Evaluating the safety and efficacy of dengue vaccines: A comprehensive systematic review and meta-analysis.

In individuals with prior dengue virus (DENV) exposure, subsequent heterotypic infection can increase the risk of severe disease. A single-dose dengue vaccine that protects against the four DENV serotypes across a wide age range and regardless of DENV serostatus is needed. Here we report the long-term safety and efficacy of Butantan dengue vaccine (Butantan-DV), a live, attenuated, tetravalent dengue vaccine, among participants ages 2-59 who were randomized 2:1 in a double-blind, placebo-controlled, phase 3 trial in Brazil. A primary objective was to evaluate vaccine efficacy (VE) against reverse transcription-PCR-positive symptomatic dengue 28 days after vaccination because of any DENV serotype, regardless of serostatus. Prespecified secondary endpoints included VE by serotype, by serostatus and against severe dengue or dengue with warning signs (combined). The primary and secondary objectives were met if the lower bound of the two-sided 95% confidence interval (CI) for VE was above 25%. Between 2016 and 2019, 16,235 participants received Butantan-DV (n = 10,259) or placebo (n = 5,976). The trial met the primary and secondary objectives. During the 5 years of follow-up, between 2016 and 2024, overall VE (95% CI) was 65.0% (57.8-71.0%). Secondary VE endpoints (95% CI) were 77.1% (67.6-83.9%) in dengue-experienced participants, 58.9% (48.0-67.6%) in dengue-naive participants, 73.0% (64.3-79.7%) against DENV-1 and 55.7% (42.3-66.1%) against DENV-2. Cases of DENV-3 or DENV-4 were not observed. VE (95% CI) against dengue with warning signs or severe dengue (secondary endpoint) was 80.5% (50.8-92.4%). The most commonly reported solicited systemic adverse event (AE) was headache (36.7% of vaccine recipients and 31.1% of placebo recipients), most of which were grade 1. The proportions of participants with unsolicited vaccine-related AEs (including serious AEs) were comparable between intervention groups. A single dose of Butantan-DV was efficacious against symptomatic virologically confirmed dengue because of DENV-1 or DENV-2, regardless of dengue serostatus at baseline, with no safety concerns observed during the 5-year follow-up (ClinicalTrials.gov: NCT02406729 ).

Compared to placebo, most vaccines reduce, or likely reduce, the proportion of participants with confirmed symptomatic COVID-19, and for some, there is high-certainty evidence that they reduce severe or critical disease. There is probably little or no difference between most vaccines and placebo for serious adverse events. Over 300 registered RCTs are evaluating the efficacy of COVID-19 vaccines, and this review is updated regularly on the COVID-NMA platform (covid-nma.com). Implications for practice Due to the trial exclusions, these results cannot be generalized to pregnant women, individuals with a history of SARS-CoV-2 infection, or immunocompromized people. Most trials had a short follow-up and were conducted before the emergence of variants of concern. Implications for research Future research should evaluate the long-term effect of vaccines, compare different vaccines and vaccine schedules, assess vaccine efficacy and safety in specific populations, and include outcomes such as preventing long COVID-19. Ongoing evaluation of vaccine efficacy and effectiveness against emerging variants of concern is also vital.

Both health and economic burdens of dengue virus (DENV), as an increasingly prevalent pathogen and global threat, exist in endemic regions. Vaccination is a key strategy in decreasing dengue morbidity and mortality. This systematic review assesses the efficacy, immune response and safety of dengue vaccines (Qdenga (TAK-003) and Dengvaxia (CYD-TDV)) in adolescents against the need for evidence-based data for dengue vaccination strategies. We performed a systematic search of six databases (Scopus, PubMed, Web of Science, Cochrane, clinical trials. gov, and MEDLINE) for studies published until October 2024. A total of 482 articles were identified, 32 studies met the inclusion criteria after removing duplicates and title and abstract screening. Immunogenicity and safety profiles for both vaccines. TAK-003 showed high seropositivity rates with all of the four DENV serotypes, especially for DENV-2, with sustained antibody responses 3years after vaccination. CYD-TDV induced neutralising antibodies with balanced activity, but such an immune response was most efficient in individuals with baseline seropositivity, for whom greater efficacy was observed. Most adverse events were mild to moderate, such as transitory pain at the injection site and headache, while serious adverse events were rare and did not correlate with vaccination. Nonetheless, specific issues regarding serotype-unique efficacy variations and the threat of vaccine-induced immune enhancement in seronegative groups contribute to worry. These findings highlighted the importance of TAK-003 and CYD-TDV in reducing the impact of dengue, especially in endemic regions. Ongoing research is essential to refine vaccine deployment strategies, optimise protection across diverse populations, and address outstanding concerns regarding long-term immunity and safety in seronegative individuals.

