ABSTRACT
The SARS-CoV-2 Delta (B.1.617.2) strain is a variant of concern (VOC) that has become the dominant strain worldwide in 2021. Its transmission capacity is approximately twice that of the original strain, with a shorter incubation period and higher viral load during infection. Importantly, the breakthrough infections of the Delta variant have continued to emerge in the first-generation vaccine recipients. There is thus an urgent need to develop a novel vaccine with SARS-CoV-2 variants as the major target. Here, receptor binding domain (RBD)-conjugated nanoparticle vaccines targeting the Delta variant, as well as the early and Beta/Gamma strains, are developed. Under both a single-dose and a prime-boost strategy, these RBD-conjugated nanoparticle vaccines induce the abundant neutralizing antibodies (NAbs) and significantly protect hACE2 mice from infection by the authentic SARS-CoV-2 Delta strain, as well as the early and Beta strains. Furthermore, the elicitation of the robust production of broader cross-protective NAbs against almost all the notable SARS-CoV-2 variants including the Omicron variant in rhesus macaques by the third re-boost with trivalent vaccines is found. These results suggest that RBD-based monovalent or multivalent nanoparticle vaccines provide a promising second-generation vaccine strategy for SARS-CoV-2 variants.
Subject(s)
COVID-19 , Nanoparticles , Animals , Broadly Neutralizing Antibodies , COVID-19/prevention & control , Macaca mulatta/metabolism , Mice , SARS-CoV-2 , Spike Glycoprotein, Coronavirus , Vaccines, ConjugateABSTRACT
Various vaccine strategies have been proposed in response to the global COVID-19 pandemic, each with unique strategies for eliciting immune responses. Here, we developed nanoparticle vaccines by covalently conjugating the self-assembled 24-mer ferritin to the receptor binding domain (RBD) and/or heptad repeat (HR) subunits of the Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) spike (S) protein. Compared to monomer vaccines, nanoparticle vaccines elicited more robust neutralizing antibodies and cellular immune responses. RBD and RBD-HR nanoparticle vaccinated hACE2 transgenic mice vaccinated with RBD and/or RBD-HR nanoparticles exhibited reduced viral load in the lungs after SARS-CoV-2 challenge. RBD-HR nanoparticle vaccines also promoted neutralizing antibodies and cellular immune responses against other coronaviruses. The nanoparticle vaccination of rhesus macaques induced neutralizing antibodies, and T and B cell responses prior to boost immunization; these responses persisted for more than three months. RBD- and HR-based nanoparticles thus present a promising vaccination approach against SARS-CoV-2 and other coronaviruses.