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1.
Viruses ; 14(6)2022 Jun 09.
Article in English | MEDLINE | ID: covidwho-1884392

ABSTRACT

To mitigate the massive COVID-19 burden caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), several vaccination campaigns were initiated. We performed a single-center observational trial to monitor the mid- (3 months) and long-term (10 months) adaptive immune response and to document breakthrough infections (BTI) in healthcare workers (n = 84) upon BNT162b2 vaccination in a real-world setting. Firstly, serology was determined through immunoassays. Secondly, antibody functionality was analyzed via in vitro binding inhibition and pseudovirus neutralization and circulating receptor-binding domain (RBD)-specific B cells were assessed. Moreover, the induction of SARS-CoV-2-specific T cells was investigated by an interferon-γ release assay combined with flowcytometric profiling of activated CD4+ and CD8+ T cells. Within individuals that did not experience BTI (n = 62), vaccine-induced humoral and cellular immune responses were not correlated. Interestingly, waning over time was more pronounced within humoral compared to cellular immunity. In particular, 45 of these 62 subjects no longer displayed functional neutralization against the delta variant of concern (VoC) at long-term follow-up. Noteworthily, we reported a high incidence of symptomatic BTI cases (17.11%) caused by alpha and delta VoCs, although vaccine-induced immunity was only slightly reduced compared to subjects without BTI at mid-term follow-up.

2.
Microb Biotechnol ; 2022 Apr 27.
Article in English | MEDLINE | ID: covidwho-1816502

ABSTRACT

Based on archived medical records and evolutionary modelling, a Coronavirus has been hypothesized as root and causative agent of the so-called 'Russian Flu' pandemic that surged in 1889-1890. In a Correspondence published in this volume of Microbial Biotechnology, Ramassy and colleagues try to support historical evidence by true experimental data using 'palaeoserology', a novel approach combining archaeology and modern immunological analysis. This Opinion piece tries to weigh arguments how strong such data may be, and where a refinement of methodology might be desirable before textbooks of medical history switch to call the 1890s pandemic 'Russian Corona'.

3.
Front Immunol ; 13: 845969, 2022.
Article in English | MEDLINE | ID: covidwho-1775680

ABSTRACT

To control the coronavirus disease 2019 (COVID-19) pandemic and the emergence of different variants of concern (VoCs), novel vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are needed. In this study, we report the potent immunogenicity and efficacy induced in hamsters by a vaccine candidate based on a modified vaccinia virus Ankara (MVA) vector expressing a human codon optimized full-length SARS-CoV-2 spike (S) protein (MVA-S). Immunization with one or two doses of MVA-S elicited high titers of S- and receptor-binding domain (RBD)-binding IgG antibodies and neutralizing antibodies against parental SARS-CoV-2 and VoC alpha, beta, gamma, delta, and omicron. After SARS-CoV-2 challenge, MVA-S-vaccinated hamsters showed a significantly strong reduction of viral RNA and infectious virus in the lungs compared to the MVA-WT control group. Moreover, a marked reduction in lung histopathology was also observed in MVA-S-vaccinated hamsters. These results favor the use of MVA-S as a potential vaccine candidate for SARS-CoV-2 in clinical trials.


Subject(s)
COVID-19 , Animals , Antibodies, Viral , COVID-19/prevention & control , COVID-19 Vaccines , Cricetinae , Humans , SARS-CoV-2 , Spike Glycoprotein, Coronavirus/genetics , Vaccinia virus/genetics
4.
Antiviral Res ; 202: 105311, 2022 06.
Article in English | MEDLINE | ID: covidwho-1773103

