Biodistribution and environmental safety of a live-attenuated YF17D-vectored SARS-CoV-2 vaccine candidate

Abstract

New platforms are needed for the design of novel prophylactic vaccines and advanced immune therapies. Live-attenuated yellow fever vaccine YF17D serves as a vector for several licensed vaccines and platform for novel candidates. On the basis of YF17D, we developed an exceptionally potent COVID-19 vaccine candidate called YF-S0. However, use of such live RNA viruses raises safety concerns, such as adverse events linked to original YF17D (yellow fever vaccine-associated neurotropic disease [YEL-AND] and yellow fever vaccine-associated viscerotropic disease [YEL-AVD]). In this study, we investigated the biodistribution and shedding of YF-S0 in hamsters. Likewise, we introduced hamsters deficient in signal transducer and activator of transcription 2 (STAT2) signaling as a new preclinical model of YEL-AND/AVD. Compared with YF17D, YF-S0 showed improved safety with limited dissemination to brain and visceral tissues, absent or low viremia, and no shedding of infectious virus. Considering that yellow fever virus is transmitted by Aedes mosquitoes, any inadvertent exposure to the live recombinant vector via mosquito bites is to be excluded. The transmission risk of YF-S0 was hence compared with readily transmitting YF-Asibi strain and non-transmitting YF17D vaccine, with no evidence for productive infection of mosquitoes. The overall favorable safety profile of YF-S0 is expected to translate to other vaccines based on the same YF17D platform. New platforms are needed for the design of novel prophylactic vaccines and advanced immune therapies. Live-attenuated yellow fever vaccine YF17D serves as a vector for several licensed vaccines and platform for novel candidates. On the basis of YF17D, we developed an exceptionally potent COVID-19 vaccine candidate called YF-S0. However, use of such live RNA viruses raises safety concerns, such as adverse events linked to original YF17D (yellow fever vaccine-associated neurotropic disease [YEL-AND] and yellow fever vaccine-associated viscerotropic disease [YEL-AVD]). In this study, we investigated the biodistribution and shedding of YF-S0 in hamsters. Likewise, we introduced hamsters deficient in signal transducer and activator of transcription 2 (STAT2) signaling as a new preclinical model of YEL-AND/AVD. Compared with YF17D, YF-S0 showed improved safety with limited dissemination to brain and visceral tissues, absent or low viremia, and no shedding of infectious virus. Considering that yellow fever virus is transmitted by Aedes mosquitoes, any inadvertent exposure to the live recombinant vector via mosquito bites is to be excluded. The transmission risk of YF-S0 was hence compared with readily transmitting YF-Asibi strain and non-transmitting YF17D vaccine, with no evidence for productive infection of mosquitoes. The overall favorable safety profile of YF-S0 is expected to translate to other vaccines based on the same YF17D platform. IntroductionRoughly 2 years after its first emergence in 2019–2020, more than 5 million people have succumbed to coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) (https://coronavirus.jhu.edu/map.html). Mass immunization is key to mitigating the expanding pandemic.1Dallmeier K. Meyfroidt G. Neyts J. COVID-19 and the intensive care unit: vaccines to the rescue.Intensive Care Med. 2021; 47: 1-4Crossref PubMed Scopus (5) Google Scholar A set of rapidly developed prophylactic vaccines plays a crucial role in global immunization against SARS-CoV-2. Several of these vaccines are first in class, based on novel platforms, including game-changer mRNA vaccines and viral vector vaccines that are unprecedented in both their high clinical efficacy and the incremental advance in breakthrough innovation.2Heinz F.X. Stiasny K. Distinguishing features of current COVID-19 vaccines: knowns and unknowns of antigen presentation and modes of action.npj Vaccin. 