RESUMO
Establishment of an mRNA vaccine platform in low- and middle-income countries (LMICs) is important to enhance vaccine accessibility and ensure future pandemic preparedness. Here, we describe the preclinical studies of a SARS-CoV-2 mRNA encoding prefusion-unstabilized ectodomain spike protein encapsulated in lipid nanoparticles (LNP) "ChulaCov19". In BALB/c mice, ChulaCov19 at 0.2, 1, 10, and 30 g given 2 doses, 21 days apart, elicited robust neutralizing antibody (NAb) and T cells responses in a dose-dependent relationship. The geometric mean titer (GMT) of micro-virus neutralizing (micro-VNT) antibody against wild-type virus was 1,280, 11,762, 54,047, and 62,084, respectively. Higher doses induced better cross-neutralizing antibody against Delta and Omicron variants. This elicited specific immunogenicity was significantly higher than those induced by homologous prime-boost with inactivated (CoronaVac) or viral vector (AZD1222) vaccine. In heterologous prime-boost study, mice primed with either CoronaVac or AZD1222 vaccine and boosted with 5 g ChulaCov19 generated NAb 7-fold higher against wild-type virus (WT) and was also significantly higher against Omicron (BA.1 and BA.4/5) than homologous CoronaVac or AZD1222 vaccination. AZD1222-prime/mRNA-boost had mean spike-specific IFN{gamma} positive T cells of 3,725 SFC/106 splenocytes, which was significantly higher than all groups except homologous ChulaCov19. Challenge study in human-ACE-2-expressing transgenic mice showed that ChulaCov19 at 1 g or 10 g protected mice from COVID-19 symptoms, prevented SARS-CoV-2 viremia, significantly reduced tissue viral load in nasal turbinate, brain, and lung tissues 99.9-100%, and without anamnestic of Ab response which indicated its protective efficacy. ChulaCov19 is therefore a promising mRNA vaccine candidate either as a primary or a boost vaccination and has entered clinical development.
RESUMO
BackgroundEffective COVID-19 mRNA vaccines are mainly available in high-income countries. ChulaCov19, a prefusion non-stabilized Spike protein-encoding, nucleoside-modified mRNA, lipid nanoparticle encapsulated vaccine development, aims to enhance accessibility of mRNA vaccine and future pandemic preparedness for low- to middle-income countries. MethodsSeventy-two eligible volunteers, 36 aged 18-55 (adults) followed by 36 aged 56-75 (elderly) enrolled in a dose escalation study of ChulaCov19 mRNA vaccine. Two doses of vaccine were given 21 days apart at 10, 25, or 50 {micro}g/dose (12/group). Safety was the primary and immunogenicity the secondary outcome. Human convalescents (HCS) and Pfizer/BioNTech vaccinees sera provided comparison panels. ResultsAll three doses of ChulaCov19 were well tolerated and elicited robust dose-dependent and age- dependent B- and T-cell responses. Transient mild/moderate injection site pain, fever, chills, fatigue, and headache were more common after the second dose. Four weeks after the second ChulaCov19: dose at 10, 25, and 50 {micro}g dose, MicroVNT-50 Geometric mean titer (GMT) against wild-type was 848, 736 and 1,140 IU/mL, respectively, versus 267 IU/mL for HCS. All dose levels elicited 100% seroconversion, with GMT ratio 4-8-fold higher than for HCS (p<0.01), and high IFN{gamma} spot-forming cells/million peripheral blood mononuclear cells. The 50 {micro}g dose induced better cross-neutralization against Alpha, Beta, Gamma, and Delta variants than lower doses. ConclusionsChulaCov19 at 50 {micro}g/dose is well tolerated and elicited higher neutralizing antibodies than HCS with strong T-cell responses. These antibodies cross neutralized four variants of concern and ChulaCov19 has therefore proceeded to phase 2 and 3 clinical trials. Trial registration numberClinicalTrials.gov Identifier NCT04566276 Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=112 SRC="FIGDIR/small/22274989v1_ufig1.gif" ALT="Figure 1"> View larger version (41K): org.highwire.dtl.DTLVardef@3f6e6corg.highwire.dtl.DTLVardef@6aa1b7org.highwire.dtl.DTLVardef@9f0c29org.highwire.dtl.DTLVardef@1d75e38_HPS_FORMAT_FIGEXP M_FIG C_FIG