ABSTRACT

Nelfinavir is an HIV protease inhibitor that has been widely prescribed as a component of highly active antiretroviral therapy, and has been reported to exert in vitro antiviral activity against SARS-CoV-2. We here assessed the effect of Nelfinavir in a SARS-CoV-2 infection model in hamsters. Despite the fact that Nelfinavir, [50 mg/kg twice daily (BID) for four consecutive days], did not reduce viral RNA load and infectious virus titres in the lung of infected animals, treatment resulted in a substantial improvement of SARS-CoV-2-induced lung pathology. This was accompanied by a dense infiltration of neutrophils in the lung interstitium which was similarly observed in non-infected hamsters. Nelfinavir resulted also in a marked increase in activated neutrophils in the blood, as observed in non-infected animals. Although Nelfinavir treatment did not alter the expression of chemoattractant receptors or adhesion molecules on human neutrophils, in vitro migration of human neutrophils to the major human neutrophil attractant CXCL8 was augmented by this protease inhibitor. Nelfinavir appears to induce an immunomodulatory effect associated with increasing neutrophil number and functionality, which may be linked to the marked improvement in SARS-CoV-2 lung pathology independent of its lack of antiviral activity. Since Nelfinavir is no longer used for the treatment of HIV, we studied the effect of two other HIV protease inhibitors, namely the combination Lopinavir/Ritonavir (Kaletra™) in this model. This combination resulted in a similar protective effect as Nelfinavir against SARS-CoV2 induced lung pathology in hamsters.


Subject(s)
COVID-19 , HIV Infections , HIV Protease Inhibitors , Animals , COVID-19/drug therapy , Cricetinae , HIV Infections/drug therapy , HIV Protease Inhibitors/pharmacology , HIV Protease Inhibitors/therapeutic use , Lopinavir/pharmacology , Lopinavir/therapeutic use , Lung , Mesocricetus , Nelfinavir/pharmacology , Nelfinavir/therapeutic use , RNA, Viral , Ritonavir/therapeutic use , SARS-CoV-2
5.
Mol Ther Methods Clin Dev ; 25: 215-224, 2022 Jun 09.
Article in English | MEDLINE | ID: covidwho-1740074

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.

6.
EuropePMC;
Preprint in English | EuropePMC | ID: ppcovidwho-327091

ABSTRACT

New platforms are urgently needed for the design of novel prophylactic vaccines and advanced immune therapies. Live-attenuated yellow fever vaccine YF17D serves as vector for several licensed vaccines and platform for novel vaccine candidates. Based on YF17D, we developed YF-S0 as exceptionally potent COVID-19 vaccine candidate. However, use of such live RNA virus vaccines raises safety concerns, i.e., adverse events linked to original YF17D (yellow fever vaccine-associated neurotropic;YEL-AND, and viscerotropic disease;YEL-AVD). In this study, we investigated the biodistribution and shedding of YF-S0 in hamsters. Likewise, we introduced hamsters deficient in STAT2 signaling as new preclinical model of YEL-AND/AVD. Compared to parental YF17D, YF-S0 showed an improved safety with limited dissemination to brain and visceral tissues, absent or low viremia, and no shedding of infectious virus. Considering 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 evaluated in comparison to readily transmitting YFV-Asibi strain and non-transmitting YF17D vaccine, with no evidence for productive infection of vector mosquitoes. The overall favorable safety profile of YF-S0 is expected to translate to other novel vaccines that are based on the same YF17D platform.

7.
Antiviral Res ; 198: 105253, 2022 02.
Article in English | MEDLINE | ID: covidwho-1654044

ABSTRACT

The emergence of SARS-CoV-2 variants of concern (VoCs) has exacerbated the COVID-19 pandemic. End of November 2021, a new SARS-CoV-2 variant namely the omicron (B.1.1.529) emerged. Since this omicron variant is heavily mutated in the spike protein, WHO classified this variant as the 5th variant of concern (VoC). We previously demonstrated that the ancestral strain and the other SARS-CoV-2 VoCs replicate efficiently in and cause a COVID19-like pathology in Syrian hamsters. We here wanted to explore the infectivity of the omicron variant in comparison to the ancestral D614G strain in the hamster model. Strikingly, in hamsters that had been infected with the omicron variant, a 3 log10 lower viral RNA load was detected in the lungs as compared to animals infected with D614G and no infectious virus was detectable in this organ. Moreover, histopathological examination of the lungs from omicron-infected hamsters revealed no signs of peri-bronchial inflammation or bronchopneumonia.


