Abstract
The outbreak of the SARS-CoV-2 virus and its rapid spread into a global pandemic made the urgent development of scalable vaccines to prevent coronavirus disease (COVID-19) a global health and economic imperative. Here, we characterized and compared the immunogenicity of two alphavirus-based DNA-launched self-replicating (DREP) vaccine candidates encoding either SARS-CoV-2 spike glycoprotein (DREP-S) or a spike ectodomain trimer stabilized in prefusion conformation (DREP-Secto). We observed that the two DREP constructs were immunogenic in mice inducing both binding and neutralizing antibodies as well as T cell responses. Interestingly, the DREP coding for the unmodified spike turned out to be more potent vaccine candidate, eliciting high titers of SARS-CoV-2 specific IgG antibodies that were able to efficiently neutralize pseudotyped virus after a single immunization. In addition, both DREP constructs were able to efficiently prime responses that could be boosted with a heterologous spike protein immunization. These data provide important novel insights into SARS-CoV-2 vaccine design using a rapid response DNA vaccine platform. Moreover, they encourage the use of mixed vaccine modalities as a strategy to combat SARS-CoV-2.
Highlights
The outbreak of the SARS-CoV-2 virus and its rapid spread into a global pandemic made the urgent development of scalable vaccines to prevent coronavirus disease (COVID-19) a global health and economic imperative
The full-length proteins, similar in size to recombinant purified spike, were detected in cell lysates for both constructs and in culture supernatant for the DNA-launched self-replicating (DREP)-Secto construct encoding the spike ectodomain, while no protein product of this size was detected in cells transfected with the control DREP expressing chikungunya virus g lycoproteins[23,28] (Fig. 1B)
In order to determine how the DREP vaccine candidates affected T helper 1 cell (Th1) and T helper 2 cell (Th2) induction, we evaluated the ratio of IgG2c and IgG1 antibody titers against SARS-CoV-2 spike antigen (Fig. 3)
Summary
The outbreak of the SARS-CoV-2 virus and its rapid spread into a global pandemic made the urgent development of scalable vaccines to prevent coronavirus disease (COVID-19) a global health and economic imperative. The DREP coding for the unmodified spike turned out to be more potent vaccine candidate, eliciting high titers of SARS-CoV-2 specific IgG antibodies that were able to efficiently neutralize pseudotyped virus after a single immunization Both DREP constructs were able to efficiently prime responses that could be boosted with a heterologous spike protein immunization. Replicon vectors have inherent adjuvant properties due to their self-amplifying activity which generates single-stranded and double-stranded RNA intermediates that stimulate different pattern recognition receptors (PRR) including the endosomal TLR3, TLR7, and TLR88,9 or the cytoplasmic MDA-510, RIG-I10,11 and P KR12,13 This results in induction of a type I interferon (IFN) response, translational shutoff of a host cell and induction of apoptosis thereby promoting antigen presentation on MHC class I molecules and cross-priming[11,14,15,16]. DREP platform combines the safety profile of conventional plasmid DNA vaccines that proved safe in multiple clinical
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