There are a variety of controlled trials addressing the effects of dietary interventions for MS with substantial variation in active treatment, comparator, and outcomes of interest. PUFA administration may not differ when compared to alternatives with regards to relapse rate, disability worsening, or overall clinical status in people with MS, but evidence is uncertain. Similarly, at present, there is insufficient evidence to determine whether supplementation with antioxidants or other dietary interventions have any impact on MS-related outcomes.

PIN7 - Dengue Vaccine Efficacy: A Systematic Review

Interventions for improving adherence to iron chelation therapy in people with sickle cell disease or thalassaemia (Review)

Clinical efficacy and safety of a novel tetravalent dengue vaccine in healthy children in Asia: a phase 3, randomised, observer-masked, placebo-controlled trial

Dengue is a vector-borne disease caused by the dengue virus (DENV) and is a major health concern worldwide, particularly in regions of endemic disease. Dengue usually presents as a self-limited febrile illness. In some cases, more severe forms with hemorrhage and shock can occur, and children are especially prone to develop it. These forms can be lethal without appropriate management, and no antiviral treatment exists today. In the absence of a curative treatment for dengue, its clinical prevention remains essential. One vaccine - the chimeric yellow fever-dengue-tetravalent dengue vaccine (CYD-TDV) - has been approved for use in some populations, and several others are currently in development, including Takeda's tetravalent dengue vaccine candidate (TAK-003).This study is a systematic review of the current literature realized to evaluate the efficacy of the dengue vaccines in preventing severe dengue in children. This review focuses on the vaccines CYD-TDV and TAK-003. This systematic review was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. PubMed, PubMed Central (PMC), Medical Literature Analysis and Retrieval System Online (MEDLINE), Cochrane Library, and Google Scholar were the databases used to find the relevant data. The articles were selected using specific inclusion and exclusion criteria, and quality appraisal was realized with standardized quality assessment tools. Overall, our study shows that the dengue vaccines CYD-TDV and TAK-003 confer protection against severe dengue in children. Some distinctions exist depending on the vaccine type, the age, and the dengue serostatus of patients. While demonstrating encouraging results, this review also emphasizes the need for more in-depth studies about the safety and efficacy of dengue vaccines.

Very low-quality evidence suggested that the differences in mortality and serious adverse events between treatments were imprecise. Low-quality evidence suggested that short-term HRQoL (four weeks to three months) was worse, and the costs were higher in the open surgical drainage group than in the EUS-guided drainage group. Low-quality or very low-quality evidence suggested that EUS-guided drainage with nasocystic drainage led to fewer adverse events than EUS-guided or endoscopic drainage, and shorter hospital stays when compared to EUS-guided drainage, endoscopic drainage, or open surgical drainage, while EUS-guided drainage led to shorter hospital stays than open surgical drainage. Low-quality evidence suggested that there was a higher need for additional invasive procedures with endoscopic drainage than EUS-guided drainage, while it was lower in the open surgical drainage than in the endoscopic drainage group.Further RCTs are needed to compare EUS-guided drainage, with or without nasocystic drainage, in symptomatic patients with pancreatic pseudocysts that require treatment. Future trials should include patient-oriented outcomes such as mortality, serious adverse events, HRQoL, hospital stay, return-to-normal activity, number of work days lost, and the need for additional procedures, for a minimum follow-up period of two to three years.

