Severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) neutralizing antibodies are shown to be effective therapeutics for providing coronavirus disease 2019 (COVID‐19) protection. However, recurrent variants arise and facilitate significant escape from current antibody therapeutics. Bispecific antibodies (bsAbs) represent a unique platform to increase antibody breadth and to reduce neutralization escape. Herein, a novel immunoglobulin G–variable domains of heavy‐chain‐only antibody (IgG–VHH) format bsAb derived from a potent human antibody R15‐F7 and a humanized nanobody P14‐F8‐35 are rationally engineered. The resulting bsAb SYZJ001 efficiently neutralizes wild‐type SARS‐CoV‐2 as well as the alpha, beta, gamma, and delta variants, with superior efficacy to its parental antibodies. Cryo‐electron microscopy structural analysis reveals that R15‐F7 and P14‐F8‐35 bind to nonoverlapping epitopes within the RBD and sterically hindered ACE2 receptor binding. Most importantly, SYZJ001 shows potent prophylactic and therapeutic efficacy against SARS‐CoV‐2 in three established mouse models. Collectively, the current results demonstrate that the novel bsAb format is feasible and effective, suggesting great potential as an inspiring antiviral strategy.

An Engineered IgG–VHH Bispecific Antibody against SARS‐CoV‐2 and Its Variants

The global outbreak of the 2022 monkeypox virus infection of human raised the public health concerns of the threat of human-to-human transmission of zoonotic diseases. Given the evidence that other orthopoxviruses including cowpox and camelpox were also reported infectious to human, and that the reemerging risk of smallpox as a bioterrorist or accidental laboratory escape exists, there is an urgent need to develop a poxvirus vaccine with a broad protection of orthopoxviruses to stockpile for future emergency. Extensive studies of vaccinia virus (VACV) suggested that multiple VACV antigens, such as A27, L1, A33 and B5, showed high level similarity in terms of immunogenicity to their respective homologous antigens of other orthopoxviruses. These findings paved the ground for VACV antigens to be used as potential vaccine targets for development of a universal poxvirus vaccine. In this study, we construct a novel poxvirus vaccine candidate, mRNA-ALAB-LNP, encoding four vaccinia viral antigens A27, L1, A33 and B5. Strong anti-L1-specific antibody and moderate anti-A33-, anti-A27- and anti-B5-specific antibody responses were induced in mice after a single immunization. The antibody responses to all four antigens were significantly boosted after the second shot with all IgG titers >5 logs and highest being anti-A33 IgG. The high level of binding antibodies showed potent neutralizing capability against vaccinia virus. Specific IFN-γ responses were detected to all four antigens with the highest cellular response being that induced by the same antigen, A33. When evaluating the cross reactivity, equivalent or better serum IgG responses were seen in responses to corresponding monkeypox antigens A35, M1, A29 and B6, in comparison to vaccinia antigens. Apparently, the mRNA vaccine encoding four vaccinia antigens induced immunity not only to vaccinia virus but also to monkeypox, suggesting that the mRNA-ALAB may be a candidate for potential vaccine development against infection of monkeypox, smallpox and possibly other orthopoxviruses.

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A Quadrivalent mRNA immunization elicits potent immune responses against vaccinia and monkeypox viral antigens – a step closer to a broad orthopoxvirus vaccine

Mpox (earlier known as monkeypox) virus infection is a recognized public health emergency. There has been little research on the treatment options. This article reviews the specific drugs used to treat mpox virus infection and the vaccines used here. Instead of focusing on the mechanistic basis, this review narrates the practical, real-life experiences of individual patients of mpox virus disease being administered these medicines. We conducted a bibliometric analysis on the treatment of the mpox virus using data from several databases like PubMed, Scopus, and Embase. The research on this topic has grown tremendously recently but it is highly concentrated in a few countries. Cidofovir is the most studied drug. This is because it is indicated and also used off-label for several conditions. The drugs used for mpox virus infection include tecovirimat, cidofovir, brincidofovir, vaccinia immune globulin, and trifluridine. Tecovirimat is used most frequently. It is a promising option in progressive mpox disease in terms of both efficacy and safety. Brincidofovir has been associated with treatment discontinuation due to elevated hepatic enzymes. Cidofovir is also not the preferred drug, often used because of the unavailability of tecovirimat. Trifluridine is used topically as an add-on agent along with tecovirimat for ocular manifestations of mpox virus disease. No study reports individual patient data for vaccinia immune globulin. Though no vaccine is currently approved for mpox virus infection, ACAM 2000 and JYNNEOS are the vaccines being mainly considered. ACAM 2000 is capable of replicating and may cause severe adverse reactions. It is used when JYNNEOS is contraindicated. Several drugs and vaccines are under development and have been discussed alongside pragmatic aspects of mpox virus treatment and prevention. Further studies can provide more insight into the safety and efficacy of Tecovirimat in actively progressing mpox virus disease.

