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In COVID-19 (coronavirus disease 2019), multi-organ complications depend on the immune system’s activity. α1-Acid glycoprotein (AGP) is a highly glycosylated positive acute-phase protein having multifaceted immunomodulatory and protective effects. We were interested in changes in serum AGP concentrations, expression of its glycans, and oxidation-reduction potential (ORP) between severe COVID-19 patients, convalescents, and healthy controls, and whether any of the analyzed parameters could serve as an additional diagnostic biomarker of severe COVID-19 and/or help monitor recovery. We were also interested in associations between the examined parameters. AGP concentrations were measured using an immunoturbidimetric method. The profile and degree of AGP glycosylation were analyzed using lectin-ELISA with lectins: sialo-specific from Sambucus nigra (SNA) and Maackia amurensis (MAA), fucose-specific from Lotus tetragonolobus (LTA) and Aleuria aurantia (AAL). The static and capacitive ORP (sORP and cORP, respectively) were measured using MiOXSYS C+^® device (Caerus Biotechnologies, Vilnius, Lithuania). Statistica13.3PL software was used for statistical analysis. AGP concentrations increased in COVID-19 patients, showing high clinical usefulness in distinguishing them from convalescents and controls. AGP α2,6-sialylation (reactivity with SNA) was reduced in COVID-19 vs. other study groups, while α2,3-sialylation (reactivity with MAA) was reduced in convalescents vs. controls. The expression of LTA-reactive fucose (Lewis^x structures, Le^x) was reduced in COVID-19 patients compared to controls and convalescents, but AGP reactivity with AAL did not differ between the study groups. The sORP was reduced, and the cORP was increased in COVID-19. The observed negative correlations between sORP and AGP levels may suggest the antioxidant effect of AGP during severe COVID-19. Higher levels of serum AGP in severe COVID-19, together with low expression of sialic acid α2,6-linked and Le^x structures, accompanied by reduced sORP, constitute a characteristic pattern of biomarker expression during severe COVID-19. The increased expression of SNA-reactive sialic acid and Le^x structures may reflect the recovery process after SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) infection. The observed negative correlations between AGP and sORP levels may suggest that serum AGP in COVID-19 also plays a role as an antioxidative molecule. Full article

Background: Numerous studies have proved the efficacy of vaccination in reducing Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) transmission and the coronavirus disease (COVID-19) burden. However, even though the COVID-19 vaccination coverage is high for primary doses, a booster dose is needed to sustain protection. Continuing our previous research, this study evaluates the immunogenicity and safety of full and half doses of two COVID-19 booster vaccines, ChAdOx1-S (AstraZeneca) and BNT162b2 (Pfizer-BioNTech), in individuals primed with ChAdOx1-S. Methods: This study was an observer-blind randomized controlled trial to evaluate the immunogenicity and safety of half and full doses of two COVID-19 booster vaccine types, BNT162b2 and ChAdOx1-S, among fully vaccinated, ChAdOx1-S-primed individuals in Jakarta, Indonesia. A total of 329 participants were randomized to receive either full or half doses of the booster vaccines, namely the ChAdOx1-S and BNT162b2 COVID-19 vaccines. Immunogenicity was assessed through SARS-CoV-2 antibody titers and neutralizing antibodies (NAbs) at 28 days post-booster, while safety was monitored via adverse event reporting. Results: The results showed that both vaccines demonstrated increased geometric mean titers (GMTs) post-booster. In the ChAdOx1-S booster group, at the baseline visit (day 0) and third visit (day 28), no statistically significant differences in GMT between the half- and full-dose groups were observed (p = 0.970 and 0.539, respectively). In the BNT162b2 group, no statistically significant difference was noted at the baseline visit, while the full dose was higher than the half dose at 28 days (Day 28, p = 0.011). Surrogate virus neutralization tests (sVNTs) and NAbs assays also revealed no significant differences between the half and full dose groups for both the Wuhan strain and the Delta variant. The BNT162b2 group compared to the ChAdOx1-S group revealed a statistically significant increase in IgG levels compared to ChAdOx1-S, with p-values of <0.001 and <0.001 for the half dose and full dose, respectively. This was also reflected in the NAbs test results, where BNT162b2 showed significantly higher levels against both the Wuhan strain and Delta variant. Adverse events were predominantly mild: 79.6% (n = 86/108) in the ChAdOx1-S full-dose group, 75.4% (n = 43/57) in the ChAdOx1-S half-dose group, 84.2% (n = 101/120) in the BNT162b2 full-dose group, and 92.6% (n = 88/95) in the BNT162b2 half-dose group, with pain at the injection site being the most common local reaction and myalgia and headache the most frequent systemic reactions. One serious adverse event was reported, assessed as unrelated to the vaccine. Conclusions: This study confirms that half doses of ChAdOx1-S and BNT162b2 are as immunogenic and safe as full doses, and a heterologous booster is more immunogenic than a homologous booster. Full article

