Biology subjects

Arunkumar, G. A.

Publications and source records attributed to Arunkumar, G. A..

3 recordsLinked to original sources

bioRxiv2025

A multivalent mRNA-LNP therapeutic vaccine with broad cross-genotype immunogenicity elicits clearance of HBV infected hepatocytes

Chronic hepatitis B remains a major global health challenge, affecting over 254 million individuals and causing over 1 million deaths annually. Despite current antiviral therapies effectively suppressing viral replication, functional cure rates are low due to HBV-induced immune dysfunction and exhaustion. Therefore, new therapeutic approaches to achieve immune control of HBV infection are needed. Following the systematic evaluation of multiple HBV mRNA antigen designs, we developed mRNA-1965, a trivalent therapeutic mRNA vaccine encoding nanoparticle-displayed PreS1 and PreS2 domains of HBsAg to bypass the immune interference caused by HBV subviral particles, along with mutant forms of HBV Core and Polymerase. In HBV naive mice, mRNA-1965 immunization induced dose-dependent HBV-neutralizing antibodies and Th1-skewed CD4+ and IFN{gamma}+ CD8+ T cell responses to all three encoded HBV antigens. In non-human primates, mRNA-1965 elicited broad antibody and T cell responses across multiple HBV genotypes. Furthermore, vaccination with mRNA-1965 achieved a strong neutralizing antibody response and complete clearance of serum and liver HBV biomarkers in in an AAV-HBV mouse model with [~]100 IU/mL baseline HBsAg. Notably, combining mRNA-1965 with immune stimulatory co-modalities targeting PD-L1 and OX40 further enhanced therapeutic efficacy in mice with [~]1000 IU/mL baseline HBsAg. Clearance of HBV in AAV-HBV mice was associated with T cell response to mRNA-encoded antigens and with activation and differentiation of Core-specific CD8+ T cells. These findings support the potential of mRNA-1965 to promote a functional cure for chronic hepatitis B by overcoming immune dysfunction and subsequently enabling robust, functional immunity.

immunology↗

bioRxiv2024

Prototype mRNA vaccines imprint broadly neutralizing human serum antibodies after Omicron variant-matched boosting

Immune imprinting is a phenomenon in which an individuals prior antigenic experiences influence responses to subsequent infection or vaccination. Here, using antibody depletion and multiplexed spike-binding assays, we characterized the type-specificity and cross-reactivity of serum antibody responses after mRNA vaccination in mice and human clinical trial participants. In mice, a single priming dose of a preclinical version of mRNA-1273 vaccine encoding Wuhan-1 spike minimally imprinted serum responses elicited by Omicron boosters, enabling a robust generation of type-specific antibodies. However, substantial imprinting was observed in mice receiving an Omicron booster after two priming doses of mRNA-1273, an effect that was mitigated by a second booster dose of Omicron mRNA vaccine. In humans who received two BA.5 or XBB.1.5 Omicron-matched boosters after two or more doses of the prototype mRNA-1273 vaccine, spike-binding and neutralizing serum antibodies cross-reacted with circulating Omicron variants as well as more distantly related sarbecoviruses. Because the serum neutralizing response against Omicron strains and other sarbecoviruses was completely abrogated after pre-clearing with the Wuhan-1 spike protein, antibodies induced by XBB.1.5 boosting in humans focus on conserved epitopes shaped and shared by the antecedent mRNA-1273 primary series. Our depletion analysis also identified cross-reactive neutralizing antibodies that recognize distinct epitopes in the receptor binding domain (RBD) and S2 proteins with differential inhibitory effects on members of the sarbecovirus subgenus. Thus, although the serum antibody response to Omicron-based boosters in humans is dominantly imprinted by prior immunizations with prototype mRNA-1273 vaccines, this outcome can be beneficial as it drives expansion of multiple classes of cross-neutralizing antibodies that inhibit infection of emerging SARS-CoV-2 variants and extend activity to distantly related sarbecoviruses.

immunology↗

bioRxiv2021

Functionality of the putative surface glycoproteins of the Wuhan spiny eel influenza virus

A panel of novel influenza-like virus sequences were recently documented in jawless fish, ray-finned fish, and amphibians. Of these, the Wuhan spiny eel influenza virus (WSEIV) was found to phylogenetically cluster with influenza B viruses as a sister clade. Influenza B viruses have been historically documented to circulate only in humans, with certain virus isolates found in harbor seals. It is therefore interesting that a similar virus was potentially found in fish. Here we characterized the functionality and antigenicity of the putative hemagglutinin (HA) and neuraminidase (NA) surface glycoproteins of the WSEIV to better understand this virus and its pandemic potential. Upon functional characterization of NA, we identified that the WSEIV NA-like protein has sialidase activity comparable to B/Malaysia/2506/2004 influenza B virus NA, making it a bona fide neuraminidase that could be inhibited by NA inhibitors. Testing of the functionality of HA was carried out including receptor specificity, stability, and preferential airway protease cleavage and showed very specific binding to monosialic ganglioside 2 (GM2). To probe the degree of conservation of target epitopes, binding of known broadly cross-reactive monoclonal antibodies targeting the influenza B HA and NA, respectively, were assessed through enzyme linked immunosorbent assays against recombinant WSEIV glycoproteins. Human serum samples of patients with antibodies to influenza B viruses were used to determine the cross-reactivity against these novel glycoproteins. Very few monoclonal antibodies - notably including pan NA antibody 1G01 - showed cross-reactivity and reactivity from human sera was basically absent. In summary, we have conducted a functional and antigenic characterization of the glycoproteins of the novel WSEIV to assess if it is indeed a bona fide influenza virus potentially circulating in ray-finned fish.

microbiology↗