The SARS-CoV-2 pandemic brought an immense advancement in vaccine development, resulting in the worldwide distribution of mRNA vaccines. Although the current vaccines against COVID-19 are highly effective in preventing severe disease, they do not protect against infection and consequently still pose a risk of onward transmission. COVID-19 vaccines are administered parenterally and thus elicit robust systemic immune responses, but they generate poor immunity at the respiratory mucosa (1–3). As the nasal cavity is the site of viral entry, the generation of mucosal immunity in the upper respiratory tract would offer a substantial benefit of preventing breakthrough infection with the potential of sterilizing immunity and reduced viral transmission. Therefore, the use of mucosal vaccines to induce a localized immune response at the site of infection is an attractive tool for preventing the dissemination of emergent respiratory viruses. However, there are many challenges for generating mucosal vaccines. Mucosal tissues are continuously exposed to different microorganisms and have thus adapted multiple layers of barrier protection, including physical factors such as mucins, immune factors such as IgA antibodies, and secreted factors, including lysozymes and proteolytic enzymes (4). Thus, subunit vaccines formulated with pathogen-derived antigens are typically degraded within the mucosal lumen and cannot cross the mucosal barrier to generate a protective immune response. Furthermore, the development of mucosal subunit vaccines has stumbled due to the lack of safe adjuvants, as there are concerns about their side effects, including Bell’s palsy (5–7). In this issue of the JCI, Kawai and coauthors report on their generation of an adjuvant-free vaccine containing the receptor-binding domain (RBD) of the SARS-CoV-2 spike protein fused with the hemagglutinin (HA) glycoprotein derived from influenza A virus (IAV) (8). The authors hypothesized that previous exposure to influenza virus would ensure the host possessed HA-specific IgG antibodies, which can bind the RBD-HA antigen to cross the mucosal barrier, presumably via neonatal Fc receptor (FcRn), for efficient antigen delivery to B cells and DCs. They elegantly show that the intranasal administration of the RBD-HA vaccine in mice that were previously infected with IAV provided marked protection against SARS-CoV-2 infection. Importantly, the preexisting immunity to IAV was a key in generating neutralizing RBD-specific IgA and IgG antibodies mucosally and systemically against SARS-CoV-2 (8) (Figure 1).

RBD-HA immunizes IAV-infected mice against SARS-CoV-2. Previous exposure to IAV infection results in the generation of specific antibodies to the immunodominant glycoprotein HA and activation of CD4+ memory T cells. Upon immunization with RBD-HA vaccine, circulating HA-specific IgG antibodies can cross the mucosal barrier and recognize HA antigens in the nasal cavity. Only HA-IgG–bound particles will have the capacity to cross the mucosal barrier potentially through transport via FcRn. Bound antigens will enter into the mucosa-associated tissue that is rich with immune cells (B cells, DCs, CD4+ memory T cells) for antigen presentation. The synergistic action of immune cells in the mucosal tissue will generate RBD-spike–specific IgG and IgA antibodies, which can cross into the nasal cavity and block viral entry during subsequent SARS-CoV-2 infection.