tetano
Editor, Senior Moderator
Microbiol Spectr
. 2023 May 16;e0065323.
doi: 10.1128/spectrum.00653-23. Online ahead of print. Immunization with Recombinant Accessory Protein-Deficient SARS-CoV-2 Protects against Lethal Challenge and Viral Transmission
Chengjin Ye[SUP] #[/SUP][SUP] 1 [/SUP], Jun-Gyu Park[SUP] #[/SUP][SUP] 1 [/SUP], Kevin Chiem[SUP] 1 [/SUP], Piyush Dravid[SUP] 2 [/SUP], Anna Allué-Guardia[SUP] 1 [/SUP], Andreu Garcia-Vilanova[SUP] 1 [/SUP], Paula Pino Tamayo[SUP] 1 [/SUP], Vinay Shivanna[SUP] 1 [/SUP], Amit Kapoor[SUP] 2 [/SUP], Mark R Walter[SUP] 3 [/SUP], James J Kobie[SUP] 4 [/SUP], Richard K Plemper[SUP] 5 [/SUP], Jordi B Torrelles[SUP] 1 [/SUP], Luis Martinez-Sobrido[SUP] 1 [/SUP]
Affiliations
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has led to a worldwide coronavirus disease 2019 (COVID-19) pandemic. Despite the high efficacy of the authorized vaccines, there may be uncertain and unknown side effects or disadvantages associated with current vaccination approaches. Live-attenuated vaccines (LAVs) have been shown to elicit robust and long-term protection by the induction of host innate and adaptive immune responses. In this study, we sought to verify an attenuation strategy by generating 3 double open reading frame (ORF)-deficient recombinant SARS-CoV-2s (rSARS-CoV-2s) simultaneously lacking two accessory ORF proteins (ORF3a/ORF6, ORF3a/ORF7a, and ORF3a/ORF7b). We report that these double ORF-deficient rSARS-CoV-2s have slower replication kinetics and reduced fitness in cultured cells compared with their parental wild-type (WT) counterpart. Importantly, these double ORF-deficient rSARS-CoV-2s showed attenuation in both K18 hACE2 transgenic mice and golden Syrian hamsters. A single intranasal dose vaccination induced high levels of neutralizing antibodies against SARS-CoV-2 and some variants of concern and activated viral component-specific T cell responses. Notably, double ORF-deficient rSARS-CoV-2s were able to protect, as determined by the inhibition of viral replication, shedding, and transmission, against challenge with SARS-CoV-2 in both K18 hACE2 mice and golden Syrian hamsters. Collectively, our results demonstrate the feasibility of implementing the double ORF-deficient strategy to develop safe, immunogenic, and protective LAVs to prevent SARS-CoV-2 infection and associated COVID-19. IMPORTANCE Live-attenuated vaccines (LAVs) are able to induce robust immune responses, including both humoral and cellular immunity, representing a very promising option to provide broad and long-term immunity. To develop LAVs for SARS-CoV-2, we engineered attenuated recombinant SARS-CoV-2 (rSARS-CoV-2) that simultaneously lacks the viral open reading frame 3a (ORF3a) in combination with either ORF6, ORF7a, or ORF7b (Δ3a/Δ6, Δ3a/Δ7a, and Δ3a/Δ7b, respectively) proteins. Among them, the rSARS-CoV-2 Δ3a/Δ7b was completely attenuated and able to provide 100% protection against an otherwise lethal challenge in K18 hACE2 transgenic mice. Moreover, the rSARS-CoV-2 Δ3a/Δ7b conferred protection against viral transmission between golden Syrian hamsters.
Keywords: SARS-CoV-2; coronavirus; immune protection; live-attenuated vaccine; viral shedding; viral transmission.
. 2023 May 16;e0065323.
doi: 10.1128/spectrum.00653-23. Online ahead of print. Immunization with Recombinant Accessory Protein-Deficient SARS-CoV-2 Protects against Lethal Challenge and Viral Transmission
Chengjin Ye[SUP] #[/SUP][SUP] 1 [/SUP], Jun-Gyu Park[SUP] #[/SUP][SUP] 1 [/SUP], Kevin Chiem[SUP] 1 [/SUP], Piyush Dravid[SUP] 2 [/SUP], Anna Allué-Guardia[SUP] 1 [/SUP], Andreu Garcia-Vilanova[SUP] 1 [/SUP], Paula Pino Tamayo[SUP] 1 [/SUP], Vinay Shivanna[SUP] 1 [/SUP], Amit Kapoor[SUP] 2 [/SUP], Mark R Walter[SUP] 3 [/SUP], James J Kobie[SUP] 4 [/SUP], Richard K Plemper[SUP] 5 [/SUP], Jordi B Torrelles[SUP] 1 [/SUP], Luis Martinez-Sobrido[SUP] 1 [/SUP]
Affiliations
- PMID: 37191507
- DOI: 10.1128/spectrum.00653-23
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has led to a worldwide coronavirus disease 2019 (COVID-19) pandemic. Despite the high efficacy of the authorized vaccines, there may be uncertain and unknown side effects or disadvantages associated with current vaccination approaches. Live-attenuated vaccines (LAVs) have been shown to elicit robust and long-term protection by the induction of host innate and adaptive immune responses. In this study, we sought to verify an attenuation strategy by generating 3 double open reading frame (ORF)-deficient recombinant SARS-CoV-2s (rSARS-CoV-2s) simultaneously lacking two accessory ORF proteins (ORF3a/ORF6, ORF3a/ORF7a, and ORF3a/ORF7b). We report that these double ORF-deficient rSARS-CoV-2s have slower replication kinetics and reduced fitness in cultured cells compared with their parental wild-type (WT) counterpart. Importantly, these double ORF-deficient rSARS-CoV-2s showed attenuation in both K18 hACE2 transgenic mice and golden Syrian hamsters. A single intranasal dose vaccination induced high levels of neutralizing antibodies against SARS-CoV-2 and some variants of concern and activated viral component-specific T cell responses. Notably, double ORF-deficient rSARS-CoV-2s were able to protect, as determined by the inhibition of viral replication, shedding, and transmission, against challenge with SARS-CoV-2 in both K18 hACE2 mice and golden Syrian hamsters. Collectively, our results demonstrate the feasibility of implementing the double ORF-deficient strategy to develop safe, immunogenic, and protective LAVs to prevent SARS-CoV-2 infection and associated COVID-19. IMPORTANCE Live-attenuated vaccines (LAVs) are able to induce robust immune responses, including both humoral and cellular immunity, representing a very promising option to provide broad and long-term immunity. To develop LAVs for SARS-CoV-2, we engineered attenuated recombinant SARS-CoV-2 (rSARS-CoV-2) that simultaneously lacks the viral open reading frame 3a (ORF3a) in combination with either ORF6, ORF7a, or ORF7b (Δ3a/Δ6, Δ3a/Δ7a, and Δ3a/Δ7b, respectively) proteins. Among them, the rSARS-CoV-2 Δ3a/Δ7b was completely attenuated and able to provide 100% protection against an otherwise lethal challenge in K18 hACE2 transgenic mice. Moreover, the rSARS-CoV-2 Δ3a/Δ7b conferred protection against viral transmission between golden Syrian hamsters.
Keywords: SARS-CoV-2; coronavirus; immune protection; live-attenuated vaccine; viral shedding; viral transmission.