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1.
Arch Toxicol ; 98(7): 2185-2197, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38607375

RESUMO

The emergence of coronavirus disease (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) led to a pandemic, prompting rapid vaccine development. Although vaccines are effective, the occurrence of rare adverse events following vaccination highlights the necessity of determining whether the benefits outweigh the risks posed by the infection itself. The recombinant Vesicular Stomatitis Virus (rVSV) platform is a promising vector for vaccines against emerging viruses. However, limited studies have evaluated the genotoxicity and safety pharmacology of this viral vector vaccine, which is crucial to ensure the safety of vaccines developed using this platform. Hence, the present study aimed to assess the genotoxicity and safety pharmacology of the rVSVInd(GML)-mspSGtc COVID-19 vaccine using micronucleus and comet assays, as well as neurobehavioral, body temperature, respiratory, and cardiovascular assessments in Sprague-Dawley rats and beagle dogs. The intramuscular administration of rVSVInd(GML)-mspSGtc at doses up to 1.5 × 109 PFU/animal did not increase the number of bone marrow micronucleated polychromatic erythrocytes or cause liver DNA damage. Additionally, it had no significant impact on neurobehavioral functions in rats and showed marginal temporary changes in body temperature, respiratory rate, heart rate, and electrocardiogram parameters in rats and dogs, all of which resolved within 24 h. Overall, following genotoxicity and pharmacological safety assessments, rVSVInd(GML)-mspSGtc displayed no notable systemic adverse effects in rats and dogs, suggesting its potential as a vaccine candidate for human clinical trials.


Assuntos
Vacinas contra COVID-19 , Testes para Micronúcleos , Ratos Sprague-Dawley , SARS-CoV-2 , Animais , Cães , Vacinas contra COVID-19/toxicidade , Ratos , Masculino , SARS-CoV-2/imunologia , SARS-CoV-2/efeitos dos fármacos , COVID-19/prevenção & controle , Feminino , Dano ao DNA/efeitos dos fármacos , Ensaio Cometa , Vesiculovirus/efeitos dos fármacos , Vacinas Sintéticas/imunologia , Temperatura Corporal/efeitos dos fármacos
2.
Regul Toxicol Pharmacol ; 142: 105438, 2023 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-37356612

RESUMO

In this study we evaluated the outcomes of non-clinical toxicity studies of various SARS-CoV-2 vaccines produced with different manufacturing technologies, with focus on Repeated Dose Toxicity (RDT) and Developmental and Reproductive Toxicity (DART) studies. We found that RDT and DART studies at doses relevant for human treatment showed no adverse effects while remaining observations were expected findings including local reactogenicity, immune response and macroscopic findings at the injection site. We have also reviewed the European Medicines Agency (EMA) nonclinical assessment reports for market authorization. Regardless of utilized vaccine manufacturing technology EMA assessment of the non-clinical studies consisted most frequently of comments related to study design, species selection and missing data. Sponsors have often submitted platform studies (vaccine studies with the same technology/construct but using other antigens) as supplementary data. Animal model-based toxicity testing has shown rather small effects, which have been never serious adverse effects. The translational value to support clinical development is mainly to inflammatory effects, indicative of the primary action of the vaccines. From a 3R perspective supportive platform technology data consisting of previously executed RDT and DART studies from the same platform technology are encouraged to be implemented in the vaccine assessment process.


Assuntos
Vacinas contra COVID-19 , COVID-19 , Animais , Humanos , COVID-19/prevenção & controle , Vacinas contra COVID-19/efeitos adversos , Vacinas contra COVID-19/toxicidade , SARS-CoV-2 , Testes de Toxicidade , Vacinas
3.
Arch Toxicol ; 96(3): 859-875, 2022 03.
Artigo em Inglês | MEDLINE | ID: mdl-35032184

