Global Disparities in Access to Vaccine Clinical Trials: A Review of the Literature.

Vaccines are an effective tool to reduce the disease burden from infectious diseases on a population, infrastructural, and individual level. Before vaccines can be administered to populations at large, they must go through rigorous testing in the form of clinical trials. While vaccine trials can be used to assess the efficacy of interventions on a local populace as well as target local endemic diseases, most clinical trials are sponsored and conducted by companies in high-income countries (HICs). This can lead to vaccines that are not optimized for low- and middle-income countries (LMICs) and that often neglect to address diseases specific to the local population. This narrative review aims to explore the factors leading to discrepancies in the execution of and access to vaccine trials between HICs and LMICs, thus guiding future efforts in confronting them. This review was written using the literature sourced from the PubMed database and supplemented with articles from Google Scholar along with grey literature. Several themes are highlighted including poorly defined regulatory and ethical guidelines, staff shortages, lack of research infrastructure, and logistical barriers. We discuss how these challenges have affected vaccine development in various capacities through case examples of SARS-CoV-2, poliovirus, and malaria. Many challenges remain in equitable vaccine clinical trial development and implementation. Facilitating the implementation of locally sponsored vaccine clinical trials in LMICs may be one avenue to address these challenges. In doing so, LMICs can become active stakeholders in the health of their citizens by addressing endemic diseases, tailoring vaccine specifications based on local needs, and implementing wide-scale vaccine access and delivery.

Delivery of costimulatory blockade to lymph nodes promotes transplant acceptance in mice.

The lymph node (LN) is the primary site of alloimmunity activation and regulation during transplantation. Here, we investigated how fibroblastic reticular cells (FRCs) facilitate the tolerance induced by anti-CD40L in a murine model of heart transplantation. We found that both the absence of LNs and FRC depletion abrogated the effect of anti-CD40L in prolonging murine heart allograft survival. Depletion of FRCs impaired homing of T cells across the high endothelial venules (HEVs) and promoted formation of alloreactive T cells in the LNs in heart-transplanted mice treated with anti-CD40L. Single-cell RNA sequencing of the LNs showed that anti-CD40L promotes a Madcam1+ FRC subset. FRCs also promoted the formation of regulatory T cells (Tregs) in vitro. Nanoparticles (NPs) containing anti-CD40L were selectively delivered to the LNs by coating them with MECA-79, which binds to peripheral node addressin (PNAd) glycoproteins expressed exclusively by HEVs. Treatment with these MECA-79-anti-CD40L-NPs markedly delayed the onset of heart allograft rejection and increased the presence of Tregs. Finally, combined MECA-79-anti-CD40L-NPs and rapamycin treatment resulted in markedly longer allograft survival than soluble anti-CD40L and rapamycin. These data demonstrate that FRCs are critical to facilitating costimulatory blockade. LN-targeted nanodelivery of anti-CD40L could effectively promote heart allograft acceptance.

Pathological significance of lipoprotein(a) in aortic valve stenosis.

BACKGROUND AND AIMS: Aortic valve stenosis (AVS) affects a significant percentage of our elderly population and younger subjects with familial hypercholesterolemia. Lipoprotein(a) [Lp(a)] has been associated with AVS in recent genetic studies. The purpose of this study was to determine the effects of Lp(a) on human aortic valve interstitial cells (HAVICs), and to identify apolipoproteins and phospholipids in diseased human aortic valves. METHODS: We examined the effects of Lp(a) on HAVICs mineralization and oxidant formation. Proteomic analyses were used to determine the effects of Lp(a) on downstream intracellular markers. We also used mass spectroscopy to identify the different lipoproteins and oxidized phospholipids in calcified aortic valves. RESULTS: HAVICs incubated with either LDL or Lp(a) had significantly higher calcium deposition, compared to control (p<0.001), with Lp(a) having the most significant effect (p<0.01) compared to LDL. Proteomic analysis after 10 days of treatment with Lp(a) resulted in enrichment of proteins involved in calcium deposition and vesicle biogenesis. Treatment of HAVICs with Lp(a) significantly increased ROS formation (p<0.05). Patients with calcific aortic stenosis had higher plasma Lp(a) concentrations compared to non-CAD individuals (p<0.001). LC-MS/MS revealed the presence of apolipoproteins and phospholipids in calcified human aortic valves. CONCLUSIONS: The present study outlines an association between Lp(a) and AVS, and suggests that Lp(a) may serve as a potential target for therapeutic purposes to manage the progression of AVS.

Fall of platelet count in children with traumatic brain injury: is it of value?

OBJECTIVE: Trauma is the leading cause of mortality and morbidity among young age groups in Saudi Arabia and developed countries. This study aimed to evaluate the fall of platelet count in children with traumatic brain injury (TBI) as a potential predictor for clinical severity and outcome. METHODS: Totally 74 patients with TBI were admitted to the Pediatric Intensive Care Unit (PICU) of our hospital from the beginning of January 2008 to the end of March 2010 (27 months). Baseline enrolling criteria were age less than or equal to 12 years, admission within 4 hours after trauma event, and abbreviated injury scale (AIS) less than 3 for extracranial injuries. Injury severity was classified as mild, moderate and severe according to their Glasgow Coma Scale (GCS) scores. Clinical outcomes at discharge were defined as poor (death, severe neurological morbidity) and favorable (moderate disability and good recovery). Platelet count was taken 2-3 times on the first day after admission and thereafter once daily. The percentage fall of platelet count (PFP) was calculated and taken as an index of change. PFP was considered zero if the platelet count was higher than the initial value. RESULTS: PFP was significantly higher in patients with poor outcomes (mean 56.0%+/-3.8%, median 55.5%) compared to those with favorable outcomes (mean 25.3%+/-3.2%, median 20.5%, P less than 0.01). PFP was also closely related to the severity of TBI, GCS score, clinical outcome and length of stay for survivors (P less than 0.01 for each). The frequency of thrombocytopenia was significantly higher in poor outcome patients than in favorable outcome patients (P less than 0.05). The validity of thrombocytopenia as a risk factor to predict poor outcome after TBI was: specificity, 77.4%; odd ratio (OR), 3.1; relative risk (RR), 2.15. Receiver operating characteristic (ROC) curve and Youden index showed that the optimum cutoff point of PFP was at 51.5%. CONCLUSION: PFP is increased with the severity of TBI and it can be taken as a significant independent predicting factor for its outcome as well.