Safety, immunogenicity, and protection provided by unadjuvanted and adjuvanted formulations of a recombinant plant-derived virus-like particle vaccine candidate for COVID-19 in nonhuman primates.

Although antivirals are important tools to control severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, effective vaccines are essential to control the current coronavirus disease 2019 (COVID-19) pandemic. Plant-derived virus-like particle (VLP) vaccine candidates have previously demonstrated immunogenicity and efficacy against influenza. Here, we report the immunogenicity and protection induced in rhesus macaques by intramuscular injections of a VLP bearing a SARS-CoV-2 spike protein (CoVLP) vaccine candidate formulated with or without Adjuvant System 03 (AS03) or cytidine-phospho-guanosine (CpG) 1018. Although a single dose of the unadjuvanted CoVLP vaccine candidate stimulated humoral and cell-mediated immune responses, booster immunization (at 28 days after priming) and adjuvant administration significantly improved both responses, with higher immunogenicity and protection provided by the AS03-adjuvanted CoVLP. Fifteen micrograms of CoVLP adjuvanted with AS03 induced a polyfunctional interleukin-2 (IL-2)-driven response and IL-4 expression in CD4 T cells. Animals were challenged by multiple routes (i.e., intratracheal, intranasal, and ocular) with a total viral dose of 106 plaque-forming units of SARS-CoV-2. Lower viral replication in nasal swabs and bronchoalveolar lavage fluid (BALF) as well as fewer SARS-CoV-2-infected cells and immune cell infiltrates in the lungs concomitant with reduced levels of proinflammatory cytokines and chemotactic factors in the BALF were observed in animals immunized with the CoVLP adjuvanted with AS03. No clinical, pathologic, or virologic evidence of vaccine-associated enhanced disease was observed in vaccinated animals. The CoVLP adjuvanted with AS03 was therefore selected for vaccine development and clinical trials.

Lack of effects on female fertility or pre- and postnatal development of offspring in rats after exposure to AS03-adjuvanted recombinant plant-derived virus-like particle vaccine candidate for COVID-19.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection resulting in the coronavirus disease 2019 (COVID-19) has afflicted tens of millions of people in a worldwide pandemic. A recently developed recombinant Plant-Derived Virus-Like Particle Vaccine candidate for COVID-19 (CoVLP) formulated with AS03 has been shown to be well-tolerated and highly immunogenic in healthy adults. Since the target population for the vaccine includes women of childbearing potential, the objective of the study was to evaluate any untoward prenatal and postnatal effects of AS03-adjuvanted CoVLP administered intramuscularly to Sprague-Dawley female rats before cohabitation for mating (22 and 8 days prior) and during gestation (Gestation Days [GD] 6 and 19). The embryo-fetal development (EFD) cohort was subjected to cesarean on GD 21 and the pre/post-natal (PPN) cohort was allowed to naturally deliver. Effects of AS03-adjuvanted CoVLP was evaluated on pregnant rats, embryo-fetal development (EFD), during parturition, lactation and the development of the F1 offspring up to weaning Vaccination with AS03-adjuvanted CoVLP induced an antibody response in F0 females and anti-SARS-CoV-2 spike-specific maternal antibodies were detected in the offspring at the end of the gestation and lactation periods. Overall, there was no evidence of untoward effects of AS03-adjuvanted CoVLP on the fertility or reproductive performance of the vaccinated F0 females. There was no evidence of untoward effects on embryo-fetal development (including teratogenicity), or early (pre-weaning) development of the F1 offspring. These results support the acceptable safety profile of the AS03-adjuvanted CoVLP vaccine for administration to women of childbearing potential.

Evaluating the efficacy of extracted squalene from seed oil in the form of microemulsion for the treatment of COVID-19: A clinical study.

This study investigates the effect of the nanostructure of squalene in the form of microemulsion on COVID-19 patients. In this blinded clinical trial, a comparison was made between the efficacy of squalene treatment and controls. A total of 30 COVID-19 patients admitted to the emergency department, and the infection ward was equally allocated to case (n = 15) and control (n = 15) groups according to their age and underlying diseases. The baseline characteristics of subjects, including age, gender, time of treatment onset, underlying condition, white blood cells count, and lymphocyte count were similar (p < 0.05). Baseline laboratory tests and computed tomography (CT) scans were performed for the study groups. The treatment group received 5 mg of intravenous squalene twice a day and standard treatment for 6 days, while controls received only standard treatment. After 6 days of treatment, clinical and CT scan changes were evaluated and compared in intervention and control groups. The need for oxygen therapy (p = 0.020), 2 days of no fever (p = 0.025), cough alleviation (p = 0.010), and lung high-resolution computed tomography improvement (p = 0.033) were significantly different between cases and controls within 7 days of admission. No adverse effects were observed in the treatment group. Our data suggest that squalene could be considered as a potential treatment for COVID-19, and further studies are required to confirm the results.

Squalene-based multidrug nanoparticles for improved mitigation of uncontrolled inflammation in rodents.

Uncontrolled inflammatory processes are at the root of numerous pathologies. Most recently, studies on confirmed COVID-19 cases have suggested that mortality might be due to virally induced hyperinflammation. Uncontrolled pro-inflammatory states are often driven by continuous positive feedback loops between pro-inflammatory signaling and oxidative stress, which cannot be resolved in a targeted manner. Here, we report on the development of multidrug nanoparticles for the mitigation of uncontrolled inflammation. The nanoparticles are made by conjugating squalene, a natural lipid, to adenosine, an endogenous immunomodulator, and then encapsulating α-tocopherol, as antioxidant. This resulted in high drug loading, biocompatible, multidrug nanoparticles. By exploiting the endothelial dysfunction at sites of acute inflammation, these multidrug nanoparticles delivered the therapeutic agents in a targeted manner, conferring survival advantage to treated animals in models of endotoxemia. Selectively delivering adenosine and antioxidants together could serve as a novel therapeutic approach for safe treatment of acute paradoxal inflammation.