , Linfócitos T CD8-Positivos/imunologiaRESUMO
IMPORTANCE: The functionality of CD8+ T cells against human immunodeficiency virus-1 (HIV-1) antigens is indicative of HIV-progression in both animal models and people living with HIV. It is, therefore, of interest to assess CD8+ T cell responses in a prophylactic vaccination setting, as this may be an important component of the immune system that inhibits HIV-1 replication. T cell responses induced by the adenovirus serotype 26 (Ad26) mosaic vaccine regimen were assessed previously by IFN-γ ELISpot and flow cytometric assays, yet these assays only measure cytokine production but not the capacity of CD8+ T cells to inhibit replication of HIV-1. In this study, we demonstrate direct anti-viral function of the clinical Ad26 mosaic vaccine regimen through ex vivo inhibition of replication of diverse clades of HIV-1 isolates in the participant's own CD4+ T cells.
Assuntos
Vacinas contra a AIDS , Linfócitos T CD8-Positivos , Infecções por HIV , Humanos , Vacinas contra a AIDS/imunologia , Antígenos Virais , Linfócitos T CD8-Positivos/imunologia , Infecções por HIV/prevenção & controle , HIV-1 , VacinaçãoRESUMO
BACKGROUND: Developing a cross-clade, globally effective HIV vaccine remains crucial for eliminating HIV. METHODS: This placebo-controlled, double-blind, phase 1/2a study enrolled healthy HIV-uninfected adults at low risk for HIV infection. They were randomized (1:4:1) to receive 4 doses of an adenovirus 26-based HIV-1 vaccine encoding 2 mosaic Gag and Pol, and 2 mosaic Env proteins plus adjuvanted clade C gp140 (referred to here as clade C regimen), bivalent protein regimen (clade C regimen plus mosaic gp140), or placebo. Primary end points were safety and antibody responses. RESULTS: In total 152/155 participants (clade C, n = 26; bivalent protein, n = 103; placebo, n = 26) received ≥1 injection. The highest adverse event (AE) severity was grade 3 (local pain/tenderness, 12%, 2%, and 0% of the respective groups; solicited systemic AEs, 19%, 15%, 0%). HIV-1 mosaic gp140-binding antibody titers were 79 595 ELISA units (EU)/mL and 137 520 EU/mL in the clade C and bivalent protein groups (P < .001) after dose 4 and 16 862 EU/mL and 25 162 EU/mL 6 months later. Antibody response breadth against clade C gp140 and clade C/non-clade C gp120 was highest in the bivalent protein group. CONCLUSIONS: Adding mosaic gp140 to the clade C regimen increased and broadened the elicited immune response without compromising safety or clade C responses. Clinical Trials Registration. NCT02935686.
Assuntos
Vacinas contra a AIDS , Infecções por HIV , HIV-1 , Adulto , Humanos , Vetores Genéticos , Anticorpos Anti-HIV , Infecções por HIV/prevenção & controle , Imunogenicidade da VacinaRESUMO
The development of immunologic interventions that can target the viral reservoir in HIV-1-infected individuals is a major goal of HIV-1 research. However, little evidence exists that the viral reservoir can be sufficiently targeted to improve virologic control following discontinuation of antiretroviral therapy. Here we show that therapeutic vaccination with Ad26/MVA (recombinant adenovirus serotype 26 (Ad26) prime, modified vaccinia Ankara (MVA) boost) and stimulation of TLR7 (Toll-like receptor 7) improves virologic control and delays viral rebound following discontinuation of antiretroviral therapy in SIV-infected rhesus monkeys that began antiretroviral therapy during acute infection. Therapeutic vaccination with Ad26/MVA resulted in a marked 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, and improved virologic control and delayed viral rebound following discontinuation of antiretroviral therapy. The breadth of cellular immune responses correlated inversely with set point viral loads and correlated directly with time to viral rebound. These data demonstrate the potential of therapeutic vaccination combined with innate immune stimulation as a strategy aimed at a functional cure for HIV-1 infection.