Subject(s)
COVID-19/veterinary , Disease Models, Animal , SARS-CoV-2/growth & development , Animals , Cricetinae , Humans , Lung/virology , Mesocricetus/virology , Species Specificity , Viral Load
8.
Vaccines (Basel) ; 9(12)2021 Dec 16.
Article in English | MEDLINE | ID: covidwho-1580389

ABSTRACT

The tremendous global impact of the current SARS-CoV-2 pandemic, as well as other current and recent outbreaks of (re)emerging viruses, emphasize the need for fast-track development of effective vaccines. Yellow fever virus 17D (YF17D) is a live-attenuated virus vaccine with an impressive efficacy record in humans, and therefore, it is a very attractive platform for the development of novel chimeric vaccines against various pathogens. In the present study, we generated a YF17D-based replicon vaccine platform by replacing the prM and E surface proteins of YF17D with antigenic subdomains from the spike (S) proteins of three different betacoronaviruses: MERS-CoV, SARS-CoV and MHV. The prM and E proteins were provided in trans for the packaging of these RNA replicons into single-round infectious particles capable of expressing coronavirus antigens in infected cells. YF17D replicon particles expressing the S1 regions of the MERS-CoV and SARS-CoV spike proteins were immunogenic in mice and elicited (neutralizing) antibody responses against both the YF17D vector and the coronavirus inserts. Thus, YF17D replicon-based vaccines, and their potential DNA- or mRNA-based derivatives, may constitute a promising and particularly safe vaccine platform for current and future emerging coronaviruses.

9.
Methods Mol Biol ; 2410: 177-192, 2022.
Article in English | MEDLINE | ID: covidwho-1575553

ABSTRACT

The SARS-CoV-2 pandemic has impacted the health of humanity after the outbreak in Hubei, China in late December 2019. Ever since, it has taken unprecedented proportions and rapidity causing over a million fatal cases. Recently, a robust Syrian golden hamster model recapitulating COVID-19 was developed in search for effective therapeutics and vaccine candidates. However, overt clinical disease symptoms were largely absent despite high levels of virus replication and associated pathology in the respiratory tract. Therefore, we used micro-computed tomography (µCT) to longitudinally visualize lung pathology and to preclinically assess candidate vaccines. µCT proved to be crucial to quantify and noninvasively monitor disease progression, to evaluate candidate vaccine efficacy, and to improve screening efforts by allowing longitudinal data without harming live animals. Here, we give a comprehensive guide on how to use low-dose high-resolution µCT to follow-up SARS-CoV-2-induced disease and test the efficacy of COVID-19 vaccine candidates in hamsters. Our approach can likewise be applied for the preclinical assessment of antiviral and anti-inflammatory drug treatments in vivo.


Subject(s)
COVID-19 Vaccines , COVID-19 , Animals , COVID-19/prevention & control , Cricetinae , X-Ray Microtomography
10.
EuropePMC; 2021.
Preprint in English | EuropePMC | ID: ppcovidwho-295991

ABSTRACT

All currently used first-generation COVID-19 vaccines are based on prototypic spike sequences from ancestral 2019 SARS-CoV-2 strains. However, it remains unclear to which extent vaccination protects against variants of concern (VOC) which fuel the ongoing pandemic. Here we show in a stringent hamster challenge model that immunization using prototypic spike expressed form a potent YF17D viral vector (Sanchez-Felipe et al. 2021) provides vigorous protection against infection with ancestral virus and VOC Alpha (B.1.1.7), however, is insufficient to provide optimal protection against the Beta (B.1.351) variant. To improve vaccine efficacy, a revised vaccine candidate was created that carries a modified spike antigen designed to cover the entire VOC spectrum. Vaccination of hamsters with this updated vaccine candidate provides full protection against intranasal challenge with all four VOC Alpha, Beta, Gamma (P.1) and Delta (B.1.617.2) resulting in complete elimination of infectious virus from the lungs and a marked improvement in lung pathology. Vaccinated hamsters did also no longer transmit the Delta variant to non-vaccinated sentinels. Overall, our data indicate that current first-generation COVID-19 vaccines need to be urgently updated to cover emerging sequence diversity of VOCs to maintain vaccine efficacy and to impede virus spread at the community level.

