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Background <p>Protein subunit vaccines have a strong track record of efficacy and safety and have been widely applied for prevention of a variety of infectious diseases. The impacts of post-translational modifications of vaccine antigens are often overlooked, despite the fact that they can vary significantly depending on the expression hosts (e.g., bacteria, yeast, plant, insect or mammalian cells) and the culture conditions used for their manufacturing.</p> Methods <p>Using SARS-CoV-2 spike trimers as model antigens, we sought to evaluate the immunological impact of modulating their state of glycosylation. Spike proteins rich in complex-type (CT), high-mannose (HM) or paucimannose (PM) N-linked glycans were produced using Chinese Hamster Ovary (CHO) cells (cultured with or without the mannosidase inhibitor kifunensine) or insect cells.</p> Results <p>Here we show that when these antigens are adjuvanted with liposomes composed of sulfated lactosyl archaeol (SLA), all glycoforms are highly immunogenic and induce abundant spike-specific serum IgG and IFN-γ producing T-cells within female C57BL/6 mice. The spike antigen with CT glycans induces a significantly more potent neutralizing immune response, which directly correlates to more abundant receptor binding domain (RBD)-specific IgG when comparing to the antigen with HM glycans. This observation remains true whether the spike is resistin- or T4 foldon-trimerized, indicating that the glycosylation effect is not trimerization domain-specific. Spike with PM glycans induces remarkably low titers of neutralizing antibodies and RBD-specific IgG.</p> Conclusions <p>The results highlight the significant impacts of a vaccine’s antigen glycosylation profile in directing the immune response, which should be an important consideration for designing efficient protein-based vaccines.</p>

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Modifying the glycosylation profile of SARS-CoV-2 spike-based subunit vaccines alters focusing of the humoral immune response in a mouse model

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年4月11日

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  • Tyler M. Renner,
  • Matthew Stuible,
  • Martin A. Rossotti,
  • Nazanin Rohani,
  • Yuneivy Cepero-Donates,
  • Janelle Sauvageau,
  • Lise Deschatelets,
  • Renu Dudani,
  • Blair A. Harrison,
  • Jason Baardsnes,
  • Izel Koyuturk,
  • Frank St. Michael,
  • Jennifer J. Hill,
  • Usha D. Hemraz,
  • Anne E. G. Lenferink,
  • Jamshid Tanha,
  • Barbara Fernandes,
  • Antonio Roldao,
  • Michael J. McCluskie,
  • Bassel Akache,
  • Yves Durocher

摘要

Background

Protein subunit vaccines have a strong track record of efficacy and safety and have been widely applied for prevention of a variety of infectious diseases. The impacts of post-translational modifications of vaccine antigens are often overlooked, despite the fact that they can vary significantly depending on the expression hosts (e.g., bacteria, yeast, plant, insect or mammalian cells) and the culture conditions used for their manufacturing.

Methods

Using SARS-CoV-2 spike trimers as model antigens, we sought to evaluate the immunological impact of modulating their state of glycosylation. Spike proteins rich in complex-type (CT), high-mannose (HM) or paucimannose (PM) N-linked glycans were produced using Chinese Hamster Ovary (CHO) cells (cultured with or without the mannosidase inhibitor kifunensine) or insect cells.

Results

Here we show that when these antigens are adjuvanted with liposomes composed of sulfated lactosyl archaeol (SLA), all glycoforms are highly immunogenic and induce abundant spike-specific serum IgG and IFN-γ producing T-cells within female C57BL/6 mice. The spike antigen with CT glycans induces a significantly more potent neutralizing immune response, which directly correlates to more abundant receptor binding domain (RBD)-specific IgG when comparing to the antigen with HM glycans. This observation remains true whether the spike is resistin- or T4 foldon-trimerized, indicating that the glycosylation effect is not trimerization domain-specific. Spike with PM glycans induces remarkably low titers of neutralizing antibodies and RBD-specific IgG.

Conclusions

The results highlight the significant impacts of a vaccine’s antigen glycosylation profile in directing the immune response, which should be an important consideration for designing efficient protein-based vaccines.