Abstract
The current pandemic of COVID-19 caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) highlights an urgent need to develop a safe, efficacious, and durable vaccine. Using a measles virus (rMeV) vaccine strain as the backbone, we developed a series of recombinant attenuated vaccine candidates expressing various forms of the SARS-CoV-2 spike (S) protein and its receptor binding domain (RBD) and evaluated their efficacy in cotton rat, IFNAR-/-mice, IFNAR-/--hCD46 mice, and golden Syrian hamsters. We found that rMeV expressing stabilized prefusion S protein (rMeV-preS) was more potent in inducing SARS-CoV-2-specific neutralizing antibodies than rMeV expressing full-length S protein (rMeV-S), while the rMeVs expressing different lengths of RBD (rMeV-RBD) were the least potent. Animals immunized with rMeV-preS produced higher levels of neutralizing antibody than found in convalescent sera from COVID-19 patients and a strong Th1-biased T cell response. The rMeV-preS also provided complete protection of hamsters from challenge with SARS-CoV-2, preventing replication in lungs and nasal turbinates, body weight loss, cytokine storm, and lung pathology. These data demonstrate that rMeV-preS is a safe and highly efficacious vaccine candidate, supporting its further development as a SARS-CoV-2 vaccine.
Highlights
In December 2019, a novel coronavirus disease (COVID-19) was first identified in Wuhan City, Hubei Province, People’s Republic of China
We constructed a series of recombinant MeV (rMeV) vaccine vectors expressing eight variants of the SARS-CoV-2 S protein: 1) full-length S (S), 2) deletion of the transmembrane domain and cytoplasmic tail reflecting the soluble ectodomain (S-dTM), 3) S1 subunit (S1), 4) three different lengths of receptor binding domain (RBD) (RBD1, RBD2, and RBD3) of S, and 5) a prefusion-stabilized soluble ectodomain with deletion of the furin cleavage site, two proline mutations, and a self-trimerizing T4 fibritin trimerization motif replacing its transmembrane and cytoplasmic domains [9] (Fig. 1A)
We examined the expression of the SARS-CoV-2 S proteins by rMeV in confluent Vero CCL81 cells inoculated at a multiplicity of infection (MOI) of 0.01
Summary
In December 2019, a novel coronavirus disease (COVID-19) was first identified in Wuhan City, Hubei Province, People’s Republic of China. More than 300 SARS-CoV-2 vaccine candidates are in preclinical development [4,5,6] and at least 30 vaccine candidates have entered human clinical trials [4, 5, 7, 8]. Preliminary results indicate that these vaccines are highly efficacious, reaching 90 to 95% effectiveness against SARS-CoV-2 infection in some cases. We generated a panel of rMeV-based vaccines with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) S antigens inserted near 3′ of the MeV genome. The rMeV expressing a soluble stabilized, prefusion spike (preS) is much more potent in triggering SARS-CoV-2–specific neutralizing antibody than rMeV-based full-length S vaccine candidate. Our results demonstrate rMeV-preS is a safe and highly efficacious bivalent vaccine candidate for SARS-CoV-2 and MeV
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