Background/Objectives: Machine learning is an extremely important issue, considering the potential to prevent the onset of long-term complications from coronavirus disease or to ensure timely detection and effective treatment. The aim of our study was to develop an algorithm and mathematical model to predict the risk of developing long COVID in children who have had acute SARS-CoV-2 viral infection, taking into account a wide range of demographic, clinical, and laboratory parameters. Methods: We conducted a cross-sectional study involving 305 pediatric patients aged from 1 month to 18 years who had recovered from acute SARS-CoV-2 infection. To perform a detailed analysis of the factors influencing the development of long-term consequences of coronavirus disease in children, two models were created. The first model included basic demographic and clinical characteristics of the acute SARS-CoV-2 infection, as well as serum levels of vitamin D and zinc for all patients from both groups. The second model, in addition to the aforementioned parameters, also incorporated laboratory test results and included only hospitalized patients. Results: Among 265 children, 138 patients (52.0%) developed long COVID, and the remaining 127 (48.0%) fully recovered. We included 36 risk factors of developing long COVID in children (DLCC) in model 1, including non-hospitalized patients, and 58 predictors in model 2, excluding them. These included demographic characteristics of the children, major comorbid conditions, main symptoms and course of acute SARS-CoV-2 infection, and main parameters of complete blood count and coagulation profile. In the first model, which accounted for non-hospitalized patients, multivariate regression analysis identified obesity, a history of allergic disorders, and serum vitamin D deficiency as significant predictors of long COVID development. In the second model, limited to hospitalized patients, significant risk factors for long-term sequelae of acute SARS-CoV-2 infection included fever and the presence of ≥3 symptoms during the acute phase, a history of allergic conditions, thrombocytosis, neutrophilia, and altered prothrombin time, as determined by multivariate regression analysis. To assess the acceptability of the model as a whole, an ANOVA analysis was performed. Based on this method, it can be concluded that the model for predicting the risk of developing long COVID in children is highly acceptable, since the significance level is p < 0.001, and the model itself will perform better than a simple prediction using average values. Conclusions: The results of multivariate regression analysis demonstrated that the presence of a burdened comorbid background—specifically obesity and allergic pathology—fever during the acute phase of the disease or the presence of three or more symptoms, as well as laboratory abnormalities including thrombocytosis, neutrophilia, alterations in prothrombin time (either shortened or prolonged), and reduced serum vitamin D levels, are predictors of long COVID development among pediatric patients. Full article

The changes in charge distribution caused by mutations in the spike protein may play a crucial role in balancing infectivity and immune evasion during the evolution of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). To explore how charge increments in spike protein variants influence viral evolution, a statistical analysis was conducted on 57 SARS-CoV-2 variants, examining relationships between charge distribution, lineage divergence, angiotensin-converting enzyme 2 (ACE2) affinity, immune evasion, and receptor-binding domain (RBD) expression. A phylogenetic tree was also reconstructed using only the charge properties of mutation sites. Results indicated that with increasing lineage divergence, overall positive charge initially rose sharply and then more gradually. Partitioning the spike protein into three domains—the RBD, the N-terminal flanking region (B-RBD), and the C-terminal flanking region (A-RBD)—revealed distinct patterns: positive charge increased in the RBD and A-RBD, whereas the B-RBD accumulated negative charge. Charge increments were negatively associated with ACE2 affinity and RBD expression but positively correlated with immune evasion. The k-mer-based tree derived from charge-reduced sequences showed a topology consistent with the whole-genome tree. These findings suggest that charge distribution in spike proteins is closely linked to viral evolution, with the opposing trends in the RBD and B-RBD potentially reflecting a balance between infectivity and immune escape. Full article

