Issue: Newsletter 11 | December 15, 2025
| Citation of Articles | PICO | Main Results | Risk of Bias |
|---|---|---|---|
| Giamarellos-Bourboulis EJ, Kotsaki A, Kotsamidi I, Efthymiou A, Koutsoukou V, Ehler J, et al. Precision immunotherapy to improve sepsis outcomes: the ImmunoSep randomized clinical trial. JAMA. 2025 Dec 8; doi:10.1001/jama.2025.24175 • Editorial Commentary: Angus DC. Precision therapy for sepsis: the end of the beginning? JAMA. 2025 Dec 8; doi:10.1001/jama.2025.24099 |
P: 276 adults with sepsis due to pneumonia (community-acquired, hospital-acquired, or ventilator-associated) or bacteremia, classified biologically as having macrophage activation–like syndrome or sepsis-induced immunoparalysis. I: Precision immunotherapy consisting of IV anakinra for patients with macrophage activation–like syndrome or subcutaneous recombinant human interferon-γ for those with sepsis-induced immunoparalysis. C: Standard care plus matching double-dummy placebo injections (IV and subcutaneous). O: A decrease of at least 1.4 points in mean SOFA score by day 9; secondary outcomes included 28-day mortality and treatment-emergent adverse events. |
Precision immunotherapy led to a higher proportion achieving ≥1.4-point SOFA score reduction by day 9 (35.1% vs 17.9%; difference 17.2%, 95% CI 6.8–27.2). No significant difference in 28-day mortality was observed. Serious adverse events were common in both groups (88.8%), with anemia occurring more frequently in the anakinra subgroup and hemorrhage in the interferon-γ subgroup. Overall, the tailored immunotherapy strategy improved organ dysfunction but did not reduce mortality. | Moderate risk: The randomized, double-blind, double-dummy design reduces performance and detection bias, but classification based on ferritin and HLA-DR introduces potential misclassification bias. High rates of serious adverse events raise concerns about differential reporting, although SOFA scoring is objective. Attrition risk is low with nearly all randomized patients analyzed, but the phase 2b sample size limits precision and external validity. |
| Alaimo C, Karaky N, Lawrence R, Bownes E, Haffner S, Kowarik M, et al. Safety and immunogenicity of a Klebsiella pneumoniae tetravalent bioconjugate vaccine (Kleb4V) administered to healthy adults: a first time in human phase I/II randomised and controlled study. J Infect Dis. 2025 Nov 25; doi:10.1093/infdis/jiaf600 |
P: 166 healthy adults (16 aged 18–40 years and 150 aged 55–70 years) enrolled in an observer-blind, randomized, placebo-controlled phase I/II trial evaluating a K. pneumoniae vaccine. I: Two intramuscular doses of the tetravalent Kleb4V bioconjugate vaccine (16 µg or 64 µg total O-antigen, with or without AS03 adjuvant) administered on days 1 and 57. C: Placebo injections given on the same schedule. O: Primary—safety and tolerability; Secondary—immunogenicity measured by IgG responses to the four O-antigen serotypes. |
Kleb4V was well tolerated, with mainly mild to moderate solicited and unsolicited adverse events. The vaccine induced IgG responses to all four serotypes, with O1v1, O2a, and O2afg responses rising by two weeks after the first dose and persisting six months after the second dose. AS03-adjuvanted formulations produced superior immune responses for three of the four serotypes. O3b responses were consistently lower than for the other antigens. | Low to moderate risk: The observer-blind, randomized, placebo-controlled design limits performance and detection bias, although full blinding was not applied to all parties. Phase I/II sample size is modest and limits precision and generalizability. Safety and immunogenicity outcomes are largely objective, reducing measurement bias. Age stratification helps applicability to the target older adult population, but small numbers in the younger group decrease robustness. |
| Sehgal IS, Agarwal R, Dhooria S, Prasad KT, Muthu V, Aggarwal AN, et al. Oral itraconazole versus oral voriconazole for treatment-naive patients with chronic pulmonary aspergillosis in India (VICTOR-CPA trial): a single-centre, open-label, randomised, controlled, superiority trial. Lancet Infect Dis. 2025 Oct 29; doi:10.1016/S1473-3099(25)00537-7 |
