Adenoviral-vectored next-generation respiratory mucosal vaccines against COVID-19.

The world is in need of next-generation COVID-19 vaccines. Although first-generation injectable COVID-19 vaccines continue to be critical tools in controlling the current global health crisis, continuous emergence of SARS-CoV-2 variants of concern has eroded the efficacy of these vaccines, leading to staggering breakthrough infections and posing threats to poor vaccine responders. This is partly because the humoral and T-cell responses generated following intramuscular injection of spike-centric monovalent vaccines are mostly confined to the periphery, failing to either access or be maintained at the portal of infection, the respiratory mucosa (RM). In contrast, respiratory mucosal-delivered vaccine can induce immunity encompassing humoral, cellular, and trained innate immunity positioned at the respiratory mucosa that may act quickly to prevent the establishment of an infection. Viral vectors, especially adenoviruses, represent the most promising platform for RM delivery that can be designed to express both structural and nonstructural antigens of SARS-CoV-2. Boosting RM immunity via the respiratory route using multivalent adenoviral-vectored vaccines would be a viable next-generation vaccine strategy.

Protocol for isolation and characterization of lung tissue resident memory T cells and airway trained innate immunity after intranasal vaccination in mice.

Vaccination route dictates the quality and localization of immune responses within tissues. Intranasal vaccination seeds tissue-resident adaptive immunity, alongside trained innate responses within the lung/airways, critical for superior protection against SARS-CoV-2. This protocol encompasses intranasal vaccination in mice, step-by-step bronchoalveolar lavage for both cellular and acellular airway components, lung mononuclear cell isolation, and detailed flow cytometric characterization of lung tissue-resident memory T cell responses, and airway macrophage-trained innate immunity. For complete details on the use and execution of this protocol, please refer to Afkhami et al. (2022).

Respiratory mucosal delivery of next-generation COVID-19 vaccine provides robust protection against both ancestral and variant strains of SARS-CoV-2.

The emerging SARS-CoV-2 variants of concern (VOCs) threaten the effectiveness of current COVID-19 vaccines administered intramuscularly and designed to only target the spike protein. There is a pressing need to develop next-generation vaccine strategies for broader and long-lasting protection. Using adenoviral vectors (Ad) of human and chimpanzee origin, we evaluated Ad-vectored trivalent COVID-19 vaccines expressing spike-1, nucleocapsid, and RdRp antigens in murine models. We show that single-dose intranasal immunization, particularly with chimpanzee Ad-vectored vaccine, is superior to intramuscular immunization in induction of the tripartite protective immunity consisting of local and systemic antibody responses, mucosal tissue-resident memory T cells and mucosal trained innate immunity. We further show that intranasal immunization provides protection against both the ancestral SARS-CoV-2 and two VOC, B.1.1.7 and B.1.351. Our findings indicate that respiratory mucosal delivery of Ad-vectored multivalent vaccine represents an effective next-generation COVID-19 vaccine strategy to induce all-around mucosal immunity against current and future VOC.

COVID-19: Current knowledge in clinical features, immunological responses, and vaccine development.

The COVID-19 pandemic has unfolded to be the most challenging global health crisis in a century. In 11 months since its first emergence, according to WHO, the causative infectious agent SARS-CoV-2 has infected more than 100 million people and claimed more than 2.15 million lives worldwide. Moreover, the world has raced to understand the virus and natural immunity and to develop vaccines. Thus, within a short 11 months a number of highly promising COVID-19 vaccines were developed at an unprecedented speed and are now being deployed via emergency use authorization for immunization. Although a considerable number of review contributions are being published, all of them attempt to capture only a specific aspect of COVID-19 or its therapeutic approaches based on ever-expanding information. Here, we provide a comprehensive overview to conceptually thread together the latest information on global epidemiology and mitigation strategies, clinical features, viral pathogenesis and immune responses, and the current state of vaccine development.