11.
2021.
Preprint in English | Other preprints | ID: ppcovidwho-295926

ABSTRACT

We have identified camelid single-domain antibodies (VHHs) that cross-neutralize SARS-CoV-1 and −2, such as VHH72, which binds to a unique highly conserved epitope in the viral receptor-binding domain (RBD) that is difficult to access for human antibodies. Here, we establish a protein engineering path for how a stable, long-acting drug candidate can be generated out of such a VHH building block. When fused to human IgG1-Fc, the prototype VHH72 molecule prophylactically protects hamsters from SARS-CoV-2. In addition, we demonstrate that both systemic and intranasal application protects hACE-2-transgenic mice from SARS-CoV-2 induced lethal disease progression. To boost potency of the lead, we used structure-guided molecular modeling combined with rapid yeast-based Fc-fusion prototyping, resulting in the affinity-matured VHH72_S56A-Fc, with subnanomolar SARS-CoV-1 and −2 neutralizing potency. Upon humanization, VHH72_S56A was fused to a human IgG1 Fc with optimized manufacturing homogeneity and silenced effector functions for enhanced safety, and its stability as well as lack of off-target binding was extensively characterized. Therapeutic systemic administration of a low dose of VHH72_S56A-Fc antibodies strongly restricted replication of both original and D614G mutant variants of SARS-CoV-2 virus in hamsters, and minimized the development of lung damage. This work led to the selection of XVR011 for clinical development, a highly stable anti-COVID-19 biologic with excellent manufacturability. Additionally, we show that XVR011 is unaffected in its neutralizing capacity of currently rapidly spreading SARS-CoV-2 variants, and demonstrate its unique, wide scope of binding across the Sarbecovirus clades.

12.
EuropePMC; 2021.
Preprint in English | EuropePMC | ID: ppcovidwho-293110

ABSTRACT

Current licensed COVID-19 vaccines are based on antigen sequences of initial SARS-CoV-2 isolates that emerged in 2019. By mid 2021 these historical virus strains have been completely replaced by new cosmopolitan SARS-CoV-2 lineages. The ongoing pandemic has been further driven by emerging variants of concern (VOC) Alpha, Beta, Gamma and, lately predominant, Delta. These are characterized by an increased transmissibility and possible escape from naturally acquired or vaccine-induced immunity. We here show, using a YF17D-vectored first-generation COVID-19 vaccine (Sanchez-Felipe et al., 2021) and a stringent hamster challenge model (Abdelnabi et al., 2021) that the immunity elicited by a prototypic spike antigen is insufficient to provide optimal protection against the Beta VoC, urging for an antigenic update. We therefore designed an updated second-generation vaccine candidate that carries the sequence of a spike antigen that includes crucial epitopes from multiple VOCs. This vaccine candidate yielded a marked change in target antigen spectrum covered as demonstrated by (i) antigenic cartography and (ii) full protection against infection and virus-induced disease caused by any of the four VOCs (Alpha, Beta, Gamma and Delta) used for challenge. This more universal COVID-19 vaccine candidate also efficiently blocked direct transmission of VOC Delta from vaccinated infected hamsters to non-vaccinated sentinels under prolonged co-housing conditions. In conclusion, our data suggest that current first-generation COVID-19 vaccines need to be adapted to cover emerging sequence diversity of VOC to preserve vaccine efficacy and to contain virus spread at the community level.

13.
Sci Transl Med ; 13(621): eabi7826, 2021 Nov 24.
Article in English | MEDLINE | ID: covidwho-1450584

ABSTRACT

Broadly neutralizing antibodies are an important treatment for individuals with coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Antibody-based therapeutics are also essential for pandemic preparedness against future Sarbecovirus outbreaks. Camelid-derived single domain antibodies (VHHs) exhibit potent antimicrobial activity and are being developed as SARS-CoV-2­neutralizing antibody-like therapeutics. Here, we identified VHHs that neutralize both SARS-CoV-1 and SARS-CoV-2, including now circulating variants. We observed that the VHHs bound to a highly conserved epitope in the receptor binding domain of the viral spike protein that is difficult to access for human antibodies. Structure-guided molecular modeling, combined with rapid yeast-based prototyping, resulted in an affinity enhanced VHH-human immunoglobulin G1 Fc fusion molecule with subnanomolar neutralizing activity. This VHH-Fc fusion protein, produced in and purified from cultured Chinese hamster ovary cells, controlled SARS-CoV-2 replication in prophylactic and therapeutic settings in mice expressing human angiotensin converting enzyme 2 and in hamsters infected with SARS-CoV-2. These data led to affinity-enhanced selection of the VHH, XVR011, a stable anti­COVID-19 biologic that is now being evaluated in the clinic.


