Pan-protective anti-alphavirus human antibodies target a conserved E1 protein epitope

Kim, Arthur S.; Kafai, Natasha M.; Winkler, Emma S.; Gilliland, Theron; Cottle, Emily L.; Earnest, James T.; Jethva, Prashant N.; Kapłonek, Paulina; Shah, Aadit P.; Fong, Rachel H.; Davidson, Edgar; Malonis, Ryan J.; Quiroz, Jose A.; Williamson, Lauren E.; Vang, Lo; Mack, Matthias; Crowe, James E.; Doranz, Benjamin J.; Lai, Jonathan R.; Alter, Galit; Gross, Michael L.; Klimstra, William B.; Fremont, Daved H.; Diamond, Michael S.

doi:10.1016/j.cell.2021.07.006

Cited by 55 publications

(44 citation statements)

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“…Other arthritogenic alphaviruses including MAYV, ONNV, and UNAV cause substantial acute and chronic human disease and contain cross-reactive neutralizing epitopes [57]. In our studies, HydroVax-CHIKV vaccination elicited substantial cross-neutralization against other alphaviruses (Fig 3D), albeit at lower titers compared to CHIKV itself, which is not unexpected since these are genetically distinct alphaviruses.…”

Section: Plos Pathogenssupporting

confidence: 65%

Development of a next-generation chikungunya virus vaccine based on the HydroVax platform

et al. 2022

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Chikungunya virus (CHIKV) is an emerging/re-emerging mosquito-borne pathogen responsible for explosive epidemics of febrile illness characterized by debilitating polyarthralgia and the risk of lethal infection among the most severe cases. Despite the public health risk posed by CHIKV, no vaccine is currently available. Using a site-directed hydrogen peroxide-based inactivation approach, we developed a new CHIKV vaccine, HydroVax-CHIKV. This vaccine technology was compared to other common virus inactivation approaches including β-propiolactone (BPL), formaldehyde, heat, and ultraviolet (UV) irradiation. Heat, UV, and BPL were efficient at inactivating CHIKV-181/25 but caused substantial damage to neutralizing epitopes and failed to induce high-titer neutralizing antibodies in vaccinated mice. HydroVax-CHIKV and formaldehyde-inactivated CHIKV retained intact neutralizing epitopes similar to live virus controls but the HydroVax-CHIKV approach demonstrated a more rapid rate of virus inactivation. HydroVax-CHIKV vaccination induced high neutralizing responses to homologous and heterologous CHIKV clades as well as to other alphaviruses including Mayaro virus, O’nyong’nyong virus, and Una virus. Following heterologous infection with CHIKV-SL15649, HydroVax-CHIKV-immunized mice were protected against viremia, CHIKV-associated arthritic disease, and lethal CHIKV infection by an antibody-dependent mechanism. In contrast, animals vaccinated with Heat- or UV-inactivated virus showed no protection against viremia in addition to demonstrating significantly exacerbated CD4+ T cell-mediated footpad swelling after CHIKV infection. Together, these results demonstrate the risks associated with using suboptimal inactivation methods that fail to elicit protective neutralizing antibody responses and show that HydroVax-CHIKV represents a promising new vaccine candidate for prevention of CHIKV-associated disease.

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Section: Plos Pathogenssupporting

confidence: 65%

Development of a next-generation chikungunya virus vaccine based on the HydroVax platform

et al. 2022

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“…Potent neutralizing MAbs specific to the E2 glycoprotein of VEEV, EEEV and WEEV have been shown to protect in mouse models ( Burke et al, 2018 ; Hunt et al, 2011 ; Kim et al, 2019 ). Non-neutralizing antibodies may also confer protection after lethal alphavirus challenge, and this protection may be inhibiting viral egress from the infected cell and facilitating monocyte-dependent antibody effector functions ( Boere et al, 1983 ; Kim et al, 2021 ; Parker et al, 2010 ; Rulker et al, 2012 ; Schmaljohn et al, 1982 ; Williamson et al, 2021 ).…”

Section: Discussionmentioning

confidence: 99%

“…Four MAbs (1A4B-6, 2A2C-3, 3A5B-1 and 3A1C-12) that recognize similar epitopes on the fusion loop of alphaviruses were found to have moderate quantities of antibody-binding sites on the surface of VEEV infected cells. Protection by cross-reactive, non-neutralizing antibodies in alphaviral infections has been attributed to Fc effector functions such as Ab-dependent cell-mediated cytotoxicity (ADCC) and Ab dependent cell phagocytosis ( Burke et al, 2018 ; Kim et al, 2019 , 2021 ; Pal et al, 2013 ; Wust et al, 1987 ). Based on the quantitative flow cytometry data showing that the epitope recognized by 1A4B-6 is readily available on the surface of paraformaldehyde-fixed infected cells and our data showing in vivo protection from VEEV infection with 1A4B-6, we hypothesize that protection may be afforded by ADCC and warrants further investigation.…”

