Potent immunogenicity and broad-spectrum protection potential of microneedle array patch-based COVID-19 DNA vaccine candidates encoding dimeric RBD chimera of SARS-CoV and SARS-CoV-2 variants

ABSTRACT

Breakthrough infections by SARS-CoV-2 variants pose a global challenge to COVID-19 pandemic control, and the development of more effective vaccines of broad-spectrum protection is needed. In this study, we constructed pVAX1-based plasmids encoding receptor-binding domain (RBD) chimera of SARS-CoV-1 and SARS-CoV-2 variants, including pAD1002 (encoding RBD^SARS/BA1), pAD1003 (encoding RBD^SARS/Beta) and pAD131 (encoding RBD^BA1/Beta). Plasmids pAD1002 and pAD131 were far more immunogenic than pAD1003 in terms of eliciting RBD-specific IgG when intramuscularly administered without electroporation. Furthermore, dissolvable microneedle array patches (MAP) greatly enhanced the immunogenicity of these DNA constructs in mice and rabbits. MAP laden with pAD1002 (MAP-1002) significantly outperformed inactivated SARS-CoV-2 virus vaccine in inducing RBD-specific IFN-γ⁺ effector and memory T cells, and generated T lymphocytes of different homing patterns compared to that induced by electroporated DNA in mice. In consistence with the high titer neutralization results of MAP-1002 antisera against SARS-CoV-2 pseudoviruses, MAP-1002 protected human ACE2-transgenic mice from Omicron BA.1 challenge. Collectively, MAP-based DNA constructs encoding chimeric RBDs of SARS-CoV-1 and SARS-CoV-2 variants, as represented by MAP-1002, are potential COVID-19 vaccine candidates worthy further translational study.

KEYWORDS:

• COVID-19
• SARS-CoV-2
• RBD chimera
• DNA vaccine
• microneedle

Acknowledgements

We thank Inovio for kindly providing CELLECTRA®2000 and needle electrode used in this study. We are also indebted to Drs. L Humeau and T Smith of Inovio for commenting on the manuscript. Zhi-Yu Zhang is a registered Msc student at Fudan University, Shanghai, China. FF, XZ, YD, XX, YZ, LW, FYG, JH, YYP performed experiments; LJ and JK prepared the MAPs. XMG, FF, BW, GFY and GZ analysed and interpreted data; FF, YD and FYG prepared the figures; HJL and ZH carried out BA.1 challenge experiments. XMG and BW provided conceptual advice and coordinated the study. XMG wrote the paper. BW, GZ and GFY reviewed and commented on the manuscript before submission .

Disclosure statement

No potential conflict of interest was reported by the author(s).

Additional information

Funding

This work was partially supported by a Major Research & Development Program grant from the Ministry of Science and Technology of the People's Republic of China (2021YFC2302500).