Subject(s)
COVID-19 , Spike Glycoprotein, Coronavirus , Animals , Antibodies, Neutralizing , Antibodies, Viral , Humans , Models, Animal , SARS-CoV-2
14.
EBioMedicine ; 72: 103595, 2021 Oct.
Article in English | MEDLINE | ID: covidwho-1433162

ABSTRACT

BACKGROUND: Favipiravir and Molnupiravir, orally available antivirals, have been reported to exert antiviral activity against SARS-CoV-2. First efficacy data have been recently reported in COVID-19 patients. METHODS: We here report on the combined antiviral effect of both drugs in a SARS-CoV-2 Syrian hamster infection model. The infected hamsters were treated twice daily with the vehicle (the control group) or a suboptimal dose of each compound or a combination of both compounds. FINDINGS: When animals were treated with a combination of suboptimal doses of Molnupiravir and Favipiravir at the time of infection, a marked combined potency at endpoint is observed. Infectious virus titers in the lungs of animals treated with the combination are reduced by ∼5 log10 and infectious virus are no longer detected in the lungs of >60% of treated animals. When start of treatment was delayed with one day a reduction of titers in the lungs of 2.4 log10 was achieved. Moreover, treatment of infected animals nearly completely prevented transmission to co-housed untreated sentinels. Both drugs result in an increased mutation frequency of the remaining viral RNA recovered from the lungs of treated animals. In the combo-treated hamsters, an increased frequency of C-to-T mutations in the viral RNA is observed as compared to the single treatment groups which may explain the pronounced antiviral potency of the combination. INTERPRETATION: Our findings may lay the basis for the design of clinical studies to test the efficacy of the combination of Molnupiravir/Favipiravir in the treatment of COVID-19. FUNDING: stated in the acknowledgment.


Subject(s)
Amides/therapeutic use , COVID-19/drug therapy , Cytidine/analogs & derivatives , Hydroxylamines/therapeutic use , Lung/virology , Pyrazines/therapeutic use , Amides/pharmacology , Animals , Antiviral Agents/pharmacology , Antiviral Agents/therapeutic use , COVID-19/transmission , Cytidine/pharmacology , Cytidine/therapeutic use , Disease Models, Animal , Drug Therapy, Combination , Female , Hydroxylamines/pharmacology , Mesocricetus , Pyrazines/pharmacology , RNA, Viral , Treatment Outcome , Viral Load
15.
EBioMedicine ; 68: 103403, 2021 Jun.
Article in English | MEDLINE | ID: covidwho-1245928

ABSTRACT

BACKGROUND: Within one year after its emergence, more than 108 million people acquired SARS-CoV-2 and almost 2·4 million succumbed to COVID-19. New SARS-CoV-2 variants of concern (VoC) are emerging all over the world, with the threat of being more readily transmitted, being more virulent, or escaping naturally acquired and vaccine-induced immunity. At least three major prototypic VoC have been identified, i.e. the United Kingdom, UK (B.1.1.7), South African (B.1.351) and Brazilian (B.1.1.28.1) variants. These are replacing formerly dominant strains and sparking new COVID-19 epidemics. METHODS: We studied the effect of infection with prototypic VoC from both B.1.1.7 and B.1.351 variants in female Syrian golden hamsters to assess their relative infectivity and virulence in direct comparison to two basal SARS-CoV-2 strains isolated in early 2020. FINDINGS: A very efficient infection of the lower respiratory tract of hamsters by these VoC is observed. In line with clinical evidence from patients infected with these VoC, no major differences in disease outcome were observed as compared to the original strains as was quantified by (i) histological scoring, (ii) micro-computed tomography, and (iii) analysis of the expression profiles of selected antiviral and pro-inflammatory cytokine genes. Noteworthy however, in hamsters infected with VoC B.1.1.7, a particularly strong elevation of proinflammatory cytokines was detected. INTERPRETATION: We established relevant preclinical infection models that will be pivotal to assess the efficacy of current and future vaccine(s) (candidates) as well as therapeutics (small molecules and antibodies) against two important SARS-CoV-2 VoC. FUNDING: Stated in the acknowledgment.


