Evaluation of the mRNA-1273 Vaccine against SARS-CoV-2 in Nonhuman Primates.
Vaccines to prevent coronavirus disease 2019 (Covid-19) are urgently needed. The effect of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines on viral replication in both upper and lower airways is important to evaluate in nonhuman primates.
Nonhuman primates received 10 or 100 μg of mRNA-1273, a vaccine encoding the prefusion-stabilized spike protein of SARS-CoV-2, or no vaccine. Antibody and T-cell responses were assessed before upper- and lower-airway challenge with SARS-CoV-2. Active viral replication and viral genomes in bronchoalveolar-lavage (BAL) fluid and nasal swab specimens were assessed by polymerase chain reaction, and histopathological analysis and viral quantification were performed on lung-tissue specimens.
The mRNA-1273 vaccine candidate induced antibody levels exceeding those in human convalescent-phase serum, with live-virus reciprocal 50% inhibitory dilution (ID50) geometric mean titers of 501 in the 10-μg dose group and 3481 in the 100-μg dose group. Vaccination induced type 1 helper T-cell (Th1)-biased CD4 T-cell responses and low or undetectable Th2 or CD8 T-cell responses. Viral replication was not detectable in BAL fluid by day 2 after challenge in seven of eight animals in both vaccinated groups. No viral replication was detectable in the nose of any of the eight animals in the 100-μg dose group by day 2 after challenge, and limited inflammation or detectable viral genome or antigen was noted in lungs of animals in either vaccine group.
Vaccination of nonhuman primates with mRNA-1273 induced robust SARS-CoV-2 neutralizing activity, rapid protection in the upper and lower airways, and no pathologic changes in the lung. (Funded by the National Institutes of Health and others.).
Corbett KS
，Flynn B
，Foulds KE
，Francica JR
，Boyoglu-Barnum S
，Werner AP
，Flach B
，O'Connell S
，Bock KW
，Minai M
，Nagata BM
，Andersen H
，Martinez DR
，Noe AT
，Douek N
，Donaldson MM
，Nji NN
，Alvarado GS
，Edwards DK
，Flebbe DR
，Lamb E
，Doria-Rose NA
，Lin BC
，Louder MK
，O'Dell S
，Schmidt SD
，Phung E
，Chang LA
，Yap C
，Todd JM
，Pessaint L
，Van Ry A
，Browne S
，Greenhouse J
，Putman-Taylor T
，Strasbaugh A
，Campbell TA
，Cook A
，Dodson A
，Steingrebe K
，Shi W
，Zhang Y
，Abiona OM
，Wang L
，Pegu A
，Yang ES
，Leung K
，Zhou T
，Teng IT
，Widge A
，Gordon I
，Novik L
，Gillespie RA
，Loomis RJ
，Moliva JI
，Stewart-Jones G
，Himansu S
，Kong WP
，Nason MC
，Morabito KM
，Ruckwardt TJ
，Ledgerwood JE
，Gaudinski MR
，Kwong PD
，Mascola JR
，Carfi A
，Lewis MG
，Baric RS
，McDermott A
，Moore IN
，Sullivan NJ
，Roederer M
，Seder RA
，Graham BS
... -
《-》
DNA vaccine protection against SARS-CoV-2 in rhesus macaques.
The global coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has made the development of a vaccine a top biomedical priority. In this study, we developed a series of DNA vaccine candidates expressing different forms of the SARS-CoV-2 spike (S) protein and evaluated them in 35 rhesus macaques. Vaccinated animals developed humoral and cellular immune responses, including neutralizing antibody titers at levels comparable to those found in convalescent humans and macaques infected with SARS-CoV-2. After vaccination, all animals were challenged with SARS-CoV-2, and the vaccine encoding the full-length S protein resulted in >3.1 and >3.7 log10 reductions in median viral loads in bronchoalveolar lavage and nasal mucosa, respectively, as compared with viral loads in sham controls. Vaccine-elicited neutralizing antibody titers correlated with protective efficacy, suggesting an immune correlate of protection. These data demonstrate vaccine protection against SARS-CoV-2 in nonhuman primates.
Yu J
，Tostanoski LH
，Peter L
，Mercado NB
，McMahan K
，Mahrokhian SH
，Nkolola JP
，Liu J
，Li Z
，Chandrashekar A
，Martinez DR
，Loos C
，Atyeo C
，Fischinger S
，Burke JS
，Slein MD
，Chen Y
，Zuiani A
，Lelis FJN
，Travers M
，Habibi S
，Pessaint L
，Van Ry A
，Blade K
，Brown R
，Cook A
，Finneyfrock B
，Dodson A
，Teow E
，Velasco J
，Zahn R
，Wegmann F
，Bondzie EA
，Dagotto G
，Gebre MS
，He X
，Jacob-Dolan C
，Kirilova M
，Kordana N
，Lin Z
，Maxfield LF
，Nampanya F
，Nityanandam R
，Ventura JD
，Wan H
，Cai Y
，Chen B
，Schmidt AG
，Wesemann DR
，Baric RS
，Alter G
，Andersen H
，Lewis MG
，Barouch DH
... -
《-》
Safety and immunogenicity of the ChAdOx1 nCoV-19 vaccine against SARS-CoV-2: a preliminary report of a phase 1/2, single-blind, randomised controlled trial.
