Fc-mediated pan-sarbecovirus protection after alphavirus vector vaccination

Adams, Lily E.; Leist, Sarah R.; Dinnon, Kenneth H.; West, Ande; Gully, Kendra L.; Anderson, Elizabeth J.; Loome, Jennifer F.; Madden, Emily A.; Powers, John M.; Schäfer, Alexandra; Sarkar, Sanjay; Castillo, Izabella N.; Maron, Jenny S; McNamara, Ryan P.; Bertera, Harry L.; R., Zweigert, Mark; Higgins, Jaclyn S.; Hampton, Brea K.; Premkumar, Lakshmanane; Alter, Galit; Montgomery, Stephanie A.; Baxter, Victoria K.; Heise, Mark T.; Baric, Ralph S.

doi:10.1016/j.celrep.2023.112326

Cited by 29 publications

(19 citation statements)

References 102 publications

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“…We note that SARS-CoV-2 S 2 subunit vaccination protected mice that did and those that did not have detectable serum neutralizing activity against SARS-CoV-2 XBB.1.5, as observed for stabilized MERS-CoV stems upon MERS-CoV challenge 45 . Although the immunological mechanisms underlying the observed protection remain to be defined, we postulate that weakly or non-neutralizing antibodies participated in protection through Fc-mediated effector functions, as described for the S2P6 stem-helix antibody 18 and for S-elicited fusion machinery-directed polyclonal antibodies upon mismatched sarbecovirus challenge 46 . Exposure to SARS-CoV-2 S has also been shown to induce robust cross-reactive T cell responses which participate in protection upon exposure 47–49 and could have played a role here as well.…”

Section: Discussionmentioning

confidence: 93%

A broadly generalizable stabilization strategy for sarbecovirus fusion machinery vaccines

Lee,

Stewart,

Schaefer

et al. 2023

Preprint

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Continuous evolution of SARS-CoV-2 alters the antigenicity of the immunodominant spike (S) receptor-binding domain and N-terminal domain, undermining the efficacy of vaccines and monoclonal antibody therapies. To overcome this challenge, we set out to develop a vaccine focusing antibody responses on the highly conserved but metastable S2subunit, which folds as a spring-loaded fusion machinery. Here, we describe a protein design strategy enabling prefusion-stabilization of the SARS-CoV-2 S2subunit and high yield recombinant expression of trimers with native structure and antigenicity. We demonstrate that our design strategy is broadly generalizable to all sarbecoviruses, as exemplified with the SARS-CoV-1 (clade 1a) and PRD-0038 (clade 3) S2fusion machineries. Immunization of mice with a prefusion-stabilized SARS-CoV-2 S2trimer vaccine elicits broadly reactive sarbecovirus antibody responses and neutralizing antibody titers of comparable magnitude against Wuhan-Hu-1 and the immune evasive XBB.1.5 variant. Vaccinated mice were protected from weight loss and disease upon challenge with SARS-CoV-2 XBB.1.5, providing proof-of-principle for fusion machinery sarbecovirus vaccines motivating future development.

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Section: Discussionmentioning

confidence: 93%

A broadly generalizable stabilization strategy for sarbecovirus fusion machinery vaccines

Lee,

Stewart,

Schaefer

et al. 2023

Preprint

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“…Recent studies in mice with SARS-CoV-2 or pan-sarbecovirus vaccines have suggested that passively administered immune sera can protect against antigenically shifted coronaviruses, even when neutralizing activity is low, through Fc effector function activity ( 15 , 21 , 22 ). Given these results, and the positive ELISA reactivity against XBB.1.5 of more recent IG products, we assessed their protective efficacy in a mouse model of SARS-CoV-2 infection.…”

Section: Resultsmentioning

confidence: 99%

Immunoglobulin replacement products confer in vivo protection against SARS-CoV-2 XBB.1.5 Omicron variant despite poor neutralizing activity

Zimmerman,

Altman Doss,

Ying

et al. 2024

JCI Insight

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Immunoglobulin (IG) replacement products are used routinely in patients with immune deficiency and other immune dysregulation disorders who have poor responses to vaccination and require passive immunity conferred by commercial antibody products. The binding, neutralizing, and protective activity of intravenously administered IG against SARS-CoV-2 emerging variants remains unknown. Here, we tested 198 different IG products manufactured from December 2019 to August 2022. We show that prepandemic IG had no appreciable cross-reactivity or neutralizing activity against SARS-CoV-2. Anti-spike antibody titers and neutralizing activity against SARS-CoV-2 WA1/2020 D614G increased gradually after the pandemic started and reached levels comparable to vaccinated healthy donors 18 months after the diagnosis of the first COVID-19 case in the United States in January 2020. The average time between production to infusion of IG products was 8 months, which resulted in poor neutralization of the variant strain circulating at the time of infusion. Despite limited neutralizing activity, IG prophylaxis with clinically relevant dosing protected susceptible K18-hACE2–transgenic mice against clinical disease, lung infection, and lung inflammation caused by the XBB.1.5 Omicron variant. Moreover, following IG prophylaxis, levels of XBB.1.5 infection in the lung were higher in FcγR-KO mice than in WT mice. Thus, IG replacement products with poor neutralizing activity against evolving SARS-CoV-2 variants likely confer protection to patients with immune deficiency disorders through Fc effector function mechanisms.

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“…This did not translate to a loss of clinical protection 9-11 , indicating that correlates beyond neutralization existed. Previous reports have shown that FcγR-binding antibodies and their corresponding effector functions were required for protection against antigenically diverged Spikes 13,25 .…”

Section: Discussionmentioning

confidence: 98%

Compartment-Specific Antibody Correlates of Protection to SARS-CoV-2 Omicron in Macaques

Tong,

Wang,

Jung

et al. 2024

Preprint

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Antibodies represent a primary mediator of protection against respiratory viruses such as SARS-CoV-2. Serum neutralizing antibodies (NAbs) are often considered a primary correlate of protection. However, detailed antibody profiles including characterization of antibody functions in different anatomic compartments are not well understood. Here we show that antibody correlates of protection against SARS-CoV-2 challenge are different in systemic versus mucosal compartments in rhesus macaques. In serum, neutralizing antibodies were the strongest correlate of protection and were linked to Spike-specific binding antibodies and other extra-neutralizing antibody functions that create a larger protective network. In contrast, in bronchiolar lavage (BAL), antibody-dependent cellular phagocytosis (ADCP) proved the strongest correlate of protection rather than NAbs. Within BAL, ADCP was linked to mucosal Spike-specific IgG, IgA/secretory IgA, and Fcγ-receptor binding antibodies. Our results support a model in which antibodies with different functions mediate protection at different anatomic sites. The correlation of ADCP and other Fc functional antibody responses with protection in BAL suggests that these antibody responses may be critical for protection against SARS-CoV-2 Omicron challenge in mucosa.

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Fc-mediated pan-sarbecovirus protection after alphavirus vector vaccination

Cited by 29 publications

References 102 publications

A broadly generalizable stabilization strategy for sarbecovirus fusion machinery vaccines

A broadly generalizable stabilization strategy for sarbecovirus fusion machinery vaccines

Immunoglobulin replacement products confer in vivo protection against SARS-CoV-2 XBB.1.5 Omicron variant despite poor neutralizing activity

Compartment-Specific Antibody Correlates of Protection to SARS-CoV-2 Omicron in Macaques

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