Subject(s)
COVID-19/pathology , Cytokines/genetics , Respiratory System/virology , SARS-CoV-2/pathogenicity , Animals , COVID-19/diagnostic imaging , COVID-19/genetics , Disease Models, Animal , Evolution, Molecular , Female , Gene Expression Profiling , Gene Expression Regulation , Mesocricetus , Respiratory System/diagnostic imaging , Respiratory System/pathology , SARS-CoV-2/classification , SARS-CoV-2/immunology , Virulence , X-Ray Microtomography
16.
Intensive Care Med ; 47(7): 786-789, 2021 07.
Article in English | MEDLINE | ID: covidwho-1241595
17.
Nat Genet ; 53(4): 435-444, 2021 04.
Article in English | MEDLINE | ID: covidwho-1123140

ABSTRACT

The ongoing COVID-19 pandemic has caused a global economic and health crisis. To identify host factors essential for coronavirus infection, we performed genome-wide functional genetic screens with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and human coronavirus 229E. These screens uncovered virus-specific as well as shared host factors, including TMEM41B and PI3K type 3. We discovered that SARS-CoV-2 requires the lysosomal protein TMEM106B to infect human cell lines and primary lung cells. TMEM106B overexpression enhanced SARS-CoV-2 infection as well as pseudovirus infection, suggesting a role in viral entry. Furthermore, single-cell RNA-sequencing of airway cells from patients with COVID-19 demonstrated that TMEM106B expression correlates with SARS-CoV-2 infection. The present study uncovered a collection of coronavirus host factors that may be exploited to develop drugs against SARS-CoV-2 infection or future zoonotic coronavirus outbreaks.


Subject(s)
COVID-19/genetics , CRISPR-Cas Systems , Genome, Human/genetics , Genome-Wide Association Study/methods , Membrane Proteins/genetics , Nerve Tissue Proteins/genetics , Bronchoalveolar Lavage Fluid/cytology , COVID-19/epidemiology , COVID-19/virology , Cell Line, Tumor , Cells, Cultured , Coronavirus 229E, Human/genetics , Epidemics , Epithelial Cells/virology , Gene Expression , Host-Pathogen Interactions , Humans , Proviruses/physiology , SARS-CoV-2/physiology , Virus Internalization
18.
Nature ; 590(7845): 320-325, 2021 02.
Article in English | MEDLINE | ID: covidwho-953381

ABSTRACT

The expanding pandemic of coronavirus disease 2019 (COVID-19) requires the development of safe, efficacious and fast-acting vaccines. Several vaccine platforms are being leveraged for a rapid emergency response1. Here we describe the development of a candidate vaccine (YF-S0) for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that uses live-attenuated yellow fever 17D (YF17D) vaccine as a vector to express a noncleavable prefusion form of the SARS-CoV-2 spike antigen. We assess vaccine safety, immunogenicity and efficacy in several animal models. YF-S0 has an excellent safety profile and induces high levels of SARS-CoV-2 neutralizing antibodies in hamsters (Mesocricetus auratus), mice (Mus musculus) and cynomolgus macaques (Macaca fascicularis), and-concomitantly-protective immunity against yellow fever virus. Humoral immunity is complemented by a cellular immune response with favourable T helper 1 polarization, as profiled in mice. In a hamster model2 and in macaques, YF-S0 prevents infection with SARS-CoV-2. Moreover, a single dose conferred protection from lung disease in most of the vaccinated hamsters within as little as 10 days. Taken together, the quality of the immune responses triggered and the rapid kinetics by which protective immunity can be attained after a single dose warrant further development of this potent SARS-CoV-2 vaccine candidate.


Subject(s)
COVID-19 Vaccines/immunology , COVID-19/immunology , COVID-19/prevention & control , Genetic Vectors/genetics , SARS-CoV-2/immunology , Vaccines, Attenuated/immunology , Yellow Fever Vaccine/genetics , Animals , COVID-19 Vaccines/administration & dosage , COVID-19 Vaccines/adverse effects , COVID-19 Vaccines/genetics , Cricetinae , Disease Models, Animal , Female , Glycosylation , Macaca fascicularis/genetics , Macaca fascicularis/immunology , Macaca fascicularis/virology , Male , Mesocricetus/genetics , Mesocricetus/immunology , Mesocricetus/virology , Mice , Safety , Spike Glycoprotein, Coronavirus/chemistry , Spike Glycoprotein, Coronavirus/genetics , Spike Glycoprotein, Coronavirus/immunology , Spike Glycoprotein, Coronavirus/metabolism , Vaccines, Attenuated/administration & dosage , Vaccines, Attenuated/adverse effects , Vaccines, Attenuated/genetics
19.
Proc Natl Acad Sci U S A ; 117(43): 26955-26965, 2020 10 27.
Article in English | MEDLINE | ID: covidwho-841910

