RESUMEN
Stabilized trimers preserving the native-like HIV envelope structure may be key components of a preventive HIV vaccine regimen to induce broadly neutralizing antibodies (bnAbs). We evaluated trimeric BG505 SOSIP.664 gp140 formulated with a novel TLR7/8 signaling adjuvant, 3M-052-AF/Alum, for safety, adjuvant dose-finding, and immunogenicity in a first-in-healthy adult (n = 17), randomized, and placebo-controlled trial (HVTN 137A). The vaccine regimen appeared safe. Robust, trimer-specific antibody, and B cell and CD4+ T cell responses emerged after vaccination. Five vaccinees developed serum autologous tier 2 nAbs (ID50 titer, 1:28-1:8647) after two to three doses targeting C3/V5 and/or V1/V2/V3 Env regions by electron microscopy and mutated pseudovirus-based neutralization analyses. Trimer-specific, B cell-derived monoclonal antibody activities confirmed these results and showed weak heterologous neutralization in the strongest responder. Our findings demonstrate the clinical utility of the 3M-052-AF/Alum adjuvant and support further improvements of trimer-based Env immunogens to focus responses on multiple broad nAb epitopes.
Asunto(s)
Vacunas contra el SIDA , Adyuvantes Inmunológicos , Compuestos de Alumbre , Anticuerpos Neutralizantes , Productos del Gen env del Virus de la Inmunodeficiencia Humana , Humanos , Anticuerpos Neutralizantes/inmunología , Vacunas contra el SIDA/inmunología , Vacunas contra el SIDA/administración & dosificación , Compuestos de Alumbre/administración & dosificación , Adulto , Adyuvantes Inmunológicos/administración & dosificación , Productos del Gen env del Virus de la Inmunodeficiencia Humana/inmunología , Anticuerpos Anti-VIH/inmunología , Femenino , VIH-1/inmunología , Masculino , Infecciones por VIH/inmunología , Infecciones por VIH/prevención & control , Linfocitos B/inmunología , Adyuvantes de Vacunas , Persona de Mediana Edad , Adulto Joven , Linfocitos T CD4-Positivos/inmunologíaRESUMEN
The greatest obstacle for scientists is to develop an effective HIV vaccine. An effective vaccine represents the last hope for halting the unstoppable global spread of HIV and its catastrophic clinical consequences. Creating this vaccine has been challenging due to the virus's extensive genetic variability and the unique role of cytotoxic T lymphocytes (CTL) in containing it. Innovative methods to stimulate CTL have demonstrated significant therapeutic advantages in nonhuman primate model systems, unlike traditional vaccination techniques that are not expected to provide safe and efficient protection against HIV. Human clinical trials are currently evaluating these vaccination strategies, which involve plasmid DNA and live recombinant vectors. This review article covers the existing vaccines and ongoing trial vaccines. It also explores the different approaches used in developing HIV vaccines, including their molecular mechanisms, target site effectiveness, and potential side effects.
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Vacunas contra el SIDA , Ensayos Clínicos como Asunto , Infecciones por VIH , Humanos , Vacunas contra el SIDA/inmunología , Infecciones por VIH/prevención & control , Infecciones por VIH/inmunología , Animales , Linfocitos T Citotóxicos/inmunología , Desarrollo de Vacunas , VIH-1/inmunología , VIH-1/genéticaRESUMEN
The HIV-1 envelope glycoprotein (Env) is the sole neutralizing determinant on the surface of the virus. The Env gp120 and gp41 subunits mediate receptor binding and membrane fusion and are generated from the gp160 precursor by cellular furins. This cleavage event is required for viral entry. One approach to generate HIV-1 neutralizing antibodies following immunization is to express membrane-bound Env anchored on the cell-surface by genetic means using the natural HIV gp41 transmembrane (TM) spanning domain. To simplify the process of Env trimer membrane expression we sought to remove the need for Env precursor cleavage while maintaining native-like conformation following genetic expression. To accomplish these objectives, we selected our previously developed 'native flexibly linked' (NFL) stabilized soluble trimers that are both near-native in conformation and cleavage-independent. We genetically fused the NFL construct to the HIV TM domain by using a short linker or by restoring the native membrane external proximal region, absent in soluble trimers, to express the full HIV Env ectodomain on the plasma membrane. Both forms of cell-surface NFL trimers, without and with the MPER, displayed favorable antigenic profiles by flow cytometry when expressed from plasmid DNA or mRNA. These results were consistent with the presence of well-ordered cell surface native-like trimeric Env, a necessary requirement to generate neutralizing antibodies by vaccination. Inoculation of rabbits with mRNA lipid nanoparticles (LNP) expressing membrane-bound stabilized HIV Env NFL trimers generated tier 2 neutralizing antibody serum titers in immunized animals. Multiple inoculations of mRNA LNPs generated similar neutralizing antibody titers compared to immunizations of matched NFL soluble proteins in adjuvant. Given the recent success of mRNA vaccines to prevent severe COVID, these are important developments for genetic expression of native-like HIV Env trimers in animals and potentially in humans.
