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Principal Investigator: paolo lusso
Organization: NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES
Fiscal Year: 2022
Award: $1,549,551
Funding agency: National Institute of Allergy and Infectious Diseases
The development of an HIV vaccine has been hampered by unprecedented challenges, primarily due to the unique properties of the HIV-1 envelope (Env) trimer, a cleverly engineered entry machinery that features an extraordinary assortment of immune-evasion tactics, including antigenic variation, heavy glycosylation of exposed surfaces and conformational masking of key neutralization sites. Further insights into the complex structure-function relationships in the HIV-1 Env trimer and its protective shield may be critical to guide the rational design of a protective vaccine and other immunoprophylaxis measures.
1) Enhancement of broadly HIV-neutralizing antibodies.
We previously reported the discovery of a second CD4-binding site in the HIV-1 Env trimer, that we defined as CD4-binding site 2 (CD4-BS2), which opened new perspectives for HIV vaccine and therapy. We also identified selected anti-CD4-BS antibodies, such as VRC03 and VRC06, which mimic the quaternary-binding mode of CD4 and establish contact with two adjacent gp120 protomers via an extended loop in their heavy chain framework region 3 (FR3). Thus, we rationally engrafted the extended FR3 loop of VRC03 onto different CD4-supersite bNAbs and tested the resulting chimeric antibodies against a wide panel of global HIV-1 strains (n = 208). FR3-loop chimerization enhanced the neutralizing activity of several potent bNAbs against a majority of global HIV-1 strains. The interactive quaternary surface was delineated by solving the crystal structure of two FR3 loop-chimeric antibodies in complex with a soluble Env trimer. Furthermore, compared to unmodified antibodies, chimeric antibodies displayed a reduced autoreactivity and a prolonged in vivo half-life in both huFcRn transgenic mice and rhesus macaques. Due to their increased neutralizing potency and favorable biological and pharmacokinetic properties, FR3-loop-chimeric bNAbs are being considered for use in HIV prevention and treatment. We have recently extended these studies to other potent bNAbs, including the N49P family from the IHV in Baltimore and 1-18 from the Klein group in Germany. Interestingly, chimerization of the N49P antibodies was successful resulting in the most potent bNAbs against the CD4-BS ever reported so far. By contrast, modification of antibody 1-18 resulted in a loss of function, confirming that successful chimerization requires specific structural features that ar4 not common to all anti-CD4-BS antibodies. Preclinical studies are underway to assess the efficacy of selected chimeric antibodies in humanized mouse models.
2) Pre-clinical evaluation of a VLP-forming mRNA vaccine for HIV-1 in macaques
The development of a protective vaccine remains a top priority for the control of the HIV/AIDS pandemic. We have designed a novel vaccine platform for HIV-1 based on messenger RNA (mRNA), the same technology used for the Covid-19 vaccines, and tested in a preclinical model in macaques. The study was conducted in collaboration with Moderna Inc. Our vaccine design includes: a) co-expression of membrane-anchored HIV-1 envelope (Env) with simian immunodeficiency virus (SIV) Gag proteins in order to generate non-infectious virus-like particles (VLPs) in vivo; b) initial priming with a germline bNAb engaging Env; and c) multiple heterologous booster immunizations with different HIV-1 clades. In preliminary experiments conducted in mice, immunization with co-formulated Env and Gag mRNAs was superior to Env mRNA alone in inducing neutralizing antibodies. In macaques, we tested a complex protocol encompassing an initial priming with a transmitted-founder clade-B Env mRNA lacking a critical glycan (N276) that covers the CD4-binding site glycan, followed by multiple booster immunizations with glycan-repaired autologous and subsequently bivalent heterologous Envs from different clades (clades A and C). All Envs were co-formulated with Gag to produce VLPs. This regimen was highly immunogenic and elicited neutralizing antibodies against the most prevalent (tier-2) HIV-1 strains accompanied by robust anti-Env CD4+ T cell responses. Vaccinated animals had a 79% per-exposure risk reduction upon repeated low-dose mucosal challenges with heterologous tier-2 simianhuman immunodeficiency virus (SHIV AD8). Thus, our multiclade envgag VLP mRNA platform represents a promising approach for the development of an HIV-1 vaccine.
