RESUMO
INTRODUCTION: As congenital cytomegalovirus (CMV) infection is one of the major causes of birth defects and developmental abnormalities, it is essential to develop vaccines and therapeutic antibodies against CMV. Clinical trials demonstrated that the subunit vaccine based on glycoprotein B, which had been believed to be the major target for neutralization, did not induce sufficient protective immunity. On the other hand, it has been reported that the immunization of animals with the Pentamer, the pentameric complex of gH/gL/UL128/UL130/UL131A, induced strong neutralizing antibodies. Here, we sought to clarify whether any polymorphic alterations present in the Pentamer of clinical isolates affect neutralization by anti-Pentamer antibodies. METHODS: Sequences of the genes encoding the Pentamer components of 25 Japanese clinical isolates were determined. Neutralization of infection by two seropositive sera and by anti-Pentamer serum was measured using a CMV reporter cell line based on ARPE-19. RESULTS: Polymorphisms of the amino acid sequence of UL128, UL130, and UL131A ORFs were limited and clustered into two major groups. The identified alterations, except UL128 I140T, were mapped outside of the reported regions recognized by neutralizing antibodies. Anti-Pentamer serum neutralized infection with all isolates to a similar degree and had no correlation with the polymorphic groups. CONCLUSIONS: Our findings indicate that Pentamer antigens prepared from Merlin Fix strain induce antibodies that neutralize infection with all isolates to a similar level and that anti-Pentamer antibodies neutralize CMV infection better than do human sera, suggesting that vaccines and therapeutic antibodies based on Pentamer as an antigen have some promise.
Assuntos
Anticorpos Neutralizantes/sangue , Antígenos Virais/genética , Infecções por Citomegalovirus/virologia , Citomegalovirus/genética , Anticorpos Antivirais/sangue , Linhagem Celular , Humanos , Glicoproteínas de Membrana/genética , Polimorfismo Genético , Proteínas do Envelope Viral/genéticaRESUMO
The development of a cytomegalovirus (CMV) vaccine has become a top priority due to its potential cost-effectiveness and associated public health benefits. However, there are a number of challenges facing vaccine development including the following: (1) CMV has many mechanisms for evading immune responses , and natural immunity is not perfect, (2) the immune correlates for protection are unclear, (3) a narrow range of CMV hosts limits the value of animal models, and (4) the placenta is a specialized organ formed transiently and its immunological status changes with time. In spite of these limitations, several types of CMV vaccine candidate, including live-attenuated, DISC , subunit, DNA, vectored, and peptide vaccines, have been developed or are currently under development. The recognition of the pentameric complex as the major neutralization target and identification of various strategies to block viral immune response evasion mechanisms have opened new avenues to CMV vaccine development. Here, we discuss the immune correlates for protection, the characteristics of the various vaccine candidates and their clinical trials, and the relevant animal models.