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Vacunas contra el SIDA , Anticuerpos Neutralizantes , Anticuerpos Anti-VIH , VIH-1 , Nanopartículas , ARN Mensajero , Productos del Gen env del Virus de la Inmunodeficiencia Humana , Animales , Anticuerpos Anti-VIH/inmunología , VIH-1/inmunología , Anticuerpos Neutralizantes/inmunología , Humanos , Productos del Gen env del Virus de la Inmunodeficiencia Humana/inmunología , Productos del Gen env del Virus de la Inmunodeficiencia Humana/genética , Vacunas contra el SIDA/inmunología , Conejos , ARN Mensajero/inmunología , ARN Mensajero/genética , Lípidos/inmunología , Multimerización de Proteína , Infecciones por VIH/inmunología , Infecciones por VIH/virología , Infecciones por VIH/prevención & control , Femenino , LiposomasRESUMEN
Over the past few decades, the development of potent and safe immune-activating adjuvant technologies has become the heart of intensive research in the constant fight against highly mutative and immune evasive viruses such as influenza, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and human immunodeficiency virus (HIV). Herein, we developed a highly modular saponin-based nanoparticle platform incorporating Toll-like receptor agonists (TLRas) including TLR1/2a, TLR4a, and TLR7/8a adjuvants and their mixtures. These various TLRa-saponin nanoparticle adjuvant constructs induce unique acute cytokine and immune-signaling profiles, leading to specific T helper responses that could be of interest depending on the target disease for prevention. In a murine vaccine study, the adjuvants greatly improved the potency, durability, breadth, and neutralization of both COVID-19 and HIV vaccine candidates, suggesting the potential broad application of these adjuvant constructs to a range of different antigens. Overall, this work demonstrates a modular TLRa-SNP adjuvant platform that could improve the design of vaccines and affect modern vaccine development.
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Adyuvantes Inmunológicos , Vacunas contra la COVID-19 , Nanopartículas , SARS-CoV-2 , Saponinas , Agonistas de los Receptores Toll-Like , Animales , Humanos , Ratones , Adyuvantes Inmunológicos/farmacología , Adyuvantes de Vacunas/química , Vacunas contra el SIDA/inmunología , COVID-19/prevención & control , COVID-19/inmunología , COVID-19/virología , Vacunas contra la COVID-19/inmunología , Citocinas/metabolismo , Nanopartículas/química , Saponinas/farmacología , Saponinas/química , Saponinas/inmunología , SARS-CoV-2/inmunologíaRESUMEN
Eliciting potent and broadly neutralizing antibodies (bnAbs) is a major goal in HIV-1 vaccine development. Here, we describe how germline-targeting immunogen BG505 SOSIP germline trimer 1.1 (GT1.1), generated through structure-based design, engages a diverse range of VRC01-class bnAb precursors. A single immunization with GT1.1 expands CD4 binding site (CD4bs)-specific VRC01-class B cells in knock-in mice and drives VRC01-class maturation. In nonhuman primates (NHPs), GT1.1 primes CD4bs-specific neutralizing serum responses. Selected monoclonal antibodies (mAbs) isolated from GT1.1-immunized NHPs neutralize fully glycosylated BG505 virus. Two mAbs, 12C11 and 21N13, neutralize subsets of diverse heterologous neutralization-resistant viruses. High-resolution structures revealed that 21N13 targets the same conserved residues in the CD4bs as VRC01-class and CH235-class bnAbs despite its low sequence similarity (~40%), whereas mAb 12C11 binds predominantly through its heavy chain complementarity-determining region 3. These preclinical data underpin the ongoing evaluation of GT1.1 in a phase 1 clinical trial in healthy volunteers.
