RESUMEN
SARS-CoV-2, severe acute respiratory syndrome coronavirus-2, causes coronavirus disease- 2019 (COVID-19). Mostly, COVID-19 causes respiratory symptoms that can resemble those of a cold, the flu, or pneumonia. COVID-19 may harm more than just lungs and respiratory systems. It may also have an impact on other parts of the body and debilitating effects on humans, necessitating the development of vaccines at an unprecedented rate in order to protect humans from infections. In response to SARS-CoV-2 infection, mRNA, viral vector-based carrier and inactivated virus-based vaccines, as well as subunit vaccines, have recently been developed. We developed Relcovax®, a dual antigen (Receptor binding domain (RBD) and Nucleocapsid (N) proteins) subunit protein vaccine candidate. Preliminary mouse preclinical studies revealed that Relcovax® stimulates cell-mediated immunity and provides broader protection against two SARS-CoV-2 variants, including the delta strain. Before conducting human studies, detailed preclinical safety assessments are required, so Relcovax® was tested for safety, and immunogenicity in 28-day repeated dose toxicity studies in rats and rabbits. In the toxicity studies, there were no mortality or morbidity, abnormal clinical signs, abnormalities in a battery of neurobehavioral observations, abnormalities in detailed clinical and ophthalmological examinations, or changes in body weights or feed consumption. In any of the studies, no abnormal changes in organ weights, haematology, clinical chemistry, urinalysis parameters, or pathological findings were observed. Immunogenicity tests on rats and rabbits revealed 100 % seroconversion. Relcovax® was therefore found to be safe in animals, with a No Observed Adverse Effect Level (NOAEL) of 20 µg/protein in rats and rabbits. In efficacy studies, Relcovax® immunised hamsters demonstrated dose-dependent protection against SARS-CoV-2 infection, with a high dose (20 µg/protein) being the most protective, while in cynomolgus macaque monkey study, lowest dose 5 µg/protein had the highest efficacy. In conclusion, Relcovax® was found to be safe, immunogenic, and efficacious in in vivo studies.
Asunto(s)
COVID-19 , Vacunas de Subunidad , Animales , Cricetinae , Humanos , Ratones , Conejos , Ratas , Anticuerpos Neutralizantes , Anticuerpos Antivirales , COVID-19/prevención & control , Inmunogenicidad Vacunal , Nucleocápside , SARS-CoV-2 , Glicoproteína de la Espiga del Coronavirus , Vacunas de Subunidad/efectos adversos , Vacunas ViralesRESUMEN
The COVID-19 pandemic has spurred an unprecedented movement to develop safe and effective vaccines against the SARS-CoV-2 virus to immunize the global population. The first set of vaccine candidates that received emergency use authorization targeted the spike (S) glycoprotein of the SARS-CoV-2 virus that enables virus entry into cells via the receptor binding domain (RBD). Recently, multiple variants of SARS-CoV-2 have emerged with mutations in S protein and the ability to evade neutralizing antibodies in vaccinated individuals. We have developed a dual RBD and nucleocapsid (N) subunit protein vaccine candidate named RelCoVax® through heterologous expression in mammalian cells (RBD) and E. coli (N). The RelCoVax® formulation containing a combination of aluminum hydroxide (alum) and a synthetic CpG oligonucleotide as adjuvants elicited high antibody titers against RBD and N proteins in mice after a prime and boost dose regimen administered 2 weeks apart. The vaccine also stimulated cellular immune responses with a potential Th1 bias as evidenced by increased IFN-γ release by splenocytes from immunized mice upon antigen exposure particularly N protein. Finally, the serum of mice immunized with RelCoVax® demonstrated the ability to neutralize two different SARS-CoV-2 viral strains in vitro including the Delta strain that has become dominant in many regions of the world and can evade vaccine induced neutralizing antibodies. These results warrant further evaluation of RelCoVax® through advanced studies and contribute towards enhancing our understanding of multicomponent subunit vaccine candidates against SARS-CoV-2.
Asunto(s)
COVID-19 , SARS-CoV-2 , Animales , Anticuerpos Neutralizantes , Anticuerpos Antivirales , COVID-19/prevención & control , Vacunas contra la COVID-19 , Escherichia coli , Humanos , Inmunidad Celular , Mamíferos , Ratones , Pandemias , Glicoproteína de la Espiga del Coronavirus/genética , Vacunas de SubunidadRESUMEN
Neurological manifestations of skeletal fluorosis have been attributed to compressive radiculomyelopathy. Experimental fluorosis has shown evidence of myopathic changes. Data on human muscle pathology is very scanty. This study included 22 patients with established osteofluorosis. 16 of them showed only EMG changes of neurogenic muscle disease. Histochemistry and histopathology of muscle biopsies showed features of muscle atrophy, evidenced by 'type I' atrophy and 'type I' grouping. No myopathic changes were observed. It may be concluded that the primary changes are related to the nerve, with muscle being affected secondarily. There was no evidence of any primary muscle pathology due to fluorosis.
Asunto(s)
Enfermedades Óseas/patología , Intoxicación por Flúor/patología , Músculo Esquelético/patología , Adenosina Trifosfatasas/metabolismo , Adulto , Anciano , Enfermedades Óseas/inducido químicamente , Enfermedades Endémicas , Femenino , Intoxicación por Flúor/epidemiología , Humanos , Masculino , Persona de Mediana EdadRESUMEN
Genetically mutant anophthalmic rats lacking a complete visual system due to the absence of eyeballs and optic nerves up to the optic chiasma were used as a model to study photo-regulated physiological activities. The photoreception in these mutant rats was determined by measuring the neuroendocrine response of the pineal gland-melatonin levels in the serum, and synaptic ribbon complexes (SRCs) in the pinealocytes. These parameters were studied in both normal and anophthalmic rats maintained under light-dark (LD 12:12), continuous dark (DD) and light (LL) conditions. Both normal and mutant anophthalmic animals showed nocturnal increases in serum melatonin levels and in the number and diameter of SRC and their vesicles in the pinealocytes in LD. The daily rhythms persisted even upon transfer to DD both in normal and mutant rats, whereas in LL, the nocturnal elevation of both the parameters disappeared. These observations suggested that congenitally blind rats can perceive light. The studies of these parameters in both normal and mutant rats in reversed-LD conditions confirmed that pineal rhythms can be entrained by light-dark cycles in congenitally anophthalmic mutant rats through a nonvisual system for light perception.