Written by | qiSince May 2022, the monkeypox virus (MPXV) outbreak has resulted in more than 90,000 cases in 115 countries around the world, and although this typical zoonotic disease has been endemic in West and Central Africa for many years, the scale of the outbreak is unprecedented, and the WHO declared it a Public Health Emergency of International Concern in July 2022. MPXV is a member of the genus Orthopoxvirus, which also includes the well-known smallpox virus, and the 2022 outbreak was mainly driven by type II MPXV and was mostly associated with less severe symptoms, while the second major outbreak reported in the Democratic Republic of the Congo the following year was caused by type I MPXV infection, which was mostly fatal。Orthopoxviruses are double-stranded DNA viruses with a high degree of similarity between antigens, so the vaccine provides cross-protective immunity against other viruses within the genus. Early vaccinia virus (VACV) vaccination has completely eradicated the smallpox virus that has ravaged for thousands of years, while also providing strong and long-lasting protection against MPXV, and the current third-generation orthopoxvirus vaccine is based on the modified Ankara vaccinia virus (MVA), a non-replicating VACV derivative, during the 2022 monkeypox outbreak, the vaccine effectiveness was only 66% in individuals who received two full doses of MVA, and the antibody response waned rapidly within two years。Therefore, there is a need to develop a vaccine that is novel, effective, durable, safe, and can be rapidly produced on a large scale. February 15, 2024, from Biontech, USAasaf poranThe team is waitingcellThe journal co-published an article entitleda multivalent mrna monkeypox virus vaccine (bnt166) protects mice and macaques from orthopoxvirus diseasearticle,They designed a highly immunogenic, safety-safe multivalent mRNA vaccine, BNT166, for the 2022-2023 global outbreak of monkeypox, and demonstrated its efficacy in multiple preclinical models to support its further evaluation in clinical trials
There are two types of viral particles, enveloped virus (EV) and mature virus (MV), each with a unique set of surface antigensBased on this, the team designed the mRNA vaccine BNT166 targeting the EV (A35 and B6) and MV (M1 and H3) antigens of IIB MPXV and evaluated the performance of two combination vaccine candidates: quadrivalent BNT166A (against all 4 antigens) and trivalent BNT166C (against A35, B6 and M1 only). The mRNA of the BNT166 vaccine can be successfully expressed in cells in vitro and located on the cell surface without interference between multiple components, and intramuscular immunization with BNT166A, BNT166C and each one-component antigen mRNA can induce antigen-specific B cells and comparable levels of T cell responses in lymph node germinal centers. By day 35 of immunization, the team measured the neutralizing antibody levels of VACV and MPXV by plaque reduction neutralization assay (PRNT) and focal spot reduction neutralization assay (FRNT), and the serum of mice immunized with EV proteins A35 and B6 alone showed no neutralizing activity, and the serum of mice immunized with mv proteins M1 and H3 alone effectively neutralized VACv and MPXV, and no significant differences were observed between the M1 and BNT166A and BNT166C groups. Next, the team evaluated the protective efficacy of the two combination vaccines against MPXV using MPXV-sensitive CAST EI mice. Mice were infected with the 2022 outbreak of MPXV strains by intranasal inoculation with BNT166A and BNT166C on days 0 and 21, respectively, followed by mice sacrificed on days 3 or 7 to measure lung MPXV virus titers. The results showed that mice immunized with the A35 and B6 antigens did not have a significant reduction in lung viral titers on day 3, but a decrease in viral titers on day 7, while BNT166A and BNT166c immunized animals showed no measurable virus at either time point. In addition, they conducted a protective study against fatal type I MPXV infection, where both combination vaccines provided 100% protection against death, while mice immunized with the A35 and B6 combinations had a small but significant survival benefit. In addition to providing protection against MPXV, the team infected mice with another lethal dose of orthopoxvirus VACV, mice immunized with H3 alone died rapidly from infection, while mice immunized with multivalent BNT166A or single components A35, B6, and M1 were completely free from death, suggesting that BNT166 has the potential to protect against multiple orthopoxviruses. Based on the above findings, the team further evaluated the protective effect of BNT166 in non-human primates (cynomolgus monkeys), two groups of cynomolgus monkeys who received prime and booster immunization on days 0 and 28, respectively, and a lethal dose of type I MPXV infection on day 60, 83Three percent of the control group died from infection, while animals inoculated with BNT166a showed only mild symptoms of the disease, such as transient viremia and weight loss. 
In summary,This work demonstrates the immunogenicity of the multivalent mRNA vaccine BNT166 encoding the MPXV antigen and provides protective immunity against a variety of orthopoxvirusesCurrently, a Phase I II clinical trial of BNT166 (NCT05988203) is underway to evaluate whether vaccination with the vaccine can be used as a safe and effective measure to mitigate the monkeypox outbreak. Original link:Plate maker: Eleven.
References
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