Biology subjects

Chang, L. A.

Publications and source records attributed to Chang, L. A..

7 recordsLinked to original sources

bioRxiv2026

Evaluation of new adjuvants in enhancing the immune response to a candidate of Severe Fever with Thrombocytopenia Syndrome Virus vaccine.

Severe fever with thrombocytopenia syndrome (SFTS) is an emerging zoonotic disease caused by the tick-borne bunyavirus SFTSV. SFTSV is primarily transmitted by Haemaphysalis longicornis ticks and can cause a hemorrhagic fever-like illness characterized by high fever, thrombocytopenia, leukopenia, and multiorgan failure, with reported case-fatality rates ranging from 10% to over 30%. Despite its growing public health relevance, no licensed vaccines or specific antiviral therapies are currently available. Here, we evaluated a beta-propiolactone-inactivated SFTSV vaccine candidate based on strain YL1, formulated with benchmark adjuvants (Addavax and Alhydrogel) or experimental innate immune agonists, including Sendai virus-derived defective interfering RNA (SDI), a RIG-I agonist, and imidazoquinoline-poly(ethylene glycol)-cholesterol conjugate (IMDQ-P-C), a TLR7/8 agonist, alone or in combination. Using an extended prime-boost regimen, we examined adjuvant-dependent modulation of humoral immunity, antigen-specific cellular recall, antibody cross-reactivity, and functional protection following passive serum transfer and live-virus challenge in IFNAR-/- mice. All adjuvanted formulations induced detectable humoral responses, with Addavax and SDI eliciting the highest virus-specific binding and neutralizing antibody titers. Antigen-specific analyses identified the nucleoprotein (NP) as the dominant target of vaccine-induced immune memory. NP elicited robust antibody response and the broadest cytokine recall profile following ex vivo stimulation. This response was broader than that induced by the whole inactivated virus and was characterized by mixed Th1-associated, Th2-associated, and proinflammatory-associated features that varied across adjuvant formulations. In contrast, the head domain of the Gn glycoprotein elicited limited cellular recall responses, consistent with its relatively weak humoral immunogenicity after both priming and boosting. Nevertheless, sera from SDI and Addavax-adjuvanted groups displayed cross-reactivity with Gn from a heterologous SFTSV strain, suggesting broader antibody recognition across viral genotypes. Functionally, sera from SDI and Addavax-immunized mice conferred partial protection following passive transfer into IFNAR-/- recipients, as reflected by reduced viral loads, delayed disease onset, and prolonged survival after lethal SFTSV challenge. Together, these findings support the immunogenicity and protective potential of a BPL-inactivated SFTSV vaccine platform and identify NP as a major target of vaccine-induced immune memory. They further highlight the importance of adjuvant selection in shaping the magnitude, antigenic focus, and functional quality of vaccine-induced antiviral immunity.

microbiology↗

bioRxiv2025

Disease modulation by TIV vaccination during secondary pneumococcal infections in influenza-infected mice.

Secondary bacterial infections can significantly worsen the clinical course of influenza virus infections and are a leading cause of morbidity and mortality during seasonal influenza epidemics. Despite being a vaccine-preventable disease, influenza-related complications from secondary bacterial infections are an important cause of death, particularly among the elderly population. Streptococcus pneumoniae (Spn) is the most common agent responsible for influenza-related secondary bacterial infections. Influenza virus vaccination serves as an effective prophylactic strategy for preventing influenza and reducing the burden of influenza-associated pathology, including secondary bacterial infection. However, whether the protective effects of influenza virus vaccination differ in the context of a secondary Spn infection at the level of the host response remains poorly characterized. Here, we present a preclinical mouse model to examine the impact of influenza vaccination in scenarios involving single infections with influenza A virus H1N1 (NC99) or Spn serotype 1; simultaneous infection with both NC99 and Spn (coinfection), or NC99 infection followed by Spn infection seven days later (superinfection). A single dose of trivalent inactivated Influenza vaccine (TIV) is able to decrease infection lethality in both secondary bacterial infection scenarios. Protection is associated with reduction in both viral and bacterial titers, decreased production of pro-inflammatory cytokines, protection of alveolar macrophages, prevention of exacerbated lung neutrophil recruitment, modulation of neutrophil activation status and induction of lung eosinophil recruitment and activation. These findings underscore the importance of influenza vaccination in modulating disease progression and preventing morbidity and mortality associated with secondary bacterial infections.