The COVID-19 pandemic resulted in high morbidity and mortality, as well as severe social and economic disruption globally. Since the pandemic began in 2019, the severe acute respiratory syndrome, coronavirus 2, has undergone numerous changes, resulting in the emergence of new variants and subvariants. The emergence of new variants of the virus poses a challenge to scientists. There is currently no SARS-CoV-2 variant meeting the criteria of variants of concern, whereas the only variant of interest is JN.1, and there are six variants under monitoring: LP8.1, NP1.8.1, XEC, KP.3, KP.3.1.1 and the latest, XFG (Stratus). Although the latter appears to be more transmissible than the others, genomic evidence indicates that it is less aggressive than some recent variants. Nevertheless, continuous genomic surveillance of COVID-19 is still important to detect any new variants that could threaten public health. Numerous therapeutic strategies, such as drugs, vaccines, and nutritional supplements, are being used to treat COVID-19. This narrative review is an overview of COVID-19 and its various facets, from the number of cases to the therapies used, the current variants, and the ongoing clinical trials, specifically focusing on the most recent studies. Full article

Since its discovery in 2019, SARS-CoV-2 has continued to be detected in both humans and animals worldwide. Currently there is limited research focusing on serological surveillance of wildlife under human care. Here we tested 230 serum samples of 134 animals from two zoological institutions collected between 2015 and 2024. To assess prior exposure and antibody responses from natural infection or vaccination, we used three serological assays: a nucleocapsid protein-based ELISA (N-ELISA), a surrogate virus neutralization test (sVNT) for spike (S) protein and a neutralization assay with S-pseudotyped viral particles. Among the 114 samples collected from 58 animals at Fort Wayne Zoo in Indiana, 37 samples from 20 vaccinated animals were sVNT-positive, and 2 of the positive animals had 2 samples prior to vaccination that tested positive by N-ELISA. Of the 116 samples from 76 animals at Brookfield Zoo in Illinois, 20 samples of 20 animals were sVNT-positive, and 19 of the positive animals had been vaccinated. Among these 20 sVNT-positive samples, only one sample from a South American Tapir was positive from prior to vaccination and 1 sample from a sloth bear was also positive by N-ELISA, marking the first documented cases of SARS-CoV-2 exposure in both species. Neutralization assays with S-pseudotyped virus revealed that some of the sVNT-positive samples have strong activity against the WH1-S pseudovirus but showed significantly reduced neutralization against the Omicron LP.8.1-S pseudovirus. These results underscore the need for updated vaccines tailored to emerging variants. Overall, our findings highlight the importance of continued serological surveillance across multiple species to detect new SARS-CoV-2 exposures and monitor vaccine-induced immunity in captive animal populations. Full article

Natural peptides derived from plants have been an important source of medical substances for several decades. Due to their mechanism of action, chemical potential, and favourable side effect profile, these peptides represent a safer alternative to synthetic pharmaceutical treatments. In this study, we report the discovery of a natural peptide derived from the Brassica napus (Canola) proteome that exhibits high functional similarity to an artificial intelligence (AI)-generated peptide that is designed to bind to the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike 1 (S1) protein receptor-binding domain (RBD) region. The results of a series of experiments including molecular docking simulations, as well as binding and inhibition assays suggest that the natural peptide exhibits functions similar to those of the AI-generated peptide in binding to the RBD region and disrupting its interaction with the human host receptor angiotensin-converting enzyme 2 (ACE2). This study demonstrates the potential of AI-designed peptides to facilitate the identification of natural peptides with similar functional properties. Full article

Immunosuppressive therapies used in clinics to reduce the risk of rejection in transplanted patients unfortunately also decrease the response of the immune system to the pathogens. Previous data has shown that the most diffuse SARS-CoV-2 variants of concern between 2020 and 2021 showed a different modulation of the host immune response in healthy subjects, with the Delta B.1.617.2 variant leading to a failure in the activation of the adaptive immune response. In this study, the transcriptomic profiles of monocyte-derived macrophages (MDM), isolated from four immunosuppressed kidney transplant patients and exposed to SARS-CoV-2 VOCs, were analyzed and compared with previously published data gathered from immune-competent subjects. Human monocytes were isolated from peripheral blood mononuclear cells (PBMCs) of four kidney transplant patients admitted to the IRCCS Policlinico San Matteo of Pavia (Italy), differentiated into macrophages, and exposed to the active and the UV-inactivated particles of the different SARS-CoV-2 VOCs (D614G, Alpha B.1.1.7, Gamma P.1, Delta B.1.617.2 and Omicron BA.1). Bulk RNA-Seq was performed and significant transcripts were assessed based on Student’s t-test (p-value < 0.05) and Fold change > 2. RNA-Seq data analyses of immunosuppressed MDMs showed that SARS-CoV-2 VOCs, although transcriptionally active, did not induce strong alterations in the transcriptomic profiles of these cells, while a strong down-regulation of key genes involved in the innate immunity pathways was observed when comparing these data to the ones obtained from immunocompetent participants. Overall, this study suggests that patients under immunosuppressive therapies do have an altered macrophage response to SARS-CoV-2 viral infection. Full article