2021; 6: 1-13Crossref PubMed Scopus (78) Google Scholar, 3Verbeke R. Lentacker I. De Smedt S.C. Dewitte H. The dawn of mRNA vaccines: the COVID-19 case.J. Controlled Release. 2021; 333: 511-520Crossref PubMed Scopus (114) Google Scholar, 4Neukirch L. Fougeroux C. Andersson A.-M.C. Holst P.J. The potential of adenoviral vaccine vectors with altered antigen presentation capabilities.Expert Rev. Vaccin. 2020; 19: 25-41Crossref PubMed Scopus (9) Google Scholar However, a global vaccine supply shortage, the dependence on an ultra-cold chain system in case of mRNA vaccines, and the continuous emergence of virus variants pose unmet challenges.5Anderson R.M. Vegvari C. Truscott J. Collyer B.S. Challenges in creating herd immunity to SARS-CoV-2 infection by mass vaccination.The Lancet. 2020; 396: 1614-1616Abstract Full Text Full Text PDF PubMed Scopus (296) Google Scholar,6Garcia-Beltran W.F. Lam E.C. Denis K.S. Nitido A.D. Garcia Z.H. Hauser B.M. Feldman J. Pavlovic M.N. Gregory D.J. Poznansky M.C. Multiple SARS-CoV-2 variants escape neutralization by vaccine-induced humoral immunity.Cell. 2021; 184: 2372-2383.e2379Abstract Full Text Full Text PDF PubMed Scopus (585) Google Scholar Unfortunately, the long-term effectiveness of current SARS-CoV-2 vaccines is waning because of the combined effect of (1) a rapid decay of virus-neutralizing antibodies (nAbs) over time and (2) emergence of new variants escaping vaccine-induced immunity.7Cromer D. Steain M. Reynaldi A. Schlub T.E. Wheatley A.K. Juno J.A. Kent S.J. Triccas J.A. Khoury D.S. Davenport M.P. Neutralising antibody titres as predictors of protection against SARS-CoV-2 variants and the impact of boosting: a meta-analysis.The Lancet Microbe. 2021; https://doi.org/10.1016/S2666-5247(21)00337-2Abstract Full Text Full Text PDF PubMed Scopus (2) Google Scholar, 8Cai C. Liu Y. Zeng S. Shen H. Han Y. The efficacy of COVID-19 vaccines against the B. 1.617. 2 (delta) variant.Mol. Ther. 2021; 29: 2890-2892Abstract Full Text Full Text PDF PubMed Scopus (8) Google Scholar, 9Lai C.-C. Chen I.-T. Chao C.-M. Lee P.-I. COVID-19 vaccines: efficacy and Rev. Vaccin. 2021; PubMed Scopus Google Scholar several COVID-19 vaccines have a high the of more and a of adverse immunization including severe adverse such as and are C. Y. Shen Chen Y. Liu C. L. A of the efficacy and safety of COVID-19 Ther. 2021; 29: Full Text Full Text PDF PubMed Scopus Google Scholar, S.C. D. A. M. of COVID-19 vaccines after of adverse events of and mRNA COVID-19 vaccines and the on immunization 2021; PubMed Scopus Google Scholar, C.-C. Chen Chen Lee P.-I. COVID-19 vaccines and with Rev. Vaccin. 2021; PubMed Scopus Google Scholar, M. K. H. D. adverse events for and COVID-19 vaccines: of and clinical in the 2021; PubMed Scopus Google Scholar, M. and after J. Med. 2021; PubMed Scopus Google Scholar, G. S. I. M. Y. after in a care J. Med. 2021; PubMed Scopus Google Scholar In is an to new and improved COVID-19 vaccines to the we an vaccine platform that the yellow fever vaccine YF17D as a M.C. R. The yellow fever virus as a platform for new live Vaccin. PubMed Scopus Google Scholar and developed a SARS-CoV-2 vaccine candidate that a of SARS-CoV-2 L. S. J. D. R. B. L. A SARS-CoV-2 vaccine 2021; PubMed