This project will test the ability of T follicular helper (Tfh) cell-targeting "genetic adjuvants" to improve immunogenicity of an advanced HIV envelope (Env) trimer. Eliciting neutralizing antibodies (nAb) against HIV will likely be required to create effective therapeutic vaccines that attenuate HIV disease progression, reduce HIV infectiousness, or even effect sustained remission in the absence of daily antiretroviral drug therapy. However, eliciting such antibodies is a challenge that can be frustrated at multiple steps in B-cell development, particularly in HIV-infected people. Of greatest relevance to this application, low-affinity germline B cells reactive to neutralizing epitopes may not successfully compete with cells binding non-neutralizing epitopes for antigen, or the amount of antigen acquired may be insufficient to stimulate Tfh cells to provide the required help. Tendel Therapies Inc. developed B-cell adjuvant technology that augments Tfh cells and is designed for use with vectored vaccines. Our preliminary data show that the adjuvant acts on both Tfh and B cells to promote uniquely intense and durable antibody responses. We propose to use these adjuvants in combination with two promising B-cell immunogens to reliably elicit tier-2 neutralizing antibodies in macaques: (i) an advanced BG505 SOSIP-like trimer designed to promote focused responses to nAb targets and minimize reactivity of non-neutralizing Env epitopes such as the V3 loop or non-neutralizing CD4 binding site sub-regions, and (ii) bacteriophage VLPs displaying the HIV fusion peptide (FP) in highly multimeric form. We hypothesize that novel Tfh-targeting adjuvants promote broader nAb responses to an advanced HIV Env immunogen via mechanisms including democratic naïve B-cell recruitment and stimulation of Tfh responses. Aim 1. Assess the intensity and durability of nAb, Tfh, and germinal center B-cell responses to an advanced HIV envelope trimer, delivered with or without Tendel adjuvants, as mRNA in lipid nanoparticles. The goals are (i) to test if Tendel adjuvants have similar potency for augmentation of antibody responses to mRNA-vectored vaccination against native-like HIV Env trimers, as previously shown for augmentation of responses against the SARS-CoV-2 receptor binding domain; and (ii) to select one regimen for evaluation in Aim 2 subsequent to fusion-peptide priming. Aim 2. Evaluate the effect of priming immunization with the HIV Env fusion peptide, FP8, on neutralization breadth achieved by Tendel adjuvants and HIV Env native-like trimers. This priming regimen is intended to provide an additional epitopic focus for nAb responses. Due to the combination of anti- FP nAbs with other nAbs provided by trimer immunization, the FP8-primed regimen should result in nAb responses of increased breadth and perhaps higher titer.
Public Health Relevance Statement: We are seeking effective regimen for therapeutic or prophylactic vaccination against the human immunodeficiency virus (HIV). The strategy is to use targeted immunostimulants to guide the immune system to production of antibodies that neutralize the virus, which are thought to be an essential component of an effective vaccine. We will test newly developed immunostimulants for their capacity to elicit such neutralizing antibodies and determine the breadth of suppression achieved against diverse HIV strains.
