A head-to-head comparative study on the immunogenicity of three platforms of COVID-19 Delta-Omicron chimeric RBD-dimer vaccines

The novel coronavirus (SARS-CoV-2) caused a global pandemic, with significant distress to human health, society stability, and development. COVID-19 vaccination has played a pivotal role to control the pandemic, with multiple vaccine approaches approved globally, including inactivated recombinant protein subunits, virus-like particles, viral vectors, mRNA, and DNA vaccines. Notably, we collaborated with Anhui Zhifei longcom Biopharmaceutical Co., Ltd. to develop a COVID-19 vaccine (ZF2001) based on recombinant protein subunit platform, using a tandem-repeat dimeric form of receptor-binding domain (RBD) of the spike protein of SARS-CoV-2 as immunogen. Besides, the adenovirus vector vaccine, Ad5-nCoV (Convidecia, CanSino), developed jointly by the Chinese Academy of Military Medical Sciences and CanSino Biologics, employs a human adenovirus type 5 vector to express the full-length S protein of SARS-CoV-2. mRNA vaccines BNT162b2 (Comirnaty), developed by BioNTech and Pfizer, and mRNA-1273 (SpikeVax), developed by Moderna, have been widely administered over the world. In phase III clinical trials, these vaccines have shown an efficacy of over 94% in preventing symptomatic infections caused by a prototype strain of the SARS-CoV-2. COVID-19 mRNA vaccines were the first globally approved mRNA vaccines. Both BNT162b2 and mRNA-1273 use gene encoding the prefusion-stabilized S-2P protein and employ lipid nanoparticles as the delivery system. Owing to the distinct characteristics of the different vaccine paltforms, there are variations in the vaccine-induced immune responses. To compare the characteristics of the immune response elicited by various COVID-19 vaccine platforms, we designed a head-to-head comparative study. We modified the RBD dimer immunogen used in the ZF2001 vaccine, to design a chimeric RBD dimer antigen composed of tandem RBDs from two different viral strains; which could induce a broader spectrum of immune responses. Using the Delta-Omicron RBD dimer as an immunogen, we selected vaccines from three platforms including recombinant protein subunit, adenovirus vector, and mRNA vaccines for a homologous and heterologous prime-boost immunization regimen in a head-to-head comparative study. We found that two doses of mRNA vaccine induced the highest antibody titers of specific IgG and neutralizing antibodies in mice, followed by the protein vaccine and AdC68 vaccine. The heterologous prime-boost studies showed that boosting with the mRNA vaccine as the second dose induced a stronger humoral immunity response, compared with protein subunit and AdC68 vaccines. In addition, the mRNA vaccine induced a strong CD4(+) T cell responses, and the AdC68 vaccine induced a strong CD8(+) T cell responses. In contrast, the protein subunit vaccine elicited a relatively weak cellular immune response. This study provides guidance for the next-generation of COVID-19 vaccine development and optimization of inoculation strategy in the real world.