Scopus Google Scholar YF-S0 was to humoral and immune in hamsters and and was to disease after in a of its YF17D YF-S0 as vaccine to yellow fever virus an for in risk for A.D. The and of yellow fever 2021; Scopus (9) Google to preclinical of such a new vaccine of its safety to preclinical to clinical In for viral vaccines such as the biodistribution of the vaccine virus after to be S.J. B. B. Chen virus vaccines based on a yellow fever vaccine with key for a PubMed Scopus Google Scholar to the viral and hence to potential to vaccine showed an safety profile in preclinical including in and and L. S. J. D. R. B. L. A SARS-CoV-2 vaccine 2021; PubMed Scopus Google Scholar However, use of such a recombinant YF17D vaccine potential S.J. B. B. Chen virus vaccines based on a yellow fever vaccine with key for a PubMed Scopus Google Scholar In and of YF-S0 in and pose a risk for vaccine-associated viscerotropic disease and vaccine-associated neurotropic disease are linked to A.D. fever and of adverse events PubMed Scopus Google Scholar this YF17D vaccine is as for in safety S.J. B. B. Chen virus vaccines based on a yellow fever vaccine with key for a PubMed Scopus Google we investigated the biodistribution and shedding of YF-S0 in with the (1) to to YF-S0 in virus dissemination to (2) to the of YF-S0 for by its and in L. S. J. D. R. B. L. 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S. the and dissemination of the yellow fever vaccine in Aedes PubMed Scopus Google Scholar YF-S0 was the first with no viral RNA or infectious virus after an infectious the of YF-S0 by is to be YF-S0 be a and vaccine candidate for the of A improved safety compared with YF17D be expected for other vaccines the same design YF17D as a M.C. R. The yellow fever virus as a platform for new live Vaccin. PubMed Scopus Google R. J. Neyts J. K. A novel vaccine candidate in 2021; Full Text Full Text PDF PubMed Scopus Google and hamsters The Lee B. in hamsters by the PubMed Scopus Google Scholar and R. S.J. R. L. J. De C. L. S. signaling viral dissemination severe in SARS-CoV-2 2020; PubMed Scopus Google Scholar of hamsters hamsters in of and and as as and for as was by the by the of by of and virus viruses this have L. S. J. D. R. B. L. A SARS-CoV-2 vaccine 2021; PubMed Scopus Google Scholar YF-S0 was a of YF17D with an of a of the SARS-CoV-2 in the YF-S0 vaccine on The and and of YF-S0 have in L. S. J. D. R. B. L. A SARS-CoV-2 vaccine 2021; PubMed Scopus Google Scholar YF17D vaccine was via the of the and in to the of the of YF17D in B. A. Neyts J. K. of the yellow fever virus in a infection PubMed Scopus Google Scholar was to YF-Asibi by recombinant The was as 2 in and by in S. The was for virus The virus was by in and the of YF-Asibi virus was by virus by on as L. S. J. D. R. B. L. A SARS-CoV-2 vaccine 2021; PubMed Scopus Google hamsters with a of YF17D or YF-S0 hamsters with of YF17D and hamsters with of YF17D or YF-S0 hamsters with of YF17D and for the first 5 other and for the and and a M. L. in to 2 virus of of Aedes the of and J. Med. PubMed Scopus Google Scholar via the of the of and the was for this In with the to to for with in and infection and to 5 as with virus to of 2 R.M. Vegvari C. Truscott J. Collyer B.S. Challenges in creating herd immunity to SARS-CoV-2 infection by mass vaccination.The Lancet. 