Efficacy and safety of vaccines to prevent respiratory syncytial virus infection in infants and older adults: A systematic review and meta-analysis

Degarelix is a gonadotropin-releasing hormone antagonist that leads to medical castration used to treat men with advanced or metastatic prostate cancer, or both. It is unclear how its effects compare to standard androgen suppression therapy. To assess the effects of degree compared with standard androgen suppression therapy for men with advanced hormone-sensitive prostate cancer. We searched multiple databases (CENTRAL, MEDLINE, Embase, Scopus, Web of Science, LILACS until September 2020), trial registries (until October 2020), and conference proceedings (until December 2020). We identified other potentially eligible trials by reference checking, citation searching, and contacting study authors. We included randomized controlled trials comparing degarelix with standard androgen suppression therapy for men with advanced prostate cancer. Three review authors independently classified studies and abstracted data from the included studies. The primary outcomes were overall survival and serious adverse events. Secondary outcomes were quality of life, cancer-specific survival, clinical progression, other adverse events, and biochemical progression. We used a random-effects model for meta-analyses and assessed the certainty of evidence for the main outcomes according to GRADE. We included 11 studies with a follow-up of between three and 14 months. We also identified five ongoing trials. Primary outcomes Data to evaluate overall survival were not available. Degarelix may result in little to no difference in serious adverse events compared to standard androgen suppression therapy (risk ratio (RR) 0.80, 95% confidence interval (CI) 0.62 to 1.05; low-certainty evidence; 2750 participants). Based on 114 serious adverse events in the standard androgen suppression group, this corresponds to 23 fewer serious adverse events per 1000 participants (43 fewer to 6 more). We downgraded the certainty of evidence for study limitations and imprecision. Secondary outcomes Degarelix likely results in little to no difference in quality of life assessed with a variety of validated questionnaires (standardized mean difference 0.06 higher, 95% CI 0.05 lower to 0.18 higher; moderate-certainty evidence; 2887 participants), with higher scores reflecting better quality of life. We downgraded the certainty of evidence for study limitations. Data to evaluate cancer-specific survival were not available. The effects of degarelix on cardiovascular events are very uncertain (RR 0.15, 95% CI 0.04 to 0.61; very low-certainty evidence; 80 participants). We downgraded the certainty of evidence for study limitations, imprecision, and indirectness as this trial was conducted in a unique group of high-risk participants with pre-existing cardiovascular morbidities. Degarelix likely results in an increase in injection site pain (RR 15.68, 95% CI 7.41 to 33.17; moderate-certainty evidence; 2670 participants). Based on 30 participants per 1000 with injection site painwith standard androgen suppression therapy, this corresponds to 440 more injection site pains per 1000 participants (192 more to 965 more). We downgraded the certainty of evidence for study limitations. We did not identify any relevant subgroup differences for different degarelix maintenance doses. We did not find trial evidence foroverall survival or cancer-specific survival comparing degarelix to standard androgen suppression, but serious adverse events and quality of life may be similar between groups. The effects of degarelixon cardiovascular events are very uncertain as the only eligible study had limitations, was small withfew events, and was conducted in a high-risk population.Degarelix likely results in an increase in injection site pain compared to standard androgen suppression therapy. Maximum follow-up of included studies was 14 months, which is short.There is a need for methodologically better designed and executed studies with long-term follow-up evaluating men with metastatic prostate cancer.