The pandemic of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) might be curtailed by vaccination. We assessed the safety, reactogenicity, and immunogenicity of a viral vectored coronavirus vaccine that expresses the spike protein of SARS-CoV-2.
We did a phase 1/2, single-blind, randomised controlled trial in five trial sites in the UK of a chimpanzee adenovirus-vectored vaccine (ChAdOx1 nCoV-19) expressing the SARS-CoV-2 spike protein compared with a meningococcal conjugate vaccine (MenACWY) as control. Healthy adults aged 18-55 years with no history of laboratory confirmed SARS-CoV-2 infection or of COVID-19-like symptoms were randomly assigned (1:1) to receive ChAdOx1 nCoV-19 at a dose of 5 × 1010 viral particles or MenACWY as a single intramuscular injection. A protocol amendment in two of the five sites allowed prophylactic paracetamol to be administered before vaccination. Ten participants assigned to a non-randomised, unblinded ChAdOx1 nCoV-19 prime-boost group received a two-dose schedule, with the booster vaccine administered 28 days after the first dose. Humoral responses at baseline and following vaccination were assessed using a standardised total IgG ELISA against trimeric SARS-CoV-2 spike protein, a muliplexed immunoassay, three live SARS-CoV-2 neutralisation assays (a 50% plaque reduction neutralisation assay [PRNT50]; a microneutralisation assay [MNA50, MNA80, and MNA90]; and Marburg VN), and a pseudovirus neutralisation assay. Cellular responses were assessed using an ex-vivo interferon-γ enzyme-linked immunospot assay. The co-primary outcomes are to assess efficacy, as measured by cases of symptomatic virologically confirmed COVID-19, and safety, as measured by the occurrence of serious adverse events. Analyses were done by group allocation in participants who received the vaccine. Safety was assessed over 28 days after vaccination. Here, we report the preliminary findings on safety, reactogenicity, and cellular and humoral immune responses. The study is ongoing, and was registered at ISRCTN, 15281137, and ClinicalTrials.gov, NCT04324606.
Between April 23 and May 21, 2020, 1077 participants were enrolled and assigned to receive either ChAdOx1 nCoV-19 (n=543) or MenACWY (n=534), ten of whom were enrolled in the non-randomised ChAdOx1 nCoV-19 prime-boost group. Local and systemic reactions were more common in the ChAdOx1 nCoV-19 group and many were reduced by use of prophylactic paracetamol, including pain, feeling feverish, chills, muscle ache, headache, and malaise (all p<0·05). There were no serious adverse events related to ChAdOx1 nCoV-19. In the ChAdOx1 nCoV-19 group, spike-specific T-cell responses peaked on day 14 (median 856 spot-forming cells per million peripheral blood mononuclear cells, IQR 493-1802; n=43). Anti-spike IgG responses rose by day 28 (median 157 ELISA units [EU], 96-317; n=127), and were boosted following a second dose (639 EU, 360-792; n=10). Neutralising antibody responses against SARS-CoV-2 were detected in 32 (91%) of 35 participants after a single dose when measured in MNA80 and in 35 (100%) participants when measured in PRNT50. After a booster dose, all participants had neutralising activity (nine of nine in MNA80 at day 42 and ten of ten in Marburg VN on day 56). Neutralising antibody responses correlated strongly with antibody levels measured by ELISA (R2=0·67 by Marburg VN; p<0·001).
ChAdOx1 nCoV-19 showed an acceptable safety profile, and homologous boosting increased antibody responses. These results, together with the induction of both humoral and cellular immune responses, support large-scale evaluation of this candidate vaccine in an ongoing phase 3 programme.
UK Research and Innovation, Coalition for Epidemic Preparedness Innovations, National Institute for Health Research (NIHR), NIHR Oxford Biomedical Research Centre, Thames Valley and South Midland's NIHR Clinical Research Network, and the German Center for Infection Research (DZIF), Partner site Gießen-Marburg-Langen.
Folegatti PM
，Ewer KJ
，Aley PK
，Angus B
，Becker S
，Belij-Rammerstorfer S
，Bellamy D
，Bibi S
，Bittaye M
，Clutterbuck EA
，Dold C
，Faust SN
，Finn A
，Flaxman AL
，Hallis B
，Heath P
，Jenkin D
，Lazarus R
，Makinson R
，Minassian AM
，Pollock KM
，Ramasamy M
，Robinson H
，Snape M
，Tarrant R
，Voysey M
，Green C
，Douglas AD
，Hill AVS
，Lambe T
，Gilbert SC
，Pollard AJ
，Oxford COVID Vaccine Trial Group
... -
《-》
ResearchGate
(全网免费下载)
钛学术
(全网免费下载)
