Clinical research

Nirmatrelvir/ritonavir can reduce COVID-19 severity when initiated within five days of symptom onset but the optimal timing within this window is unknown. Here, the authors emulate a randomised trial using electronic health records from Hong Kong and find evidence for a benefit of early treatment initiation.

Understanding the immune responses of school-aged children to SARS-CoV-2 is important for designing public health measures. Here, the authors report findings from cross-sectional and longitudinal anti-SARS-CoV-2 antibody measurements in a school-based study in Zurich, Switzerland, from 2020-2022.

Here, Heitmann et al. report results from a Phase I/II trial evaluating CoVac-1, a peptide-based T-cell activator, in patients with B-cell deficiency, demonstrating potent induction of SARS-CoV-2-specific T-cell responses along with a favorable safety profile.

Here the authors provide safety and immunogenicity data for an AdV5-based SARS-CoV-2 vaccine, administered intramuscularly as heterologous booster after three-doses of inactivated SARS-CoV-2 vaccine in Chinese adults.

Here the authors show in a phase 1 trial that a recombinant subunit vaccine based on the gamma variant of SARS-CoV-2 exhibits a satisfactory safety profile, and induces a broad booster response of neutralizing antibodies and a booster effect on T cell immunity in individuals previously immunized with different SARS-CoV-2 vaccine platforms.

Palmer et al. present interim findings from their clinical trial; they describe the reactogenicity and immunogenicity results of a self-amplifying mRNA SARS-CoV-2 booster vaccine within an older population (≥60 years of age).

Authors study antibody responses elicited against Omicron BA.1 and variants, by Omicron BA.1-bivalent mRNA-1273.214 vaccine compared with mRNA-1273 vaccination, when administered as a second booster, 90 days post-administration.

The extent to which COVID-19 vaccination protects against long COVID is not well understood. Here, the authors use electronic health record data from the United States and find that, for people who received their vaccination prior to infection, vaccination was associated with lower incidence of long COVID.

Dewald et al. show a high Spike-IgG seroprevalence (95%) in a multicenter study with 1,411 participants. They determined a substantially reduced serum neutralization against the SARS-CoV-2 VOCs BA.4/5 and BQ.1.1. and explored predictive factors of neutralizing activity.

Extending the interval between doses of mRNA Covid-19 vaccines has been linked with a reduced risk of myocarditis in children and adolescents, but impacts on vaccine effectiveness are not known. Here, the authors perform a nested case-control study using data from Hong Kong and find evidence of reduced risk of infection following a longer dosing interval.

This study investigates the impact of maternal COVID-19 vaccination during pregnancy on infant infection during the first six months of life. Using data from California, USA, the authors find that protection against infection during the period of Delta dominance was high, but that it declined during the Omicron period.

Authors have previously reported on the efficacy and safety of the recombinant spike protein nanoparticle vaccine, NVX-CoV2373, in healthy adults. In this work, they assess anti-spike binding IgG, anti-RBD binding IgG and neutralising antibody titer as correlates of risk and protection against COVID-19.

Emergence of the Omicron BA.1/2 SARS-CoV-2 subvariants led to a wave of infection South Africa. Here, the authors use serological data from a prospective household study to characterise infection rates in the context of diverse immune histories following vaccination and exposure to different variants.

The authors previously reported the primary outcomes of a randomized phase II trial comparing neoadjuvant durvalumab (anti-PD-L1) alone or in combination with stereotactic radiotherapy in patients with early-stage NSCLC. Here, the authors report the secondary outcomes of the trial and post hoc analysis.

HER2 targeted therapy combined with chemotherapy represents a standard approach for treating HER2-positive metastatic breast cancer (MBC). Here the authors report the results of a phase II trial of the small molecule tyrosine kinase inhibitor pyrotinib plus docetaxel as a first-line treatment for HER2-positive MBC.

Preclinical studies indicate that myeloproliferative neoplasms (MPN) may be sensitive to the estrogen receptor modulator, tamoxifen. Here, the authors present a phase II clinical trial reporting the efficacy of tamoxifen in MPN and analysis of peripheral haematopoietic stem cells to identify potential predictive signatures of responders.

Due to high rate of metastasis, lymphadenectomy is a cornerstone of the surgical treatment of gastric cancer however the accurate dissection of lymph nodes (LN) can be challenging. Here, the authors present the long-term outcomes of a randomised control trial investigating indocyanine green fluorescence image-guided LN retrieval in gastric cancer patients undergoing laparoscopic gastrectomy.