Assuntos
Adenoviridae/genética , Vacinas contra a SAIDS/imunologia , Síndrome de Imunodeficiência Adquirida dos Símios/imunologia , Síndrome de Imunodeficiência Adquirida dos Símios/terapia , Vírus da Imunodeficiência Símia/imunologia , Receptor 7 Toll-Like/imunologia , Vaccinia virus/genética , Vacinas contra a AIDS/genética , Vacinas contra a AIDS/imunologia , Animais , Antirretrovirais/administração & dosagem , DNA Viral/análise , DNA Viral/sangue , Feminino , Vetores Genéticos/genética , Infecções por HIV/imunologia , Infecções por HIV/terapia , Imunidade Celular , Imunidade Inata , Macaca mulatta , Masculino , RNA Viral/análise , RNA Viral/sangue , Vacinas contra a SAIDS/genética , Síndrome de Imunodeficiência Adquirida dos Símios/virologia , Vírus da Imunodeficiência Símia/genética , Vírus da Imunodeficiência Símia/crescimento & desenvolvimento , Vírus da Imunodeficiência Símia/isolamento & purificação , Fatores de Tempo , Receptor 7 Toll-Like/genética , Carga Viral/imunologiaRESUMO
Background: Mosaic immunogens are bioinformatically engineered human immunodeficiency virus type 1 (HIV-1) sequences designed to elicit clade-independent coverage against globally circulating HIV-1 strains. Methods: This phase 1, double-blinded, randomized, placebo-controlled trial enrolled healthy HIV-uninfected adults who received 2 doses of a modified vaccinia Ankara (MVA)-vectored HIV-1 bivalent mosaic immunogen vaccine or placebo on days 0 and 84. Two groups were enrolled: those who were HIV-1 vaccine naive (n = 15) and those who had received an HIV-1 vaccine (Ad26.ENVA.01) 4-6 years earlier (n = 10). We performed prespecified blinded cellular and humoral immunogenicity analyses at days 0, 14, 28, 84, 98, 112, 168, 270, and 365. Results: All 50 planned vaccinations were administered. Vaccination was safe and generally well tolerated. No vaccine-related serious adverse events occurred. Both cellular and humoral cross-clade immune responses were elicited after 1 or 2 vaccinations in all participants in the HIV-1 vaccine-naive group. Env-specific responses were induced after a single immunization in nearly all subjects who had previously received the prototype Ad26.ENVA.01 vaccine. Conclusions: No safety concerns were identified, and multiclade HIV-1-specific immune responses were elicited. Clinical Trials Registration: NCT02218125.
Assuntos
Vacinas contra a AIDS/administração & dosagem , Vacinas contra a AIDS/imunologia , Infecções por HIV/prevenção & controle , HIV-1/imunologia , Vacinas contra a AIDS/efeitos adversos , Vacinas contra a AIDS/genética , Adulto , Método Duplo-Cego , Portadores de Fármacos , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/epidemiologia , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/patologia , Feminino , Vetores Genéticos , Humanos , Imunidade Celular , Imunidade Humoral , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Placebos/administração & dosagem , Resultado do Tratamento , Vacinas de Subunidades Antigênicas/administração & dosagem , Vacinas de Subunidades Antigênicas/efeitos adversos , Vacinas de Subunidades Antigênicas/genética , Vacinas de Subunidades Antigênicas/imunologia , Vacinas Sintéticas/administração & dosagem , Vacinas Sintéticas/efeitos adversos , Vacinas Sintéticas/genética , Vacinas Sintéticas/imunologia , Vaccinia virus/genética , Adulto JovemRESUMO
Preclinical studies of human immunodeficiency virus type 1 (HIV-1) vaccine candidates have typically shown post-infection virological control, but protection against acquisition of infection has previously only been reported against neutralization-sensitive virus challenges. Here we demonstrate vaccine protection against acquisition of fully heterologous, neutralization-resistant simian immunodeficiency virus (SIV) challenges in rhesus monkeys. Adenovirus/poxvirus and adenovirus/adenovirus-vector-based vaccines expressing SIV(SME543) Gag, Pol and Env antigens resulted in an 80% or greater reduction in the per-exposure probability of infection against repetitive, intrarectal SIV(MAC251) challenges in rhesus monkeys. Protection against acquisition of infection showed distinct immunological correlates compared with post-infection virological control and required the inclusion of Env in the vaccine regimen. These data demonstrate the proof-of-concept that optimized HIV-1 vaccine candidates can block acquisition of stringent, heterologous, neutralization-resistant virus challenges in rhesus monkeys.
