Control of Highly Transmissible Respiratory Viruses Through Physical and Immunological Interventions

Varma, Aparna (2026) Control of Highly Transmissible Respiratory Viruses Through Physical and Immunological Interventions. PhD thesis, Indian Institute of Science Education and Research Kolkata.

Text (PhD thesis of Aparna Varma (20RS010)) 20RS010.pdf - Submitted Version Restricted to Repository staff only Download (10MB)

Abstract

Highly transmissible respiratory viruses remain a significant threat to global healthcare systems in the form of epidemics and pandemics, underscoring the need for appropriate preparedness strategies to be in place. The increasing trend of human infections with the emerging Type A influenza virus (IV), as well as the recent pandemic caused by the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) virus, has highlighted critical limitations in both environmental containment and immunological countermeasures for controlling viral spread. In particular, the Coronavirus disease (COVID-19), caused by the SARS-CoV-2 virus, has led to an extensive reliance on single-use personal protective equipment (PPE), exposing critical constraints associated with demand and supply, and amplifying environmental pollution. This highlights the importance of accessible and effective PPE reuse strategies, particularly in small-scale occupational settings. This work addresses these challenges through straightforward yet integrated approaches that encompass both physical and immunological strategies to limit viral transmission and mitigate immune escape. The first part of this work examines ultraviolet-C (UV-C)-based virus photoinactivation as a scalable, non-chemical approach for reducing viral persistence in PPE. Using the H1N1 influenza virus and the prototype of human coronavirus (OC43), this work demonstrates how controlled UV-C exposure can achieve maximum viral inactivation, providing an evidence-based framework for the safe reuse of PPE under a small-scale setup. While physical inactivation provides an essential means of limiting environmental transmission of emerging respiratory viruses, long-term solutions ultimately rely on durable host immunity achieved through active immunization. To this end, the second part of the study focuses on designing a rational, futuristic vaccine construct against SARS-CoV-2, based on the receptor-binding domain (RBD) of the spike glycoprotein, a critical determinant of viral entry and the principal target of inducing neutralizing antibodies. Recognising the limitations of strain-matched vaccines in the face of convergent and rapid viral evolution, this work introduces the Evolutionary Pressure and Immune Constraint-Translational (EPIC-T) approach. We applied EPIC-T as a mutation-informed, antigen design framework to design a synthetic, evolutionarily plausible master RBD (mRBD) sequence that integrates its natural mutation frequency, immune escape propensity, and preservation of B- and T-cell epitopes under explicit constraints. To fully explore the potential of this all-inclusive, next-generation mRBD-based vaccine construct, we engineered a live-vector mucosal delivery platform by bioengineering a food-grade lactic acid bacterium (LAB), Lactococcus lactis (L. lactis). To this end, we employed a second-generation L. lactis-based nisin-inducible controlled expression (NICE) system to generate recombinant L. lactis (rL. lactis) surface-expressing the mRBD protein, providing a safe, convenient, and nature-mimicking strategy as part of the translational validation of the present vaccine concept. We demonstrated that mucosal (oro-nasal) delivery of rL.lactis-expressing mRBD in a murine model can elicit systemic and localised immune responses in the systemic circulation, intestine and upper respiratory tract. The functional capacity of both mucosal and systemic antibodies elicited against the mRBD antigen following delivery via rL. lactis was demonstrated by the robust neutralisation of SARS-CoV-2 spike-pseudotyped lentiviral particles, as well as the authentic Wuhan-Hu-1 SARS-CoV-2 isolate. By integrating evolution-aware antigen design with an innovative mucosal immunization modality, this work establishes a complementary platform with the potential to elicit broad and variant-resilient immune responses against highly transmissible respiratory viruses. Collectively, the present study proposes a layered mitigation strategy that combines physical viral inactivation with a computationally guided mucosal immunization strategy to address both transmission and immune escape in current and future respiratory virus outbreaks.

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