Development of safe and highly protective live-attenuated SARS-CoV-2 vaccine candidates by genome recoding

Abstract

Safe and effective vaccines are urgently needed to stop the pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). We constructed a series of live attenuated vaccine candidates by large-scale recoding of the SARS-CoV-2 genome, and assessed their safety and efficacy in Syrian hamsters. Animals were vaccinated with a single dose of the respective recoded virus and challenged 21 days later. Two of the tested viruses did not cause clinical symptoms, but were highly immunogenic and induced strong protective immunity. Attenuated viruses replicated efficiently in the upper but not in the lower airways, causing only mild pulmonary histopathology. After challenge, hamsters developed no signs of disease and rapidly cleared challenge virus: at no time could infectious virus be recovered from the lungs of infected animals. The ease with which attenuated virus candidates can be produced and administered favors their further development as vaccines to combat the ongoing pandemic.

Live attenuated virus vaccine protects against SARS-CoV-2 variants of concern B.1.1.7 (Alpha) and B.1.351 (Beta)

“…We constructed a series of live attenuated SARS-CoV-2 vaccine candidates by large-scale recoding of the SARS-CoV-2 genome ( 21 ). The SARS-CoV-2 genome was modified by codon pair deoptimization (CPD), an approach that has resulted in rapid and efficient attenuation of a variety of RNA ( 22 , 23 ) and DNA viruses ( 24 , 25 ).…”

“…In our previous study, we have evaluated live attenuated virus candidates and have shown that some of them are strongly attenuated, induce strong immune responses, and protect Syrian hamsters from a challenge with ancestral wild-type (WT) SARS-CoV-2 ( 21 ). In that study, we also showed that the lead live attenuated virus candidate sCPD9 ( Fig.…”

“…1A ) is strongly attenuated in the Roborovski dwarf hamster ( Phodopus roborovskii ), which is highly susceptible to severe COVID-19–like disease ( 27 ). Despite the high susceptibility of this hamster species, sCPD9 did not cause clinical disease or considerable lung pathology ( 21 ).…”

Natural and Experimental SARS-CoV-2 Infection in Domestic and Wild Animals

“…Hamsters, particularly Syrian golden hamsters, are the most promising pre-clinical model of SARS-CoV-2 due to their consistent clinical signs and ability to transmit the virus to other hamsters, combined with their relative ease of housing and handling in biocontainment facilities. Syrian golden hamsters have already been used extensively to gain insights into the basic science of SARS-CoV-2 pathogenesis [ 156 , 157 , 158 , 159 , 160 , 161 ] and to test therapeutic interventions [ 162 , 163 , 164 , 165 , 166 , 167 ] and vaccines [ 168 , 169 , 170 , 171 , 172 ]. Moreover, there is clear evidence that older Syrian golden hamsters and Roborovski hamsters develop respiratory disease and lung pathology that recapitulates the severe disease found in older COVID-19 patients, and therefore could be highly informative models [ 77 , 81 ].…”

Vaccines against COVID-19: Priority to mRNA-Based Formulations

“…In addition, promising new experimental vaccination approaches such as, for example, aerosolized adenovirus [11], adeno-associated viral (AAV)-based vaccines [12], live attenuated vaccines that can be applied intranasally [13,14], or other vector vaccines such as modified vaccinia virus Ankara (MVA)-based approaches [15] are being developed. However, they will not be further detailed here.…”