Recombinant SARS-CoV-2 spike S1-Fc fusion protein induced high levels of neutralizing responses in nonhuman primates

Ren, Wenlin; Sun, Hunter; Gao, George F.; Chen, Jianxin; Sun, Sean X.; Zhao, Renxin; Gao, G.F.; Hu, Yalin; Zhao, Gan; Chen, Yuxin; Jin, Xia; Fang, Feng; Chen, Jinggong; Wang, Qi; Gong, Sitao; Gao, Wen Yi; Sun, Yufei; Su, Junchi; He, Ailiang; Cheng, Xin; Li, Min; Xia, Chenxi; Li, Maohua; Sun, Le

doi:10.1016/j.vaccine.2020.06.066

Cited by 61 publications

(50 citation statements)

References 14 publications

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“…No antibody-dependent enhancement of infection, immunopathologies, or Th2 bias has been observed with the SARS-CoV-2 RBD subunit derivatives examined so far ( 42 , 43 , 44 , 45 ). Three independent studies used RBD-Fc fusions with one study using RBD residues 331 to 527, another used RBD-Fc from Sino Biologicals (residues not mentioned), and a third used a full-length S1-Fc fusion (residues 14–685) reporting viral neutralizing antibody titers of ∼100 to 400, 1280, and NT 50 derived from pseudoviral neutralizations of 378 respectively ( 43 , 44 , 46 ). One study employed a week-long intraperitoneal immunization regime that is difficult to implement in large-scale human vaccination programs ( 46 ).…”

Section: Discussionmentioning

confidence: 88%

Design of a highly thermotolerant, immunogenic SARS-CoV-2 spike fragment

Malladi

Singh

Pandey

et al. 2021

Journal of Biological Chemistry

125

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Virtually all SARS-CoV-2 vaccines currently in clinical testing are stored in a refrigerated or frozen state prior to use. This is a major impediment to deployment in resource-poor settings. Furthermore, several of them use viral vectors or mRNA. In contrast to protein subunit vaccines, there is limited manufacturing expertise for these nucleic acid-based modalities, especially in the developing world. Neutralizing antibodies, the clearest known correlate of protection against SARS-CoV-2, are primarily directed against the Receptor Binding Domain (RBD) of the viral spike protein, suggesting that a suitable RBD construct might serve as a more accessible vaccine ingredient. We describe a monomeric, glycan engineered RBD protein fragment that is expressed at a purified yield of 214 mg/L in unoptimized, mammalian cell culture and, in contrast to a stabilized spike ectodomain, is tolerant of exposure to temperatures as high as 100 °C when lyophilized, up to 70 °C in solution and stable for over four weeks at 37 °C. In prime:boost guinea pig immunizations, when formulated with the MF59-like adjuvant AddaVax™, the RBD derivative elicited neutralizing antibodies with an endpoint geometric mean titer of ~415 against replicative virus, comparing favourably with several vaccine formulations currently in the clinic. These features of high yield, extreme thermotolerance and satisfactory immunogenicity suggest that such RBD subunit vaccine formulations hold great promise to combat COVID-19.

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Section: Discussionmentioning

confidence: 88%

Design of a highly thermotolerant, immunogenic SARS-CoV-2 spike fragment

Malladi

Singh

Pandey

et al. 2021

Journal of Biological Chemistry

125

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“…A prior study by Ren et al, which used whole spike S1-Fc as an immunogen in macaques and a complex immunization schedule with ve doses and multiple adjuvants, reported the successful generation of neutralizing antibody titers (44). We sought to test an immunization schedule with fewer administrations.…”

Section: Discussionmentioning

confidence: 99%

A Recombinant Protein SARS-CoV-2 Candidate Vaccine Elicits High-titer Neutralizing Antibodies in Macaques.

Baisa

Rancour²,

Mansfield

et al. 2021

Preprint

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BackgroundVaccines that generate robust and long-lived protective immunity against SARS-CoV-2 infection are urgently required. MethodsWe assessed the potential of vaccine candidates based on the SARS-CoV-2 spike in cynomolgus macaques (M. fascicularis) by examining their ability to generate spike binding antibodies with neutralizing activity. Antigens were derived from two distinct regions of the spike S1 subunit, either the N-terminal domain or an extended C-terminal domain containing the receptor-binding domain and were fused to the human IgG1 Fc domain. Three groups of 2 animals each were immunized with either antigen, alone or in combination. The development of antibody responses was evaluated through 20 weeks post-immunization. ResultsA robust IgG response to the spike protein was detected as early as 2 weeks after immunization with either protein and maintained for over 20 weeks. Sera from animals immunized with antigens derived from the RBD were able to prevent binding of soluble spike proteins to the ACE2 receptor, shown by in vitro binding assays, while sera from animals immunized with the N-terminal domain alone lacked this activity. Crucially, sera from animals immunized with the extended receptor binding domain but not the N-terminal domain had potent neutralizing activity against SARS-CoV-2 pseudotyped virus, with titers in excess of 10,000, greatly exceeding that typically found in convalescent humans. Neutralizing activity persisted for more than 20 weeks. ConclusionsThese data support the utility of spike subunit-based antigens as a vaccine for use in humans.

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“…Immunization will be the best preventive strategy to address the current COVID-19 pandemic, although therapeutic alternatives cannot be neglected as a vaccine that would trigger long-term protection is not a certainty ( Amanat and Krammer, 2020 ; Moore and Klasse, 2020 ; Morris, 2020 ). Yet results from preclinical and clinical studies are encouraging and has started to lead to commercialization approval ( Erasmus et al, 2020 ; Folegatti et al, 2020 ; Gao et al, 2020 ; Guebre-Xabier et al, 2020 ; Jackson et al, 2020 ; Keech et al, 2020 ; Logunov et al, 2020 ; Mercado et al, 2020 ; Moore and Klasse, 2020 ; Mulligan et al, 2020 ; Polack et al, 2020 ; Ravichandran et al, 2020 ; Ren et al, 2020 ; Smith et al, 2020 ; Walls et al, 2020 ; Wang et al, 2020 ; Xia et al, 2021 ; Yu et al, 2020 ; Zhu et al, 2020a ). How efficient and how long Nabs will be present in vaccinated people remains an open question that will only be answered with time ( Moore and Klasse, 2020 ).…”

Section: Discussionmentioning

confidence: 99%