Several PD-(L)1 inhibitors have been approved or are in development for the treatment of NSCLC, showing promising efficacy and tolerable safety profiles. Here, the authors present a randomized phase II clinical trial comparing two different anti-PD-1 antibodies, dostarlimab and pembrolizumab, both combined with chemotherapy as first-line treatment in patients with metastatic NSCLC.

Preclinical studies have shown that blockade of the CD73-adenosinergic pathway could improve anti-tumor immunity and response to other immune checkpoint inhibitors. Here the authors report the results of a randomized phase II trial of first-line durvalumab, paclitaxel and carboplatin with or without the anti-CD73 antibody oleclumab in patients with advanced triple-negative breast cancer.

Standard of care for unfavorable-risk cancer of unknown primary (CUP) comprises platinum-based chemotherapy as first-line treatment, however therapeutic options remain limited. Here the authors report the results of a phase II trial of combined nivolumab (anti-PD1) and ipilimumab (anti-CTLA4) in patients with unfavorable CUP.

Recent evidence suggests the feasibility of neoadjuvant immune checkpoint inhibitors plus chemotherapy-based therapy for patients with early triple-negative breast cancer (TNBC). Here the authors report the results of a single-arm phase II trial of neoadjuvant camrelizumab (anti-PD-1) plus nab-paclitaxel and epirubicin for early TNBC.

Total mesorectal excision (TME) for rectal cancer can require partial resection of Denonvilliers’ fascia (DVF). Here the authors report the secondary outcomes of a randomized trial to evaluate the safety and effect of DVF preservation during laparoscopic TME on postoperative urogenital function and oncological safety in male patients with mid-low rectal cancer.

Dalpiciclib is a CDK4/6 inhibitor, recently approved for treatment in advanced breast cancer patients in China. Here, the authors report the results of a phase II trial investigating oral dalpiciclib (CDK4/6 inhibitor) and pyrotinib (pan-HER inhibitor) in patients with HER2-positive metastatic breast cancer.

The NIBIT-M4 trial was designed to assess the safety, biological and clinical activity of anti-CTLA4 ipilimumab with the DNA hypomethylating agent guadecitabine in advanced melanoma patients. Here the authors report the five-year follow-up results of the trial and an integrated multi-omics analysis of pre- and on-treatment tumor biopsies.

Even in patients who are initially sensitive, patients treated with platinum-based therapies often go on to relapse and have limited treatment options. Here, the authors report the efficacy and safety of a phase II trial investigating olaparib, pembrolizumab and bevacizumab as maintenance therapy in platinum-sensitive recurrent ovarian cancer.

Stereotactic ablative radiotherapy (SABR) is standard-of-care for patients with medically inoperable early-stage non-small cell lung cancer (NSCLC), however the risk of systemic recurrences remains high. Here the authors report the results of a phase I study testing the addition of atezolizumab (anti-PD-L1) to SABR in high risk, medically inoperable, early-stage, NSCLC.

By using tumor-specific fluorescent tracers, fluorescence molecular imaging (FMI) can be used to visualize tumor tissues with high specificity. Here the authors report the results of a phase II trial to evaluate the diagnostic accuracy of an EGFR-targeted FMI for intraoperative margin assessment in patients with oral squamous cell carcinoma.

Combination of immune checkpoint inhibitors with anti-angiogenic targeted therapy has shown efficacy in some solid tumours. Here the authors report the results of a phase 2 trial of camrelizumab (anti-PD1) plus apatinib as a second-line or later-line treatment regimen in platinum-resistant (cohort 1) or PD-1 inhibitor-resistant (cohort 2) Recurrent/Metastatic Nasopharyngeal Carcinoma patients.

Neoadjuvant chemotherapy followed by gastrectomy is considered standard of care for locally advanced gastric and gastroesophageal junction (G/GEJ) cancers. Here the authors report the results of a phase 2 trial of neoadjuvant sintilimab (anti-PD1) plus chemoradiotherapy in patients with locally advanced G/GEJ tumors.

Afatinib is a second-generation EGFR tyrosine kinase inhibitor recommended as the first-line treatment for patients with advanced EGFR mutant non-small cell lung cancer (NSCLC). Here the authors report the results of a phase II clinical trial of neoadjuvant afatinib for stage III EGFR mutant NSCLC.

The majority of cancer patients do not respond to single agent immune checkpoint blockade and several combinatorial approaches have now been tested. Here the authors report the results of a phase I dose escalation trial of nivolumab (anti-PD1) in combination with IFN-γ in patients with advanced solid tumors.

