Evaluation of the broad-spectrum immunogenicity of RBD dimer mRNA vaccines against SARS-CoV-2 variants
Severe acute respiratory syndrome coronavirus 2(SARS-CoV-2),the causative agent of coronavirus disease 2019(COVID-19),has been spreading globally since the end of 2019.During this period,the virus has undergone mutations that led to the emergence of multiple variants with high transmissibility or capability of immune evasion.To prevent the spread of the virus,large-scale vaccination campaigns were conducted in many countries.However,as SARS-CoV-2 continues to mutate,the prevalent COVID-19 vaccines,which were primarily designed using the SARS-CoV-2 prototype(PT)and effectively safeguarded against early SARS-CoV-2 variants,have displayed considerably diminished efficacy against subsequent Omicron sub-variants,especially against the more recent BF.7,BQ.1.1,CH.1.1,XBB,and XBB.1.5 that has higher capability immune escape.Therefore,there is an urgent need to develop a new generation of broad-spectrum vaccines that can generate high levels of neutralizing antibodies against multiple SARS-CoV-2 variants.Previously,our group developed the ZF2001 vaccine with a tandem repeat homodimer of the SARS-CoV-2 receptor-binding domain(RBD),which has been approved in 4 countries and vaccinated over 300 million doses worldwide.To tackle the Omicron variant,we also upgraded the RBD homodimer of ZF2001 vaccine to a Delta-BA.l chimeric heterodimer and developed protein subunit and mRNA vaccine that both demonstrated potent broad-spectrum immunogenicity against pre-Omicron variants as well as some Omicron sub-variants such as BA.1 and BA.2.With further evolution of Omicron,the prevalent XBB derivatives have displayed severe immune escape to the BA.1 immunogen.Therefore,we aim to further broaden the immunogenicity of RBD dimer vaccines by upgrading the Delta-BA.1 RBD dimer immunogen using the RBDs of more recent Omicron sub-variants.In this study,we developed six novel RBD dimer mRNA vaccines,each incorporating an RBD dimer consisting of Delta RBD or the RBD from specific Omicron sub-variants such as BA.1,BA.2,or BA.5.By systematically evaluating the expression and immunogenicity of these RBD dimer mRNA vaccines,we validated their immunogenicity and potential as booster shots following two doses of inactivated vaccine,as these vaccines demonstrated potent humoral and cellular immunogenicity against a wide range of SARS-CoV-2 variants.Notably,the neutralization antibodies elicited by Delta-BA.2(DO2)and Delta-BA.5(DO5)vaccines showed complementary spectra of neutralization.In other words,DO2 and DO5 are more effective against SARS-CoV-2 variants that emerged before BA.2 and after BA.5,respectively.Thus,we further designed a cocktail vaccine by mixing the DO2 and DO5 vaccines,aiming to achieve a more broad-spectrum immunogenicity.Neutralization data showed that the cocktail vaccine successfully expanded the spectrum of immunogenicity compared with the DO2 or DO5 vaccine.Moreover,by administering a third booster dose,the DO5 and DO2+DO5 cocktail vaccines effectively stimulated high levels of neutralizing antibodies targeting CH.1.1,XBB,and XBB.1.5.These findings contribute to our understanding of the spectrum neutralization across diverse variants,offering insights for the development of broad-spectrum COVID-19 vaccines.
万方数据
维普
