On January 8, Gao Fu Research Group, a member of the Chinese Academy of Sciences and a researcher at the Institute of Microbiology of the Chinese Academy of Sciences/Beijing Institute of Life Sciences of the Chinese Academy of Sciences, and a researcher from the Institute of Microbiology, a research group, and Paul R. Young, Ph.D., In collaboration with Daniel Watterson' research team, a research paper published in Science entitled A broadly protective antibody that targets the flavivirus NS1 protein found a monoclonal antibody 1G5.3 that protects against a variety of yellow viruses, and for the first time revealed the mechanism of NS1 broad-spectrum protective antibodies, pointing out that the yellow virus nonstructive protein NS1 can be a new target for generic vaccine design and effectively avoid ADE effects.
yellow virus is a class of viruses transmitted mainly by mosquito, including dengue virus (DENV), West Nile virus (WNV) and Zika virus (ZIKV), in tropical and subtropical areas, the epidemic, the harm is great.
currently, there are no effective antiviral drugs or vaccines for most yellow viruses.
development of broad-spectrum protective therapies and vaccines has become a key and unreal goal in the field of yellow virus prevention and control. Prior to
, yellow virus treatment targets and vaccine design focused on E proteins on the surface of the virus cystic membrane, and in 2016 the Gaofu team analyzed the mechanism of operation of monoclonal antibody 2A10G6, which targets E proteins and cross-protects the Zika virus, and identified highly effective, specific monoclonal antibodies targeting Zika virus E proteins from patients recovering from Zika in China.
However, E-protein-induced antibody protection is limited, and more importantly, dengue virus infection and vaccine development process, it is found that E-protein immunity induces the production of cross-reactive and neutralized antibodies, when the body is infected with different types of dengue virus, these antibodies produce antibody dependence enhancement (ADE) effect, but will lead to more serious infections.
this poses a challenge to the development of safe and effective broad-spectrum vaccines.
yellow viruses such as the Zika virus encode 10 proteins, of which the non-structural protein NS1 is the only important protein secreted by the virus and interacts with the host, playing a key role in virus replication, disease-caused and immune escape.
NS1 forms a congenital dipolymer in the cell, binds to lipids in the endocystral system, participates in virus replication, and NS1 can also form a congener hemoglomeration consisting of three dipolymers, secreted out of cells in soluble form, interacting with the host immune system and other host factors, helping the immune virus escape and strengthening pathogenicity.
From 2016 to 2017, Gao Fu and Shi's team analyzed the C-side molecular structure of zika virus NS1, revealed different surface charge distributions of different yellow virus NS1, then analyzed the dimonth structure of the full-length protein of Zika virus NS1, discovered the key areas of NS1 membrane binding, and gained a deeper understanding of NS1 from the structure.
2015, the Paul R. Young team found that DENV NS1 was a key pathogenic factor for DENV, which can disrupt the integrity of the endotial cell layer of blood vessels by activating the TLR4 path, or may be associated with symptoms of vascular leakage in dengue patients.
NS1 is secreted by infected cells and is present in the blood of infected patients, antibodies targeting NS1 can have an antiviral effect by inhibiting NS1's function.
previous studies have found that mice vaccinated against NS1 are protected from the virus in a variety of yellow virus infection models.
NS1 protein is different from the E protein and is not located on the surface of the virus, so the ADE risk associated with NS1 antibodies is low.
although these characteristics indicate that NS1 is a promising vaccine and therapeutic antibody target, the scope and mechanism of broad-spectrum NS1 antibody mediated protection remain unclear.
based on these studies, the researchers hope to find broad-spectrum interventions that target NS1 to achieve broad-spectrum resistance to multiple yellow viruses.
the study screened a monoclonal antibody 1G5.3 and found that it binds to both DENV and ZIKV NS1.
through structural biology, the composite structure of 1G5.3 and DENV-2 and ZIKV NS1 was analyzed, and it was found that it was combined at the top of the β trapezoidal domain at the NS1 C end, so that it could be combined with NS1 djumer and NS1 hexagon secreted to the extracellular cell (Figure 1).