A protective Zika virus E-dimer-based subunit vaccine engineered to abrogate antibody-dependent enhancement of dengue infection

Slon-Campos, J; Dejnirattisai, Wanwisa; Jagger, Brett W.; López-Camacho, César; Wongwiwat, Wiyada; Durnell, Lorellin A.; Winkler, Emma S.; Chen, Rita E.; Reyes-Sandoval, Arturo; Rey, F.A.; Diamond, Michael S.; Mongkolsapaya, Juthathip; Screaton, Gavin

doi:10.1038/s41590-019-0477-z

Cited by 74 publications

(49 citation statements)

References 52 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Recently, a characterization of two dimeric E antigens was published, dimerization was achieved by the A264C mutation or replacing the E transmembrane domain with the FC fragment of a human IgG (39). While this manuscript was under preparation, two other articles reported development and evaluation of dimer-based subunit vaccines similar to that described in here (40,41). The authors showed that in all three cases the antigens were able to induce in mice the production of neutralizing antibodies.…”

Section: Discussionmentioning

confidence: 99%

Zika Virus-Like Particles Bearing a Covalent Dimer of Envelope Protein Protect Mice from Lethal Challenge

Lorenzo

Tandavanitj

Doig

et al. 2020

J Virol

View full text Add to dashboard Cite

Zika virus (ZIKV) envelope (E) protein is the major target of neutralizing antibodies in infected host, and thus represents a candidate of interest for vaccine design. However, a major concern in the development of vaccines against ZIKV and the related dengue virus is the induction of cross-reactive poorly neutralizing antibodies that can cause antibody-dependent enhancement (ADE) of infection. This risk necessitates particular care in vaccine design. Specifically, the engineered immunogens should have their cross-reactive epitopes masked, and they should be optimized for eliciting virus-specific strongly neutralizing antibodies upon vaccination. Here, we developed ZIKV subunit- and virus-like particle (VLP)-based vaccines displaying E in its wild type form, or E locked in a covalently linked dimeric (cvD) conformation to enhance the exposure of E dimers to the immune system. Compared with their wild-type derivatives, cvD immunogens elicited antibody with higher capacity of neutralizing virus infection of cultured cells. More importantly, these immunogens protected animals from lethal challenge with both the African and Asian lineages of ZIKV, impairing virus dissemination to brain and sexual organs. Moreover, the locked conformation of E reduced the exposure of epitopes recognized by cross-reactive antibodies and therefore showed a lower potential to induce ADE in vitro. Our data demonstrated a higher efficacy of the VLPs in comparison with the soluble dimer and support VLP-cvD as a promising ZIKV vaccine. Author Summary Infection with Zika virus (ZIKV) leads to the production by host of antibodies that target the viral surface envelope (E) protein. A subset of these antibodies can inhibit virus infection, thus making E as a suitable candidate for the development of vaccine against the virus. However, the anti-ZIKV E antibodies can cross-react with the E protein of the related dengue virus on account of the high level of similarity exhibited by the two viral proteins. Such a scenario may lead to severe dengue disease. Therefore, the design of a ZIKV vaccine requires particular care. Here, we tested two candidate vaccines containing a recombinant form of the ZIKV E protein that is forced in a covalently stable dimeric conformation (cvD). They were generated with an explicit aim to reduce the exposure of the cross-reactive epitopes. One vaccine is composed of a soluble form of the E protein (sE-cvD), the other is a more complex virus-like particle (VLP-cvD). We used the two candidate vaccines to immunize mice and later infected with ZIKV. The animals produced high level of inhibitory antibodies and were protected from the infection. The VLP-cvD was the most effective and we believe it represents a promising ZIKV vaccine candidate.

show abstract

Section: Discussionmentioning

confidence: 99%

Zika Virus-Like Particles Bearing a Covalent Dimer of Envelope Protein Protect Mice from Lethal Challenge

Lorenzo

Tandavanitj

Doig

et al. 2020

J Virol

View full text Add to dashboard Cite

show abstract

“…Alternatively, cross-linking of two E80 proteins through additional disulfate bonds in domain II and domain III could stabilize the anti-parallel structure of the soluble E80 dimer, limiting the exposure of fusion-loop, but enabling the presentation of cross-serocomplex broadly neutralizing EDE epitopes (Rouvinski et al, 2017; Figure 1B). Consistently, in a recent study, the covalently stabilized ZIKV E dimer has successfully elicited protective antibody responses against ZIKV infection in mice, without causing cross-reactivity to dengue viruses or ADE of DENV (Slon-Campos et al, 2019). Currently, both Zika EDIII and Dengue tetravalent EDIII vaccines are under development.…”