Assuntos
Anticorpos Neutralizantes/imunologia , Macaca mulatta/imunologia , Vacinas contra a SAIDS/imunologia , Vírus da Imunodeficiência Símia/imunologia , Vacinas contra a AIDS/imunologia , Adenoviridae/genética , Adenoviridae/imunologia , Animais , Ensaio de Imunoadsorção Enzimática , Feminino , HIV-1/imunologia , Masculino , Testes de Neutralização , Vacinas Virais/imunologiaRESUMO
BACKGROUND: Defining mucosal immune responses and inflammation to candidate human immunodeficiency virus type 1 (HIV-1) vaccines represents a current research priority for the HIV-1 vaccine field. In particular, it is unclear whether intramuscular immunization can elicit immune responses at mucosal surfaces in humans. METHODS: In this double-blind, randomized, placebo-controlled clinical trial, we evaluated systemic and mucosal immune responses to a candidate adenovirus serotype 26 (Ad26) vectored HIV-1 envelop (Env) vaccine in baseline Ad26-seronegative and Ad26-seropositive healthy volunteers. Systematic mucosal sampling with rectal Weck-Cel sponges and rectal biopsies were performed. RESULTS: Intramuscular immunization elicited both systemic and mucosal Env-specific humoral and cellular immune responses in the majority of subjects. Individuals with preexisting Ad26-specific neutralizing antibodies had vaccine-elicited immune responses comparable to those of subjects who were Ad26 seronegative. We also observed no increase in activated total or vector-specific mucosal CD4+ T lymphocytes following vaccination by either histopathology or flow cytometry. CONCLUSIONS: These data demonstrate that a single intramuscular administration of this Ad26-vectored HIV-1 Env vaccine elicited both systemic and mucosal immune responses in humans. Induction of antigen-specific humoral and cellular mucosal immunity was not accompanied by a detectable increase in mucosal inflammation. CLINICAL TRIALS REGISTRATION: NCT01103687.
Assuntos
Vacinas contra a AIDS/imunologia , Adenovírus Humanos/imunologia , HIV-1/imunologia , Imunidade nas Mucosas/imunologia , Vacinas contra a AIDS/administração & dosagem , Vacinas contra a AIDS/efeitos adversos , Adulto , Linfócitos T CD4-Positivos/imunologia , Colo/imunologia , Colo/patologia , Citocinas/sangue , Ensaio de Imunoadsorção Enzimática , Feminino , Anticorpos Anti-HIV/sangue , Anticorpos Anti-HIV/imunologia , Infecções por HIV/prevenção & controle , Humanos , Injeções Intramusculares , Mucosa Intestinal/imunologia , Mucosa Intestinal/patologia , Masculino , Pessoa de Meia-Idade , Adulto Jovem , Produtos do Gene env do Vírus da Imunodeficiência Humana/imunologiaRESUMO
A recombinant adenovirus serotype 5 (rAd5) vector-based vaccine for HIV-1 has recently failed in a phase 2b efficacy study in humans. Consistent with these results, preclinical studies have demonstrated that rAd5 vectors expressing simian immunodeficiency virus (SIV) Gag failed to reduce peak or setpoint viral loads after SIV challenge of rhesus monkeys (Macaca mulatta) that lacked the protective MHC class I allele Mamu-A*01 (ref. 3). Here we show that an improved T-cell-based vaccine regimen using two serologically distinct adenovirus vectors afforded substantially improved protective efficacy in this challenge model. In particular, a heterologous rAd26 prime/rAd5 boost vaccine regimen expressing SIV Gag elicited cellular immune responses with augmented magnitude, breadth and polyfunctionality as compared with the homologous rAd5 regimen. After SIV(MAC251) challenge, monkeys vaccinated with the rAd26/rAd5 regimen showed a 1.4 log reduction of peak and a 2.4 log reduction of setpoint viral loads as well as decreased AIDS-related mortality as compared with control animals. These data demonstrate that durable partial immune control of a pathogenic SIV challenge for more than 500 days can be achieved by a T-cell-based vaccine in Mamu-A*01-negative rhesus monkeys in the absence of a homologous Env antigen. These findings have important implications for the development of next-generation T-cell-based vaccine candidates for HIV-1.
