Biology subjects

Chackerian, B.

Publications and source records attributed to Chackerian, B..

3 recordsLinked to original sources

bioRxiv2021

A VLP-based vaccine targeting ANGPTL3 lowers plasma triglycerides in mice

Elevated triglycerides (TGs) are an important risk factor for the development of coronary heart disease (CHD) and in acute pancreatitis. Angiopoietin-like proteins 3 (ANGPTL3) and 4 (ANGPTL4) are critical regulators of TG metabolism that function by inhibiting the activity of lipoprotein lipase (LPL), which is responsible for hydrolyzing triglycerides in lipoproteins into free fatty acids. Interestingly, individuals with loss-of-function mutations in ANGPTL3 and ANGPTL4 have low plasma TG levels, have a reduced risk of CHD, and are otherwise healthy. Consequently, interventions targeting ANGPTL3 and ANGPTL4 have emerged as promising new approaches for reducing elevated TGs. Here, we developed virus-like particle (VLP) based vaccines that target the LPL binding domains of ANGPTL3 and ANGPTL4. ANGPTL3 VLPs and ANGPTL4 VLPs are highly immunogenic in mice and vaccination with ANGPTL3 VLPs, but not ANGPTL4 VLPs, was associated with reduced steady state levels of TGs. Immunization with ANGPTL3 VLPs rapidly cleared circulating TG levels following an oil gavage challenge and enhanced plasma LPL activity. These data indicate that targeting ANGPTL3 by active vaccination is potential alternative to other ANGPTL3-inhibiting therapies. HighlightsO_LIANGPTL3 and ANGPTL4 are mediators of lipoprotein metabolism that inhibit lipoprotein lipase (LPL) activity. C_LIO_LIVaccination using virus-like particles (VLPs) targeting ANGPTL3 and ANGPTL4 elicits high-titer IgG antibody responses. C_LIO_LIImmunization with ANGPTL3 VLPs lowers steady-state plasma triglycerides and enhances LPL activity. C_LI

immunology↗

bioRxiv2020

Virus-Like Particle Based-Vaccines Elicit Neutralizing Antibodies against the HIV-1 Fusion Peptide

Broadly neutralizing antibodies (bnAbs) isolated from HIV-infected individuals delineate vulnerable sites on the HIV envelope glycoprotein that are potential vaccine targets. A linear epitope at the N-terminal region of the HIV-1 fusion peptide (FP8) is the primary target of VRC34.01, a bnAb that neutralizes ~50% of primary HIV isolates. FP8 has attracted attention as a potential HIV vaccine target because it is a simple linear epitope. Here, we used platform technologies based on RNA bacteriophage virus-like particles (VLPs) to develop multivalent vaccines targeting the FP8 epitope. We produced recombinant MS2 VLPs displaying the FP8 peptide and we chemically conjugated synthetic FP8 peptides to Q{beta} VLPs. Both recombinant and conjugated FP8-VLPs induced high titers of FP8-specific antibodies in mice. A heterologous prime-boost-boost regimen employing the two FP8-VLP vaccines and native envelope trimer was the most effective approach for eliciting HIV-1 neutralizing antibodies. Given the potent immunogenicity of VLP-based vaccines, this vaccination strategy - inspired by bnAb-guided epitope mapping, VLP bioengineering, and optimal prime-boost immunization strategies - may be an effective strategy for eliciting bnAb responses against HIV.

immunology↗

bioRxiv2020

An Epitope-based Malaria Vaccine Targeting the Junctional Domain of Circumsporozoite Protein

A malaria vaccine that elicits long-lasting protection and is suitable for use in endemic areas remains urgently needed. Here, we assessed the immunogenicity and prophylactic efficacy of a vaccine targeting a recently described epitope on the major surface antigen on Plasmodium falciparum sporozoites, circumsporozoite protein (CSP). Using a virus-like particle (VLP)-based vaccine platform technology, we developed a vaccine that targets the junctional region between the N-terminal and central repeat domains of CSP. This region is recognized by monoclonal antibodies, including mAb CIS43, that have been shown to potently prevent liver invasion in animal models. We show that CIS43 VLPs elicit high titer and long-lived anti-CSP antibody responses in mice and non-human primates. Immunization with CIS43 VLPs confers partial protection from malaria infection in a mouse model, and both immunogenicity and protection were enhanced when mice were immunized with CIS43 VLPs in combination with adjuvants including delta inulin polysaccharide particles and TLR9 agonists. Passive transfer of serum from immunized macaques also inhibited parasite liver invasion in the mouse infection model. Our findings demonstrate that a Q{beta} VLP-based vaccine targeting the CIS43 epitope combined with various adjuvants is highly immunogenic in mice and macaques, elicits long-lasting anti-CSP antibodies, and inhibits parasite infection in a mouse model. Thus, the CIS43 VLP vaccine is a promising pre-erythrocytic malaria vaccine candidate.

immunology↗