In a study published online in "Nature-Immunology" on July 15, academician Gao Fu of the Institute of Microbiology of the Chinese Academy of Sciences, researcher Dai Lianpan, researcher Yan Jinghua, etc.
As we all know, the most notorious effect of Zika virus is the cause of infantile microcephaly and other irreversible serious birth defects in newborns
The new vaccine "kills two birds with one stone" can not only protect the Zika virus from invading the fetus, but also cut off the severe antibody-dependent enhancement (ADE) effect of Zika pre-existing antibodies against dengue virus infection
In this paper titled "Protective Zika Vaccine Enhanced to Eliminate Dengue Infection through Immune Dominance Conversion", the author proposes a new strategy of protective Zika vaccine to eliminate dengue ADE
The vaccine dilemma
The vaccine dilemma Zika virus is mainly transmitted by Aedes aegypti and was first isolated from monkeys in the Zika Forest in Uganda in 1947
Normally, Zika virus infects humans and only causes symptoms such as low-grade fever, maculopapular rash, joint pain, conjunctivitis, etc.
The WHO believes that the development of vaccines is a top priority to deal with future epidemics
"Zika virus and dengue virus are both Flaviviruses, their antigenicity is close, and they belong to a superserum family
The ADE between Zika and Dengue serotypes is a key safety issue that urgently needs to be resolved in vaccine development.
In this regard, Gao Fu and others stated in the article that an ideal Zika vaccine should have three characteristics: prevention of mother-to-child transmission of Zika virus; prevention of dengue ADE caused by Zika virus infection; prevention of Zika vaccine immunization Dengue ADE
"Cut" can be cut, "reason" is not chaotic
"Cut" can be cut, "reason" is not chaotic To solve the safety problem of Zika vaccine development, it is necessary to find the "link" that connects the "cross-species" ADE effect between Zika and Dengue virus and cut it
Previous studies have shown that the cross-antibodies that cause the ADE effect of Zika or Dengue virus mainly target the conserved region of the fusion peptide (FL) of the virus surface structural protein prM and E protein
"However, in the mouse model, neither of these two vaccine methods can produce sufficient protective immune responses and completely block the vertical transmission of Zika virus from mother to child
How can we "kill" the conservative FL epitope and at the same time block the mother-to-child transmission of Zika virus?
In order to solve this problem, the Gaofu team has carried out research on Zika virus since 2016, and analyzed the crystal structure of the protective immunogen E protein of Zika virus (the E protein on the surface of the flavivirus is like a key to help the virus open The gate of the host cell), a series of neutralizing/protecting antibodies targeting different domains of E protein have been isolated, and the structural basis of representative ADE antibodies targeting FL epitopes has been analyzed
In the new study, the authors adopted a reverse vaccinology strategy of "antibody-guided vaccine design"
They replaced the FL of the Zika E protein with the homologous sequence of the insect-specific flavivirus in the flavivirus genus with the furthest evolutionary relationship through the method of homologous substitution, thereby changing the three FL epitopes that bind ADE antibodies.
Key amino acids
.
Subsequently, they further used a series of neutralizing protective antibodies and ADE antibodies to screen the modified E protein antigens positively and negatively to obtain a construction that satisfies both FL epitope elimination and neutralization epitope maintenance
.
Two of the designs, MutB and MutC, were prepared as chimpanzee adenovirus vector (AdC7) vaccines for evaluation
.
The result is "two birds with one stone"
.
On the one hand, a single immunization with the MutB/C vaccine can produce a clear immune response, which completely protects mice against the Zika virus challenge.
The viral load is undetectable in all target tissues infected by the virus, which can completely block Zika.
Mother-to-child transmission of the virus
.
On the other hand, the two vaccine immune sera completely eliminated the ADE of the four serotypes of dengue virus; the adoptive test of the serum confirmed that the MutB/C vaccine immune sera would not cause the ADE of dengue virus infection, while the wild-type construction (WT) It will accelerate the death of animals and aggravate the disease
.
"This is a very good study.
The structure-based antigen design is used to solve the problem of ADE in Zika vaccines
.
" Sequence substitution not only maintains the conformation and immunogenicity of the antigen, but also avoids the binding of FL-specific antibodies
.
Based on the structure of ADE antibody targeting FL epitope to guide the rational design of antigens.
Image courtesy of the author
Enriching the "Arsenal" of Anti-epidemic
Enriching the "Arsenal" of Anti-epidemic The researchers did not stop there
.
Knowing this, but also knowing why, they further explored the immunological basis of the modified vaccine MutB/C to eliminate ADE
.
Using the single-cell sequencing method of B cell receptor (BCR), they analyzed the characteristics of antigen-specific BCR in the lymph nodes of mice after immunization
.
The results showed that the humoral immunity stimulated by the wild-type vaccine has obvious immunodominance, and more than 60% of BCR use 3 sets of germline genes
.
However, MutB/C breaks the original immune advantage and makes the germline genes used by antigen-specific BCR distributed in a distributed manner
.
The researchers finally analyzed the molecular basis of one of the antigen-modified E protein MutC binding neutralizing antibodies, and found that MutC can still maintain the dimer structure of E protein through new forces, which is very important for activating effective neutralizing antibodies
.
In addition, the modified FL amino acids produce steric hindrance and charge repulsion to ADE antibodies, thus revealing the structural basis for MutC not to induce the production of ADE antibodies
.
The new research will help enrich our country’s “arms arsenal” in fighting the epidemic
.
As another reviewer said: "This study proposes a beautiful solution to a long-standing problem in this field
.
Reasonably designing an improved Zika virus immunogen, eliminating ADE is the development of an effective Zika vaccine An important step
.
"
Gao Fu and others also pointed out in the article that this study provides immunological trends for future clinical trials of vaccines through mouse models, and also provides new insights for vaccine-oriented protein design
.
The rational design of a new Zika vaccine that eliminates ADE will guide the future clinical use of Zika vaccine
.
(Source: Feng Lifei, China Science News)
Related article information: https://doi.
org/10.
1038/s41590-021-00966-6
https://doi.
org/10.
1038/s41590-021-00966-6 https://doi.
org/10.
1038/s41590-021-00966-6
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