Assuntos
Linfócitos T CD4-Positivos/imunologia , Macaca mulatta/imunologia , Macaca mulatta/virologia , Vacinas contra a SAIDS/imunologia , Síndrome de Imunodeficiência Adquirida dos Símios/imunologia , Vírus da Imunodeficiência Símia/imunologia , Adenoviridae/genética , Animais , Anticorpos Antivirais/imunologia , Infecções por HIV/imunologia , Infecções por HIV/prevenção & controle , Humanos , Testes de Neutralização , Vacinas contra a SAIDS/administração & dosagem , Síndrome de Imunodeficiência Adquirida dos Símios/mortalidade , Síndrome de Imunodeficiência Adquirida dos Símios/prevenção & controle , Síndrome de Imunodeficiência Adquirida dos Símios/virologia , Vacinação , Carga ViralRESUMO
BACKGROUND: We report the first-in-human safety and immunogenicity assessment of a prototype hexon chimeric adenovirus (Ad) serotype 5 (Ad5) vector containing the hexon hypervariable regions of Ad serotype 48 (Ad48) and expressing human immunodeficiency virus (HIV) type 1 EnvA. METHODS: Forty-eight Ad5 and Ad48 seronegative, HIV-uninfected subjects were enrolled in a randomized, double-blind, placebo-controlled, dose escalation phase 1 study. Four groups of 12 subjects received 10(9) to 10(11) viral particles (vp) of the Ad5HVR48.EnvA.01 vaccine (n = 10 per group) or placebo (n = 2 per group) at week 0 or weeks 0, 4, and 24. Safety and immunogenicity were assessed. RESULTS: Self-limited reactogenicity was observed after the initial immunization in the highest (10(11) vp) dose group. Responses in vaccinees included Ad48 neutralizing antibody (nAb) titers higher than Ad5 nAb titers, EnvA-specific enzyme-linked immunosorbent assay titers, and EnvA-specific enzyme-linked immunospot assay responses, and these responses generally persisted at week 52. At week 28 in the 10(9), 10(10), and 10(11) vp 3-dose groups, geometric mean EnvA enzyme-linked immunosorbent assay titers were 5721, 10 929, and 3420, respectively, and Ad48 nAb titers were a median of 1.7-fold higher than for Ad5. CONCLUSIONS: Ad5HVR48.ENVA.01 was safe, well tolerated, and immunogenic at all doses tested. Vector-elicited nAb responses were greater for Ad48 than Ad5, confirming that Ad-specific nAbs in humans are primarily, but not exclusively, directed against the hexon hypervariable regions. Clinical Trials Registration. NCT00695877.
Assuntos
Vacinas contra a AIDS/efeitos adversos , Vacinas contra a AIDS/imunologia , Adenovírus Humanos/genética , Proteínas do Capsídeo/genética , Expressão Gênica , HIV-1/genética , Produtos do Gene env do Vírus da Imunodeficiência Humana/genética , Vacinas contra a AIDS/administração & dosagem , Vacinas contra a AIDS/genética , Adolescente , Adulto , Anticorpos Neutralizantes/sangue , Método Duplo-Cego , Portadores de Fármacos , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/epidemiologia , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/patologia , Ensaio de Imunoadsorção Enzimática , ELISPOT , Feminino , Vetores Genéticos , Anticorpos Anti-HIV/sangue , Humanos , Leucócitos Mononucleares/imunologia , Masculino , Pessoa de Meia-Idade , Placebos/administração & dosagem , Vacinas Sintéticas/administração & dosagem , Vacinas Sintéticas/efeitos adversos , Vacinas Sintéticas/genética , Vacinas Sintéticas/imunologia , Adulto JovemRESUMO
BACKGROUND: Adenovirus serotype 26 (Ad26) has been developed as a novel candidate vaccine vector for human immunodeficiency virus type 1 (HIV-1) and other pathogens. The primary safety and immunogenicity data from the Integrated Preclinical/Clinical AIDS Vaccine Development Program (IPCAVD) 001 trial, the first-in-human evaluation of a prototype Ad26 vector-based vaccine expressing clade A HIV-1 Env (Ad26.ENVA.01), are reported concurrently with this article. Here, we characterize in greater detail the humoral and cellular immune responses elicited by Ad26.ENVA.01 in humans. METHODS: Samples from the IPCAVD 001 trial were used for humoral and cellular immunogenicity assays. RESULTS: We observed a dose-dependent expansion of the magnitude, breadth, and epitopic diversity of Env-specific binding antibody responses elicited by this vaccine. Antibody-dependent cell-mediated phagocytosis, virus inhibition, and degranulation functional activity were also observed. Env-specific cellular immune responses induced by the vaccine included multiple CD8(+) and CD4(+) T-lymphocyte memory subpopulations and cytokine secretion phenotypes, although cellular immune breadth was limited. Baseline vector-specific T-lymphocyte responses were common but did not impair Env-specific immune responses in this study. CONCLUSION: Ad26.ENVA.01 elicited a broad diversity of humoral and cellular immune responses in humans. These data support the further clinical development of Ad26 as a candidate vaccine vector. CLINICAL TRIALS REGISTRATION: NCT00618605.