P: 116 treatment-naive adults aged ≥18 years with chronic cavitary or chronic fibrosing pulmonary aspergillosis, recruited from a single tertiary-care chest clinic in India and randomly assigned after screening 150 individuals. I: Oral voriconazole 200 mg twice daily for 6 months. C: Oral itraconazole 200 mg twice daily for 6 months. O: Primary—favourable clinical and radiological response at 6 months in a modified intention-to-treat population; Secondary—safety outcomes including treatment-related adverse events. |
Favourable response rates at 6 months were similar between voriconazole and itraconazole (69% vs 67%; absolute risk reduction –0.02, 95% CI –0.20 to 0.15; p=0.84), indicating no superiority of voriconazole. Treatment-related adverse events were significantly more common with voriconazole (55% vs 34%; p=0.025). Four deaths occurred, all in the voriconazole group, though none were judged directly treatment-related. | High to moderate risk: The open-label design introduces substantial performance and detection bias, particularly for clinical outcomes, although radiological assessment was masked. Single-centre recruitment limits external validity. Modified intention-to-treat analysis minimizes attrition bias, but subjective components of clinical improvement may be influenced by knowledge of assignment. Safety outcome reporting is vulnerable to differential attribution given lack of blinding. |
| Elangovan S, Cai Y, Mitchell BG, Graves N. Seven-day vs four-day infusion set replacement interval and catheter-related infections. JAMA Netw Open. 2025 Dec 2;8(12):e2546398; doi:10.1001/jamanetworkopen.2025.46398 |
P: 2,941 hospitalized adults requiring central venous access devices in 10 Australian hospitals, with a median age of 59 years and 62.9% male, many admitted to ICU or medical/hematology/emergency surgical specialties. I: Replacement of infusion sets every 7 days. C: Standard practice of infusion set replacement every 4 days. O: Changes in total costs, catheter-related bloodstream infections (CRBSIs), life-years, and cost-effectiveness probabilities from a hospital perspective. |
Extending infusion set replacement from 4 to 7 days reduced annual hospital costs by approximately A$52 million, but increased CRBSI risk from 1.46% to 1.78%, resulting in an estimated 395 additional infections, 103 excess deaths, and 1,724 life-years lost at the population level. Probabilistic analyses indicated a 50.3% likelihood of cost-effectiveness and 72.5% likelihood of worse health outcomes. While cost savings were substantial, the modest increase in infection risk could lead to significant adverse health impacts. | Moderate risk: The economic evaluation relied on decision-analytic modeling based on trial data rather than direct patient-level outcomes, introducing potential modeling assumptions bias. The underlying RSVP trial was randomized and multicenter, reducing selection bias, but the analysis excluded peripheral arterial catheters and was limited to a hospital perspective, which may underestimate broader societal costs or benefits. Uncertainty in model parameters was addressed with probabilistic sensitivity analyses, but results depend heavily on assumptions about infection costs and life-year losses. |
| Gbesemete D, Ramasamy MN, Ibrahim M, Hill AR, Raud L, Ferreira DM, et al. Efficacy, immunogenicity, and safety of the live attenuated nasal pertussis vaccine, BPZE1, in the UK: a randomised, placebo-controlled, phase 2b trial using a controlled human infection model with virulent Bordetella pertussis. Lancet Microbe. 2025; doi:10.1016/j.lanmic.2025.101211 |
P: 53 healthy adults aged 18–50 years, fully vaccinated against SARS-CoV-2, without recent pertussis vaccination or illness, enrolled at two UK sites and assessed for compliance with protocol restrictions such as no smoking or nasal sprays. I: Single intranasal dose of 10⁹ CFU of BPZE1, followed 60–120 days later by a controlled challenge with 10⁵ CFU of virulent Bordetella pertussis. C: Placebo (lyophilised buffer) intranasal dose, followed by identical virulent challenge. O: Primary—absence of detectable B. pertussis colonisation in nasal washes on days 9, 11, and 14 post-challenge; Secondary—safety and tolerability (solicited and unsolicited adverse events). |
