The emergence of new SARS-CoV-2 variants/subvariants of concern (VOCs) and the dynamics of infection cases and deaths worldwide have suggested that the COVID-19 pandemic will become endemic, which will require periodic vaccination. Vaccines currently in use have been effective in preventing severe disease after booster doses, but they fail to control viral replication and prevent mild to moderate disease in individuals infected with the SARS-CoV-2 variants. This is due to the waning of vaccine-induced immunity and mutations in the variants that enable immune escape of immunity induced by early wild-type SARS-CoV-2-based vaccines.

DNA-based vaccines have been shown to be promising candidates for COVID-19, demonstrating consistent results in stimulating both humoral and cellular immune responses. Importantly, DNA vaccines add advantages such as low cost, high stability at room temperature, and relatively easy production and distribution.

In this context, we produced and tested an experimental vaccine based on plasmid DNA containing the sequence encoding the S protein of the wild type Wuhan SARS-CoV-2 (pCTV-WS), and evaluated its efficacy in protecting against VOCs. Using K18-hACE2 mice and hamsters as models for severe and moderate COVID-19, respectively, high levels of neutralizing antibodies (nAbs) and robust T cell responses were obtained in both models. 

In order to verify the protective role of nAbs and T cells in immunity elicited by pCTV-WS, we performed experiments of adoptive transfer of either sera or T cells, anti-CD4 and anti-CD8 depletion as well as B cell-deficient K18-hACE2 mice. Regarding wild type SARS-CoV-2 and variants, we observed that nAbs induced by two doses three weeks apart of pCTV-WS were critical for controlling infection with the ancestral (Wuhan) SARS-CoV-2 and the Delta variant. On the other hand, T cells induced by the DNA vaccine were shown critical for controlling viral load, disease progression and lethality in mice infected with either the Gamma or Omicron variants.

The emergence and rapid spread of Omicron variant/subvariants, which escape nAbs induced by previous infection or by vaccines based on wild type SARS-CoV-2 but cause moderate disease, highlighted the importance of T cells in controlling infection. Thus, although there was a significant number of breakthrough infection cases, vaccine-induced memory T cells showed preserved responses to the most recent variant. Altogether, our findings reinforce the hypothesis that T cells are critical for virus control during infection by the Omicron variant.