Assuntos
Vacinas contra a AIDS/imunologia , Adenovírus Humanos/genética , Produtos do Gene env/imunologia , Anticorpos Anti-HIV/sangue , HIV-1/imunologia , Imunidade Celular/imunologia , Vacinas contra a AIDS/administração & dosagem , Vacinas contra a AIDS/efeitos adversos , Adenovírus Humanos/classificação , Método Duplo-Cego , Produtos do Gene env/genética , Infecções por HIV/imunologia , Infecções por HIV/prevenção & controle , Humanos , Leucócitos Mononucleares/imunologia , Resultado do Tratamento , Vacinas Sintéticas/administração & dosagem , Vacinas Sintéticas/efeitos adversos , Vacinas Sintéticas/imunologiaRESUMO
BACKGROUND: We report the first-in-human safety and immunogenicity assessment of a prototype Ad26 vector-based human immunodeficiency virus (HIV) vaccine in humans. METHODS: Sixty Ad26-seronegative, healthy, HIV-uninfected subjects were enrolled in a randomized, double-blinded, placebo-controlled, dose-escalation phase 1 study. Five groups of 12 subjects received 10(9)-10(11) vp of the Ad26-EnvA vaccine (N = 10/group) or placebo (N = 2/group) at weeks 0 and 24 or weeks 0, 4, and 24. Safety and immunogenicity were assessed. RESULTS: Self-limited reactogenicity was observed after the initial immunization at the highest (10(11) vp) dose. No product-related SAEs were observed. All subjects who received the Ad26-EnvA vaccine developed Ad26 NAb titers, EnvA-specific enzyme-linked immunosorbent assays (ELISA) titers, and EnvA-specific enzyme-linked immunospot assays (ELISPOT) responses. These responses persisted at week 52. At week 28 in the 10(9), 10(10), 10(11) vp 3-dose and the 10(10) and 5 × 10(10) vp 2-dose groups, geometric mean EnvA ELISA titers were 6113, 12 470, 8545, 3470, and 9655 and mean EnvA ELISPOT responses were 397, 178, 736, 196, and 1311 SFC/10(6) peripheral blood mononuclear cells, respectively. CONCLUSION: This Ad26 vectored vaccine was generally safe and immunogenic at all doses tested. Reactogenicity was minimal with doses of 5 × 10(10) vp or less. Ad26 is a promising new vaccine vector for HIV-1. CLINICAL TRIALS REGISTRATION: NCT00618605.
Assuntos
Vacinas contra a AIDS/efeitos adversos , Vacinas contra a AIDS/imunologia , Adenovírus Humanos/genética , Produtos do Gene env/imunologia , Infecções por HIV/prevenção & controle , HIV-1/imunologia , Vacinas contra a AIDS/administração & dosagem , Adenovírus Humanos/classificação , Método Duplo-Cego , Feminino , Produtos do Gene env/genética , Anticorpos Anti-HIV/sangue , Infecções por HIV/imunologia , Humanos , Leucócitos Mononucleares/imunologia , Masculino , Resultado do Tratamento , Vacinas Sintéticas/administração & dosagem , Vacinas Sintéticas/efeitos adversos , Vacinas Sintéticas/imunologiaRESUMO
BACKGROUND: HIV type 1 (HIV-1) remains a global health concern, with the greatest burden in sub-Saharan Africa. Despite 40 years of research, no vaccine candidate has shown durable and protective efficacy against HIV-1 acquisition. Although pre-exposure prophylaxis in groups with high vulnerability can be very effective, barriers to its use, such as perceived low acquisition risk, fear of stigma, and concerns about side-effects, remain. Thus, a population-based approach, such as an HIV-1 vaccine, is needed. The current study aimed to evaluate the efficacy and safety of a heterologous HIV-1 vaccine regimen, consisting of a tetravalent mosaic adenovirus 26-based vaccine (Ad26.Mos4.HIV) and aluminium phosphate-adjuvanted clade C glycoprotein (gp) 140, in young women at risk of acquiring HIV-1 in southern Africa. METHODS: This randomised, double-blind, phase 2b study enrolled sexually active women without HIV-1 or HIV-2 aged 18-35 years at 23 clinical research sites in Malawi, Mozambique, South Africa, Zambia, and Zimbabwe. Participants were centrally randomly assigned (1:1) to receive intramuscular injections of vaccine or saline placebo in stratified permuted blocks via an interactive web response system. Study participants, study site personnel (except those with primary responsibility for study vaccine preparation and dispensing), and investigators were masked to treatment group allocation. The vaccine regimen consisted of Ad26.Mos4.HIV administered at months 0 and 3 followed by Ad26.Mos4.HIV administered concurrently with aluminium phosphate-adjuvanted clade C gp140 at months 6 and 