Coronavirus SARS-CoV-2, a novel member of the Coronaviridae family, caused a global outbreak of COVID-19 in late 2019 and was subsequently declared a pandemic by the World Health Organization in March 2020 (1). Since then, the disease has infected over 770 million people worldwide and resulted in nearly 7 million deaths as of 2024 (2). Although the majority of cases are asymptomatic or mild, intensive care units were necessary for 5%, and hospitalization was observed in 14% of affected individuals (3, 4). Severe presentations are often associated with systemic complications, including acute respiratory distress syndrome, septic shock, and multiorgan failure (5). The primary driver of this deterioration is an excessive release of proinflammatory cytokines, commonly referred to as a “cytokine storm,” which contributes to widespread tissue damage, hyperinflammation, and immune dysregulation (6).

Multiple systemic comorbidities have been identified as major risk factors for severe COVID-19, including cardiovascular disease, diabetes mellitus, chronic kidney and lung disorders, liver disease, asthma, and obesity (3, 5). Poor oral health, particularly periodontitis, has been recognized as an additional contributor to poor outcomes (7–10). Periodontitis is a chronic, multifactorial inflammatory condition, affecting the supporting structures of the teeth and is strongly associated with systemic comorbidities such as diabetes, obesity, and cardiovascular disease (11–13). The overlap of risk factors between periodontitis and COVID-19 highlights the possibility of shared immunoinflammatory pathways that may influence both disease susceptibility and severity (7, 9).

At the molecular level, SARS-CoV-2 gains entry into host cells primarily through angiotensin-converting enzyme 2 (ACE2) and the transmembrane serine protease 2 (TMPRSS2), which are abundantly expressed in oral tissues, including the tongue epithelium, gingiva, periodontal pockets, salivary glands, and oral mucosa (14, 15). The widespread expression of these receptors underscores the potential role of the oral cavity as a site of viral uptake, replication, and transmission.

Emerging evidence further suggests a bidirectional relationship between periodontal disease and COVID-19 severity (7, 9, 16, 17). Individuals with periodontitis appear to be at increased risk of developing more severe outcomes, potentially through multiple biological mechanisms. Chronic periodontal inflammation contributes to sustained release of proinflammatory cytokines, which have been implicated in pulmonary tissue damage and heightened susceptibility to infection (18). Moreover, the dysregulated immune response associated with periodontitis may compromise host defense, thereby reducing the ability to effectively control SARS-CoV-2 infection (19). In addition, translocation of periodontal pathogens or their by-products into the lower respiratory tract may exacerbate pulmonary inflammation, further complicating the clinical course of COVID-19 (9, 19).

The mucosal immune system of the upper respiratory tract represents a critical first line of defense against SARS-CoV-2. Saliva has emerged as a valuable diagnostic fluid for monitoring mucosal antibody responses, even in mild or asymptomatic infections (15, 20, 21). Antibody responses generated by B cells at both systemic and mucosal sites have shown inverse associations with the risk of infection (21, 22). Vaccination against COVID-19 has been demonstrated to elicit robust increases in both serum and salivary SARS-CoV-2 specific IgG antibodies, which are sustained over extended periods (21–23). In contrast, mucosal IgA responses appear more transient, with stronger responses reported in individuals with prior SARS-CoV-2 exposure (21–23). Despite their short-lived nature, salivary IgA antibodies have been linked to enhanced protection against breakthrough infections, highlighting their importance in mucosal immunity (20–23).

In this study, we employed an in-house enzyme-linked immunosorbent assay (ELISA), previously validated for seroprevalence research (24, 25), to quantify spike-specific anti-SARS-CoV-2 IgG, IgA, and secretory IgA (sIgA) levels in saliva samples from COVID-19 non-infected, 3^rd dose vaccinated individuals with periodontal disease, and compared these responses with those of periodontally healthy controls. A comprehensive periodontal examination was performed for all participants, including assessment of gingival bleeding on probing (BOP, % of sites), probing depth (PD, mm), clinical attachment level (CAL, mm), and radiographic bone loss.