IgE antibodies have shown anti-tumor activity, even superior to IgG, in preclinical models. However, all monoclonal antibodies in clinical use for cancer therapy are members of the IgG class. Here the authors report the results of a phase I clinical trial of a chimeric monoclonal IgE antibody, specific for the folate receptor-alpha, in patients with advanced solid cancer.

A combination of chemoradiotherapy followed by brachytherapy is recommended for patients with locally-advanced cervical cancer (LACC), however there is still a high risk of disease recurrence. Here the authors report clinical outcomes and immunologic correlates of a clinical trial of the PD-1 inhibitor nivolumab in combination with chemoradiotherapy in LACC patients.

GM-CSF-secreting whole-cell cancer vaccine (GVAX) promotes T-cell response against a range of tumor associated antigens in patients with pancreatic adenocarcinoma (PDA). Here the authors report the results of the initial three treatment arms of a platform trial of neoadjuvant and adjuvant GVAX alone or in combination with PD-1 antagonist and CD137 agonist antibodies in patients with resectable PDA.

Patients with non-small cell lung cancer (NSCLC) with EGFR exon 20 insertions are resistant to early generation EGFR tyrosine kinase inhibitors (TKI). Here, the authors report the safety and preliminary efficacy of a phase I clinical trial JMT101, an anti-EGFR antibody, combined with EGFR-TKI, afatinib or osimertinib, in patients with NSCLC.

HER2 amplification in metastatic colorectal cancer (mCRC) identifies a group of patients with poorer prognosis. Here, the authors report the results of a phase II clinical trial assessing the clinical response and safety of trastuzumab deruxtecan as a third-line treatment in patients with mCRC with different HER2 expression levels

Single immune checkpoint blockade has shown limited activity in patients with neuroendocrine neoplasms (NENs). Here the authors report the results of a phase II clinical trial of durvalumab (anti-PD-L1) and tremelimumab (anti CTLA-4) in patients with advanced NENs of gastroenteropancreatic and lung origin.

Dual PD-1 and CTLA-4 checkpoint blockade has proven effective in several cancer types. Here the authors report the results of a clinical trial of anti-PD1 (nivolumab) and anti-CTLA4 (ipilimumab) in patients with recurrent/metastatic EBV-positive nasopharyngeal carcinoma.

Critical illness leads to altered metabolic states and bioenergetic failure caused by impaired utilisation of glucose, fatty acids and amino acids. Here the authors show ketogenic diets may provide a safe and acceptable alternative metabolic fuel enabling energy production and maintaining tissue homeostasis.

Mazdutide is a once-weekly glucagon-like peptide-1 (GLP-1) and glucagon receptor dual agonist. Here, the authors show mazdutide was well tolerated over 24 weeks and demonstrated significant and clinically meaningful body weight loss, compared with placebo, in Chinese overweight adults or adults with obesity.

Target trial emulation (TTE) simulates randomized controlled trials using real world data (RWD). Here, authors show the effectiveness of different TTE strategies to identify drug candidates that could be potentially repurposed to Alzheimer’s disease using two large scale RWD warehouses.

Oral nicotinamide riboside (NR) at a dose of 3000 mg daily for 30 days is safe and associated with a pronounced systemic augmentation of the NAD metabolome, but no methyl donor depletion.

The faster a drug enters the brain, the greater its addictive potential. Using simultaneous PET-fMRI in humans, here the authors report a neural circuit responding to fast but not slow dopamine increases from intravenous versus oral methylphenidate delivery.

The authors report data from a Phase IIa randomised, double-blind trial in patients with NASH showing that BI 1467335 strongly and dose-dependently inhibited AOC3 activity (involved in hepatic inflammation) and was well tolerated at all tested doses.

Non-alcoholic fatty liver disease is a growing health burden with limited treatment options worldwide. Herein the authors report a randomized, double-blind, placebo-controlled, multiple-dose trial of a first-in-class pan-phosphodiesterase inhibitor ZSP1601 in NAFLD patients.

Genotype patterns may modify diet effects on weight loss, with greater weight loss on genotype-concordant diets. Here, the authors show that with the current ability to genotype participants as fat- or carbohydrate-responders, evidence does not support greater weight loss on genotype-concordant diets.

Neuroinflammation and autophagy are two pillars of ALS pathogenesis targeted by rapamycin. Here, in a randomized, double-blind, phase 2 clinical trial, the authors find rapamycin to be safe and well tolerated in ALS patients, supporting further studies.

A beneficial effect of parasitic worms on metabolic health has been postulated based on epidemiological and animal studies. Here, the authors show in a phase I clinical trial that treatment of people at risk of type 2 diabetes with hookworms is safe and may improve key measures of metabolic health.