microbiology↗

bioRxiv2025

A combination TLR7/8 and RIG-I agonist adjuvant reverts asthmatic allergic sensitization and prevents aggravated influenza infection in OVA-sensitized mice.

Allergen-specific immunotherapy (AIT) is the only disease-modifying treatment currently available to treat allergy. However, it has limitations, as most allergens are poorly immunogenic, resulting in an AIT process that can take years. Therefore, adjuvant selection becomes critical to achieve a more efficacious therapy. Our group has developed and tested an amphiphilic TLR7/8 agonist (IMDQ) and a RIG-I agonist (SDI) that used alone, or in combination, have demonstrated strong adjuvant activity for influenza and SARS-CoV-2 vaccines in preclinical models. Here we describe the effect of these adjuvants in the sensitization of preclinical models with the ovalbumin (OVA) asthmatic allergic model via an in-depth humoral and cellular immune profiling. We assess their immune skewing and tolerance inducing capacities in previously sensitized preclinical models with different genetic backgrounds (C57BL/6 vs. BALB/c mice). Moreover, we evaluate their effect in an unrelated antigenic challenge with influenza. Finally, we investigate the role of IgG subclasses and T-cell subpopulations in the protection against OVA challenge conferred by the combination of IMDQ and SDI. We demonstrate that OVA-immunization in combination with IMDQ+SDI prevents allergic sensitization via the induction of a balanced Type 1/Type 2 response. Furthermore, it can revert the allergic phenotype in mice previously sensitized with OVA-Alum, through reducing lung eosinophilia, as well as IL-4 and IL-5 production. However, this was dependent on genetic background. IMDQ+SDI sensitization also led to reduced morbidity of a secondary influenza challenge in OVA-sensitized mice. Finally, we demonstrated that IgG2c, by itself, cannot protect from allergic sensitization and that both CD4+ and CD8+ T-cells are needed for IMDQ+SDI prevention of eosinophil recruitment and activation upon intranasal OVA-challenge.

immunology↗

bioRxiv2025

Transient lung eosinophilia during breakthrough influenza infection in vaccinated mice is associated with protective and balanced Type 1/2 immune responses.

Eosinophils are agile cells that participate in a multitude of homeostatic and inflammatory responses in the lung, ranging from allergic asthma to antiviral defense against respiratory viral infection. In the context of vaccination followed by viral infection, such as breakthrough infection, eosinophils have been linked to aberrant Th2 responses like vaccine-enhanced respiratory disease (VAERD). Here, we demonstrate that the lung immune cell composition, cytokine and chemokine repertoire, histopathological profile, and systemic humoral response of breakthrough influenza infection in mice is distinct from that of primary influenza infection or allergic sensitization, canonical Type 1 and 2 immune responses, respectively. Longitudinal comparison of breakthrough infection with allergic sensitization and primary influenza infection demonstrated major differences in lung immunity between treatment groups in female, BALB/c mice. Breakthrough infection mice exhibit lung eosinophil infiltration that peaks at 7-10 days post-challenge, enriched for the Siglec-Fhi subset, but in the absence of overt pro-inflammatory cytokine/chemokine signals, high viral titers, severe lung lesions, goblet cell hyperplasia, allergic levels of total IgE, or enhanced morbidity. Multiparameter fluorescence imaging corroborated findings from flow cytometry and also unveiled interactions between CD101+Siglec-F+ cells with CD3+ cells in the lung tissue space. Imaging also revealed a marked absence of eosinophil or neutrophil extracellular traps in the lungs of breakthrough infection mice, in contrast with allergic sensitization and primary influenza infection, respectively. Altogether, our findings provide a deeper understanding of the kinetics and cell-cell interplay during non-pathological, balanced Type 1/2 immune responses in vaccinated hosts during breakthrough infection.

immunology↗

bioRxiv2024

Enhanced mucosal B- and T-cell responses against SARS-CoV-2 after heterologous intramuscular mRNA prime/intranasal protein boost vaccination with a combination adjuvant.