Terms: <2019-nCoV vaccine><AIDS Virus><AIDS prevention><AIDS/HIV><AIDS/HIV problem><Acquired Immune Deficiency Syndrome Virus><Acquired Immunodeficiency Syndrome Virus><Animal Model><Animal Models and Related Studies><Animals><Antibodies><Antigen Variation><Antigenic Variability><Antigenic Variation><Antigens><Autologous><Baltimore><Binding><Binding Sites><Biological><Booster Immunization><CD4 Cells><CD4 Positive T Lymphocytes><CD4 T cells><CD4 helper T cell><CD4 lymphocyte><CD4+ T-Lymphocyte><CD4-Positive Lymphocytes><COVID-19 vaccine><COVID19 vaccine><Collaborations><Combining Site><Complex><Crystallization><Development><Dose><Drug Kinetics><Engineering><Family><Framework Regions><Generations><Germany><Glycans><Glycoproteins><Goals><HIV><HIV Envelope Glycoprotein gp120><HIV Envelope Protein gp120><HIV Infections><HIV Prevention><HIV env Protein gp120><HIV therapy><HIV vaccine><HIV-1><HIV-1 vaccine><HIV-I><HIV/AIDS><HIV/AIDS Vaccines><HIV/AIDS prevention><HIV/AIDS problem><HIV1><HIV1 vaccine><HTLV-III Infections><HTLV-III gp120><HTLV-III-LAV Infections><Half-Life><Human Immunodeficiency Virus Type 1><Human Immunodeficiency Viruses><Human T-Lymphotropic Virus Type III Infections><Human immunodeficiency virus 1><Immune Evasion><Immunization><Immunodeficiency Disorder><Immunodeficiency Syndrome><Immunologic Deficiency Syndromes><Immunologic Sensitization><Immunologic Stimulation><Immunological Deficiency Syndromes><Immunological Sensitization><Immunological Stimulation><Immunostimulation><Investigation><Knowledge><LAV-HTLV-III><Lymphadenopathy-Associated Virus><M mulatta><M. mulatta><Macaca><Macaca mulatta><Macaque><Masks><Measures><Membrane><Messenger RNA><Metabolic Glycosylation><Mice><Mice Mammals><Modification><Molecular Configuration><Molecular Conformation><Molecular Interaction><Molecular Stereochemistry><Mucosa><Mucosal Tissue><Mucous Membrane><Murine><Mus><Pharmacokinetics><Polysaccharides><Pre-Clinical Model><Preclinical Models><Prevention><Property><Protocol><Protocols documentation><Protomer><Reactive Site><Receptor Protein><Regimen><Reporting><Retroviral Antigen gag Protein><Rhesus Macaque><Rhesus Monkey><Risk Reduction><Rodent><Rodentia><Rodents Mammals><SARS-CoV-2 vaccine><SARS-CoV2 vaccine><SARS-coronavirus-2 vaccine><SHIV><SIV><Secondary Immunization><Severe Acute Respiratory Syndrome CoV 2 vaccine><Severe acute respiratory syndrome coronavirus 2 vaccine><Simian Immunodeficiency Viruses><Site><Structure><Structure-Activity Relationship><Surface><T cell response><T4 Cells><T4 Lymphocytes><Technology><Test Result><Testing><Transgenic Mice><Vaccinated><Vaccine Design><Vaccines><Viral gag Proteins><Virus><Virus-HIV><Virus-like particle><autoreactivity><base><biologic><booster vaccination><chemical structure function><chimeric antibody><conformation><conformational state><corona virus disease 2019 vaccine><coronavirus disease 2019 vaccine><coronavirus disease-19 vaccine><design><designing><developmental><evaluate vaccines><experiment><experimental research><experimental study><gag Antigens><gag Gene Products><gag Polyproteins><gag Protein><glycosylation><gp120><gp120 ENV Glycoprotein><gp120(HIV)><group specific antigen><human immunodeficiency virus vaccine><humanized mice><humanized mouse><hypoimmunity><immune deficiency disorder><immunodeficiency><immunogen><immunogenic><immunoprophylaxis><improved><in vivo><insight><loss of function><mRNA><membrane structure><model of animal><model organism><mouse model><murine model><natural antibodies><neutralizing antibody><new vaccines><next generation vaccines><novel><novel vaccines><pandemic><pandemic disease><pre-clinical evaluation><pre-clinical study><preclinical evaluation><preclinical study><prevent><preventing><rational design><receptor><repair><repaired><simian HIV><simian human immunodeficiency virus><structure function relationship><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 evaluation><vaccine for novel coronavirus><vaccine platform><vaccine screening><vaccine testing><virus-like nanoparticles><viruslike particle>