12. The primary efficacy outcome was vaccine efficacy in preventing laboratory-confirmed HIV-1 acquisition diagnosed between visits at month 7 and month 24 after the first vaccination (VE[7-24]) in the per-protocol population, which included participants who had not acquired HIV-1 4 weeks after the third vaccination, received all planned vaccinations at the first three vaccination visits within the protocol-specified windows, and had no major protocol deviations that could affect vaccine efficacy. Primary safety outcomes were assessed in randomly assigned participants who received one study injection or more based on the actual injection received. The primary safety endpoints were the incidences of unsolicited adverse events (AEs), solicited local and systemic AEs, serious AEs, AEs of special interest, and AEs leading to discontinuation of vaccination. This trial is registered with ClinicalTrials.gov, NCT03060629, and is complete. FINDINGS: Between Nov 3, 2017, and June 30, 2019, 2654 women were randomly assigned, of whom 2636 women (median age of 23 years [IQR 20-25]) were enrolled and received at least one study injection (1313 assigned vaccine, 1323 placebo; 1317 received vaccine, 1319 placebo). Analysis of the primary efficacy outcome in the per-protocol cohort included 1080 women in the vaccine group and 1108 women in the placebo group; the incidence of HIV-1 acquisition per 100 person-years over months 7-24 after the first vaccination was 3·38 (95% CI 2·54-4·41) in the vaccine group and 3·94 (3·04-5·03) in the placebo group, with an estimated VE(7-24) of 14·10% (95% CI -22·00 to 39·51; p=0·40). There were no serious unsolicited AEs, AEs of special interest, or deaths related to the study vaccine. In the vaccine group, 663 (50·3%) of 1317 participants had grade 1 or 2 solicited local AEs and ten (0·8%) of 1317 participants had grade 3 or 4 solicited local AEs. In the placebo group, 305 (23·1%) of 1319 participants had grade 1 or 2 solicited local AEs and three (0·2%) of 1319 participants had grade 3 or 4 solicited local AEs. 863 (65·5%) of 1317 participants in the vaccine group had grade 1 or 2 solicited systemic AEs and 34 (2·6%) of 1317 participants had grade 3 or 4 solicited systemic AEs. 763 (57·8%) of 1319 participants in the placebo group had grade 1 or 2 solicited systemic AEs and 20 (1·5%) of 1319 participants had grade 3 or 4 solicited systemic AEs. Overall, three (0·2%) of 1317 participants in the vaccine group and three (0·2%) of 1319 participants in the placebo group discontinued vaccination due to an unsolicited AE, and three (0·2%) of 1317 participants in the vaccine group and one (0·1%) of 1319 participants in the placebo group discontinued vaccination due to a solicited AE. INTERPRETATION: The heterologous Ad26.Mos4.HIV and clade C gp140 vaccine regimen was safe and well tolerated but did not show efficacy in preventing HIV-1 acquisition in a population of young women in southern Africa at risk of HIV-1. FUNDING: Division of AIDS at the National Institute of Allergy and Infectious Diseases through the HIV Vaccine Trials Network, Bill & Melinda Gates Foundation, Janssen Vaccines & Prevention, US Army Medical Materiel Development Activity, and Ragon Institute.
RESUMO
A heterologous Ad26/MVA vaccine was given prior to an analytic treatment interruption (ATI) in people living with HIV-1 (mainly CRF01_AE) who initiated antiretroviral treatment (ART) during acute HIV-1. We investigate the impact of Ad26/MVA vaccination on antibody (Ab)-mediated immune responses and their effect on time to viral rebound. The vaccine mainly triggers vaccine-matched binding Abs while, upon viral rebound post ATI, infection-specific CRF01_AE binding Abs increase in all participants. Binding Abs are not associated with time to viral rebound. The Ad26/MVA mosaic vaccine profile consists of correlated non-CRF01_AE binding Ab and Fc effector features, with strong Ab-dependent cellular phagocytosis (ADCP) responses. CRF01_AE-specific ADCP responses (measured either prior to or post ATI) are significantly higher in individuals with delayed viral rebound. Our results suggest that vaccines eliciting cross-reactive responses with circulating viruses in a target population could be beneficial and that ADCP responses may play a role in viral control post treatment interruption.