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Vacunas contra el SIDA , Anticuerpos Neutralizantes , Antígenos CD4 , Anticuerpos Anti-VIH , VIH-1 , Animales , Vacunas contra el SIDA/inmunología , Ratones , Humanos , Anticuerpos Anti-VIH/inmunología , Anticuerpos Neutralizantes/inmunología , VIH-1/inmunología , Antígenos CD4/inmunología , Sitios de Unión/inmunología , Infecciones por VIH/inmunología , Infecciones por VIH/prevención & control , Vacunación , Anticuerpos Monoclonales/inmunología , FemeninoRESUMEN
HIV envelope immunogen designed to activate germline B cell precursors of CD4 binding site-specific neutralizing antibodies shows promise in monkeys.
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Anticuerpos Neutralizantes , Antígenos CD4 , Anticuerpos Anti-VIH , Animales , Humanos , Anticuerpos Anti-VIH/inmunología , Anticuerpos Neutralizantes/inmunología , Antígenos CD4/inmunología , Antígenos CD4/metabolismo , VIH-1/inmunología , Infecciones por VIH/inmunología , Vacunas contra el SIDA/inmunología , Sitios de Unión/inmunología , Anticuerpos ampliamente neutralizantes/inmunología , Linfocitos B/inmunologíaRESUMEN
Adolescents are a growing population of people living with HIV. The period between weaning and sexual debut presents a low-risk window for HIV acquisition, making early childhood an ideal time for implementing an immunization regimen. Because the elicitation of broadly neutralizing antibodies (bnAbs) is critical for an effective HIV vaccine, our goal was to assess the ability of a bnAb B cell lineage-designed HIV envelope SOSIP (protein stabilized by a disulfide bond between gp120-gp41-named "SOS"-and an isoleucine-to-proline point mutation-named "IP"-at residue 559) to induce precursor CD4 binding site (CD4bs)-targeting bnAbs in early life. Infant rhesus macaques received either a BG505 SOSIP, based on the infant BG505 transmitted/founder virus, or the CD4bs germ line-targeting BG505 SOSIP GT1.1 (n = 5 per group). Although both strategies induced durable, high-magnitude plasma autologous virus neutralization responses, only GT1.1-immunized infants (n = 3 of 5) exhibited VRC01-like CD4bs bnAb precursor development. Thus, a multidose immunization regimen with bnAb lineage-designed SOSIPs shows promise for inducing early B cell responses with the potential to mature into protective HIV bnAbs before sexual debut.
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Vacunas contra el SIDA , Anticuerpos Anti-VIH , Macaca mulatta , Animales , Anticuerpos Anti-VIH/inmunología , Vacunas contra el SIDA/inmunología , Vacunas contra el SIDA/administración & dosificación , Anticuerpos Neutralizantes/inmunología , Anticuerpos ampliamente neutralizantes/inmunología , Inmunización , Productos del Gen env del Virus de la Inmunodeficiencia Humana/inmunología , VIH-1/inmunología , Infecciones por VIH/inmunología , Infecciones por VIH/prevención & control , Humanos , Células Germinativas/inmunologíaRESUMEN
Nucleoside-modified mRNA technology has revolutionized vaccine development with the success of mRNA COVID-19 vaccines. We used modified mRNA technology for the design of envelopes (Env) to induce HIV-1 broadly neutralizing antibodies (bnAbs). However, unlike SARS-CoV-2 neutralizing antibodies that are readily made, HIV-1 bnAb induction is disfavored by the immune system because of the rarity of bnAb B cell precursors and the cross-reactivity of bnAbs targeting certain Env epitopes with host molecules, thus requiring optimized immunogen design. The use of protein nanoparticles (NPs) has been reported to enhance B cell germinal center responses to HIV-1 Env. Here, we report our experience with the expression of Env-ferritin NPs compared with membrane-bound Env gp160 when encoded by modified mRNA. We found that well-folded Env-ferritin NPs were a minority of the protein expressed by an mRNA design and were immunogenic at 20 µg but minimally immunogenic in mice at 1 µg dose in vivo and were not expressed well in draining lymph nodes (LNs) following intramuscular immunization. In contrast, mRNA encoding gp160 was more immunogenic than mRNA encoding Env-NP at 1 µg dose and was expressed well in draining LN following intramuscular immunization. Thus, analysis of mRNA expression in vitro and immunogenicity at low doses in vivo are critical for the evaluation of mRNA designs for optimal immunogenicity of HIV-1 immunogens.IMPORTANCEAn effective HIV-1 vaccine that induces protective antibody responses remains elusive. We have used mRNA technology for designs of HIV-1 immunogens in the forms of membrane-bound full-length envelope gp160 and envelope ferritin nanoparticle. Here, we demonstrated in a mouse model that the membrane-bound form induced a better response than envelope ferritin nanoparticle because of higher in vivo protein expression. The significance of our research is in highlighting the importance of analysis of mRNA design expression and low-dose immunogenicity studies for HIV-1 immunogens before moving to vaccine clinical trials.