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Pharmacological treatment and vaccines in monkeypox virus: a narrative review and bibliometric analysis

Nanobodies with cross-neutralizing activity provide prominent therapeutic efficacy in mild and severe COVID-19 rodent models.

https://doi.org/10.1016/j.micpath.2023.106156

Progress and prospects on vaccine development against monkeypox infection

ABSTRACT The re-emerging mpox (formerly monkeypox) virus (MPXV), a member of Orthopoxvirus genus together with variola virus (VARV) and vaccinia virus (VACV), has led to public health emergency of international concern since July 2022. Inspired by the unprecedent success of coronavirus disease 2019 (COVID-19) mRNA vaccines, the development of a safe and effective mRNA vaccine against MPXV is of high priority. Based on our established lipid nanoparticle (LNP)-encapsulated mRNA vaccine platform, we rationally constructed and prepared a panel of multicomponent MPXV vaccine candidates encoding different combinations of viral antigens including M1R, E8L, A29L, A35R, and B6R. In vitro and in vivo characterization demonstrated that two immunizations of all mRNA vaccine candidates elicit a robust antibody response as well as antigen-specific Th1-biased cellular response in mice. Importantly, the penta- and tetra-component vaccine candidates AR-MPXV5 and AR-MPXV4a showed superior capability of inducing neutralizing antibodies as well as of protecting from VACV challenge in mice. Our study provides critical insights to understand the protection mechanism of MPXV infection and direct evidence supporting further clinical development of these multicomponent mRNA vaccine candidates.

https://doi.org/10.1080/22221751.2023.2192815

Rational development of multicomponent mRNA vaccine candidates against mpox

PA-E18G substitution in influenza A virus confers resistance to ZX-7101, a cap-dependent endonuclease inhibitor.

<p indent="0mm">Emerging viral infectious diseases are diverse, fast-spreading and dangerous and have caused many outbreaks and epidemics worldwide, with serious and far-reaching effects on human health, social stability and economic development. At present, vaccines, small-molecule drugs and monoclonal antibodies (mAbs) are important tools for addressing new outbreaks of viral infectious diseases and have played key roles in the prevention and treatment of multiple viral infectious diseases. In particular, mAbs can effectively prevent a virus from entering host cells and block reinfection by progeny virus. mAbs can also facilitate the clearance of viruses and virus-infected cells via Fc-mediated effector functions. In addition, the effects of mAbs are related to several characteristics, such as their high specificity, ability to enhance immune responses and low toxicity. Thus, mAbs are appealing as potential therapeutics and prophylactics for viral infections. However, traditional mAb technology still has some limitations, such as complex production processes, high quality control requirements, high manufacturing costs, high treatment costs, and the need for strict cold chain storage and transportation, making it unsuitable for large-scale population use. Unfortunately, to date, only a small number of mAb drugs have been used to treat or prevent infectious diseases. Therefore, there is a need to rapidly develop a novel antiviral tool. As a type of novel biological agent, nucleic acid-encoded antibodies are DNA and mRNA molecules that encode virus-specific neutralizing antibodies that are appropriately sequenced and optimally regulated to obtain stably expressed DNA and mRNA molecules <italic>in vitro</italic>, which are then introduced into a host through a special delivery vehicle. Then, the host cells are used as individual bioreactors, and the protein synthesis mechanism is used to express structurally and functionally intact antibodies, which in turn act as neutralizing agents <italic>in vivo</italic>. Compared to traditional mAbs, nucleic acid-encoded antibodies have many potential advantages, such as ease and speed of design and testing, ease of rapid scale-up and manufacturing, ease of storage and transportation, and cost-effectiveness; consequently, they are considered an ideal alternative to traditional mAb technology. At present, nucleic acid-encoded antibodies have been used in preclinical studies on diseases caused by many viruses, such as human immunodeficiency virus, influenza virus, Chikungunya virus, Zika virus and SARS-CoV-2. Specifically, three nucleic acid-encoded antibodies have entered phase I clinical trials and have promising applications in the prevention and treatment of emerging viral infectious diseases. In this paper, we summarize the principles and current research status of nucleic acid-encoded antibodies in antiviral control and highlight the advantages of nucleic acid-encoded antibodies over traditional protein antibodies, the advantages and disadvantages of different nucleic acid-encoded antibodies, and the potential challenges and possible strategies for the future development of these agents to provide new research ideas for the application of nucleic acid-encoded antibodies in the control of future emerging viral infectious diseases. 

Suoqun Zhao

Papers

Rational development of multicomponent mRNA vaccine candidates against mpox

An Engineered IgG–VHH Bispecific Antibody against SARS‐CoV‐2 and Its Variants

PA-E18G substitution in influenza A virus confers resistance to ZX-7101, a cap-dependent endonuclease inhibitor.

Application of nucleic acid-encoded antibodies in prevention and treatment of emerging viral infectious diseases