Upper respiratory tract mucosal immunity for SARS-CoV-2 vaccines

Abstract

SARS-CoV-2 vaccination significantly reduces morbidity and mortality, but has less impact on viral transmission rates, thus aiding viral evolution, and the longevity of vaccine-induced immunity rapidly declines. Immune responses in respiratory tract mucosal tissues are crucial for early control of infection, and can generate long-term antigen-specific protection with prompt recall responses. However, currently approved SARS-CoV-2 vaccines are not amenable to adequate respiratory mucosal delivery, particularly in the upper airways, which could account for the high vaccine breakthrough infection rates and limited duration of vaccine-mediated protection. In view of these drawbacks, we outline a strategy that has the potential to enhance both the efficacy and durability of existing SARS-CoV-2 vaccines, by inducing robust memory responses in the upper respiratory tract (URT) mucosa.

Keywords: SARS-CoV-2 vaccines; interferon-1; upper respiratory tract mucosal immunity; vaccine breakthrough infections; waning immunity.

Figure 1

Key figure. Proposed protection conferred by vaccine alone versus vaccine plus intranasal interferon (IFN)-α. (A) Currently licensed SARS-CoV-2 vaccines and their routes of administration activate antigen-presenting cells (APCs) at the injection site, which produce antigenic and inflammatory signals to activate predominantly systemic responses, with limited delivery to the respiratory tract mucosae. Robust systemic responses can prevent progression to severe disease in the short term, but in the absence of upper respiratory tract mucosal immunity, does not prevent infection and subsequent community transmission. (B) Intranasal coadministration of a clinically approved IFN-α formulation, as a vaccine adjuvant alongside licensed parenteral SARS-CoV-2 vaccination programmes, may increase the efficacy and durability of existing SARS-CoV-2 vaccines via the induction of upper respiratory tract mucosal memory responses, trained immunity, and enhanced overall immunogenicity. Early control of SARS-CoV-2 infection in the upper respiratory tract could help to reduce transmission rates, enhance the durability of vaccine-mediated protection, increase vaccine efficacy even in individuals with compromised intrinsic antiviral mechanisms, and slow down viral evolution.