RESUMO

rVSV-ΔG-SARS-CoV-2-S is a clinical stage (Phase 2) replication competent recombinant vaccine against SARS-CoV-2. To evaluate the safety profile of the vaccine, a series of non-clinical safety, immunogenicity and efficacy studies were conducted in four animal species, using multiple doses (up to 108 Plaque Forming Units/animal) and dosing regimens. There were no treatment-related mortalities or any noticeable clinical signs in any of the studies. Compared to unvaccinated controls, hematology and biochemistry parameters were unremarkable and no adverse histopathological findings. There was no detectable viral shedding in urine, nor viral RNA detected in whole blood or serum samples seven days post vaccination. The rVSV-ΔG-SARS-CoV-2-S vaccination gave rise to neutralizing antibodies, cellular immune responses, and increased lymphocytic cellularity in the spleen germinal centers and regional lymph nodes. No evidence for neurovirulence was found in C57BL/6 immune competent mice or in highly sensitive type I interferon knock-out mice. Vaccine virus replication and distribution in K18-human Angiotensin-converting enzyme 2-transgenic mice showed a gradual clearance from the vaccination site with no vaccine virus recovered from the lungs. The nonclinical data suggest that the rVSV-ΔG-SARS-CoV-2-S vaccine is safe and immunogenic. These results supported the initiation of clinical trials, currently in Phase 2.


Assuntos
Vacinas contra COVID-19/toxicidade , Animais , Anticorpos Neutralizantes/sangue , Anticorpos Antivirais/sangue , Vacinas contra COVID-19/imunologia , Cricetinae , Feminino , Glicoproteínas de Membrana/genética , Mesocricetus , Camundongos , Camundongos Endogâmicos C57BL , Coelhos , Suínos , Vacinação , Vacinas Sintéticas/toxicidade , Proteínas do Envelope Viral/genética
5.
Front Immunol ; 12: 766112, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34938290

RESUMO

The coronavirus disease 2019 (COVID-19) pandemic caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has become a global health concern. The development of vaccines with high immunogenicity and safety is crucial for controlling the global COVID-19 pandemic and preventing further illness and fatalities. Here, we report the development of a SARS-CoV-2 vaccine candidate, Nanocovax, based on recombinant protein production of the extracellular (soluble) portion of the spike (S) protein of SARS-CoV-2. The results showed that Nanocovax induced high levels of S protein-specific IgG and neutralizing antibodies in three animal models: BALB/c mouse, Syrian hamster, and a non-human primate (Macaca leonina). In addition, a viral challenge study using the hamster model showed that Nanocovax protected the upper respiratory tract from SARS-CoV-2 infection. Nanocovax did not induce any adverse effects in mice (Mus musculus var. albino) and rats (Rattus norvegicus). These preclinical results indicate that Nanocovax is safe and effective.


Assuntos
Vacinas contra COVID-19/imunologia , Vacinas contra COVID-19/toxicidade , COVID-19/prevenção & controle , Imunogenicidade da Vacina/imunologia , Glicoproteína da Espícula de Coronavírus/imunologia , Animais , Anticorpos Neutralizantes/imunologia , Anticorpos Antivirais/imunologia , Cricetinae , Macaca , Camundongos , Ratos , SARS-CoV-2 , Vacinas Sintéticas/imunologia , Vacinas Sintéticas/toxicidade
6.
Reprod Toxicol ; 104: 134-142, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34324966

RESUMO

AZD1222 (ChAdOx1 nCoV-19) is a COVID-19 vaccine that is not yet licensed for use during pregnancy. To support the inclusion of pregnant and breastfeeding people in AZD1222 clinical studies, a non-clinical developmental and reproductive toxicity study was performed to evaluate its effects on fertility and reproductive processes of female CD-1 mice during the embryofetal development phase, and postnatal outcomes during the littering phase. Immunogenicity assessments were also made in dams, fetuses, and pups. There were no vaccine-related unscheduled deaths throughout the study. Furthermore, there were no vaccine-related effects on female reproduction, fetal or pup survival, fetal external, visceral, or skeletal findings, pup physical development, and no abnormal gross pathology findings in pups or dams. Antibody responses raised in dams were maintained throughout gestation and postnatal periods, and seroconversion in fetuses and pups indicate placental and lactational transfer of immunoglobulins. Together with clinical data from non-pregnant people, these results support the inclusion of pregnant and breastfeeding people in AZD1222 clinical studies.