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Ferritinas , VIH-1 , Nanopartículas , Animales , VIH-1/inmunología , VIH-1/genética , Ratones , Ferritinas/inmunología , Ferritinas/genética , Humanos , Productos del Gen env del Virus de la Inmunodeficiencia Humana/inmunología , Productos del Gen env del Virus de la Inmunodeficiencia Humana/genética , ARN Mensajero/inmunología , ARN Mensajero/genética , Anticuerpos Anti-VIH/inmunología , Femenino , Anticuerpos Neutralizantes/inmunología , Vacunas contra el SIDA/inmunología , Vacunas contra el SIDA/administración & dosificación , Vacunas contra el SIDA/genética , Ratones Endogámicos BALB C , Vacunas contra la COVID-19/inmunología , Vacunas contra la COVID-19/administración & dosificación , SARS-CoV-2/inmunología , SARS-CoV-2/genética , Inmunogenicidad Vacunal , Infecciones por VIH/inmunología , Infecciones por VIH/prevención & control , Infecciones por VIH/virologíaRESUMEN
Substantial advances have been made in the development of promising HIV vaccines to eliminate HIV-1 infection. For the first time, one hundred of the most submitted HIV subtypes and CRFs were retrieved from the LANL database, and the consensus sequences of the eleven HIV proteins were obtained to design vaccines for human and mouse hosts. By using various servers and filters, highly qualified B-cell epitopes, as well as HTL and CD8 + epitopes that were common between mouse and human alleles and were also located in the conserved domains of HIV proteins, were considered in the vaccine constructs. With 90% coverage worldwide, the human vaccine model covers a diverse allelic population, making it widely available. Codon optimization and in silico cloning in prokaryotic and eukaryotic vectors guarantee high expression of the vaccine models in human and E. coli hosts. Molecular dynamics confirmed the stable interaction of the vaccine constructs with TLR3, TLR4, and TLR9, leading to a substantial immunogenic response to the designed vaccine. Vaccine models effectively target the humoral and cellular immune systems in humans and mice; however, experimental validation is needed to confirm these findings in silico.
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Vacunas contra el SIDA , Biología Computacional , Infecciones por VIH , VIH-1 , Vacunología , Humanos , Vacunas contra el SIDA/inmunología , Vacunas contra el SIDA/genética , Animales , Biología Computacional/métodos , Vacunología/métodos , VIH-1/inmunología , VIH-1/genética , Ratones , Infecciones por VIH/prevención & control , Infecciones por VIH/inmunología , Simulación de Dinámica Molecular , Epítopos de Linfocito T/inmunología , Epítopos de Linfocito T/genética , Genoma Viral , Epítopos de Linfocito B/inmunología , Epítopos de Linfocito B/genética , Desarrollo de VacunasRESUMEN
Human immunodeficiency virus type 1 (HIV-1) vaccine immunogens capable of inducing broadly neutralizing antibodies (bNAbs) remain obscure. HIV-1 evades immune responses through enormous diversity and hides its conserved vulnerable epitopes on the envelope glycoprotein (Env) by displaying an extensive immunodominant glycan shield. In elite HIV-1 viremic controllers, glycan-dependent bNAbs targeting conserved Env epitopes have been isolated and are utilized as vaccine design templates. However, immunological tolerance mechanisms limit the development of these antibodies in the general population. The well characterized bNAbs monoclonal variants frequently exhibit extensive levels of somatic hypermutation, a long third heavy chain complementary determining region, or a short third light chain complementarity determining region, and some exhibit poly-reactivity to autoantigens. This review elaborates on the obstacles to engaging and manipulating the Env glycoprotein as an effective immunogen and describes an alternative reverse vaccinology approach to develop a novel category of bNAb-epitope-derived non-cognate immunogens for HIV-1 vaccine design.