This study investigated the relationship between periodontal disease severity and salivary antibody responses following 3^rd dose of mRNA SARS-CoV-2 vaccination in non-infected COVID-19 individuals. Three principal findings emerged: first, salivary anti-spike IgG levels, but not IgA or sIgA, were significantly elevated in individuals with periodontitis compared with periodontally healthy controls. Second, salivary IgG levels showed a strong positive correlation with periodontal bleeding scores. Third, the coordinated correlation between IgG and IgA observed in healthy and mild-moderate (Stage I/II) periodontitis groups was absent in individuals with severe (Stage III/IV) periodontitis. Collectively, these findings indicate that periodontitis, particularly in its advanced stages, is associated with altered salivary anti–SARS-CoV-2 antibody patterns in vaccinated individuals.

The most intriguing finding of this study is the significant elevation of salivary anti-spike IgG in individuals with periodontitis. IgG in saliva is generally regarded as being largely derived from the systemic circulation (27), and the strong positive correlation between salivary IgG levels and periodontal bleeding score (r = 0.52, p < 0.0001) in our cohort supports the possibility that inflamed and ulcerated sulcular epithelium may facilitates increased passage of serum-derived IgG into the oral cavity (27, 28). Nevertheless, serum anti-spike IgG titers, gingival crevicular fluid (GCF) antibodies, and epithelial permeability markers such as albumin or lactoferrin, which have been used to assess transudation across inflamed periodontal tissues (28), were not measured. Consequently, the extent to which elevated salivary IgG reflects passive serum leakage versus other systemic or local factors cannot be determined. The serum-leakage mechanism should therefore be viewed as a plausible working hypothesis rather than a definitive explanation, and future studies incorporating paired serum-saliva-GCF sampling and barrier integrity markers will be required to test this directly.

In contrast to IgG, the levels of salivary IgA and sIgA did not differ significantly across periodontal health groups. sIgA, the predominant dimeric IgA form in oral secretions, is actively produced by mucosal plasma cells and transported to epithelial surfaces, where it constitutes a principal immunological barrier at mucosal surfaces (29). Prior studies have demonstrated the superior neutralizing capacity of dimeric IgA compared with monomeric IgA and IgG against SARS-CoV-2 (20, 30), underscoring the relevance of mucosal sIgA responses in vaccine-induced immunity. The stability of IgA and sIgA binding levels observed in our cohort can therefore be framed as quantitatively preserved mucosal IgA output despite periodontal inflammation. Although transforming growth factor-β (TGF-β) and interleukin-6 (IL-6), both of which are upregulated in periodontal inflammation, are central regulators of IgA class-switch recombination and plasma-cell differentiation (31, 32), enhanced cytokine signaling does not necessarily translate into increased salivary IgA concentrations, as effective mucosal IgA secretion depends on additional processes including plasma-cell homing, J-chain–dependent polymerization, and polymeric immunoglobulin receptor–mediated epithelial transport (27, 31). Chronic inflammatory and dysbiotic environments, such as those characteristic of periodontitis, may perturb these tightly regulated steps, resulting in preserved bulk IgA levels while altering coordination or functional quality. At the same time, our findings speak only to IgA quantity, not functional quality, as we did not assess neutralizing activity, nor did we measure cytokine milieu or plasma-cell homing pathways. Consistent with the compartmental regulation, IgA showed only a weak association with bleeding (r = 0.18, p = 0.003), and sIgA showed no significant association (r = 0.09, p = 0.12), in contrast to IgG, which is more dependent on vascular permeability (27, 28).

Perhaps the most novel aspect of this study is the disrupted antibody isotype coordination observed in severe periodontitis. In healthy individuals and those with mild–moderate periodontitis (stages I/II), salivary IgG and IgA levels were strongly correlated, indicating coordinated salivary antibody patterns across isotypes potentially mediated by shared regulatory networks or aligned plasma-cell differentiation and homing pathways. In severe periodontitis (Stages III/IV), however, this relationship was no longer evident: correlations between IgG and IgA became non-significant, and the IgG–sIgA association trended inversely. Such a disruption aligns with the profound immunopathology of advanced periodontitis, which is characterized by a dysbiotic oral microbiome and sustained hyper-inflammatory responses (31). Multi-omics studies further demonstrate that periodontal dysbiosis alters not only microbial composition but also the metabolic and immunomodulatory capacity of the oral microbiome, thereby reshaping local immune signaling networks (33, 34). Within such inflammatory environments, cytokines such as TNF-α, IL-1β, and IL-6, known to be elevated in severe periodontitis, may influence plasma-cell activity or affect epithelial transport pathways relevant to IgA secretion (31, 32). In addition, mucosal immunology literature indicates that effective secretory IgA responses depend on coordinated plasma-cell localization, J-chain–dependent assembly, and polymeric immunoglobulin receptor (pIgR)–mediated epithelial transport; perturbations in these tightly regulated processes within chronically inflamed tissues could contribute to altered antibody coordination (32). Taken together, these microbial and immunological considerations provide a biologically plausible framework for interpreting the loss of IgG–IgA coordination in severe periodontitis as reflecting altered salivary antibody organization, rather than a simple quantitative variation or direct evidence of systemic immune dysregulation.

