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Background: Current L1-based human papillomavirus (HPV) vaccines provide type-specific protection but offer limited cross-protection against non-vaccine HPV types. Therefore, developing a broad-spectrum HPV vaccine is highly desirable. Methods: In this study, we optimized mRNA constructs and developed a multivalent L2-based mRNA vaccine encoding L2 aa 2-130, which includes all known neutralizing epitopes from four prevalent HPV types (HPV-6, -11, -16, and -18). We evaluated its immunogenicity in a mouse model and compared the efficacy of a commercially available mRNA delivery reagent with a custom-synthesized lipid nanoparticle (LNP) formulation. Results: We identified that a construct containing E01 (a 5′-untranslated region) and SL2.7 (a poly(A) polymerase recruitment sequence) significantly increased protein expression. The L2-based mRNA vaccine induced robust and long-lasting humoral immune responses, with significant titers of cross-reactive serum IgG antibodies against L2 epitopes. Notably, the vaccine elicited cross-neutralizing antibodies and conferred cross-protective immunity not only against vaccine-targeted HPV types but also against non-vaccine HPV types, following intravaginal challenge in mice. We also found that LNP delivered mRNA more effectively in vivo. Conclusions: The L2-based mRNA vaccine developed in this study shows significant potential for broad-spectrum protection against multiple HPV types. This approach offers a promising strategy for reducing the global burden of HPV-associated cancers.

Introduction: Idiopathic multicentric Castleman disease (MCD) has been reported to form lung cysts at a relatively high rate. However, the radiological and pathological features of cystic formation in MCD are unclear. Methods: To clarify these questions, we retrospectively investigated the radiological and pathological findings of cysts in MCD patients. Eight consecutive patients who underwent surgical lung biopsies in our center from 2000 to 2019 were included. Results: The median age was 44.5 years, with three males and five females. On the initial computed tomography, cyst formation was found in seven patients (87.5%). All of the cysts were multiple, round, and thin walled, accompanying ground-glass attenuation (GGA) around cysts. In six patients (75%), cysts increased during their clinical courses, and the new cysts had emerged from GGA, although GGA was improved by treatment. In all four cases, whose pulmonary cysts could be pathologically evaluated, a marked plasma cell infiltration around the cyst wall, and loss of elastic fibers of the alveolar wall were observed. Conclusions: Pulmonary cysts emerged in the area of GGA pathologically consistent with plasma cell infiltration. Cysts in MCD may be formed by the loss of elastic fibers due to marked plasma cell infiltration and may be considered irreversible changes.