Project Terms: Immunoactivators; Immunoadjuvants; Immunological Adjuvant; Immunopotentiators; Immunostimulants; immune adjuvant; Immunologic Adjuvants; aminoacid; Amino Acids; Antibodies; Ab response; Antibody Production; antibody biosynthesis; immunoglobulin biosynthesis; Antibody Formation; Antigenic Determinants; Binding Determinants; Epitopes; immunogen; Antigens; B-Lymphocytes; B blood cells; B cell; B cells; B-Cells; B-cell; Bacteriophages; Phages; bacterial virus; Binding Sites; Combining Site; Reactive Site; Cells; Cell Body; Clinical Trials; Pharmacotherapy; Drug Therapy; drug treatment; Frustration; Goals; Government; Hand; hands; Helper-Inducer T-Lymphocyte; Helper Cells; Helper T-Cells; Helper T-Lymphocytes; Helper-Inducer T-Cells; Inducer Cells; Inducer T-Lymphocytes; HIV; AIDS Virus; Acquired Immune Deficiency Syndrome Virus; Acquired Immunodeficiency Syndrome Virus; Human Immunodeficiency Viruses; LAV-HTLV-III; Lymphadenopathy-Associated Virus; Virus-HIV; HIV-1; HIV-I; HIV1; Human Immunodeficiency Virus Type 1; Human immunodeficiency virus 1; Human; Modern Man; Immune system; Immunization; Infection; Macaca; Macaque; Persons; Peptides; Polymers; polymer; polymeric; Primates; Primates Mammals; Messenger RNA; mRNA; Technology; Testing; Vaccination; Vaccine Therapy; VAC-TX; therapeutic vaccination; Vaccines; Attenuated Vaccines; Live-attenuated Vaccine; live vaccine; live vaccines; Virus; Work; HIV/AIDS Vaccines; human immunodeficiency virus vaccine; HIV vaccine; improved; Left; Surface; Series; Evaluation; non-human primate; nonhuman primate; Disease Progression; Funding; Germinal Center; Structure of germinal center of lymph node; Genetic; Frequencies; neutralizing antibody; Disease remission; Remission; HIV envelope protein; HIV envelope; receptor binding; receptor bound; vaccine development; develop a vaccine; develop vaccines; development of a vaccine; vector vaccine; plasmid vaccine; Anti-Retroviral Agents; Antiretroviral Agents; anti-retroviral; antiretroviral; novel; response; Molecular Interaction; Binding; Affinity; B-Cell Development; Data; research clinical testing; Clinical Evaluation; Clinical Testing; clinical test; V3 Loop; V3 Loop of HIV-1; Adjuvant; Development; developmental; vector; immunogenicity; designing; design; NH2-terminal; N-terminal; Regimen; Antibody Response; Preventative Immunization; Preventive Immunization; Preventive vaccination; Prophylactic immunization; Prophylactic vaccination; Preventative vaccination; experiment; experimental research; experiments; experimental study; recruit; lipid based nanoparticle; lipid nanoparticle; 2019 novel corona virus; 2019 novel coronavirus; COVID-19 virus; COVID19 virus; CoV-2; CoV2; SARS corona virus 2; SARS-CO-V2; SARS-COVID-2; SARS-CoV-2; SARS-CoV2; SARS-associated corona virus 2; SARS-associated coronavirus 2; SARS-coronavirus-2; SARS-related corona virus 2; SARS-related coronavirus 2; SARSCoV2; Severe Acute Respiratory Coronavirus 2; Severe Acute Respiratory Distress Syndrome CoV 2; Severe Acute Respiratory Distress Syndrome Corona Virus 2; Severe Acute Respiratory Distress Syndrome Coronavirus 2; Severe Acute Respiratory Syndrome CoV 2; Severe Acute Respiratory Syndrome-associated coronavirus 2; Severe Acute Respiratory Syndrome-related coronavirus 2; Severe acute respiratory syndrome associated corona virus 2; Severe acute respiratory syndrome coronavirus 2; Severe acute respiratory syndrome related corona virus 2; Wuhan coronavirus; coronavirus disease 2019 virus; coronavirus disease-19 virus; hCoV19; nCoV2; 2019-nCoV; 2019-nCoV vaccine; COVID19 vaccine; SARS-CoV-2 vaccine; SARS-CoV2 vaccine; SARS-coronavirus-2 vaccine; Severe Acute Respiratory Syndrome CoV 2 vaccine; Severe acute respiratory syndrome coronavirus 2 vaccine; corona virus disease 2019 vaccine; coronavirus disease 2019 vaccine; coronavirus disease-19 vaccine; nCoV vaccine; nCoV-19 vaccine; nCoV19 vaccine; vaccine against 2019-nCov; vaccine against SARS-CoV-2; vaccine against SARS-CoV2; vaccine against SARS-coronavirus-2; vaccine against Severe Acute Respiratory Syndrome CoV 2; vaccine against Severe acute respiratory syndrome coronavirus 2; vaccine for novel coronavirus; COVID-19 vaccine; therapeutically effective; vaccination protocol; vaccine protocol
