RESUMO
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been responsible for one of the worst pandemics in modern history. Several prevention and treatment strategies have been designed and evaluated in recent months either through the repurposing of existing treatments or the development of new drugs and vaccines. In this study, we show that L-carnitine tartrate supplementation in humans and rodents led to significant decreases of key host dependency factors, notably angiotensin-converting enzyme 2 (ACE2), transmembrane protease serine 2 (TMPRSS2), and Furin, which are responsible for viral attachment, viral spike S-protein cleavage, and priming for viral fusion and entry. Interestingly, pre-treatment of Calu-3, human lung epithelial cells, with L-carnitine tartrate led to a significant and dose-dependent inhibition of the infection by SARS-CoV-2. Infection inhibition coincided with a significant decrease in ACE2 mRNA expression levels. These data suggest that L-carnitine tartrate should be tested with appropriate trials in humans for the possibility to limit SARS-CoV-2 infection.
Assuntos
Enzima de Conversão de Angiotensina 2/metabolismo , Tratamento Farmacológico da COVID-19 , Carnitina/administração & dosagem , Tartaratos/administração & dosagem , Adulto , Idoso , Enzima de Conversão de Angiotensina 2/sangue , Animais , COVID-19/metabolismo , Carnitina/farmacologia , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Feminino , Furina/sangue , Furina/metabolismo , Humanos , Inflamação/metabolismo , Masculino , Pessoa de Meia-Idade , Ratos , SARS-CoV-2 , Serina Endopeptidases/sangue , Serina Endopeptidases/metabolismo , Tartaratos/farmacologia , Adulto JovemRESUMO
A highly efficacious vaccine is required to counteract a threat of an avian influenza pandemic. Increasing the potency of vaccines by adjuvation is essential not only to overcome generally low immunogenicity of pandemic strains, but also to allow dose sparing and as such to make it feasible to satisfy huge global production demands. In this study we evaluated the ability of four distinct adjuvants to further increase immune responses to a virosomal adjuvanted avian H9N2 influenza vaccine in mice. Currently registered adjuvants aluminium phosphate, aluminium hydroxide and MF59, as well as a novel promising adjuvant MATRIX-M were included in the study. Our results demonstrate that all adjuvants significantly increased the H9N2 haemagglutinin (HA) inhibition and ELISA antibody titers induced with the virosomal adjuvanted vaccine. The adjuvants exhibited different effect on the isotype of virus specific antibodies, with MATRIX-M inducing the most pronounced skewing to IgG2a, i.e. towards Th1 type of response. While the virosomal adjuvanted pandemic influenza vaccine efficiently induced CD4(+) T-cell response, with no further increase upon adjuvation, the CD8(+) T-cell responses induced with virosomal adjuvanted vaccine could be significantly improved upon additional adjuvation with MATRIX-M or MF59. All adjuvants demonstrated a dose sparing effect, i.e. in combination with the virosomal adjuvanted pandemic influenza vaccine they increased immune responses to comparable level independent of the tested vaccine dose. In conclusion, our results demonstrate that immune responses to a virosomal adjuvanted pandemic influenza vaccine can be further enhanced by add-on adjuvants, with MATRIX-M being overall the most potent adjuvant in combination with virosomes, followed by MF59 and finally aluminium-based adjuvants.
Assuntos
Adjuvantes Imunológicos/farmacologia , Anticorpos Antivirais/sangue , Vírus da Influenza A Subtipo H9N2/imunologia , Vacinas contra Influenza/imunologia , Influenza Aviária/prevenção & controle , Linfócitos T/imunologia , Adjuvantes Imunológicos/administração & dosagem , Compostos de Alumínio/administração & dosagem , Compostos de Alumínio/farmacologia , Hidróxido de Alumínio/administração & dosagem , Hidróxido de Alumínio/farmacologia , Animais , Aves , Ensaio de Imunoadsorção Enzimática , Feminino , Testes de Inibição da Hemaglutinação , Subpopulações de Linfócitos/imunologia , Camundongos , Camundongos Endogâmicos BALB C , Fosfatos/administração & dosagem , Fosfatos/farmacologia , Polissorbatos/administração & dosagem , Polissorbatos/farmacologia , Esqualeno/administração & dosagem , Esqualeno/farmacologia , Vacinas Virossomais/imunologiaRESUMO
Previously, we have shown the potency of recombinant Adenovirus serotype 35 viral vaccines (rAd35) to induce strong immune response against the circumsporozoite protein (CS) of the plasmodium parasite. To further optimize immunogenicity of Ad35-based malaria vaccines we formulated rAd35.CS vaccine with aluminium phosphate adjuvant (AlPO(4)). In contrast to the conventional protein based vaccines no absorption to aluminium adjuvant was observed and rAd35 viral in vitro infectivity in mammalian cells was preserved. Immunization with Ad35.CS formulated with AlPO(4) resulted in significantly higher CS specific T and B cell responses in mice upon either single or prime-boost vaccination regimens as compared to rAd35.CS alone. With these results we report for the first time the feasibility of using an AlPO(4) adjuvant to increase the potency of a live adenovirus serotype 35-based vaccine.