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Exploring cutting-edge nanoparticle-based vaccine design using electron cryo-microscopy: the development of ADDoCoV and Gigabody

Structure of the ADDoCoV particle

The model shows the ADDoCoV (gray) particle with epitopes encompassing 33 amino acids of the ancestral SARS-CoV-2 Receptor binding domain (red) inserted into variable loop regions on its surface.

Structure of the Gigabody particle

The image depicts the Gigabody particle comprising 12 ADAH11-trimers bound via fiber tail peptides to pentons of the ADDomer scaffold. Thus, the Gigabody displays a total of 36 ADAH11 nanobodies.

19 November 2023

In the realm of combating infectious diseases, a groundbreaking publication stands as a testament to the power of interdisciplinary collaboration, innovative technologies, and pioneering methodologies. This research represents a pivotal stride forward in the development of nanoparticle-based reagents targeting infectious pathogens, harnessing the integration of synthetic, computational, and high-resolution structural methods. The synthesis of these diverse approaches culminated in the creation of two fascinating innovations: ADDoCoV, a thermostable COVID-19 nanoparticle vaccine designed for nasal administration, and a novel Gigabody, a multivalent superbinder - both tailored to combat SARS-CoV-2 and its immune-evading variants.

ADDoCoV presents a configuration displaying 60 copies of an epitope derived from the RBM (Receptor Binding Motif) of SARS-CoV-2. Its development followed a meticulous path, combining high-resolution electron cryo-microscopy for a structure driven design, in vitro selection techniques to verify the authenticity and accessibility of the displayed epitope, followed by in vivo immunization studies in murine models. This comprehensive approach illuminated the vaccine's capability to provoke specific immune responses through diverse administration routes, particularly highlighting the effectiveness of nasal administration in inducing mucosal immunity—a crucial aspect in defending against respiratory pathogens like SARS-CoV-2.

Simultaneously, the successful implementation of Gigabody, a multivalent superbinder constructed from neutralizing nanobodies attached to the ADDomer scaffold underscores the versatility of the underlying principle. Gigabody's design, utilising a previously unexplored docking feature of the scaffold, exhibited remarkable potential in obstructing virion attachment to ACE2-expressing cells—an attribute that may pave the way for passive immunization strategies.

The varied immune responses triggered by different routes of vaccine administration—subcutaneous (SC), intramuscular (IM), and intranasal (IN)—unveiled the intricate relationship between administration routes and the immune responses elicited. IN administration notably triggered mucosal immunity in murine models, shedding light on the significance of targeted vaccine delivery to evoke desired immune responses at crucial entry points of the infectious agent.

Moreover, the research delved into the exploration of T cell epitopes within the ADDomer scaffold—a significant insight with implications for enhancing cellular immunity. While the current epitope design primarily induces B cell responses, the potential inclusion of validated SARS-CoV-2 T epitopes in the ADDomer scaffold holds promise in bolstering T cell-mediated immune responses, contributing to a more comprehensive defense against the virus.

The findings from this study open doors to entirely new possibilities in vaccine development. Understanding how the body responds differently to vaccines administered via various routes offers crucial insights. This knowledge can guide scientists in designing more effective vaccines tailored to provide targeted protection at the sites where viruses usually enter the body.

The ability of the ADDoCoV vaccine to induce immune responses in the nose and lungs following nasal administration is a significant discovery. It highlights the importance of considering alternative administration methods beyond conventional injections. This could revolutionize vaccine delivery, making it more accessible and potentially more effective, especially against respiratory viruses like SARS-CoV-2.

Intriguingly, the creation of Gigabody, a powerful shield against the virus, demonstrates the potential for developing passive immunization strategies. Gigabody's ability to prevent the virus from entering cells may offer temporary protection to individuals, particularly those already exposed to the virus or with weakened immune systems.

In conclusion, this research provides valuable insights into the complex world of vaccines and immune responses. By harnessing the power of innovative technologies like the ADDomer scaffold and exploring different delivery methods, scientists have made strides in vaccine design. These advancements hold promise not just for combatting SARS-CoV-2 but also for future vaccine development against various infectious pathogens.

The integration of synthetic biology, protein design, computation, structural methods, and immunization techniques showcase the potential for a multidisciplinary approach to tackle global health challenges. These findings mark a significant step forward in the quest for more effective and accessible vaccines, underscoring the importance of innovative research in shaping a healthier, more resilient world.

Further information

This project was carried out by the Bristol COVID-19 Emergency Ressearch group (Bristol UNCOVER) and Bristol vaccine innovator startup Imophoron Ltd, during the pandemic lockdowns. 

Buzas D. et al. In vitro generated antibodies guide thermostable ADDomer nanoparticle design for nasal vaccination and passive immunization against SARS-CoV-2Antibody Therapeutics, 2023

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