ABSTRACT

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) rapidly spread around the globe after its emergence in Wuhan in December 2019. With no specific therapeutic and prophylactic options available, the virus has infected millions of people of which more than half a million succumbed to the viral disease, COVID-19. The urgent need for an effective treatment together with a lack of small animal infection models has led to clinical trials using repurposed drugs without preclinical evidence of their in vivo efficacy. We established an infection model in Syrian hamsters to evaluate the efficacy of small molecules on both infection and transmission. Treatment of SARS-CoV-2-infected hamsters with a low dose of favipiravir or hydroxychloroquine with(out) azithromycin resulted in, respectively, a mild or no reduction in virus levels. However, high doses of favipiravir significantly reduced infectious virus titers in the lungs and markedly improved lung histopathology. Moreover, a high dose of favipiravir decreased virus transmission by direct contact, whereas hydroxychloroquine failed as prophylaxis. Pharmacokinetic modeling of hydroxychloroquine suggested that the total lung exposure to the drug did not cause the failure. Our data on hydroxychloroquine (together with previous reports in macaques and ferrets) thus provide no scientific basis for the use of this drug in COVID-19 patients. In contrast, the results with favipiravir demonstrate that an antiviral drug at nontoxic doses exhibits a marked protective effect against SARS-CoV-2 in a small animal model. Clinical studies are required to assess whether a similar antiviral effect is achievable in humans without toxic effects.


Subject(s)
Amides/therapeutic use , Antiviral Agents/therapeutic use , Betacoronavirus/drug effects , Hydroxychloroquine/therapeutic use , Pyrazines/therapeutic use , Amides/pharmacokinetics , Animals , COVID-19/drug therapy , Chlorocebus aethiops , Coronavirus Infections/drug therapy , Coronavirus Infections/virology , Cricetinae , Disease Models, Animal , Disease Transmission, Infectious/prevention & control , Dose-Response Relationship, Drug , Drug Evaluation, Preclinical , Female , Hydroxychloroquine/pharmacokinetics , Lung/drug effects , Lung/pathology , Lung/virology , Pyrazines/pharmacokinetics , SARS-CoV-2 , Treatment Outcome , Vero Cells , Viral Load/drug effects
20.
Nature ; 586(7830): 509-515, 2020 10.
Article in English | MEDLINE | ID: covidwho-792975

ABSTRACT

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the aetiological agent of coronavirus disease 2019 (COVID-19), an emerging respiratory infection caused by the introduction of a novel coronavirus into humans late in 2019 (first detected in Hubei province, China). As of 18 September 2020, SARS-CoV-2 has spread to 215 countries, has infected more than 30 million people and has caused more than 950,000 deaths. As humans do not have pre-existing immunity to SARS-CoV-2, there is an urgent need to develop therapeutic agents and vaccines to mitigate the current pandemic and to prevent the re-emergence of COVID-19. In February 2020, the World Health Organization (WHO) assembled an international panel to develop animal models for COVID-19 to accelerate the testing of vaccines and therapeutic agents. Here we summarize the findings to date and provides relevant information for preclinical testing of vaccine candidates and therapeutic agents for COVID-19.


Subject(s)
Coronavirus Infections/drug therapy , Coronavirus Infections/prevention & control , Disease Models, Animal , Pandemics/prevention & control , Pneumonia, Viral/drug therapy , Pneumonia, Viral/prevention & control , Animals , Betacoronavirus/drug effects , Betacoronavirus/immunology , COVID-19 , COVID-19 Vaccines , Coronavirus Infections/immunology , Ferrets/virology , Humans , Mesocricetus/virology , Mice , Pneumonia, Viral/immunology , Primates/virology , SARS-CoV-2 , Viral Vaccines/immunology
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