Protective neutralizing antibodies from human survivors of Crimean-Congo hemorrhagic fever

Fels, J. Maximilian; Maurer, Daniel P.; Herbert, Andrew S.; Wirchnianski, Ariel S.; Vergnolle, Olivia; Cross, Robert W.; Abelson, Dafna M.; Moyer, Crystal L.; Mishra, Akaash K.; Aguilan, Jennifer; Kuehne, Ana I.; Pauli, Noel T.; Bakken, Russell R.; Nyakatura, Elisabeth K.; Hellert, Jan; Quevedo, Gregory; Lobel, Leslie; Balinandi, Stephen; Lutwama, Julius J.; Zeitlin, Larry; Geisbert, Thomas W.; Rey, F.A.; Sidoli, Simone; McLellan, Jason S.; Lai, Jonathan R.; Bornholdt, Zachary A.; Dye, John M.; Walker, Laura M.; Chandran, Kartik

doi:10.1016/j.cell.2021.05.001

Cited by 48 publications

(101 citation statements)

References 88 publications

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“…2, A and F). Our structure is thus consistent with the yeast-display-based epitope mapping, which identified Trp1199 as critical for ADI-37801 binding (15).…”

supporting

confidence: 86%

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Structural basis of synergistic neutralization of Crimean-Congo hemorrhagic fever virus by human antibodies

Mishra

Hellert

Freitas

et al. 2022

Science

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A block to viral cell entry Crimean-Congo hemorrhagic fever virus is a tickborne virus that can cause severe disease and even death in humans. Disease occurrence is linked to the geographic range of the tick vector, and climate change may increase this range. Infection of host cells requires the fusion glycoprotein Gc, which is the main target of neutralizing antibodies. Mishra et al . build on previous work that identified a combination of two Gc-targeting antibodies that gave postexposure protection in an animal model. The authors determined the structure of the antigen-binding fragments of the two antibodies bound to a prefusion form of Gc and also the structure of Gc after the conformational change into the trimeric postfusion form. The structures show how the antibodies work together to block membrane fusion. —VV

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“…2, A and F). Our structure is thus consistent with the yeast-display-based epitope mapping, which identified Trp1199 as critical for ADI-37801 binding (15).…”

supporting

confidence: 86%

“…1B). As with most bunyaviruses, CCHFV Gc is predicted to be a class II membrane fusion protein ( 11 , 12 ) and is the only known target of CCHFV-neutralizing antibodies ( 15 ).…”

mentioning

confidence: 99%

Structural basis of synergistic neutralization of Crimean-Congo hemorrhagic fever virus by human antibodies

Mishra

Hellert

Freitas

et al. 2022

Science

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“…More remarkably, a study that screened broadly occurring virus-specific memory B cells taken from convalescent human survivors described complete neutralizing Abs in vitro that targeted the viral Gn/Gc complex in several CCHFV clades and virus isolates, and this broadly neutralizing bispecific Ab afforded full protection in immunocompromised mice, even when a single dose was administered. This study shows the importance of specific neutralizing Ab development in the serologic response after natural infection in humans [ 55 ]. Furthermore, a plasmid DNA vaccine encoding the CCHFV Gn, Gc, and N regions linked with ubiquitin in a state-of-the-art treatment to induce the cellular immune response produced a successful Th1-type immune response in all IFNAR KO survivors.…”

Section: Discussionmentioning

confidence: 94%

Development of a protective inactivated vaccine against Crimean–Congo hemorrhagic fever infection

Berber

Çanakoğlu

Tonbak

et al. 2021

Heliyon

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Crimean-Congo hemorrhagic fever (CCHF) is an emerging zoonotic infectious disease caused by Crimean-Congo hemorrhagic fever virus (CCHFV). The first clinical CCHF infection was described in 1944 in the Crimean Peninsula, exclusively in humans, with case-fatality rates exceeding 30%. The increasing number of cases, high mortality rate, and lack of effective therapy make CCHF a serious threat to public health and a potential bioterrorism agent. The present study evaluated the development, immunogenicity, and immune response durations for cell-culture-derived inactivated vaccine (CCVax) formulations in comparison with those of mouse-brainderived vaccine (MBVax) formulations. In this study, the Kelkit06 CCHF virus strain was propagated in both suckling mice and Vero E6 cells, and purified with a sucrose gradient. Formalin-inactivated vaccine candidates were formulated at various doses [low dose (LD), 5 μg; medium dose (MD), 10 μg; high dose (HD), 20 μg)] and mixed with an alum adjuvant. BALB/c mice received the same doses of the vaccine formulations three times at 3week intervals. The humoral endpoint IgG responses were evaluated and compared for the MBVax and CCVax treatments. The duration of the presence of IgG and neutralizing antibody (Ab) titers was evaluated and compared until up to 1 year after immunization. The humoral IgG responses indicated that the CCVax and MBVax candidates enhanced the IgG endpoint titers in a dose-dependent manner, which were induced more strongly in all the CCVax groups than in the MBVax mice. The fold changes in neutralizing Ab levels were also found to be higher in the CCVax groups: between 2-and 7.6-fold after the second week of the last immunization. The neutralization titers peaked 4 months after immunization in all the vaccine-receiving groups, but these were still comparable at the end of the first year. The CCVax formulations induced higher IgG and neutralizing Ab titers at all the measured time points. In this study, we showed that cell-culture-purified and formalin-inactivated vaccine candidates induced strong and robust immunity in vaccinated mice dose-dependently, more so than mouse-brain-derived vaccines.

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“…Recent research has identified six antigenic sites on CCHFV Gc that protective neutralizing antibodies target: site 1 (Trp 1185, Trp 1199), site 2 (Ser 1309, Val 1314, Asp 1352, Gly 1353), site 3 (Leu 1307, Ile 1229), site 4 (Lys 1297, Asn 1386, Lys 1393), site 5 (Val 1124, Ser 1128, Val 1093) and site 6 (Glu 1500, Asp 1504, Leu 1450, Ile 1522, Leu 1518, Phe 1520) ( Fels et al., 2021 ). We mapped these residues onto the CCHFV Gc trimer and protomer structures ( Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Many Gc-specific antibodies have neutralizing activity but only a subset of these antibodies shows protection of neonatal mice in passive-immunization experiments. In a recent report, a recombinant polyprotein bait (rGn/Gc) was used to isolate protective neutralizing antibodies from CCHF-convalescent donors ( Fels et al., 2021 ). The resulting mAbs mainly targeted some conserved epitopes in Gc, and structural characterization of Gc was required for mapping these antigenic sites ( Fels et al., 2021 ).…”

Section: Introductionmentioning

confidence: 99%

Cryo-EM structure of glycoprotein C from Crimean-Congo hemorrhagic fever virus

Li¹,

Rao²,

Li³

et al. 2022

Virologica Sinica

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Protective neutralizing antibodies from human survivors of Crimean-Congo hemorrhagic fever

Cited by 48 publications

References 88 publications

Structural basis of synergistic neutralization of Crimean-Congo hemorrhagic fever virus by human antibodies

Structural basis of synergistic neutralization of Crimean-Congo hemorrhagic fever virus by human antibodies

Development of a protective inactivated vaccine against Crimean–Congo hemorrhagic fever infection

Cryo-EM structure of glycoprotein C from Crimean-Congo hemorrhagic fever virus

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