In the modified intention-to-treat population, 58% (14/24) of BPZE1 recipients had no detectable colonisation compared with 33% (7/21) of placebo recipients (p=0.091). In the per-protocol adequate inoculum population, protection was greater with BPZE1: 60% (12/20) vs 25% (4/16) without colonisation (p=0.033). Most participants reported at least one mild solicited adverse event within 7 days post-vaccination (85% vs 81%), and unsolicited adverse events within 28 days were similar between groups (27% vs 33%). No serious adverse events or discontinuations occurred, demonstrating a favorable safety profile. | Moderate risk: Randomisation and masking of study staff administering the vaccine reduce allocation and performance bias, but participants and some clinical staff were not fully blinded, introducing potential detection bias. Small sample size and single-country setting limit statistical power and generalizability. Objective primary outcome (nasal culture) minimizes measurement bias, and high follow-up completion mitigates attrition bias. |
| Elmesiry AM, Elsheikh MR, Elshimy KM, Abotaleb AM. Role of vitamin C infusion in postoperative mechanically ventilated neonates with sepsis: a randomized controlled trial. Eur J Pediatr. 2025 Nov 29;184:806; doi:10.1007/s00431-025-06625-4 |
P: 50 full-term neonates who required mechanical ventilation and developed confirmed sepsis following surgical interventions. I: Standard sepsis management plus intravenous vitamin C infusion (0.5 g/kg loading dose followed by 0.5 g/kg/h for 6 hours daily, continued for 7–10 days). C: Standard sepsis management plus placebo infusion. O: Primary—respiratory parameters (respiratory rate, peak inspiratory pressure, FiO₂ requirements, SpO₂/FiO₂); Secondary—duration of mechanical ventilation, need for inotropic support, length of NICU/hospital stay, and mortality. |
Vitamin C administration significantly improved respiratory parameters, with lower respiratory rate and peak inspiratory pressure at 24, 72, and 120 hours, and reduced FiO₂ requirements at 72 and 120 hours compared with placebo. SpO₂/FiO₂ ratios were higher in the vitamin C group at 72 and 120 hours. Duration of mechanical ventilation (4.44 ± 1.23 vs 5.64 ± 2.2 days, p=0.021) and requirement for inotropic support (40% vs 76%, p=0.010) were also significantly reduced. There were no significant differences in NICU or hospital length of stay or mortality between groups. | Moderate risk: The double-blind design reduces performance and detection bias, but small sample size limits statistical power and generalizability. Objective respiratory outcomes reduce measurement bias, though clinical management decisions could still influence secondary outcomes. No significant attrition was reported, minimizing attrition bias, but the single-center setting may affect external validity. |
| Heath PT, Zuma-Gwala N, Helmig RB, Horne E, Kjærbye-Thygesen A, Wiinblad Crusell MK, et al. Immunogenicity and safety of a group B Streptococcus vaccine (GBS-AlpN) in pregnant women and their infants: a phase 2, multicentre, observer-blind, randomised, placebo-controlled study. Lancet Infect Dis. 2025 Dec 9; doi:10.1016/S1473-3099(25)00659-0 |
P: 272 healthy pregnant women (gestational age 21–23+6 weeks) across South Africa, Denmark, and the UK. I: Two doses of GBS-AlpN vaccine (various schedules across groups 1–3) or one dose (group 4). C: Placebo (group 5). O: Umbilical cord or infant blood IgG concentrations against AlphaCN, RibN, Alp1N, Alp2/3N; proportion of infants exceeding prespecified IgG thresholds; maternal and infant safety. |
Highest infant IgG concentrations were observed in the two-dose vaccine groups, followed by the one-dose group; group 4 had lower but still ≥21-fold higher IgG levels than placebo. Proportion of infants with IgG >1.0 μg/mL ranged from 87–94% in group 1, 67–91% in group 2, 82–93% in group 3, and 61–80% in group 4; no placebo infants reached this threshold. Maternal adverse events were common (87–97%), mostly mild–moderate; nine infant deaths occurred, none related to vaccination. | Low–moderate risk: Observer-blind design and stratified randomisation reduce performance and selection bias. High follow-up and evaluable samples support reliability, though small group sizes (especially placebo, n=30) may limit precision for rare safety events. |
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