Different classes of biologic therapeutics have been assessed in the context of Vogt-Koyanagi-Harada disease. Here the authors compared cyclosporine immunosuppression or adalimumab in a randomised clinical trial for the treatment of patients with Vogt-Koyanagi-Harada disease and found non-inferiority upon treatment with cyclosporine.

Neurostimulation has been proposed as a potential approach for treatment-resistant PTSD. Here in a pilot study the authors show that amygdala theta activity is heightened during aversive and symptomatic experiences in patients with treatment-resistant post-traumatic stress disorder, and reduced following significant clinical improvement associated with closed-loop stimulation.

In a multicenter randomized trial, researchers found that electronic alerts increased the rate of discontinuation of potential nephrotoxins. This did not translate into improved clinical outcomes, except among those exposed to proton-pump inhibitors.

The effect of head positioning in acute stroke is controversial. Here, the authors report the results of a clinical trial suggesting that the procedure, initiated within 24 hours of onset, is safe and feasible, but does not improve functional outcome in acute moderate stroke patients with large artery atherosclerosis.

Here, the authors employ data from the population-based Norwegian HUNT cohort (n = 5196, including women and men) to associate the presence of three gut microbial species – Coprococcus comes, Dorea longicatena, and Eubacterium ventriosum – with higher lean mass.

Dorzagliatin, which acts on the glucose sensor glucokinase, is a new class of anti-diabetic medicine. Here the authors report that in a phase I open-label trial co-administration of dorzagliatin and sitagliptin (a different class of anti-diabetic medicine) does not significantly change the pharmacokinetics of either medicine in patients with type 2 diabetes and obesity.

Glucocorticoids prescribed to limit inflammation, have significant adverse effects. Here the authors show that co-administration of AZD4017 with prednisolone in men is a potential strategy to limit adverse glucocorticoid effects.

This study found that a prebiotic intervention was well-tolerated and safe, beneficially changed the microbiome, decreased inflammation and a marker of neurodegeneration, with possible clinical effects in Parkinson’s disease (PD) patients. This study offers the rationale for further investigations using prebiotic fibers in PD.

Here the authors report initial findings of a phase 1 clinical trial, showing that an investigational, mRNA-based vaccine for seasonal influenza (mRNA-1010) has no safety concerns and produces immune responses in adults that are similar or higher than a licensed comparator vaccine.

The gut microbiome is causally linked to body weight in preclinical models. Here, in a controlled feeding study, the authors show that greater delivery of gut-microbiome fermentable dietary substrates to the colon leads to a net negative energy balance that is accompanied by robust microbial and host responses.

Nigeria has the highest incidence of pneumococcal disease in Africa and introduced the 10-valent pneumococcal vaccine for infants between 2014 and 2016. Here, the authors conduct repeated cross-sectional surveys to analyse the impact of the vaccination campaign on pneumococcal carriage and serotype distribution.

The timing of measles vaccination in infants affects the risk of infection in young children and the duration of protection provided. Here, the authors investigate optimal vaccination timing by characterising antibody kinetics following different vaccine schedules in two cohorts of children in southern China.

Here, the authors comparatively analyze the impact of three successful clinical preventive interventions against NEC in preterm, VLBW infants and demonstrate a major impact of especially probiotic-based strategies on the development and maturation of the gut microbiome.

Here the authors present results from a randomized, double-blinded Phase 1 clinical trial, testing a thermostable presentation of a clinical-stage adjuvanted subunit tuberculosis vaccine candidate. The vaccine candidate is safe and well tolerated, and elicits comparable or improved immune responses compared to the non-thermostable presentation.

Here, using metagenomics, the authors show that the gut microbiome of rural Zimbabwean infants undergoes programmed maturation that is unresponsive to sanitation and nutrition interventions but is strongly associated with maternal HIV infection and can moderately predict linear growth.

Here, in a randomized trial, the authors comparatively evaluate the effect of a copper intrauterine device versus other contraceptive options on the vaginal environment after one and six consecutive months of use, finding to exert changes on the vaginal microbiota that may potentially lead to detrimental sex and reproductive health.

A gB/MF59 vaccine candidate for human cytomegalovirus (HCMV) provided partial protection in organ transplant patients. Here, the authors identify antibody responses in trial participants that target virally infected cells to control cell-to-cell spread of HCMV, providing a potential mechanism for the observed protection.

Hand, foot and mouth disease, caused by enterovirus A71 (EV-A71) infection, is common in children in China. Here, the authors estimate EV-A71 incidence and seroprevalence using data from two longitudinal cohorts and find that, despite high infection rates, a large proportion of children under 6 are susceptible.