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Vacunas contra el SIDA , Anticuerpos Neutralizantes , Anticuerpos Anti-VIH , VIH-1 , VIH-1/inmunología , Humanos , Vacunas contra el SIDA/inmunología , Anticuerpos Neutralizantes/inmunología , Anticuerpos Anti-VIH/inmunología , Polisacáridos/inmunología , Infecciones por VIH/inmunología , Imitación Molecular/inmunología , Epítopos/inmunología , Productos del Gen env del Virus de la Inmunodeficiencia Humana/inmunología , LigandosRESUMEN
Over the past several years, messenger RNA (mRNA) vaccine has evolved from a term familiar only to vaccine scientists into one easily recognized by much of the general population. This change occurred because of the remarkable success of effective and safe mRNA vaccines during the COVID-19 pandemic that saved countless lives. Although mRNA vaccine technology has a clear use for combating future emerging diseases, its role in fighting currently known pathogens, such as HIV-1, is not well defined. This review summarizes mRNA vaccine technology, highlighting its success during the COVID-19 pandemic. It then addresses past and current efforts to develop a vaccine for HIV-1, including how mRNA vaccine technology has created opportunities in the ongoing search for an effective HIV-1 vaccine.
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Vacunas contra el SIDA , Vacunas contra la COVID-19 , COVID-19 , Infecciones por VIH , VIH-1 , SARS-CoV-2 , Vacunas de ARNm , Humanos , Vacunas contra el SIDA/inmunología , Vacunas contra la COVID-19/inmunología , COVID-19/prevención & control , SARS-CoV-2/inmunología , SARS-CoV-2/genética , VIH-1/genética , VIH-1/inmunología , Infecciones por VIH/prevención & control , Vacunas Sintéticas/inmunología , Desarrollo de VacunasRESUMEN
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.
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Vacunas contra el SIDA , Alelos , Infecciones por VIH , VIH-1 , Productos del Gen env del Virus de la Inmunodeficiencia Humana , Productos del Gen gag del Virus de la Inmunodeficiencia Humana , Humanos , Vacunas contra el SIDA/inmunología , Vacunas contra el SIDA/administración & dosificación , VIH-1/inmunología , VIH-1/genética , Infecciones por VIH/inmunología , Infecciones por VIH/virología , Infecciones por VIH/genética , Infecciones por VIH/prevención & control , Productos del Gen gag del Virus de la Inmunodeficiencia Humana/inmunología , Productos del Gen gag del Virus de la Inmunodeficiencia Humana/genética , Productos del Gen env del Virus de la Inmunodeficiencia Humana/inmunología , Productos del Gen env del Virus de la Inmunodeficiencia Humana/genética , Antígenos de Histocompatibilidad Clase I/inmunología , Antígenos de Histocompatibilidad Clase I/genética , Masculino , Carga Viral , Adulto , Femenino , Linfocitos T CD8-positivos/inmunologíaRESUMEN
HIV vaccine development has been hindered by significant challenges over four decades. Despite persistent efforts, all efficacy trials to date have yielded disappointing results. This has pushed the field back to the discovery phase and created uncertainty about the future involvement of large pharmaceutical companies. Currently, the HIV vaccine landscape is dominated by startup biotech firms, which face a complex array of obstacles. These include evolving HIV prevention methods, waning interest in vaccine research, and difficulties securing sustainable funding. This viewpoint explores the challenges faced by these biotech companies and the support mechanisms necessary for their continued involvement in HIV vaccine development. By leveraging insights from both pharmaceutical and biotech sectors, we propose a multi-faceted approach that includes enhanced communication, fostering innovation, and implementing strategic funding models.