2020; 396: 1614-1616Abstract Full Text Full Text PDF PubMed Scopus (296) Google Scholar for both YF17D and and 5 W.F. Lam E.C. Denis K.S. Nitido A.D. Garcia Z.H. Hauser B.M. Feldman J. Pavlovic M.N. Gregory D.J. Poznansky M.C. Multiple SARS-CoV-2 variants escape neutralization by vaccine-induced humoral immunity.Cell. 2021; 184: 2372-2383.e2379Abstract Full Text Full Text PDF PubMed Scopus (585) Google Scholar for for viral and the with of both with and and and in and The and for or for RNA and and in a in for 5 to and RNA was by RNA virus and of mosquito RNA virus was for RNA for was as L. S. J. D. R. B. L. A SARS-CoV-2 vaccine 2021; PubMed Scopus Google Scholar and the L. G. M. G. S. the and dissemination of the yellow fever vaccine in Aedes PubMed Scopus Google Scholar on an was based on of YF17D with a virus and with in and for with 2 and as in a in and for 5 to viral the and neutralization of antibodies and a of YF17D virus as L. S. J. D. R. B. L. A SARS-CoV-2 vaccine 2021; PubMed Scopus Google Scholar In was and with of for and to in for the infection was by on a platform the infection of virus as by in are as and for was and IntroductionRoughly 2 years after its first emergence in 2019–2020, more than 5 million people have succumbed to coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) (https://coronavirus.jhu.edu/map.html). Mass immunization is key to mitigating the expanding pandemic.1Dallmeier K. Meyfroidt G. Neyts J. COVID-19 and the intensive care unit: vaccines to the rescue.Intensive Care Med. 2021; 47: 1-4Crossref PubMed Scopus (5) Google Scholar A set of rapidly developed prophylactic vaccines plays a crucial role in global immunization against SARS-CoV-2. Several of these vaccines are first in class, based on novel platforms, including game-changer mRNA vaccines and viral vector vaccines that are unprecedented in both their high clinical efficacy and the incremental advance in breakthrough innovation.2Heinz F.X. Stiasny K. Distinguishing features of current COVID-19 vaccines: knowns and unknowns of antigen presentation and modes of action.npj Vaccin. 2021; 6: 1-13Crossref PubMed Scopus (78) Google Scholar, 3Verbeke R. Lentacker I. De Smedt S.C. Dewitte H. The dawn of mRNA vaccines: the COVID-19 case.J. Controlled Release. 2021; 333: 511-520Crossref PubMed Scopus (114) Google Scholar, 4Neukirch L. Fougeroux C. Andersson A.-M.C. Holst P.J. The potential of adenoviral vaccine vectors with altered antigen presentation capabilities.Expert Rev. Vaccin. 2020; 19: 25-41Crossref PubMed Scopus (9) Google Scholar However, a global vaccine supply shortage, the dependence on an ultra-cold chain system in case of mRNA vaccines, and the continuous emergence of virus variants pose unmet challenges.5Anderson R.M. Vegvari C. Truscott J. Collyer B.S. Challenges in creating herd immunity to SARS-CoV-2 infection by mass vaccination.The Lancet. 2020; 396: 1614-1616Abstract Full Text Full Text PDF PubMed Scopus (296) Google Scholar,6Garcia-Beltran W.F. Lam E.C. Denis K.S. Nitido A.D. Garcia Z.H. Hauser B.M. Feldman J. Pavlovic M.N. Gregory D.J. Poznansky M.C. Multiple SARS-CoV-2 variants escape neutralization by vaccine-induced humoral immunity.Cell. 2021; 184: 2372-2383.e2379Abstract Full Text Full Text PDF PubMed Scopus (585) Google Scholar Unfortunately, the long-term effectiveness of current SARS-CoV-2 vaccines is waning because of the combined effect of (1) a rapid decay of virus-neutralizing antibodies (nAbs) over time and (2) emergence of new variants escaping vaccine-induced immunity.7Cromer D. Steain M. Reynaldi A. Schlub T.E. Wheatley A.K. Juno J.A. Kent S.J. Triccas J.A. Khoury D.S. Davenport M.P. Neutralising antibody titres as predictors of protection against SARS-CoV-2 variants and the impact of boosting: a meta-analysis.The Lancet Microbe. 