Ocrelizumab is a humanised anti-CD20 monoclonal antibody developed for the treatment of multiple sclerosis (MS). It was approved by the Food and Drug Administration (FDA) in March 2017 for using in adults with relapsing-remitting multiple sclerosis (RRMS) and primary progressive multiple sclerosis (PPMS). Ocrelizumab is the only disease-modifying therapy (DMT) approved for PPMS. In November 2017, the European Medicines Agency (EMA) also approved ocrelizumab as the first drug for people with early PPMS. Therefore, it is important to evaluate the benefits, harms, and tolerability of ocrelizumab in people with MS. To assess the benefits, harms, and tolerability of ocrelizumab in people with RRMS and PPMS. We searched MEDLINE, Embase, CENTRAL, and two trials registers on 8 October 2021. We screened reference lists, contacted experts, and contacted the main authors of studies. All randomised controlled trials (RCTs) involving adults diagnosed with RRMS or PPMS according to the McDonald criteria, comparing ocrelizumab alone or associated with other medications, at the approved dose of 600 mg every 24 weeks for any duration, versus placebo or any other active drug therapy. We used standard methodological procedures expected by Cochrane. Four RCTs met our selection criteria. The overall population included 2551 participants; 1370 treated with ocrelizumab 600 mg and 1181 controls. Among the controls, 298 participants received placebo and 883 received interferon beta-1a. The treatment duration was 24 weeks in one study, 96 weeks in two studies, and at least 120 weeks in one study. One study was at high risk of allocation concealment and blinding of participants and personnel; all four studies were at high risk of bias for incomplete outcome data. For RRMS, compared with interferon beta-1a, ocrelizumab was associated with: 1. lower relapse rate (risk ratio (RR) 0.61, 95% confidence interval (CI) 0.52 to 0.73; 2 studies, 1656 participants; moderate-certainty evidence); 2. a lower number of participants with disability progression (hazard ratio (HR) 0.60, 95% CI 0.43 to 0.84; 2 studies, 1656 participants; low-certainty evidence); 3. little to no difference in the number of participants with any adverse event (RR 1.00, 95% CI 0.96 to 1.04; 2 studies, 1651 participants; moderate-certainty evidence); 4. little to no difference in the number of participants with any serious adverse event (RR 0.79, 95% CI 0.57 to 1.11; 2 studies, 1651 participants; low-certainty evidence); 5. a lower number of participants experiencing treatment discontinuation caused by adverse events (RR 0.58, 95% CI 0.37 to 0.91; 2 studies, 1651 participants; low-certainty evidence); 6. a lower number of participants with gadolinium-enhancing T1 lesions on magnetic resonance imaging (MRI) (RR 0.27, 95% CI 0.22 to 0.35; 2 studies, 1656 participants; low-certainty evidence); 7. a lower number of participants with new or enlarging T2-hyperintense lesions on MRI (RR 0.63, 95% CI 0.57 to 0.69; 2 studies, 1656 participants; low-certainty evidence) at 96 weeks. For PPMS, compared with placebo, ocrelizumab was associated with: 1. a lower number of participants with disability progression (HR 0.75, 95% CI 0.58 to 0.98; 1 study, 731 participants; low-certainty evidence); 2. a higher number of participants with any adverse events (RR 1.06, 95% CI 1.01 to 1.11; 1 study, 725 participants; moderate-certainty evidence); 3. little to no difference in the number of participants with any serious adverse event (RR 0.92, 95% CI 0.68 to 1.23; 1 study, 725 participants; low-certainty evidence); 4. little to no difference in the number of participants experiencing treatment discontinuation caused by adverse events (RR 1.23, 95% CI 0.55 to 2.75; 1 study, 725 participants; low-certainty evidence) for at least 120 weeks. There were no data for number of participants with gadolinium-enhancing T1 lesions on MRI and number of participants with new or enlarging T2-hyperintense lesions on MRI. For people with RRMS, ocrelizumab probably results in a large reduction in relapse rate and little to no difference in adverse events when compared with interferon beta-1a at 96 weeks (moderate-certainty evidence). Ocrelizumab may result in a large reduction in disability progression, treatment discontinuation caused by adverse events, number of participants with gadolinium-enhancing T1 lesions on MRI, and number of participants with new or enlarging T2-hyperintense lesions on MRI, and may result in little to no difference in serious adverse events (low-certainty evidence). For people with PPMS, ocrelizumab probably results in a higher rate of adverse events when compared with placebo for at least 120 weeks (moderate-certainty evidence). Ocrelizumab may result in a reduction in disability progression and little to no difference in serious adverse events and treatment discontinuation caused by adverse events (low-certainty evidence). Ocrelizumab was well tolerated clinically; the most common adverse events were infusion-related reactions and nasopharyngitis, and urinary tract and upper respiratory tract infections.