Background/Objectives: Dendritic cell vaccines are a promising cancer immunotherapy. AV-OVA-1 is a patient-specific vaccine consisting of autologous dendritic cells (DCs) loaded with autologous tumor antigens (ATA) from a lysate of irradiated self-renewing cells enriched for tumor-initiating cells (TICs). A multicenter, double-blind, randomized phase 2 trial was designed to determine manufacturing feasibility, safety, and efficacy. Methods: Patients had newly diagnosed stage 3 or 4 ovarian cancer. Short-term cell cultures were established from freshly resected tumor specimens. Patients were screened for randomization seven months after initial diagnosis, after completing neoadjuvant and/or adjuvant chemotherapy and surgery. Eligibility included a successful cell culture, cryopreservation of sufficient monocyte numbers for differentiation into DCs, and good performance status. Patients were stratified by whether they had persistent disease; then, they were randomized 2:1 to AV-OVA-1 or autologous monocytes (MC). Cryopreserved doses of AV-OVA-1 and MC were thawed and admixed with granulocyte–macrophage colony-stimulating factor just before subcutaneous injections at weeks 1, 2, 3, 8, 12, 16, 20, and 24. Results: Study accrual was terminated early during the SARS-CoV-2 pandemic. Manufacturing success rates for TICs, monocyte intermediate products, and AV-OVA-1 were 70/72 (97.2%) and 47/50 (94.0%), and 29/30 (96.7%), respectively. A total of 29 participants were treated with AV-OVA-1 and 15 with MC. Patients received an average of 7.4 injections. Adverse-event frequencies were similar in both arms, mild to moderate in severity, and self-limited. T-cell immune responses increased only after AV-OVA-1. There were no survival differences in this underpowered study. Conclusions: AV-OVA-1 was manufactured reliably and injections were well tolerated. Full article

Pandemic preparedness is a complex of threat-agnostic countermeasures developed in advance which would be efficient against a future outbreak regardless of its causative agent, and broad-spectrum antivirals constitute a critical component of this complex. Plant polyphenols are known to suppress viruses of unrelated families by acting on multiple viral and cellular structures. We therefore searched for broad-spectrum antivirals among polyphenols that have been confirmed as safe to humans. The ellagitannin geraniin and galloylglucose constituents of the drug Rutan (1,2,3,4,6-penta-O-galloyl-β-D-glucose [R5], 3-bis-O-galloyl-1,2,4,6-tetra-O-galloyl-β-D-glucose [R6], 2,4-bis-O-galloyl-1,3,6-tri-O-galloyl-β-D-glucose [R7], 2,3,4-bis-O-galloyl-1,6-di-O-galloyl-β-D-glucose [R8]) were isolated from Geranium sanguineum and sumac (Rhus coriaria), respectively. We revealed their activity towards herpes simplex viruses (HSV-1 and HSV-2), human cytomegalovirus (CMV), and the Epstein–Barr virus (EBV). R5 suppressed HSV-1 and HSV-2 with equal efficiency, while Rutan and R7 were more active against HSV-1, and geraniin against HSV-2. Rutan and R5 also inhibited the intracellular replication of CMV and EBV (contrary to our expectations, geraniin and polyphenols R6–R8 showed no activity). Thus, we have shown for the first time that sumac polyphenols are capable of suppressing—in addition to HIV, influenza virus, and SARS-CoV-2—the reproduction of representatives of all three Orthoherpesviridae subfamilies, meeting the criteria for further development as broad-spectrum antivirals. Full article

