Mucosal immunization with an adenoviral vector vaccine confers superior protection against RSV compared to natural immunity

Abstract

Respiratory syncytial virus (RSV) infections are the leading cause of severe respiratory illness in early infancy. Although the majority of children and adults mount immune responses against RSV, recurrent infections are frequent throughout life. Humoral and cellular responses contribute to an effective immunity but also their localization at respiratory mucosae is increasingly recognized as an important factor. In the present study, we evaluate a mucosal vaccine based on an adenoviral vector encoding for the RSV fusion protein (Ad-F), and we investigate two genetic adjuvant candidates that encode for Interleukin (IL)-1β and IFN-β promoter stimulator I (IPS-1), respectively. While vaccination with Ad-F alone was immunogenic, the inclusion of Ad-IL-1β increased F-specific mucosal immunoglobulin A (IgA) and tissue-resident memory T cells (TRM). Consequently, immunization with Ad-F led to some control of virus replication upon RSV infection, but Ad-F+Ad-IL-1β was the most effective vaccine strategy in limiting viral load and weight loss. Subsequently, we compared the Ad-F+Ad-IL-1β-induced immunity with that provoked by a primary RSV infection. Systemic F-specific antibody responses were higher in immunized than in previously infected mice. However, the primary infection provoked glycoprotein G-specific antibodies as well eventually leading to similar neutralization titers in both groups. In contrast, mucosal antibody levels were low after infection, whereas mucosal immunization raised robust F-specific responses including IgA. Similarly, vaccination generated F-specific TRM more efficiently compared to a primary RSV infection. Although the primary infection resulted in matrix protein 2 (M2)-specific T cells as well, they did not reach levels of F-specific immunity in the vaccinated group. Moreover, the infection-induced T cell response was less biased towards TRM compared to vaccine-induced immunity. Finally, our vaccine candidate provided superior protection against RSV infection compared to a primary infection as indicated by reduced weight loss, virus replication, and tissue damage. In conclusion, our mucosal vaccine candidate Ad-F+Ad-IL-1β elicits stronger mucosal immune responses and a more effective protection against RSV infection than natural immunity generated by a previous infection. Harnessing mucosal immune responses by next-generation vaccines is therefore a promising option to establish effective RSV immunity and thereby tackle a major cause of infant hospitalization.

Intranasal booster using an Omicron vaccine confers broad mucosal and systemic immunity against SARS-CoV-2 variants

“…7 Some studies on respiratory viruses such as respiratory syncytial virus (RSV) and influenza virus provide substantial evidence that mucosal immunity is key to the effective control of respiratory viruses. [8][9][10] The Global COVID-19 Vaccination Strategy in a Changing World updated in July 2022 posted by the WHO mentioned the importance of mucosal immunity in reducing SARS-CoV-2 transmission, which can help prevent the emergence of new VOCs and their global disease waves and related health and economic consequences. 11 However, almost all COVID-19 vaccines approved for human usage, including inactivated virus, lipid nanoparticle-encapsulated mRNA, protein subunit of spike or RBD, and adenovirus vectored vaccines, are administered via intramuscular injection.…”

Respiratory viruses and the inflammasome: The double-edged sword of inflammation

“…However, more recently, the role of IL-1R signaling in initiating the adaptive immune response has been explored. IL-1 family cytokines have been shown to increase T cell activation and memory formation leading to their use as experimental vaccine adjuvants [ 44 , 45 ]. Though the inflammasomes play a key role in antiviral immunity, their activation is also strongly associated with immunopathology in the lung ( Fig 1 ).…”

“…These viral factors led to impaired CD8 T cell memory responses and viral clearance suggesting viruses have evolved to specifically evade enhanced T cell function through IL-1R signaling [ 43 ]. These findings have prompted the use of IL-1β as a vaccine adjuvant to boost antigen-specific memory formation [ 44 , 45 ]. Mucosal immunization against IAV with IL-1β as an adjuvant displayed significantly increased IgG, IgG1, and IgG2a antibody levels as compared to 23 other interleukins.…”

“…An RSV adenoviral vector vaccine expressing IL-1β as an adjuvant also displayed significantly increased RSV-specific IgG and IgA production as compared to controls and an IFN-inducing adjuvant. Mice immunized with IL-1β as an adjuvant also exhibited enhanced memory responses and a higher total number of RSV-specific tissue resident memory CD8 T cells within the lung that correlated with increased viral clearance [ 44 ]. These findings highlight the potential for IL-1R signaling in modulating adaptive immune responses beyond the canonical role of IL-1 family cytokines in mediating early viral restriction and innate immunity.…”

Rapid and Highly Efficient Genetic Transformation and Application of Interleukin-17B Expressed in Duckweed as Mucosal Vaccine Adjuvant

“…Therefore, cytokines are considered to be safe and strong as adjuvants for vaccines, including mucosal vaccines [ 32 ]. According to previous reports, different types of cytokines, such as interleukins [ 33 ], interferon [ 34 ], and TNF-α [ 35 ] have been investigated for mucosal vaccines against respiratory tract disease. Interleukin-17B (IL-17B), a member of the IL-17 family, plays a key role in regulating the expression of proinflammatory cytokines.…”