Broad-spectrum Delta-BA.2 tandem-fused heterodimer mRNA vaccine delivered by lipopolyplex

Since the beginning of the coronavirus disease 2019 (COVID-19) pandemic, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of COVID-19, continues to mutate and generates new variants with increasingly severe immune escape, urging the upgrade of COVID-19 vaccines. Here, based on a similar dimeric RBD design as our previous ZF2001 vaccine, we developed a novel broad-spectrum COVID-19 mRNA vaccine, SWIM516, with chimeric Delta-BA.2 RBD dimer delivered by lipopolyplex (LPP). Unlike the popular lipid nanoparticle (LNP), this LPP-delivered mRNA expresses only in the injection site, which avoids potential toxicity to the liver. We demonstrated the broad-spectrum humoral and cellular immunogenicity of this vaccine to Delta and Omicron sub-variants in naive mice and as booster shots. When challenged with Delta or Omicron live virus, vaccinated hACE2 transgenic mice and rhesus macaques were both protected, displaying significantly reduced viral loads and markedly relieved pathological damages. We believe the SWIM516 vaccine qualifies as a candidate for the next-generation broad-spectrum COVID-19 vaccine. mRNA vaccines have demonstrated their advantages in immunogenicity and development speed during the coronavirus disease 2019 (COVID-19) pandemic. However, the significant immune escape caused by the evolution of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has presented a considerable challenge to the effectiveness of COVID-19 vaccines. Moreover, concerns have arisen about the potential liver toxicity associated with the lipid nanoparticles (LNP) used in approved mRNA vaccines, raising questions about their safety. To address these challenges, we have developed the SWIM516 vaccine, which utilizes a chimeric Delta-BA.2 RBD dimer immunogen to provide broad-spectrum protection and a lipopolyplex (LPP) delivery system to enhance safety. This vaccine has demonstrated its ability to induce broad-spectrum immunogenicity in mice and offers protection to both mice and monkeys when exposed to live SARS-CoV-2 challenges, qualifying it as a next-generation broad-spectrum COVID-19 vaccine.