Background: Cytokines participate in regulating the immune response of lymphocytes. Interleukin 2 (IL-2) is the main modulator of T lymphocyte development, homeostasis, and function, whereas interleukin 7 (IL-7) regulates the development and homeostasis of immune cells and plays a crucial role in the maintenance of memory cells. The study aims to assess the blood IL-2 and IL-7 concentration in relation to the obtained cellular and humoral response in adults, six months after vaccination against COVID-19. Methods: We measured the concentration of IL-2 and IL-7 with ELISA, CoV2-IgG with an indirect chemiluminescence test, and the levels of IFN-γ with interferon gamma release assay (IGRA) post SARS-CoV-2 antigen stimulation. The study group (n = 76; F = 66, M = 10) was divided into 41 individuals, who did not report any chronic disorder (ChrD-Neg), and 35, who did (ChrD-Pos). Results: ChrD-Pos group presented higher IL-7 compared to ChrD-Neg (p = 0.023). Negative correlations were observed in the entire study population between IL-2 and age (R = −0.252, p = 0.028), as well as between IL-7 and IFN-γ (R = −0.295, p = 0.010). We found a positive correlation between IL-2 and IL-7 concentrations in the entire study population (R = 0.305, p = 0.007) and the ChrD-Pos group (R = 0.358, p = 0.035), and people with a positive IGRA result (R = 0.359, p = 0.005). Conclusions: The interaction of IL-2 and IL-7 may be important for achieving post-vaccination immunity, especially in adults with chronic diseases. Age is a factor modifying the post-vaccination response (decreased IL-2), whereas IL-7 may be an important factor in achieving a satisfactory post-vaccine response in people with chronic diseases. Full article

Background/Objectives: β-Carotene oxygenase-2 (BCO2) is a mitochondrial carotenoid-cleaving enzyme expressed in multiple tissues, including the lungs. While BCO2 regulates carotenoid handling, its role in shaping pulmonary immune architecture and antiviral responses is unknown. We hypothesized that BCO2 deficiency reprograms epithelial–innate circuits and alters antiviral outcomes. Methods: BCO2-knockout (KO) and C57BL/6J wild-type (WT) mice underwent lung single-cell RNA sequencing (scRNA-seq), immunoblotting, and intranasal SARS-CoV-2 challenge to assess cell-type heterogeneity, pathway programs (by gene set variation analysis, GSVA), and antiviral responses. Results: scRNA-seq resolved 14 major lung cell populations with cell-type-specific pathway shifts. Compared with WT, BCO2 KO lungs showed increased conventional dendritic cells and natural killer (NK) cells, with reductions in macrophages, B cells, and endothelial cells. In KO alveolar type II cells, GSVA indicated a stress-adapted metabolic program. Ciliated epithelium exhibited vitamin-K-responsive and axoneme-remodeling signatures with attenuated glucocorticoid and very-low-density lipoprotein remodeling. Innate lymphoid type 2 cells favored fatty acid oxidation and chromatin dynamics with reduced mitochondrial activity. NK cells were biased toward constitutive chemokine/cytokine secretion and counter-inflammatory signaling. Immunoblotting confirmed the elevated level of interferon regulatory factor-3 protein in BCO2-KO lungs. Functionally, BCO2-KO mice had improved outcomes after intranasal SARS-CoV-2 exposure. Conclusions: Loss of BCO2 reconfigures the pulmonary immune landscape and enhances antiviral responsiveness in mice. These findings identify BCO2 as a nutrient-linked enzyme with immunomodulatory impact and highlight cell-state changes as candidate mechanisms for improved antiviral tolerance. Full article

Background and Objectives: This research aimed to examine the impact of sociodemographic characteristics on mental health during the COVID-19 pandemic, with religiosity as a moderator. Materials and Methods: The cross-sectional study was conducted in family medicine clinics within the Primary Healthcare Center of Virovitica-Podravina County among 1131 participants, divided into 2 groups: RC (Recovered from COVID-19; N = 423) and NRC (Not Recovered from COVID-19; N = 708). To ensure clear differentiation, RC participants were defined as individuals with documented positive PCR results for SARS-CoV-2 (prior infection and clinical recovery), whereas NRC participants exhibited consistently negative PCR results and lacked any clinical history of the disease. Group allocation was rigorously based on the review of medical records and corresponding PCR documentation obtained both at the time of recruitment and retrospectively. All data were collected through a questionnaire from September 2022 to September 2023. Participants completed questionnaires measuring their sociodemographic characteristics (gender, age, education, and marital status), levels of depression, anxiety, stress, and level of religiosity. Results: Older participants were more prone to depression, whereas younger participants showed relatively better mental-health indicators. Sociodemographic characteristics were significantly associated with mental health during the pandemic. Religiosity was found to be a significant moderator in the relationship between sociodemographic characteristics and mental health. Individuals with higher levels of religiosity reported higher levels of depression and anxiety, suggesting that religiosity may act as a negative factor in times of crisis. Conclusions: Sociodemographic characteristics were significant predictors of mental health during the pandemic. Religiosity emerged as an important factor, particularly in moderating the relationship between sociodemographic characteristics and mental health. Further research is recommended to develop targeted interventions for vulnerable groups such as women, younger individuals, and those with lower incomes. Full article

