The systemic-prime, mucosal-boost vaccine regimen for protection against respiratory viruses

Thesis

Respiratory viruses, such as influenza, respiratory syncytial virus (RSV), and SARS-CoV-2, continue to impose a significant global health burden despite the availability of licensed vaccines. While current vaccines that are generally administered via the intramuscular (IM) route are effective in preventing severe disease, they fail to elicit robust mucosal immunity needed for the prevention of viral infection and transmission. Additionally, immunological imprinting from prior exposures to influenza strains and SARS-CoV-2 variants can limit the effectiveness of the responses to updated annual booster vaccines. In this PhD, the use of the intranasal (IN) route for boosting was explored in a mouse immunisation model, with a focus on overcoming the shortcomings of IM vaccination, and inducing dual systemic and mucosal immunity. In a heterologous boosting scenario, IN-boosting of an omicron vaccine in mice that were IM-primed with wildtype vaccine exceeded IM-boosting immunogenicity by multiple mechanisms. Notably, the IN route overcame suppressive immunological imprinting, elicited robust cross-reactive memory T cell, de novo B cell and IgA and IgG responses both in the respiratory mucosa and systemically, highlighting its potential to induce sterilising immunity. In contrast, both the IM-boosting of IM-primed mice and the IN-boosting of IN-primed mice were constrained by the effects of imprinting and elicited suboptimal responses to the omicron strain, revealing a unidirectional relationship between IM and IN vaccination routes and their capacity to stimulate the systemic and/or mucosal immune compartments. IN-boosting was then tested in a homologous antigen setting using a bivalent RSV-influenza vaccine, where the dual-mode IM-IN route once again outperformed the standard IM-IM and IN-IN single-mode regimens, providing superior protection against both infection and disease. These findings underscore the potential of mucosal vaccination strategies, particularly IM-prime followed by IN-boost, to overcome hurdles such as immunological imprinting, and enhance mucosal immunity.

Authors: Bissett, C

• DOI: 10.5287/ora-44vjnx6mg
• Type of award: DPhil
• Level of award: Doctoral
• Awarding institution: University of Oxford
• Language: English
• Keywords: immunology; mucosal immunity; viruses; vaccines
• Subjects: Vaccine immunology