Pulmonary surfactant–biomimetic nanoparticles potentiate heterosubtypic influenza immunity

Abstract

Current influenza vaccines only confer protection against homologous viruses. We synthesized pulmonary surfactant (PS)–biomimetic liposomes encapsulating 2′,3′-cyclic guanosine monophosphate–adenosine monophosphate (cGAMP), an agonist of the interferon gene inducer STING (stimulator of interferon genes). The adjuvant (PS-GAMP) vigorously augmented influenza vaccine–induced humoral and CD8+ T cell immune responses in mice by simulating the early phase of viral infection without concomitant excess inflammation. Two days after intranasal immunization with PS-GAMP–adjuvanted H1N1 vaccine, strong cross-protection was elicited against distant H1N1 and heterosubtypic H3N2, H5N1, and H7N9 viruses for at least 6 months while maintaining lung-resident memory CD8+ T cells. Adjuvanticity was then validated in ferrets. When alveolar epithelial cells (AECs) lacked Sting or gap junctions were blocked, PS-GAMP–mediated adjuvanticity was substantially abrogated in vivo. Thus, AECs play a pivotal role in configuring heterosubtypic immunity.

Aluminum Nanoparticles Acting as a Pulmonary Vaccine Adjuvant-Delivery System (VADS) Able to Safely Elicit Robust Systemic and Mucosal Immunity

“…Contrarily, ANs can be administered to the lung and approach individually the site of alveola to trigger APCs, perhaps mainly, AMPs (alveolar macrophages), which instruct the related cells such as DCs and AECs (alveolar epithelial cells) into an active state to make an immune response [47]. Pulmonary vaccination favors setup of mucosal immunity across most of human organs, especially, the respiratory system and should be particularly beneficial for defending against the airborne pathogens, such as flu, MERS and SARS-CoV2, which is now just rapidly spreading throughout the world [48].…”

“…It is well known that the trachea and bronchi show the mucus-covered epithelial mucosa, however, the alveoli surfaces are mainly coated with a lipid-rich surfactant that has bacteriostatic effects against certain bacterial species [53]. The pulmonary surfactant (PSF) layer is reported to pose a challenge to delivering vaccines to lung APCs by a nanoparticulate VADS vaccines, because the PSF generates a strong barrier to not only pathogen but also nanoparticle accessing mucosa [47,54]. However, PSF was also described to possess potent adjuvanticities and has been employed as a VADS for enhancing APC uptake and presentation of vaccines [47,55].…”

“…The pulmonary surfactant (PSF) layer is reported to pose a challenge to delivering vaccines to lung APCs by a nanoparticulate VADS vaccines, because the PSF generates a strong barrier to not only pathogen but also nanoparticle accessing mucosa [47,54]. However, PSF was also described to possess potent adjuvanticities and has been employed as a VADS for enhancing APC uptake and presentation of vaccines [47,55]. The influence of PSF on the immunostimulatory activity of AN-based pulmonary VADS remains now unclear and deserves obviously a deepening exploration.…”

The LRRC8A:C Heteromeric Channel Is a cGAMP Transporter and the Dominant cGAMP Importer in Human Vasculature Cells

“…The crucial importance of cGAMP transfer was recently highlighted even when exogenously administered as an intranasal influenza vaccine adjuvant. Although cGAMP-containing pulmonary surfactant biomimetic nanoparticles are first taken up by alveolar macrophages, subsequent intercellular transfer of cGAMP to alveolar epithelial cells and STING activation in these stromal cells are required for generation of heterosubtypic antiviral immunity (Wang et al, 2020). Recently, we reported a new cGAMP paracrine signaling mechanism: cGAMP is directly exported into the extracellular space in a soluble, non-membrane bound form (Carozza et al, 2020).…”

Protecting against different subtypes of influenza viruses: a nanoparticle approach

“…Wang et al hypothesized that nanoparticles consisting of cGAMP, an agonist of STING alongside an adjuvanted H1N1 vaccine, will induce an immune response by CD8 + T cells, which can yield heterosubtypic immunity. 5 The authors at first successfully synthesized nanoparticles with the correct size, function, and safety. They tested the effects of the nanoparticles in vitro (bone marrow-derived macrophages) and in an in vivo model of infection.…”