Extracellular adenosine is a major immunosuppressive metabolite of the tumor microenvironment and a key barrier to anti-tumor immunity. Generated from ATP by the ectonucleotidases CD39 and CD73, it signals mainly through the high-affinity A2A adenosine receptor (A2AR). Although A2AR is regarded as an inhibitory immune checkpoint, recent work shows that its functions extend beyond immediate effector suppression to the regulation of metabolic fitness, mitochondrial homeostasis, and CD8+ T-cell differentiation. Notably, both sustained A2AR activation and complete receptor deficiency can drive terminal exhaustion through distinct mechanisms, and CD73 and extracellular adenosine are not biologically equivalent. Here we summarize adenosine signaling, the cell-specific roles of the A2AR axis, and the clinical development of A2AR-targeting immunotherapies. We identify the principal obstacles to therapeutic translation and advance biomarker-guided, calibrated modulation of A2AR signaling as a testable hypothesis rather than an established therapeutic principle, one that now requires comparative exposure–response and longitudinal intervention studies.
The urgent need for COVID-19 vaccines led to rapid mRNA vaccine development, making safety evaluation essential for current vaccination programs and future mRNA vaccines, particularly in children. To systematically evaluate adverse events (AEs) following two BNT162b2 doses in 5–11-year-old children, including those with comorbidities, a national telephone survey (January–March 2022) was conducted among parents of children who had received the second BNT162b2 dose 21–30 days prior. Children were randomly sampled from the national vaccination registry. For each dose, multivariable logistic regression identified associations between children’s characteristics and any AE. Overall, 2,229 children participated (response rate 76.0%); 9.6% had chronic diseases, and 9.2% had pre-existing allergic conditions. Any AE was reported in 58.5%, mainly local (55.7%) or systemic (20.2%); the most common were local pain (54.7%) and fatigue (14.6%), respectively. Most local and systemic AEs resolved within 3 days; medical care was sought for only 1.0% of local and 5.7% of systemic AEs, and no hospitalizations were reported. For both doses, any AE was significantly associated with younger age (first/second doses: aOR = 0.94, 95% CI: 0.90–0.98; aOR = 0.96, 95% CI: 0.92–0.99), female sex (aOR = 1.38, 95% CI: 1.15–1.64 for both), and pre-existing allergic conditions (first/second doses: aOR = 1.99, 95% CI: 1.45–2.74; aOR = 1.71, 95% CI: 1.24–2.35). AE onset, duration, and relative severity were similar regardless of pre-existing allergic status. Exacerbation of chronic and allergic conditions occurred in 4.8% and 2.2%, respectively. BNT162b2 demonstrated a favorable short-term safety profile among children, including those with comorbidities. This study may help inform development and implementation of new mRNA vaccine targets for children.
Human papillomavirus (HPV) infection is widespread and a leading cause of preventable cancers, yet HPV vaccination uptake among adult men remains suboptimal. Qualitative evidence on multilevel determinants of men’s vaccination decisions and healthcare responses remains limited. This qualitative meta-synthesis aimed to synthesize barriers and facilitators to HPV vaccination among adult men guided by the Social Ecological Model (SEM), and to explore how vaccination-related health needs are reflected in healthcare resources and translated into service utilization using a health service evaluation framework informed by WHO health service concepts. Ten electronic databases, including PubMed, Embase, and PsycINFO, were searched from inception to December 2025 using controlled vocabulary and free-text terms. Ten studies across four countries were included. The evidence base was concentrated among sexual minority men, sex workers, and healthcare-engaged men, with fewer studies among general male populations; six of the ten studies were conducted in the United States, limiting generalizability to adult men more broadly. Thematic synthesis followed Thomas and Harden’s approach, with findings organized across five SEM levels. Key barriers included gendered perceptions of HPV, low perceived susceptibility, stigma and disclosure concerns, provider communication failures, economic constraints, and structural access challenges. Facilitators included provider recommendation, supportive relationships, integrated care pathways, and health information access. Health service evaluation identified gaps between needs, resources, and utilization, particularly outside preventive care. These findings highlight that improving HPV vaccination among adult men requires multilevel behavioral strategies alongside healthcare system improvements that better recognize and respond to men’s vaccination needs.
Middle East respiratory syndrome coronavirus (MERS-CoV) causes serious infection in humans with up to 40% mortality. As MERS-CoV infects humans via nasopharyngeal mucosa, local mucosal immunization may provide an effective vaccination strategy. Nasopharynx-associated lymphoid tissues (NALT, comprising adenotonsillar tissues) are immune induction sites for intranasal vaccines. We studied the capacity of a viral vectored MERS candidate vaccine (ChAdOx1 MERS) and inactivated MERS-CoV in activating cellular and antibody responses in the NALT. Mononuclear cells isolated from adenotonsillar tissues from children and adults were stimulated with ChAdOx1 MERS and heat- or radiation-inactivated MERS-CoV, followed by analysis of anti-MERS IgG antibody and cytokines (IFNγ and TNFα) in cell culture supernatants by ELISA. CD4+ and CD8+ T cell responses, including proliferation and expression of cytokines and cytotoxic molecules were evaluated by flow cytometry. ChAdOx1 MERS induced marked spike-specific anti-MERS IgG antibody responses, which were significantly stronger than those induced by inactivated MERS-CoV. ChAdOx1 MERS also activated higher CD4+ and CD8+ T cell proliferative responses, cytokine expression (IFNγ, TNFα) by CD4+ T cells and cytotoxic perforin and granzyme B expression by CD8+ T cells than by inactivated MERS-CoV. Both antibody and T cell responses were shown stronger in adults than in children. There was a positive correlation between CD4+ T cell proliferation and the antibody response. Human NALT offers an efficient immune induction site for Spike-specific anti-MERS antibody and T cell response. Viral vectored ChAdOx1 MERS induces marked antibody and T cell responses in the NALT, supporting its potential as a mucosal (e.g. intranasal) vaccine against MERS.
Evidence on the real-world effectiveness of seasonal influenza vaccination among older adults in China remains limited and varies by season and circulating virus. We used a test-negative case–control design to estimate the effectiveness of the 2025–2026 trivalent influenza vaccine against medically attended, laboratory-confirmed influenza among adults aged ≥60 years attending two sentinel hospitals in Shengzhou, Zhejiang Province. Participants vaccinated ≥14 days before symptom onset were considered vaccinated; those vaccinated 0–13 days before onset were excluded from the primary analysis. Vaccine effectiveness (VE) was calculated as (1 − adjusted odds ratio) × 100% using multivariable logistic regression. Among 532 participants in the primary analysis, 156 were influenza-positive cases and 376 were test-negative controls. Effective current-season vaccination was recorded in 32.7% of cases and 48.4% of controls. Adjusted VE against any influenza was 46% (95% confidence interval [CI], 18–64). Type-specific VE was 42% (95% CI, 8–63) against influenza A and 60% (95% CI, 14–81) against influenza B. Subtype-specific estimates were less precise, and interaction analyses did not identify differences by age group or chronic-disease status. The overall estimate remained stable across diagnostic restrictions and alternative model specifications. The 2025–2026 trivalent influenza vaccine was associated with moderate protection against medically attended influenza in older adults under routine program conditions, supporting continued seasonal vaccination and multi-season surveillance.
