Intranasal Delivery of Thermostable Subunit Vaccine for Cross-Reactive Mucosal and Systemic Antibody Responses Against SARS-CoV-2

Abstract

Despite the remarkable efficacy of currently approved COVID-19 vaccines, there are several opportunities for continued vaccine development against SARS-CoV-2 and future lethal respiratory viruses. In particular, restricted vaccine access and hesitancy have limited immunization rates. In addition, current vaccines are unable to prevent breakthrough infections, leading to prolonged virus circulation. To improve access, a subunit vaccine with enhanced thermostability was designed to eliminate the need for an ultra-cold chain. The exclusion of infectious and genetic materials from this vaccine may also help reduce vaccine hesitancy. In an effort to prevent breakthrough infections, intranasal immunization to induce mucosal immunity was explored. A prototype vaccine comprised of receptor-binding domain (RBD) polypeptides formulated with additional immunoadjuvants in a chitosan (CS) solution induced high levels of RBD-specific antibodies in laboratory mice after 1 or 2 immunizations. Antibody responses were durable with high titers persisting for at least five months following subcutaneous vaccination. Serum anti-RBD antibodies contained both IgG1 and IgG2a isotypes suggesting that the vaccine induced a mixed Th1/Th2 response. RBD vaccination without CS formulation resulted in minimal anti-RBD responses. The addition of CpG oligonucleotides to the CS plus RBD vaccine formulation increased antibody titers more effectively than interleukin-12 (IL-12). Importantly, generated antibodies were cross-reactive against RBD mutants associated with SARS-CoV-2 variants of concern, including alpha, beta and delta variants, and inhibited binding of RBD to its cognate receptor angiotensin converting enzyme 2 (ACE2). With respect to stability, vaccines did not lose activity when stored at either room temperature (21-22°C) or 4°C for at least one month. When delivered intranasally, vaccines induced RBD-specific mucosal IgA antibodies, which may protect against breakthrough infections in the upper respiratory tract. Altogether, data indicate that the designed vaccine platform is versatile, adaptable and capable of overcoming key constraints of current COVID-19 vaccines.

Natural Polymeric Composites Derived from Animals, Plants, and Microbes for Vaccine Delivery and Adjuvant Applications: A Review

“…On the other hand, chitosan was used as a vaccine adjuvant in MN target SARS-CoV-2 nucleocapsid protein [ 129 ] and RBD polypeptides vaccine for COVID-19 [ 130 ]. The MN-based vaccines resulted in a balanced ratio of IgG1 and IgG2A nucleocapsid antibodies [ 129 ].…”

“…The MN-based vaccines resulted in a balanced ratio of IgG1 and IgG2A nucleocapsid antibodies [ 129 ]. The RBD polypeptide vaccine intracutaneously administered in mice produced RBD-specific antibodies, which was sustained for five months [ 130 ]. Cross-reactivity was also observed against RBD antibodies with various SARS-CoV-2 variants (i.e., alpha, beta, and delta variants).…”

The impact of primary immunization route on the outcome of infection with SARS-CoV-2 in a hamster model of COVID-19

“…It has been well established that the parenteral route of administration does not induce an effective mucosal immune response required for the protection of mucosal surfaces of the upper respiratory tract where respiratory viruses like SARS-CoV-2 first enter the body ( Park and Lee, 2021 ). Another challenge is that the IM injections of the current mRNA-based vaccines require administration by healthcare professionals ( Nguyen et al, 2022 ).…”

“…Given that the upper respiratory tract also provides the first line of defense against respiratory pathogens, it is prudent to further analyze the viability of intranasal (IN) immunization as a potential platform for overcoming many of the challenges associated with the route of administration of current COVID-19 vaccine ( Johnson et al, 2022 ). IN immunization has been proposed as a potential way to offer stronger and more durable protection against pulmonary infectious diseases, such as SARS-CoV-2, with encouraging findings indicating a reduced risk of breakthrough infections ( Tiboni et al, 2021 ; Chiuppesi et al, 2022 ; Nguyen et al, 2022 ; Nouailles et al, 2023 ). The current study used Syrian hamsters to compare immune responses and protective efficacy induced by immunization via SC and intranasal (IN) routes, followed by an IN challenge.…”

A multiadjuvant polysaccharide-amino acid-lipid (PAL) subunit nanovaccine generates robust systemic and lung-specific mucosal immune responses against SARS-CoV-2 in mice

“…Several adjuvants that target multiple PRRs, including RLRs (retinoic inducible gene 1: (RIG-I)-like receptors) and Toll-like receptors (TLRs: 4, 7/8, 9), either alone or in combination, have been utilized in studies related to SARS-CoV-2 mucosal vaccines. While these adjuvants have shown promising results in animal models, they are not able to provide complete protection against infection (13,21,(35)(36)(37). However, RIG-I agonists are mainly used to enhance antiviral immunity in other viral infections such as influenza or the west nile virus (38)(39)(40)(41).…”