RESUMO
The identification of human broadly neutralizing antibodies (bnAbs) targeting the hemagglutinin (HA) stem revitalized hopes of developing a universal influenza vaccine. Using a rational design and library approach, we engineered stable HA stem antigens ("mini-HAs") based on an H1 subtype sequence. Our most advanced candidate exhibits structural and bnAb binding properties comparable to those of full-length HA, completely protects mice in lethal heterologous and heterosubtypic challenge models, and reduces fever after sublethal challenge in cynomolgus monkeys. Antibodies elicited by this mini-HA in mice and nonhuman primates bound a wide range of HAs, competed with human bnAbs for HA stem binding, neutralized H5N1 viruses, and mediated antibody-dependent effector activity. These results represent a proof of concept for the design of HA stem mimics that elicit bnAbs against influenza A group 1 viruses.
Assuntos
Glicoproteínas de Hemaglutininação de Vírus da Influenza/química , Glicoproteínas de Hemaglutininação de Vírus da Influenza/imunologia , Vírus da Influenza A Subtipo H1N1/imunologia , Virus da Influenza A Subtipo H5N1/imunologia , Vacinas contra Influenza/imunologia , Influenza Humana/prevenção & controle , Animais , Anticorpos Neutralizantes/imunologia , Anticorpos Antivirais/imunologia , Humanos , Camundongos , Multimerização Proteica , Estrutura Secundária de ProteínaRESUMO
NYVAC-C (vP2010), a recombinant vector expressing HIV subtype C gag, pol, env and nef antigens, was tested in a phase I study in healthy, HIV negative volunteers in London and Lausanne. Twenty-four participants were randomised to receive NYVAC-C (20) or matching placebo (4) at weeks 0 and 4, and assessed for safety and immunogenicity over 48 weeks. There were no serious adverse events, and no clinical or laboratory abnormalities or other events that led to withdrawal, interruption or dose reduction of the NYVAC-C/placebo. Half of the 10 assessed responded in the ELISpot assay under stringent criteria, which informed the sample size for a DNA-NYVAC-C comparison to NYVAC-C alone.
Assuntos
Vacinas contra a AIDS/administração & dosagem , Vacinas contra a AIDS/imunologia , Vacinas Virais/administração & dosagem , Vacinas Virais/imunologia , Vacinas contra a AIDS/química , Adulto , Feminino , Infecções por HIV/prevenção & controle , HIV-1/imunologia , Humanos , Masculino , Pessoa de Meia-Idade , Peptídeos/química , Vacinas Virais/química , Vacinas Virais/uso terapêuticoRESUMO
The currently recommended treatment for individuals exposed to rabies virus is the combined administration of rabies vaccine and rabies immune globulin (RIG). This review sets out the criteria used to guide development of a cocktail of human monoclonal antibodies as a replacement for RIG. Using this process as a model, the general requirements for development of safe and efficacious monoclonal antibody alternatives to currently used polyclonal serum products are discussed.