Intranasal Multiepitope PD‐L1‐siRNA‐Based Nanovaccine: The Next‐Gen COVID‐19 Immunotherapy

• Published in: Advanced science 2024-10, Vol.11 (40), p.e2404159-n/a
• Main Authors: Acúrcio, Rita C., Kleiner, Ron, Vaskovich‐Koubi, Daniella, Carreira, Bárbara, Liubomirski, Yulia, Palma, Carolina, Yeheskel, Adva, Yeini, Eilam, Viana, Ana S., Ferreira, Vera, Araújo, Carlos, Mor, Michael, Freund, Natalia T., Bacharach, Eran, Gonçalves, João, Toister‐Achituv, Mira, Fabregue, Manon, Matthieu, Solene, Guerry, Capucine, Zarubica, Ana, Aviel‐Ronen, Sarit, Florindo, Helena F., Satchi‐Fainaro, Ronit
• Format: Article
• Language: English
• Subjects: Adjuvants; Antibodies; Antigen presentation; Cold storage; COVID-19 vaccines; Dendritic cells; Disease transmission; Immunity (Disease); Infections; Intranasal; Ligands; Manufacturing; MHC class I and MHC class II peptides; Microscopy; Nanotechnology; Nanovaccines; PD‐1/PD‐L1 immune checkpoints; Peptides; Polylactic acid; Proteins; SARS‐CoV‐2; Severe acute respiratory syndrome coronavirus 2; siRNA; Viral infections
• ISSN: 2198-3844; 2198-3844
• DOI: 10.1002/advs.202404159

The first approved vaccines for human use against severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) are nanotechnology‐based. Although they are modular, rapidly produced, and can reduce disease severity, the currently available vaccines are restricted in preventing infection, stressing the global demand for novel preventive vaccine technologies. Bearing this in mind, we set out to develop a flexible nanovaccine platform for nasal administration to induce mucosal immunity, which is fundamental for optimal protection against respiratory virus infection. The next‐generation multiepitope nanovaccines co‐deliver immunogenic peptides, selected by an immunoinformatic workflow, along with adjuvants and regulators of the PD‐L1 expression. As a case study, we focused on SARS‐CoV‐2 peptides as relevant antigens to validate the approach. This platform can evoke both local and systemic cellular‐ and humoral‐specific responses against SARS‐CoV‐2. This led to the secretion of immunoglobulin A (IgA), capable of neutralizing SARS‐CoV‐2, including variants of concern, following a heterologous immunization strategy. Considering the limitations of the required cold chain distribution for current nanotechnology‐based vaccines, it is shown that the lyophilized nanovaccine is stable for long‐term at room temperature and retains its in vivo efficacy upon reconstitution. This makes it particularly relevant for developing countries and offers a modular system adaptable to future viral threats. Next‐generation thermostable multiepitope nanovaccine generates mucosal immunity and regulates PD‐1/PD‐L1 axis within the dendritic cell (DC)‐T cell interface, coordinating CD4 and CD8 T‐cell immunities and activating robust neutralizing antibody responses against SARS‐CoV‐2.