Assuntos
Anticorpos Antivirais/sangue , Vacinas contra COVID-19/administração & dosagem , Imunogenicidade da Vacina , Vacinação , Animais , Biomarcadores/sangue , Vacinas contra COVID-19/toxicidade , ChAdOx1 nCoV-19 , Feminino , Feto/efeitos dos fármacos , Feto/imunologia , Feto/metabolismo , Idade Gestacional , Lactação/imunologia , Lactação/metabolismo , Troca Materno-Fetal , Camundongos , Placenta/imunologia , Placenta/metabolismo , Gravidez , Efeitos Tardios da Exposição Pré-Natal , Medição de Risco , Soroconversão
7.
Reprod Toxicol ; 103: 28-35, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34058573

RESUMO

BNT162b2 is a vaccine developed to prevent coronavirus disease 2019 (COVID-19). BNT162b2 is a lipid nanoparticle formulated nucleoside-modified messenger RNA (mRNA) encoding the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein locked in its prefusion conformation. A developmental and reproductive toxicity study was conducted in rats according to international regulatory guidelines. The full human BNT162b2 dose of 30 µg mRNA/dose (>300 times the human dose on a mg/kg basis) was administered intramuscularly to 44 female rats 21 and 14 days prior to mating and on gestation days 9 and 20. Half of the rats were subject to cesarean section and full fetal examination at the end of gestation, and the other half were allowed to deliver and were monitored to the end of lactation. A robust neutralizing antibody response was confirmed prior to mating and at the end of gestation and lactation. The presence of neutralizing antibodies was also confirmed in fetuses and offspring. Nonadverse effects, related to the local injection site reaction, were noted in dams as expected from other animal studies and consistent with observations in humans. There were no effects of BNT162b2 on female mating performance, fertility, or any ovarian or uterine parameters nor on embryo-fetal or postnatal survival, growth, physical development or neurofunctional development in the offspring through the end of lactation. Together with the safety profile in nonpregnant people, this ICH-compliant nonclinical safety data supports study of BNT162b2 in women of childbearing potential and pregnant and lactating women.


Assuntos
Vacinas contra COVID-19/toxicidade , Fertilidade , Desenvolvimento Fetal , Animais , Anticorpos Neutralizantes/sangue , Anticorpos Antivirais/sangue , Vacina BNT162 , Vacinas contra COVID-19/farmacologia , Cesárea , Feminino , Lactação , Gravidez , Ratos , Ratos Wistar
8.
Food Chem Toxicol ; 152: 112239, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33901607

RESUMO

The outbreak of COVID-19 has posed a serious threat to global public health. Vaccination may be the most effective way to prevent and control the spread of the virus. The safety of vaccines is the focus of preclinical research, and the repeated dose toxicity test is the key safety test to evaluate the vaccine before clinical trials. The purpose of this study was (i) to observe the toxicity and severity of an inactivated SARS-CoV-2 vaccine (Vero cells) in rodent Sprague Dawley rats after multiple intramuscular injections under the premise of Good Laboratory Practice principles and (ii) to provide a basis for the formulation of a clinical trial scheme. The results showed that all animals in the experimental group were in good condition, no regular changes related to the vaccine were found in the detection of various toxicological indexes, and no noticeable stimulating reaction related to the vaccine was found in the injected local tissues. The neutralizing antibodies in the low- and high-dose vaccine groups began to appear 14 days after the last administration. In the negative control group, no neutralizing antibodies were observed from the administration period to the recovery period. Therefore, the repeated administration toxicity test of the inactivated SARS-CoV-2 vaccine (Vero cells) in Sprague Dawley rats showed no obvious toxic reaction. It was preliminarily confirmed that the vaccine can stimulate production of neutralizing antibodies and is safe in Sprague Dawley rats.


Assuntos
Anticorpos Neutralizantes/sangue , Anticorpos Antivirais/sangue , Vacinas contra COVID-19/imunologia , Animais , COVID-19 , Vacinas contra COVID-19/toxicidade , Feminino , Masculino , Ratos Sprague-Dawley , Testes de Toxicidade , Vacinas de Produtos Inativados/imunologia , Vacinas de Produtos Inativados/toxicidade
9.
Sci Rep ; 11(1): 5804, 2021 03 11.
Artigo em Inglês | MEDLINE | ID: mdl-33707532