The SARS-CoV-2 spike protein, through its receptor binding domain (S1-RBD), binds to the angiotensin-converting enzyme 2 (ACE2) receptor on the host cell membrane, leading to viral infection. Several mutations in S1-RBD in SARS-CoV-2 variants are known to enhance infection through an increased affinity for ACE2. While many reports are available describing the SARS-CoV-2 infection mechanism, there is a dearth of studies towards understanding the initial interaction of the S1-RBD with ACE2 on living host cells and the role of endocytosis and cytoskeleton in the process. Here, we reconstituted the interaction between S1-RBD- and ACE2-expressing host cells in a hybrid live cell-supported lipid bilayer (SLB) platform enabling live monitoring of the interaction between S1-RBD on SLBs and the ACE2 receptor on living cells and showed that cells depleted Omicron S1-RBD from SLB corrals, likely through endocytosis. Specifically, interaction of living host cells with S1-RBD-functionalized SLB substrates resulted in the enrichment of S1-RBD and ACE2 at the cell–SLB interface. Interaction of host cells with wild type (WT), Omicron, and Omicron Revertant S1-RBD functionalized on micron-scale SLB corrals, which mimic viral membranes but are flat, also resulted in their enrichment. However, cells interacting with Omicron S1-RBD revealed a depletion of the protein from many corrals, which was generally not observed with the WT S1-RBD and was reduced with the Omicron Revertant, which contains the Q493R mutation reversion, S1-RBD. Further, S1-RBD depletion coincided with the localization of the early endosomal marker EEA1. Importantly, treatment of cells with the clathrin inhibitor, pitstop 2, but not the myosin II inhibitor, blebbistatin, significantly reduced Omicron S1-RBD depletion. Collectively, these observations suggest that the SARS-CoV-2 Omicron variant has evolved, through mutations in its S1-RBD, to take advantage of the cellular endocytic pathway for enhanced infection, which is not observed with the parental SARS-CoV-2 and appears to be lost in the Omicron Revertant variant. Additionally, these results underscore the significance of the hybrid live cell–SLB platform in studying SARS-CoV-2 S1-RBD-ACE2 interaction and the potential impact of mutations in the S1-RBD on adapting to a specific cellular entry mechanism. Full article

Objectives: Prevention of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and the disease COVID-19 is a public health priority. The efficacy of non-pharmaceutical interventions such as wearing face masks to prevent SARS-CoV-2 infection has been well established in controlled settings. However, evidence for the effectiveness of face masks in preventing SARS-CoV-2 transmission within real-world settings is limited and mixed. The present systematic review evaluated the effectiveness of face mask policies and mask wearing to prevent SARS-CoV-2 transmission and COVID-19 in real-world settings. Methods: Following PRISMA guidelines, scientific databases, and gray literature, were searched through June 2023. Inclusion criteria were as follows: (1) studies/reports written in or translated to English; (2) prospectively assessed incidence of SARS-CoV-2 or COVID-19; (3) assessed the behavior and/or policy of mask-wearing; and (4) conducted in community/public settings (i.e., not laboratory). Studies were excluded if they did not parse out data specific to the effect of mask wearing (behavior and/or policy) and subsequent SARS-CoV-2 transmission or COVID-19 disease or if they relied solely on statistical models to estimate the effects of mask wearing on transmission. A total of 2616 studies were initially identified, and 470 met inclusion and exclusion criteria for full-text review. The vote counting method was used to evaluate effectiveness, and risk of bias was assessed using JBI critical appraisal tools. Results: A total of 79 unique studies met the final inclusion criteria, and their data were abstracted and evaluated. Study settings included community/neighborhood settings (n = 34, 43%), healthcare settings (n = 30, 38%), and school/universities (n = 15, 19%). A majority of studies (n = 61, 77%) provided evidence to support the effectiveness of wearing face masks and/or face mask policies to reduce the transmission of SARS-CoV-2 and/or prevention of COVID-19. Effectiveness of mask wearing did not vary substantially by study design (67–100%), type of mask (77–100%), or setting (80–91%), while 85% of masking policies specifically reported a benefit. Conclusions: This systematic literature review supports public health recommendations and policies that encourage the public to wear face masks to reduce the risk of SARS-CoV-2 infection and COVID-19 in multiple real-world settings. Effective communication strategies are needed to encourage and support the use of face masks by the general public, particularly during peak infection cycles. Full article