Assuntos
Vacinas contra a AIDS , Infecções por HIV , HIV-1 , Fagocitose , Carga Viral , Humanos , HIV-1/imunologia , Infecções por HIV/imunologia , Infecções por HIV/virologia , Infecções por HIV/tratamento farmacológico , Masculino , Vacinas contra a AIDS/imunologia , Vacinas contra a AIDS/administração & dosagem , Adulto , Feminino , Anticorpos Anti-HIV/imunologia , Pessoa de Meia-Idade , Interrupção do TratamentoRESUMO
BACKGROUND: Though clinically similar, Ebola virus disease and Marburg virus disease are caused by different viruses. Of the 30 documented outbreaks of these diseases in sub-Saharan Africa, eight were major outbreaks (≥200 cases; five caused by Zaire ebolavirus [EBOV], two by Sudan ebolavirus [SUDV], and one by Marburg virus [MARV]). Our purpose is to develop a multivalent vaccine regimen protecting against each of these filoviruses. This first-in-human study assessed the safety and immunogenicity of several multivalent two-dose vaccine regimens that contain Ad26.Filo and MVA-BN-Filo. METHODS: Ad26.Filo combines three vaccines encoding the glycoprotein (GP) of EBOV, SUDV, and MARV. MVA-BN-Filo is a multivalent vector encoding EBOV, SUDV, and MARV GPs, and Taï Forest nucleoprotein. This Phase 1, randomized, double-blind, placebo-controlled study enrolled healthy adults (18-50 years) into four groups, randomized 5:1 (active:placebo), to assess different Ad26.Filo and MVA-BN-Filo vaccine directionality and administration intervals. The primary endpoint was safety; immune responses against EBOV, SUDV, and MARV GPs were also assessed. RESULTS: Seventy-two participants were randomized, and 60 (83.3%) completed the study. All regimens were well tolerated with no deaths or vaccine-related serious adverse events (AEs). The most frequently reported solicited local AE was injection site pain/tenderness. Solicited systemic AEs most frequently reported were headache, fatigue, chills, and myalgia; most solicited AEs were Grade 1-2. Solicited/unsolicited AE profiles were similar between regimens. Twenty-one days post-dose 2, 100% of participants on active regimen responded to vaccination and exhibited binding antibodies against EBOV, SUDV, and MARV GPs; neutralizing antibody responses were robust against EBOV (85.7-100%), but lower against SUDV (35.7-100%) and MARV (0-57.1%) GPs. An Ad26.Filo booster induced a rapid further increase in humoral responses. CONCLUSION: This study demonstrates that heterologous two-dose vaccine regimens with Ad26.Filo and MVA-BN-Filo are well tolerated and immunogenic in healthy adults. CLINICALTRIALS.GOV: NCT02860650.
Assuntos
Vacinas contra Ebola , Ebolavirus , Doença pelo Vírus Ebola , Marburgvirus , Adolescente , Adulto , Animais , Anticorpos Neutralizantes , Anticorpos Antivirais , Glicoproteínas , Humanos , Pessoa de Meia-Idade , Nucleoproteínas , Vacinas Combinadas , Vaccinia virus , Adulto JovemRESUMO
Developing an intervention that results in virologic control following discontinuation of antiretroviral therapy (ART) is a major objective of HIV-1 cure research. In this study, we investigated the therapeutic efficacy of a vaccine consisting of adenovirus serotype 26 (Ad26) and modified vaccinia Ankara (MVA) with or without an SIV Envelope (Env) gp140 protein with alum adjuvant in combination with the TLR7 agonist vesatolimod (GS-9620) in 36 ART-suppressed, SIVmac251-infected rhesus macaques. Ad26/MVA therapeutic vaccination led to robust humoral and cellular immune responses, and the Env protein boost increased antibody responses. Following discontinuation of ART, virologic control was observed in 5/12 animals in each vaccine group, compared with 0/12 animals in the sham control group. These data demonstrate therapeutic efficacy of Ad26/MVA vaccination with vesatolimod but no clear additional benefit of adding an Env protein boost. SIV-specific cellular immune responses correlated with virologic control. Our findings show partial efficacy of therapeutic vaccination following ART discontinuation in SIV-infected rhesus macaques.
RESUMO
The latent viral reservoir is the critical barrier for developing an HIV-1 cure. Previous studies have shown that therapeutic vaccination or broadly neutralizing antibody (bNAb) administration, together with a Toll-like receptor 7 (TLR7) agonist, enhanced virologic control or delayed viral rebound, respectively, following discontinuation of antiretroviral therapy (ART) in SIV- or SHIV-infected rhesus macaques. Here we show that the combination of active and passive immunization with vesatolimod may lead to higher rates of post-ART virologic control compared to either approach alone. Therapeutic Ad26/MVA vaccination and PGT121 administration together with TLR7 stimulation with vesatolimod resulted in 70% post-ART virologic control in SHIV-SF162P3-infected rhesus macaques. These data suggest the potential of combining active and passive immunization targeting different immunologic mechanisms as an HIV-1 cure strategy.