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Vacunas contra el SIDA , Biotecnología , Infecciones por VIH , Desarrollo de Vacunas , Vacunas contra el SIDA/inmunología , Vacunas contra el SIDA/administración & dosificación , Humanos , Infecciones por VIH/prevención & control , Industria Farmacéutica/economía , Desarrollo de Medicamentos/tendencias , Desarrollo de Medicamentos/economíaRESUMEN
Minimal immunogen vaccines are being developed to focus antibody responses against otherwise challenging targets, including human immunodeficiency virus (HIV), but multimerization of the minimal peptide immunogen on a carrier platform is required for activity. Star copolymers comprising multiple hydrophilic polymer chains ("arms") radiating from a central dendrimer unit ("core") were recently reported to be an effective platform for arraying minimal immunogens for inducing antibody responses in mice and primates. However, the impact of different parameters of the star copolymer (e.g., minimal immunogen density and hydrodynamic size) on antibody responses and the optimal synthetic route for controlling those parameters remains to be fully explored. We synthesized a library of star copolymers composed of poly[N-(2-hydroxypropyl)methacrylamide] hydrophilic arms extending from poly(amidoamine) dendrimer cores with the aim of identifying the optimal composition for use as minimal immunogen vaccines. Our results show that the length of the polymer arms has a crucial impact on the star copolymer hydrodynamic size and is precisely tunable over a range of 20-50 nm diameter, while the dendrimer generation affects the maximum number of arms (and therefore minimal immunogens) that can be attached to the surface of the dendrimer. In addition, high-resolution images of selected star copolymer taken by a custom-modified environmental scanning electron microscope enabled the acquisition of high-resolution images, providing new insights into the star copolymer structure. Finally, in vivo studies assessing a star copolymer vaccine comprising an HIV minimal immunogen showed the criticality of polymer arm length in promoting antibody responses and highlighting the importance of composition tunability to yield the desired biological effect.
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Dendrímeros , Animales , Dendrímeros/química , Ratones , Polímeros/química , Portadores de Fármacos/química , Vacunas/inmunología , Vacunas/química , Vacunas/administración & dosificación , Humanos , Vacunas contra el SIDA/inmunología , Vacunas contra el SIDA/química , Vacunas contra el SIDA/administración & dosificación , PoliaminasRESUMEN
SUMMARYThe success of the Severe Acute Respiratory Syndrome Coronavirus 2 mRNA vaccines to lessen/prevent severe COVID-19 opened new opportunities to develop RNA vaccines to fight other infectious agents. HIV-1 is a lentivirus that integrates into the host cell genome and persists for the lifetime of infected cells. Multiple mechanisms of immune evasion have posed significant obstacles to the development of an effective HIV-1 vaccine over the last four decades since the identification of HIV-1. Recently, attempts to address some of these challenges have led to multiple studies that manufactured, optimized, and tested, in different animal models, mRNA-based HIV-1 vaccines. Several clinical trials have also been initiated or are planned to start soon. Here, we review the current strategies applied to HIV-1 mRNA vaccines, discuss different targeting approaches, summarize the latest findings, and offer insights into the challenges and future of HIV-1 mRNA vaccines.
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Vacunas contra el SIDA , Infecciones por VIH , VIH-1 , Humanos , VIH-1/inmunología , VIH-1/genética , Vacunas contra el SIDA/inmunología , Infecciones por VIH/prevención & control , Infecciones por VIH/inmunología , Animales , Vacunas de ARNm , ARN Mensajero/genética , ARN Mensajero/inmunología , Vacunas Sintéticas/inmunología , SARS-CoV-2/inmunología , SARS-CoV-2/genética , COVID-19/prevención & control , COVID-19/inmunologíaRESUMEN
The lack of success in clinical trials for HIV vaccines highlights the need to explore novel strategies for vaccine development. Research on highly exposed seronegative (HESN) HIV-resistant Kenyan female sex workers revealed naturally protective immunity is correlated with a focused immune response mediated by virus-specific CD8 T cells. Further studies indicated that the immune response is unconventionally focused on highly conserved sequences around HIV viral protease cleavage sites (VPCS). Thus, taking an unconventional approach to HIV vaccine development, we designed lipid nanoparticles loaded with mRNA that encodes multi-epitopes of VPCS (MEVPCS-mRNA LNP), a strategic design to boost antigen presentation by dendritic cells, promoting effective cellular immunity. Furthermore, we developed a novel cold-chain compatible mRNA LNP formulation, ensuring long-term stability and compatibility with cold-chain storage/transport, widening accessibility of mRNA LNP vaccine in low-income countries. The in-vivo mouse study demonstrated that the vaccinated group generated VPCS-specific CD8 memory T cells, both systemically and at mucosal sites of viral entry. The MEVPCS-mRNA LNP vaccine-induced CD8 T cell immunity closely resembled that of the HESN group and displayed a polyfunctional profile. Notably, it induced minimal to no activation of CD4 T cells. This proof-of-concept study underscores the potential of the MEVPCS-mRNA LNP vaccine in eliciting CD8 T cell memory specific to the highly conserved multiple VPCS, consequently having a broad coverage in human populations and limiting viral escape mutation. The MEVPCS-mRNA LNP vaccine holds promise as a candidate for an effective prophylactic HIV vaccine.