Prostaglandins are naturally occurring lipids that are synthesised from arachidonic acid. Multiple studies have evaluated the benefits of prostaglandins in reducing ischaemia reperfusion injury after liver transplantation. New studies have been published since the previous review, and hence it was important to update the evidence for this intervention. To evaluate the benefits and harms of prostaglandins in adults undergoing liver transplantation compared with placebo or standard care. We used standard, extensive Cochrane search methods. The latest search date was 27 December 2022. We included randomised clinical trials evaluating prostaglandins initiated in the perioperative period compared with placebo or standard care for adults undergoing liver transplantation. We included trials irrespective of reported outcomes. We used standard Cochrane methods. Our primary outcomes were 1. all-cause mortality, 2. serious adverse events, and 3. health-related quality of life. Our secondary outcomes were 4. liver retransplantation, 5. early allograft dysfunction, 6. primary non-function of the allograft, 7. acute kidney failure, 8. length of hospital stay, and 9. adverse events considered non-serious. We used GRADE to assess certainty of evidence. We included 11 randomised clinical trials with 771 adult liver transplant recipients (mean age 47.31 years, male 61.48%), of whom 378 people were randomised to receive prostaglandins and 393 people were randomised to either placebo (272 participants) or standard care (121 participants). All trials were published between 1993 and 2016. Ten trials were conducted in high- and upper-middle-income countries. Prostaglandins may reduce all-cause mortality up to one month (risk ratio (RR) 0.86, 95% confidence interval (CI) 0.61 to 1.23; risk difference (RD) 21 fewer per 1000, 95% CI 63 fewer to 36 more; 11 trials, 771 participants; low-certainty evidence). Prostaglandins may result in little to no difference in serious adverse events (RR 0.92, 95% CI 0.60 to 1.40; RD 81 fewer per 1000, 95% CI 148 fewer to 18 more; 6 trials, 568 participants; low-certainty evidence). None of the included trials reported health-related quality of life. Prostaglandins may result in little to no difference in liver retransplantation (RR 0.98, 95% CI 0.49 to 1.96; RD 1 fewer per 1000, 95% CI 33 fewer to 62 more; 6 trials, 468 participants; low-certainty evidence); early allograft dysfunction (RR 0.62, 95% CI 0.33 to 1.18; RD 137 fewer per 1000, 95% CI 241 fewer to 47 more; 1 trial, 99 participants; low-certainty evidence); primary non-function of the allograft (RR 0.58, 95% CI 0.26 to 1.32; RD 23 fewer per 1000, 95% CI 40 fewer to 16 more; 7 trials, 624 participants; low-certainty evidence); and length of hospital stay (mean difference (MD) -1.15 days, 95% CI -5.44 to 3.14; 4 trials, 369 participants; low-certainty evidence). Prostaglandins may result in a large reduction in the development of acute kidney failure requiring dialysis (RR 0.42, 95% CI 0.24 to 0.73; RD 100 fewer per 1000, 95% CI 132 fewer to 49 fewer; 5 trials, 477 participants; low-certainty evidence). The evidence is very uncertain about the effect of prostaglandins on adverse events considered non-serious (RR 1.19, 95% CI 0.42 to 3.36; RD 225 fewer per 1000, 95% CI 294 fewer to 65 fewer; 4 trials, 329 participants; very low-certainty evidence). Two trials reported receiving funding; one of these was with vested interests. We found one registered ongoing trial. Eleven trials evaluated prostaglandins in adult liver transplanted recipients. Based on low-certainty evidence, prostaglandins may reduce all-cause mortality up to one month; may cause little to no difference in serious adverse events, liver retransplantation, early allograft dysfunction, primary non-function of the allograft, and length of hospital stay; and may have a large reduction in the development of acute kidney injury requiring dialysis. We do not know the effect of prostaglandins on adverse events considered non-serious. We lack adequately powered, high-quality trials evaluating the effects of prostaglandins for people undergoing liver transplantation.

Based on the low to high certainty of evidence, several combinations of immune checkpoint inhibitors appear to be superior to single-agent targeted therapy in terms of PFS and OS, and with a favourable AE profile. Some single-agent targeted therapies demonstrated a similar or improved oncological outcome compared to others; minor differences were observed for AE within this group. The certainty of evidence was variable ranging from high to very low and all comparisons were based on single trials.

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