Section: Discussionmentioning

confidence: 99%

“… Fox et al (2015) also showed that broadly cross-reactive MAbs recognizing an epitope on the B domain of the alphavirus E2 protein elicited broad alphavirus protection in vivo . Even though the E1 protein elicits mostly non-neutralizing cross-reactive MAbs, these MAbs may still confer protection in vivo ( Boere et al, 1983 ; Burke et al, 2018 ; Kim et al, 2021 ; Rico et al, 2016 ; Schmaljohn et al, 1982 ; Williamson et al, 2021 ). This protection has been associated with MAb interactions with “cryptic” E1 epitopes not accessible on the mature virion surface.…”

Section: Introductionmentioning

confidence: 99%

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Exposing cryptic epitopes on the Venezuelan equine encephalitis virus E1 glycoprotein prior to treatment with alphavirus cross-reactive monoclonal antibody allows blockage of replication early in infection

et al. 2022

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Eastern equine encephalitis virus (EEEV), western equine encephalitis virus (WEEV) and Venezuelan equine encephalitis virus (VEEV) can cause fatal encephalitis in humans and equids. Some MAbs to the E1 glycoprotein are known to be cross-reactive, weakly neutralizing in vitro but can protect from disease in animal models. We investigated the mechanism of neutralization of VEEV infection by the broadly cross-reactive E1-specific MAb 1A4B-6. 1A4B-6 protected 3-week-old Swiss Webster mice prophylactically from lethal VEEV challenge. Likewise, 1A4B-6 inhibited virus growth in vitro at a pre-attachment step after virions were incubated at 37 °C and inhibited virus-mediated cell fusion. Amino acid residue N100 in the fusion loop of E1 protein was identified as critical for binding. The potential to elicit broadly cross-reactive MAbs with limited virus neutralizing activity in vitro but that can inhibit virus entry and protect animals from infection merits further exploration for vaccine and therapeutic developmental research.

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“…Further, mAbs to the highly conserved fusion loop of E1 (which lies below the B-region of the E2 protein in the intact virus) have crossneutralizing activity [39], confirming that diverse AV have a similar mechanisms of cell entry. Humans infected with EEEV can produce antibodies that also limit infection with VEEV or CHIKV [39], while those infected with CHIKV can produce antibodies that protect against multiple alphaviruses [40]. Most of the neutralizing mAbs against CHIKV and EEEV that have been structurally characterized bind to surface-exposed regions of the A and B domain of the E2 protein [41][42][43][44].…”

Section: Introductionmentioning

confidence: 99%

Peptide and protein alphavirus antigens for broad spectrum vaccine design

Schein

Schmidt

Braun

et al. 2022

Preprint

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Vaccines based on proteins and peptides may be safer and more broad-spectrum than other approaches Physicochemical property consensus (PCPcon) alphavirus antigens from the B-domain of the E2 envelope protein were designed and synthesized recombinantly. Those based on individual species (eastern or Venezuelan equine encephalitis (EEEVcon, VEEVcon), or chikungunya (CHIKVcon) viruses generated species-specific antibodies. Peptides designed to surface exposed areas of the E2-A-domain were added to the inocula to provide neutralizing antibodies against CHIKV. EVCcon, based on the three different alphavirus species, combined with E2-A-domain peptides from AllAV, a PCPcon of 24 diverse alphavirus, generated broad spectrum antibodies. The antibodies in the sera bound and neutralized diverse alphaviruses with less than 35% amino acid identity to each other. These included VEEV and its relative Mucambo virus, EEEV and the related Madariaga virus, and CHIKV strain 181/25. Further understanding of the role of coordinated mutations in the envelope proteins may yield a single, protein and peptide vaccine against all alphaviruses.

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Pan-protective anti-alphavirus human antibodies target a conserved E1 protein epitope

Cited by 55 publications

References 84 publications

Development of a next-generation chikungunya virus vaccine based on the HydroVax platform

Development of a next-generation chikungunya virus vaccine based on the HydroVax platform

Exposing cryptic epitopes on the Venezuelan equine encephalitis virus E1 glycoprotein prior to treatment with alphavirus cross-reactive monoclonal antibody allows blockage of replication early in infection

Peptide and protein alphavirus antigens for broad spectrum vaccine design

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