Maltseva Mariam, Galipeau Yannick, Renner Tyler M, Deschatelets Lise, Durocher Yves, Akache Bassel, Langlois Marc-André
Department of Biochemistry, Microbiology & Immunology, Faculty of Medicine, University of Ottawa, Ottawa, ON K1H 8M5, Canada.
National Research Council Canada, Human Health Therapeutics, Ottawa, ON K1A 0R6, Canada.
Vaccines (Basel). 2022 Dec 23;11(1):30. doi: 10.3390/vaccines11010030.
Continuous viral evolution of SARS-CoV-2 has resulted in variants capable of immune evasion, vaccine breakthrough infections and increased transmissibility. New vaccines that invoke mucosal immunity may provide a solution to reducing virus transmission. Here, we evaluated the immunogenicity of intranasally administered subunit protein vaccines composed of a stabilized SARS-CoV-2 spike trimer or the receptor binding domain (RBD) adjuvanted with either cholera toxin (CT) or an archaeal lipid mucosal adjuvant (AMVAD). We show robust induction of immunoglobulin (Ig) G and IgA responses in plasma, nasal wash and bronchoalveolar lavage in mice only when adjuvant is used in the vaccine formulation. While the AMVAD adjuvant was more effective at inducing systemic antibodies against the RBD antigen than CT, CT was generally more effective at inducing overall higher IgA and IgG titers against the spike antigen in both systemic and mucosal compartments. Furthermore, vaccination with adjuvanted spike led to superior mucosal IgA responses than with the RBD antigen and produced broadly targeting neutralizing plasma antibodies against ancestral, Delta and Omicron variants in vitro; whereas adjuvanted RBD elicited a narrower antibody response with neutralizing activity only against ancestral and Delta variants. Our study demonstrates that intranasal administration of an adjuvanted protein subunit vaccine in immunologically naïve mice induced both systemic and mucosal neutralizing antibody responses that were most effective at neutralizing SARS-CoV-2 variants when the trimeric spike was used as an antigen compared to RBD.
严重急性呼吸综合征冠状病毒2（SARS-CoV-2）的持续病毒进化已产生了能够逃避免疫、突破疫苗感染并增加传播性的变种。引发黏膜免疫的新型疫苗可能为减少病毒传播提供解决方案。在此，我们评估了鼻内给药的亚单位蛋白疫苗的免疫原性，这些疫苗由稳定的SARS-CoV-2刺突三聚体或受体结合域（RBD）组成，并佐以霍乱毒素（CT）或古细菌脂质黏膜佐剂（AMVAD）。我们发现，只有在疫苗配方中使用佐剂时，才能在小鼠的血浆、鼻腔冲洗液和支气管肺泡灌洗液中强烈诱导免疫球蛋白（Ig）G和IgA反应。虽然AMVAD佐剂在诱导针对RBD抗原的全身性抗体方面比CT更有效，但CT通常在诱导全身和黏膜区室中针对刺突抗原的总体更高IgA和IgG滴度方面更有效。此外，接种佐剂化刺突疫苗比接种RBD抗原能产生更优越的黏膜IgA反应，并在体外产生针对原始毒株、德尔塔变种和奥密克戎变种的广泛靶向中和血浆抗体；而佐剂化RBD引发的抗体反应较窄，仅对原始毒株和德尔塔变种具有中和活性。我们的研究表明，在免疫初免小鼠中鼻内给药佐剂化蛋白亚单位疫苗可诱导全身和黏膜中和抗体反应，与RBD相比，当使用三聚体刺突作为抗原时，该反应在中和SARS-CoV-2变种方面最为有效。