Section: Universal B Cell Vaccines For Denv and Zikvmentioning

confidence: 67%

“…Besides, other forms of ZIKV vaccine, such as protein based subunit vaccine (Medina et al, 2018;Metz et al, 2019;Slon-Campos et al, 2019) and live attenuated Zika vaccines (Richner et al, 2017b;Xie et al, 2018;Shan et al, 2019) are also under development at the pre-clinical stage. Considering the crossreactivity and ADE between ZIKV and DENV, newly developed ZIKV vaccine should also be tested for DENV enhancement activity.…”

Section: Zika Vaccines In Clinical Trialsmentioning

confidence: 99%

Defeat Dengue and Zika Viruses With a One-Two Punch of Vaccine and Vector Blockade

Jin

Zheng

et al. 2020

Front. Microbiol.

View full text Add to dashboard Cite

Dengue virus (DENV) and Zika virus (ZIKV) are two mosquito-borne flaviviruses afflicting nearly half of the world population. Human infection by these viruses can either be asymptomatic or manifest as clinical diseases from mild to severe. Despite more cases are presented as self-limiting febrile illness, severe dengue disease can be manifested as hemorrhagic fever and hemorrhagic shock syndrome, and ZIKV infection has been linked to increased incidence of peripheral neuropathy Guillain-Barre syndrome and central neural disease such as microcephaly. The current prevention and treatment of these infectious diseases are either non-satisfactory or entirely lacking. Because DENV and ZIKV have much similarities in genomic and structural features, almost identical mode of mosquito-mediated transmission, and probably the same pattern of host innate and adaptive immunity toward them, it is reasonable and often desirable to investigate these two viruses side-by-side, and thereby devise common countermeasures against both. Here, we review the existing knowledge on DENV and ZIKV regarding epidemiology, molecular virology, protective immunity and vaccine development, discuss recent new discoveries on the functions of flavivirus NS1 protein in viral pathogenesis and transmission, and propose a one-two punch strategy using vaccine and vector blockade to overcome antibody-dependent enhancement and defeat Dengue and Zika viruses.

show abstract

“…To model a rapid response to a previously known pathogen, we used a mAb discovery approach that assumed the envelope protein (ZIKV E protein) on the virion surface is a key protective antigen 5,6,21,22 . We used memory B cells from previously infected human subjects as the source for antibody discovery ( Supplementary Table 1 ).…”

Section: Resultsmentioning

confidence: 99%

Integrated technology platform for accelerated discovery of antiviral antibody therapeutics

Gilchuk

Bombardi

Erasmus

et al. 2020

Preprint

Self Cite

View full text Add to dashboard Cite

The emergence and reemergence of highly virulent viral pathogens with pandemic potential has created an urgent need for accelerated discovery of antiviral therapeutics. Antiviral human monoclonal (mAbs) are promising drug candidates to prevent or treat severe viral diseases, but the long timelines needed for discovery limits their rapid deployment and use. Here, we report the development of an integrated sequence of technologies incorporating advances in single-cell mRNA sequence analysis, bioinformatics, synthetic biology, and high-throughput functional analysis that allowed us to discover highly potent antiviral human mAbs and validate their activity in vivo at an unprecedented scale, speed, and efficiency. In a 78-day study, modeling deployment of a rapid response platform to an outbreak, we isolated >100 individual Zika virus (ZIKV) specific human mAbs, assessed their function, identified 29 broadly-neutralizing mAbs, and verified therapeutic potency of lead candidates with antibody-encoding mRNA formulation and/or IgG protein delivery in mice and nonhuman primates. Our work provides a roadmap for the rapid antibody discovery programs against viral pathogens of global concern.

show abstract

A protective Zika virus E-dimer-based subunit vaccine engineered to abrogate antibody-dependent enhancement of dengue infection

Cited by 74 publications

References 52 publications

Zika Virus-Like Particles Bearing a Covalent Dimer of Envelope Protein Protect Mice from Lethal Challenge

Zika Virus-Like Particles Bearing a Covalent Dimer of Envelope Protein Protect Mice from Lethal Challenge

Defeat Dengue and Zika Viruses With a One-Two Punch of Vaccine and Vector Blockade

Integrated technology platform for accelerated discovery of antiviral antibody therapeutics

Contact Info

Product

Resources

About