These findings parallel evidence from the gut, where microbiota composition strongly influences systemic vaccine responses. Animal models have shown that germ-free or antibiotic-treated mice exhibit reduced antibody production and impaired T-cell activation following influenza vaccination (35, 36). Such data emphasize the critical role of host–microbiota interactions in shaping both mucosal and systemic immunity. By extension, dysbiotic oral microbial communities may exert underappreciated effects on vaccine responsiveness, immune coordination, and antibody dynamics (37, 38). In this context, the IgG–IgA decoupling observed in severe periodontitis (stages III/IV) may represent a candidate biomarker of mucosal immune dysregulation, offering a novel perspective on how chronic oral inflammation could influence vaccine-related immune pathways.

This study has several notable strengths, including a relatively large sample size, stratification by well-defined periodontal stages, and rigorous periodontal examination (high ICCs). The use of validated in-house ELISAs with high concordance to a commercial kit further strengthens the analytical robustness of the findings. Several methodological decisions were also intentionally undertaken to mitigate potential confounders—for example, restricting inclusion to triple-vaccinated individuals minimized variability in vaccine exposure, and excluding gingivitis cases provided clearer contrast between periodontal health and established periodontitis. Nonetheless, several limitations should be acknowledged. First, the cross-sectional design precludes causal inference. Elevated salivary IgG levels may reflect passive transudation from inflamed periodontal tissues, higher systemic antibody titers, or other unmeasured host factors; paired serum, gingival crevicular fluid (GCF), and epithelial permeability markers were not collected, although the strong correlation between salivary IgG and bleeding scores provides supportive contextual evidence. Second, antibody binding levels were quantified without assessment of neutralizing activity or IgA subclass distribution, limiting conclusions regarding the functional quality of mucosal immunity. Third, the assay targeted the spike protein of the ancestral Wuhan-Hu-1 strain; however, despite ongoing viral evolution under immune pressure (39), vaccine-induced antibodies have been shown to recognize conserved epitopes and exhibit cross-reactivity across emerging variants (40–42). Although age differed significantly between periodontal groups, consistent with the epidemiology of periodontitis, multivariable analyses adjusting for age and other demographic and clinical variables did not identify age as an independent correlate of salivary anti-spike antibody levels, suggesting that age was unlikely to account for the observed antibody patterns. In addition, saliva flow rate and total protein normalization were not performed due to sample-volume constraints, although standardized collection protocols were applied to minimize variability. Finally, we did not assess local factors such as oral microbiota, proteases, or mucosal cytokines, all of which are increasingly recognized as critical modulators of salivary antibody stability and production (43).

Future longitudinal studies should examine antibody dynamics before and after periodontal therapy to clarify causal relationships. Mechanistic investigations into the homing of vaccine-induced plasma cells to oral tissues and the influence of periodontal inflammation on mucosal immune coordination are also warranted.

In vaccinated, non-infected individuals, salivary anti-spike IgG binding levels, but not IgA or sIgA, were associated with periodontitis and correlated with bleeding scores, reflecting the close link between periodontal inflammation and salivary antibody patterns. The distinct isotype correlation profiles observed across periodontal disease stages suggest that advancing periodontal inflammation may influence systemic–mucosal vaccine-induced antibody relationships; however, determining any functional consequences for mucosal IgA will require additional assessments such as neutralization assays. Collectively, these findings emphasize the importance of accounting for periodontal health status when interpreting salivary antibody measurements in vaccinated individuals and highlight the need for future studies that integrate serum, saliva, and GCF antibody profiles with key mucosal biological factors including the oral microbiota, protease activity, and cytokine signaling to more fully contextualize salivary antibody responses within oral and systemic immunity.