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Vacunas contra el SIDA , Linfocitos T CD8-positivos , Infecciones por VIH , Vacunas de ARNm , Vacunas contra el SIDA/inmunología , Vacunas contra el SIDA/administración & dosificación , Vacunas contra el SIDA/genética , Animales , Ratones , Linfocitos T CD8-positivos/inmunología , Femenino , Infecciones por VIH/prevención & control , Infecciones por VIH/inmunología , Infecciones por VIH/virología , Humanos , VIH-1/inmunología , VIH-1/genética , Nanopartículas/química , Proteasa del VIH/genética , Proteasa del VIH/inmunología , Kenia , Trabajadores Sexuales , Células Dendríticas/inmunología , Epítopos de Linfocito T/inmunología , Epítopos de Linfocito T/genética , Epítopos/inmunología , Epítopos/genética , ARN Mensajero/genética , ARN Mensajero/inmunología , LiposomasRESUMEN
Development of a safe and effective human immunodeficiency virus (HIV) vaccine is a persistent challenge despite decades of research. Previous strategies utilizing protein subunit and viral vector vaccines were safe but not protective. Current strategies seek to induce broadly neutralizing antibodies, with multiple early phase trials in progress seeking to achieve this through sequential vaccination, mRNA, or updated viral-vectored vaccines. A safe and effective vaccine is critical to ending the HIV epidemic.
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Vacunas contra el SIDA , Infecciones por VIH , Humanos , Vacunas contra el SIDA/inmunología , Vacunas contra el SIDA/administración & dosificación , Infecciones por VIH/prevención & control , Anticuerpos Neutralizantes/inmunología , VIH-1/inmunología , Anticuerpos Anti-VIH/inmunología , Desarrollo de VacunasRESUMEN
Introduction: The HVTN 105 vaccine clinical trial tested four combinations of two immunogens - the DNA vaccine DNA-HIV-PT123, and the protein vaccine AIDSVAX B/E. All combinations induced substantial antibody and CD4+ T cell responses in many participants. We have now re-examined the intracellular cytokine staining flow cytometry data using the high-resolution SWIFT clustering algorithm, which is very effective for enumerating rare populations such as antigen-responsive T cells, and also determined correlations between the antibody and T cell responses. Methods: Flow cytometry samples across all the analysis batches were registered using the swiftReg registration tool, which reduces batch variation without compromising biological variation. Registered data were clustered using the SWIFT algorithm, and cluster template competition was used to identify clusters of antigen-responsive T cells and to separate these from constitutive cytokine producing cell clusters. Results: Registration strongly reduced batch variation among batches analyzed across several months. This in-depth clustering analysis identified a greater proportion of responders than the original analysis. A subset of antigen-responsive clusters producing IL-21 was identified. The cytokine patterns in each vaccine group were related to the type of vaccine - protein antigens tended to induce more cells producing IL-2 but not IFN-γ, whereas DNA vaccines tended to induce more IL-2+ IFN-γ+ CD4 T cells. Several significant correlations were identified between specific antibody responses and antigen-responsive T cell clusters. The best correlations were not necessarily observed with the strongest antibody or T cell responses. Conclusion: In the complex HVTN105 dataset, alternative analysis methods increased sensitivity of the detection of antigen-specific T cells; increased the number of identified vaccine responders; identified a small IL-21-producing T cell population; and demonstrated significant correlations between specific T cell populations and serum antibody responses. Multiple analysis strategies may be valuable for extracting the most information from large, complex studies.