RESUMO

COVID-19 outbreak caused by SARS-CoV-2 created an unprecedented health crisis since there is no vaccine for this novel virus. Therefore, SARS-CoV-2 vaccines have become crucial for reducing morbidity and mortality. In this study, in vitro and in vivo safety and efficacy analyzes of lyophilized vaccine candidates inactivated by gamma-irradiation were performed. The candidate vaccines in this study were OZG-3861 version 1 (V1), an inactivated SARS-CoV-2 virus vaccine, and SK-01 version 1 (V1), a GM-CSF adjuvant added vaccine. The candidate vaccines were applied intradermally to BALB/c mice to assess toxicity and immunogenicity. Preliminary results in vaccinated mice are reported in this study. Especially, the vaccine models containing GM-CSF caused significant antibody production with neutralization capacity in absence of the antibody-dependent enhancement feature, when considered in terms of T and B cell responses. Another important finding was that the presence of adjuvant was more important in T cell in comparison with B cell response. Vaccinated mice showed T cell response upon restimulation with whole inactivated SARS-CoV-2 or peptide pool. This study shows that the vaccines are effective and leads us to start the challenge test to investigate the gamma-irradiated inactivated vaccine candidates for infective SARS-CoV-2 virus in humanized ACE2 + mice.


Assuntos
Vacinas contra COVID-19/imunologia , Imunogenicidade da Vacina , Vacinas de Produtos Inativados/imunologia , Animais , Vacinas contra COVID-19/toxicidade , Feminino , Raios gama , Genoma Viral , Humanos , Masculino , Camundongos Endogâmicos BALB C , SARS-CoV-2/genética , Vacinas de Produtos Inativados/toxicidade
10.
Sci Rep ; 11(1): 3238, 2021 02 05.
Artigo em Inglês | MEDLINE | ID: mdl-33547334

RESUMO

The rampant spread of COVID-19, an infectious disease caused by SARS-CoV-2, all over the world has led to over millions of deaths, and devastated the social, financial and political entities around the world. Without an existing effective medical therapy, vaccines are urgently needed to avoid the spread of this disease. In this study, we propose an in silico deep learning approach for prediction and design of a multi-epitope vaccine (DeepVacPred). By combining the in silico immunoinformatics and deep neural network strategies, the DeepVacPred computational framework directly predicts 26 potential vaccine subunits from the available SARS-CoV-2 spike protein sequence. We further use in silico methods to investigate the linear B-cell epitopes, Cytotoxic T Lymphocytes (CTL) epitopes, Helper T Lymphocytes (HTL) epitopes in the 26 subunit candidates and identify the best 11 of them to construct a multi-epitope vaccine for SARS-CoV-2 virus. The human population coverage, antigenicity, allergenicity, toxicity, physicochemical properties and secondary structure of the designed vaccine are evaluated via state-of-the-art bioinformatic approaches, showing good quality of the designed vaccine. The 3D structure of the designed vaccine is predicted, refined and validated by in silico tools. Finally, we optimize and insert the codon sequence into a plasmid to ensure the cloning and expression efficiency. In conclusion, this proposed artificial intelligence (AI) based vaccine discovery framework accelerates the vaccine design process and constructs a 694aa multi-epitope vaccine containing 16 B-cell epitopes, 82 CTL epitopes and 89 HTL epitopes, which is promising to fight the SARS-CoV-2 viral infection and can be further evaluated in clinical studies. Moreover, we trace the RNA mutations of the SARS-CoV-2 and ensure that the designed vaccine can tackle the recent RNA mutations of the virus.


Assuntos
Vacinas contra COVID-19 , Aprendizado Profundo , SARS-CoV-2/imunologia , Glicoproteína da Espícula de Coronavírus/imunologia , Alérgenos , COVID-19/prevenção & controle , Vacinas contra COVID-19/efeitos adversos , Vacinas contra COVID-19/química , Vacinas contra COVID-19/imunologia , Vacinas contra COVID-19/toxicidade , Uso do Códon , Biologia Computacional , Desenho de Fármacos , Epitopos de Linfócito B/imunologia , Epitopos de Linfócito T/imunologia , Humanos , Imunogenicidade da Vacina , Modelos Moleculares , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Mutação , Conformação Proteica , RNA Viral , SARS-CoV-2/química , SARS-CoV-2/genética , Solubilidade , Glicoproteína da Espícula de Coronavírus/química , Glicoproteína da Espícula de Coronavírus/genética , Linfócitos T Citotóxicos/imunologia , Linfócitos T Auxiliares-Indutores/imunologia , Vacinas de Subunidades Antigênicas/química , Vacinas de Subunidades Antigênicas/imunologia
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