2021; https://doi.org/10.1016/S2666-5247(21)00337-2Abstract Full Text Full Text PDF PubMed Scopus (2) Google Scholar, 8Cai C. Liu Y. Zeng S. Shen H. Han Y. The efficacy of COVID-19 vaccines against the B. 1.617. 2 (delta) variant.Mol. Ther. 2021; 29: 2890-2892Abstract Full Text Full Text PDF PubMed Scopus (8) Google Scholar, 9Lai C.-C. Chen I.-T. Chao C.-M. Lee P.-I. COVID-19 vaccines: efficacy and Rev. Vaccin. 2021; PubMed Scopus Google Scholar several COVID-19 vaccines have a high the of more and a of adverse immunization including severe adverse such as and are C. Y. Shen Chen Y. Liu C. L. A of the efficacy and safety of COVID-19 Ther. 2021; 29: Full Text Full Text PDF PubMed Scopus Google Scholar, S.C. D. A. M. of COVID-19 vaccines after of adverse events of and mRNA COVID-19 vaccines and the on immunization 2021; PubMed Scopus Google Scholar, C.-C. Chen Chen Lee P.-I. COVID-19 vaccines and with Rev. Vaccin. 2021; PubMed Scopus Google Scholar, M. K. H. D. adverse events for and COVID-19 vaccines: of and clinical in the 2021; PubMed Scopus Google Scholar, M. and after J. Med. 2021; PubMed Scopus Google Scholar, G. S. I. M. Y. after in a care J. Med. 2021; PubMed Scopus Google Scholar In is an to new and improved COVID-19 vaccines to the we an vaccine platform that the yellow fever vaccine YF17D as a M.C. R. The yellow fever virus as a platform for new live Vaccin. PubMed Scopus Google Scholar and developed a SARS-CoV-2 vaccine candidate that a of SARS-CoV-2 L. S. J. D. R. B. L. A SARS-CoV-2 vaccine 2021; PubMed Scopus Google Scholar YF-S0 was to humoral and immune in hamsters and and was to disease after in a of its YF17D YF-S0 as vaccine to yellow fever virus an for in risk for A.D. The and of yellow fever 2021; Scopus (9) Google to preclinical of such a new vaccine of its safety to preclinical to clinical In for viral vaccines such as the biodistribution of the vaccine virus after to be S.J. B. B. Chen virus vaccines based on a yellow fever vaccine with key for a PubMed Scopus Google Scholar to the viral and hence to potential to vaccine showed an safety profile in preclinical including in and and L. S. J. D. R. B. L. A SARS-CoV-2 vaccine 2021; PubMed Scopus Google Scholar However, use of such a recombinant YF17D vaccine potential S.J. B. B. Chen virus vaccines based on a yellow fever vaccine with key for a PubMed Scopus Google Scholar In and of YF-S0 in and pose a risk for vaccine-associated viscerotropic disease and vaccine-associated neurotropic disease are linked to A.D. fever and of adverse events PubMed Scopus Google Scholar this YF17D vaccine is as for in safety S.J. B. B. Chen virus vaccines based on a yellow fever vaccine with key for a PubMed Scopus Google we investigated the biodistribution and shedding of YF-S0 in with the (1) to to YF-S0 in virus dissemination to (2) to the of YF-S0 for by its and in L. S. J. D. R. B. L. A SARS-CoV-2 vaccine 2021; PubMed Scopus Google Scholar the for and to to viral RNA in this any for shedding of recombinant infectious virus. is a and YF-S0 YF17D as a YF-S0 pose an risk to this we the of YF-S0 on Aedes to its transmission was as mosquito because of its high vector for M. Y. L. B. Chen of yellow fever virus transmission in the 2020; PubMed Scopus Google Scholar is that YF-Asibi and in YF17D the and is to to K. J. B. S. of yellow fever for vaccine in infection of Aedes PubMed Scopus Google L. G. M. G. S. the and dissemination of the yellow fever vaccine in Aedes PubMed Scopus Google Scholar these as to transmission of YF-S0 by a we the favorable safety profile of YF-S0 by limited dissemination and shedding in hamsters and no risk for

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