Current COVID-19 mRNA vaccines delivered intramuscularly (IM) induce effective systemic immunity, but with suboptimal immunity at mucosal sites, limiting their ability to impart sterilizing immunity. There is strong interest in rerouting immune responses induced in the periphery by parenteral vaccination to the portal entry site of respiratory viruses, such as SARS-CoV-2, by mucosal vaccination. We previously demonstrated the combination adjuvant, NE/IVT, consisting of a nanoemulsion (NE) and an RNA-based RIG-I agonist (IVT) induces potent systemic and mucosal immune responses in protein-based SARS-CoV-2 vaccines administered intranasally (IN). Herein, we demonstrate priming IM with mRNA followed by heterologous IN boosting with NE/IVT adjuvanted recombinant antigen induces strong mucosal and systemic antibody responses and enhances antigen-specific T cell responses in mucosa-draining lymph nodes compared to IM/IM and IN/IN prime/boost regimens. While all regimens induced cross-neutralizing antibodies against divergent variants and sterilizing immunity in the lungs of challenged mice, mucosal vaccination, either as homologous prime/boost or heterologous IN boost after IM mRNA prime was required to impart sterilizing immunity in the upper respiratory tract. Our data demonstrate the benefit of hybrid regimens whereby strong immune responses primed via IM vaccination are rerouted by IN vaccination to mucosal sites to provide optimal protection to SARS-CoV-2.

immunology↗

bioRxiv2023

Breakthrough infections by SARS-CoV-2 variants boost cross-reactive hybrid immune responses in mRNA-vaccinated Golden Syrian Hamsters

Hybrid immunity to SARS-CoV-2 provides superior protection to re-infection. We performed immune profiling studies during breakthrough infections in mRNA-vaccinated hamsters to evaluate hybrid immunity induction. mRNA vaccine, BNT162b2, was dosed to induce binding antibody titers against ancestral spike, but inefficient serum virus neutralization of ancestral SARS-CoV-2 or variants of concern (VoCs). Vaccination reduced morbidity and controlled lung virus titers for ancestral virus and Alpha but allowed breakthrough infections in Beta, Delta and Mu-challenged hamsters. Vaccination primed T cell responses that were boosted by infection. Infection back-boosted neutralizing antibody responses against ancestral virus and VoCs. Hybrid immunity resulted in more cross-reactive sera. Transcriptomics post-infection reflects both vaccination status and disease course and suggests a role for interstitial macrophages in vaccine-mediated protection. Therefore, protection by vaccination, even in the absence of high titers of neutralizing antibodies in the serum, correlates with recall of broadly reactive B and T-cell responses.

microbiology↗

bioRxiv2020

SARS-CoV-2 mRNA Vaccine Development Enabled by Prototype Pathogen Preparedness

A SARS-CoV-2 vaccine is needed to control the global COVID-19 public health crisis. Atomic-level structures directed the application of prefusion-stabilizing mutations that improved expression and immunogenicity of betacoronavirus spike proteins. Using this established immunogen design, the release of SARS-CoV-2 sequences triggered immediate rapid manufacturing of an mRNA vaccine expressing the prefusion-stabilized SARS-CoV-2 spike trimer (mRNA-1273). Here, we show that mRNA-1273 induces both potent neutralizing antibody and CD8 T cell responses and protects against SARS-CoV-2 infection in lungs and noses of mice without evidence of immunopathology. mRNA-1273 is currently in a Phase 2 clinical trial with a trajectory towards Phase 3 efficacy evaluation.

immunology↗