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Vacunas contra el SIDA , Linfocitos T CD4-Positivos , Citocinas , Citometría de Flujo , Infecciones por VIH , Humanos , Vacunas contra el SIDA/inmunología , Linfocitos T CD4-Positivos/inmunología , Citometría de Flujo/métodos , Análisis por Conglomerados , Infecciones por VIH/inmunología , Infecciones por VIH/virología , Citocinas/metabolismo , Citocinas/inmunología , Inmunidad Humoral , Anticuerpos Anti-VIH/inmunología , Anticuerpos Anti-VIH/sangre , VIH-1/inmunología , Vacunas de ADN/inmunología , Interleucinas/inmunologíaRESUMEN
BACKGROUND: An effective vaccine is required to end the HIV pandemic. We evaluated the safety and immunogenicity of a DNA (DNA-HIV-PT123) vaccine with low- or high-dose bivalent (TV1.C and 1086.C glycoprotein 120) subtype C envelope protein combinations, adjuvanted with MF59 or AS01B. METHODS: HIV Vaccine Trials Network (HVTN)108 was a randomized, placebo-controlled, double-blind, phase 1/2a trial conducted in the United States and South Africa. HIV-negative adults were randomly assigned to 1 of 7 intervention arms or placebo to assess DNA prime with DNA/protein/adjuvant boosts, DNA/protein/adjuvant co-administration, and low-dose protein/adjuvant regimens. HVTN111 trial participants who received an identical regimen were also included. Outcomes included safety and immunogenicity 2 weeks and 6 months after final vaccination. RESULTS: From June 2016 to July 2018, 400 participants were enrolled (N = 334 HVTN108, N = 66 HVTN111); 370 received vaccine and 30 received placebo. There were 48 grade 3 and 3 grade 4 reactogenicity events among 39/400 (9.8%) participants, and 32 mild/moderate-related adverse events in 23/400 (5.8%) participants. All intervention groups demonstrated high IgG response rates (>89%) and high magnitudes to HIV-1 Env gp120 and gp140 proteins; response rates for AS01B-adjuvanted groups approached 100%. V1V2 IgG magnitude, Fc-mediated functions, IgG3 Env response rates, and CD4+ T-cell response magnitudes and rates were higher in the AS01B-adjuvanted groups. The AS01B-adjuvanted low-dose protein elicited greater IgG responses than the higher protein dose. CONCLUSIONS: The vaccine regimens were generally well tolerated. Co-administration of DNA with AS01B-adjuvanted bivalent Env gp120 elicited the strongest humoral responses; AS01B-adjuvanted regimens elicited stronger CD4+ T-cell responses, justifying further evaluation.ClinicalTrials.gov registration: NCT02915016, registered 26 September 2016.
Asunto(s)
Vacunas contra el SIDA , Adyuvantes Inmunológicos , Anticuerpos Anti-VIH , Proteína gp120 de Envoltorio del VIH , Infecciones por VIH , VIH-1 , Polisorbatos , Escualeno , Vacunas de ADN , Humanos , Vacunas contra el SIDA/inmunología , Vacunas contra el SIDA/administración & dosificación , Vacunas contra el SIDA/efectos adversos , Vacunas de ADN/inmunología , Vacunas de ADN/administración & dosificación , Vacunas de ADN/efectos adversos , Femenino , Masculino , Adulto , Escualeno/administración & dosificación , Polisorbatos/administración & dosificación , Proteína gp120 de Envoltorio del VIH/inmunología , Adyuvantes Inmunológicos/administración & dosificación , VIH-1/inmunología , Infecciones por VIH/inmunología , Infecciones por VIH/prevención & control , Anticuerpos Anti-VIH/sangre , Método Doble Ciego , Persona de Mediana Edad , Adulto Joven , Adyuvantes de Vacunas/administración & dosificación , Sudáfrica , Inmunogenicidad Vacunal , Adolescente , Estados UnidosRESUMEN
African Green (Vervet) monkeys have been extensively studied to understand the pathogenesis of infectious diseases. Using vervet monkeys as pre-clinical models may be an attractive option for low-resourced areas as they are found abundantly and their maintenance is more cost-effective than bigger primates such as rhesus macaques. We assessed the feasibility of using vervet monkeys as animal models to examine the immunogenicity of HIV envelope trimer immunogens in pre-clinical testing. Three groups of vervet monkeys were subcutaneously immunized with either the BG505 SOSIP.664 trimer, a novel subtype C SOSIP.664 trimer, CAP255, or a combination of BG505, CAP255 and CAP256.SU SOSIP.664 trimers. All groups of vervet monkeys developed robust binding antibodies by the second immunization with the peak antibody response occurring after the third immunization. Similar to binding, antibody dependent cellular phagocytosis was also observed in all the monkeys. While all animals developed potent, heterologous Tier 1 neutralizing antibody responses, autologous neutralization was limited with only half of the animals in each group developing responses to their vaccine-matched pseudovirus. These data suggest that the vervet monkey model may yield distinct antibody responses compared to other models. Further study is required to further determine the utility of this model in HIV immunization studies.