Assuntos
Infecções por HIV , HIV-1 , Síndrome de Imunodeficiência Adquirida dos Símios , Vírus da Imunodeficiência Símia , Animais , Infecções por HIV/tratamento farmacológico , Imunização Passiva , Macaca mulatta , Receptor 7 Toll-Like , Carga ViralRESUMO
BACKGROUND: Bioinformatically designed mosaic antigens increase the breadth of HIV vaccine-elicited immunity. This study compared the safety, tolerability, and immunogenicity of a newly developed, tetravalent Ad26 vaccine with the previously tested trivalent formulation. METHODS: This randomised, parallel-group, placebo-controlled, double-blind, phase 1/2a study (TRAVERSE) was done at 11 centres in the USA and one centre in Rwanda. Eligible participants were adults aged 18 to 50 years, who were HIV-uninfected, healthy at screening based on their medical history and a physical examination including laboratory assessment and vital sign measurements, and at low risk of HIV infection in the opinion of study staff, who applied a uniform definition of low-risk guidelines that was aligned across sites. Enrolled participants were randomly assigned at a 2:1 ratio to tetravalent and trivalent groups. Participants in tetravalent and trivalent groups were then further randomly assigned at a 5:1 ratio to adenovirus 26 (Ad26)-vectored vaccine and placebo subgroups. Randomisation was stratified by region (USA and Rwanda) and based on a computer-generated schedule using randomly permuted blocks prepared under the sponsor's supervision. We masked participants and investigators to treatment allocation throughout the study. On day 0, participants received a first injection of tetravalent vaccine (Ad26.Mos4.HIV or placebo) or trivalent vaccine (Ad26.Mos.HIV or placebo), and those injections were repeated 12 weeks later. At week 24, vaccine groups received a third dose of tetravalent or trivalent together with clade C gp140, and this was repeated at week 48, with placebos again administered to the placebo group. All study vaccines and placebo were administered by intramuscular injection in the deltoid muscle. We assessed adverse events in all participants who received at least one study injection (full analysis set) and Env-specific binding antibodies in all participants who received at least the first three vaccinations according to the protocol-specified vaccination schedule, had at least one measured post-dose blood sample collected, and were not diagnosed with HIV during the study (per-protocol set). This study is registered with Clinicaltrials.gov, NCT02788045. FINDINGS: Of 201 participants who were enrolled and randomly assigned, 198 received the first vaccination: 110 were in the tetravalent group, 55 in the trivalent group, and 33 in the placebo group. Overall, 185 (93%) completed two scheduled vaccinations per protocol, 180 (91%) completed three, and 164 (83%) completed four. Solicited, self-limiting local, systemic reactogenicity and unsolicited adverse events were similar in vaccine groups and higher than in placebo groups. All participants in the per-protocol set developed clade C Env binding antibodies after the second vaccination, with higher total IgG titres after the tetravalent vaccine than after the trivalent vaccine (10â413 EU/mL, 95% CI 7284-14â886 in the tetravalent group compared with 5494 EU/mL, 3759-8029 in the trivalent group). Titres further increased after the third and fourth vaccinations, persisting at least through week 72. Other immune responses were also higher with the tetravalent vaccine, including the magnitude and breadth of binding antibodies against a cross-clade panel of Env antigens, and the magnitude of IFNγ ELISPOT responses (median 521 SFU/106 peripheral blood mononuclear cells [PBMCs] in the tetravalent group and median 282 SFU/106 PBMCs in the trivalent group after the fourth vaccination) and Env-specific CD4+ T-cell response rates after the third and fourth vaccinations. No interference by pre-existing Ad26 immunity was identified. INTERPRETATION: The tetravalent vaccine regimen was generally safe, well-tolerated, and found to elicit higher immune responses than the trivalent regimen. Regimens that use this tetravalent vaccine component are being advanced into field trials to assess efficacy against HIV-1 infection. FUNDING: National Institutes of Health, Henry M Jackson Foundation for Advancement of Military Medicine and the US Department of Defense, Ragon Institute of MGH, MIT, & Harvard, Bill & Melinda Gates Foundation, and Janssen Vaccines & Prevention.
Assuntos
Vacinas contra a AIDS/imunologia , Infecções por HIV/imunologia , HIV-1/imunologia , Imunogenicidade da Vacina , Vacinas contra a AIDS/administração & dosagem , Vacinas contra a AIDS/efeitos adversos , Adulto , Feminino , Anticorpos Anti-HIV/imunologia , Infecções por HIV/prevenção & controle , Voluntários Saudáveis , Humanos , Esquemas de Imunização , Masculino , Pessoa de Meia-Idade , Resultado do Tratamento , Vacinação , Adulto JovemRESUMO
We administered Ad26, modified vaccinia Ankara vectors containing mosaic HIV-1 antigens or placebo in 26 individuals who initiated antiretroviral therapy during acute human immunodeficiency virus infection as an exploratory study to determine the safety and duration of viremic control after treatment interruption. The vaccine was safe and generated robust immune responses, but delayed time to viral rebound compared to that in placebo recipients by only several days and did not lead to viremic control after treatment interruption (clinical trial NCT02919306).