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1.
Nat Med ; 27(11): 2032-2040, 2021 11.
Article in English | MEDLINE | ID: covidwho-1526097

ABSTRACT

The global supply of COVID-19 vaccines remains limited. An understanding of the immune response that is predictive of protection could facilitate rapid licensure of new vaccines. Data from a randomized efficacy trial of the ChAdOx1 nCoV-19 (AZD1222) vaccine in the United Kingdom was analyzed to determine the antibody levels associated with protection against SARS-CoV-2. Binding and neutralizing antibodies at 28 days after the second dose were measured in infected and noninfected vaccine recipients. Higher levels of all immune markers were correlated with a reduced risk of symptomatic infection. A vaccine efficacy of 80% against symptomatic infection with majority Alpha (B.1.1.7) variant of SARS-CoV-2 was achieved with 264 (95% CI: 108, 806) binding antibody units (BAU)/ml: and 506 (95% CI: 135, not computed (beyond data range) (NC)) BAU/ml for anti-spike and anti-RBD antibodies, and 26 (95% CI: NC, NC) international unit (IU)/ml and 247 (95% CI: 101, NC) normalized neutralization titers (NF50) for pseudovirus and live-virus neutralization, respectively. Immune markers were not correlated with asymptomatic infections at the 5% significance level. These data can be used to bridge to new populations using validated assays, and allow extrapolation of efficacy estimates to new COVID-19 vaccines.

2.
Lancet Microbe ; 2021 Nov 03.
Article in English | MEDLINE | ID: covidwho-1505678

ABSTRACT

Background: ChAdOx1-vectored vaccine candidates against several pathogens have been developed and tested in clinical trials and ChAdOx1 nCoV-19 has now been licensed for emergency use for COVID-19. We assessed the safety and immunogenicity of the ChAdOx1 MERS vaccine in a phase 1b trial in healthy Middle Eastern adults. Method: MERS002 is an open-label, non-randomised, dose-escalation, phase 1b trial. Healthy Middle Eastern adults aged 18-50 years were included in the study. ChAdOx1 MERS was administered as a single intramuscular injection into the deltoid muscle of the non-dominant arm at three different dose groups: 5·0 × 109 viral particles in a low-dose group, 2·5 × 1010 viral particles in an intermediate-dose group, and 5·0 × 1010 viral particles in a high-dose group. The primary objective was to assess the safety and tolerability of ChAdOx1 MERS, measured by the occurrence of solicited and unsolicited adverse events after vaccination for up to 28 days and occurrence of serious adverse events up to 6 months. The study is registered with ClinicalTrials.gov, NCT04170829. Findings: Between Dec 17, 2019, and June 1, 2020, 24 participants were enrolled (six to the low-dose, nine to the intermediate-dose, and nine to the high-dose group) and received a dose; 23 were available for follow-up at 6 months. The one dose of ChAdOx1 MERS vaccine was well tolerated with no serious adverse event reported during the 6 months of follow-up. Most adverse events were mild (67, 74%) and moderate (17, 19%). Six (7%) severe adverse events were reported by two participants in the intermediate-dose group (two feverish, two headache, one joint pain, and one muscle pain). Pain at the injection site was the most common local and overall adverse event, reported by 15 (63%) of the 24 participants. The most common systemic adverse event was headache, reported by 14 (58%), followed by muscle pain reported by 13 (54%). The vaccine induced both antibody and T cell immune responses in all volunteers; antibodies peaked at day 28 and T cell responses peaked at day 14; and continued until the end of follow-up at 6 months. Interpretation: The acceptable safety and immunogenicity data from this phase 1b trial of ChAdOx1 MERS vaccine candidate in Healthy Middle Eastern adults, combined with previous safety and immunogenicity data from a trial in the UK, support selecting the ChAdOx1 MERS vaccine for advancement into phase 2 clinical evaluation. Funding: UK Department of Health and Social Care, using UK Aid funding, managed by the UK National Institute for Health Research; and King Abdullah International Medical Research Center.

3.
Nat Commun ; 12(1): 5868, 2021 10 07.
Article in English | MEDLINE | ID: covidwho-1462005

ABSTRACT

We investigated ChAdOx1 nCoV-19 (AZD1222) vaccine efficacy against SARS-CoV-2 variants of concern (VOCs) B.1.1.7 and B.1.351 in Syrian hamsters. We previously showed protection against SARS-CoV-2 disease and pneumonia in hamsters vaccinated with a single dose of ChAdOx1 nCoV-19. Here, we observe a 9.5-fold reduction of virus neutralizing antibody titer in vaccinated hamster sera against B.1.351 compared to B.1.1.7. Vaccinated hamsters challenged with B.1.1.7 or B.1.351 do not lose weight compared to control animals. In contrast to control animals, the lungs of vaccinated animals do not show any gross lesions. Minimal to no viral subgenomic RNA (sgRNA) and no infectious virus can be detected in lungs of vaccinated animals. Histopathological evaluation shows extensive pulmonary pathology caused by B.1.1.7 or B.1.351 replication in the control animals, but none in the vaccinated animals. These data demonstrate the effectiveness of the ChAdOx1 nCoV-19 vaccine against clinical disease caused by B.1.1.7 or B.1.351 VOCs.


Subject(s)
COVID-19 Vaccines/immunology , COVID-19/immunology , COVID-19/prevention & control , SARS-CoV-2/immunology , Administration, Intranasal , Amino Acid Substitution , Animals , Antibodies, Neutralizing/immunology , Antibodies, Viral/immunology , COVID-19/virology , Female , Lung/immunology , Lung/pathology , Lung/virology , Mesocricetus , Spike Glycoprotein, Coronavirus/immunology , Vaccination
4.
Nat Commun ; 12(1): 5861, 2021 10 06.
Article in English | MEDLINE | ID: covidwho-1454761

ABSTRACT

Several COVID-19 vaccines have shown good efficacy in clinical trials, but there remains uncertainty about the efficacy of vaccines against different variants. Here, we investigate the efficacy of ChAdOx1 nCoV-19 (AZD1222) against symptomatic COVID-19 in a post-hoc exploratory analysis of a Phase 3 randomised trial in Brazil (trial registration ISRCTN89951424). Nose and throat swabs were tested by PCR in symptomatic participants. Sequencing and genotyping of swabs were performed to determine the lineages of SARS-CoV-2 circulating during the study. Protection against any symptomatic COVID-19 caused by the Zeta (P.2) variant was assessed in 153 cases with vaccine efficacy (VE) of 69% (95% CI 55, 78). 49 cases of B.1.1.28 occurred and VE was 73% (46, 86). The Gamma (P.1) variant arose later in the trial and fewer cases (N = 18) were available for analysis. VE was 64% (-2, 87). ChAdOx1 nCoV-19 provided 95% protection (95% CI 61%, 99%) against hospitalisation due to COVID-19. In summary, we report that ChAdOx1 nCoV-19 protects against emerging variants in Brazil despite the presence of the spike protein mutation E484K.


Subject(s)
COVID-19 Vaccines/immunology , COVID-19/immunology , COVID-19/virology , Phylogeny , SARS-CoV-2/immunology , Adolescent , Adult , Aged , Brazil , Cohort Studies , Dose-Response Relationship, Immunologic , Female , Hospitalization , Humans , Male , Middle Aged , Treatment Outcome , Vaccination , Viral Load/immunology , Young Adult
5.
Nat Med ; 27(11): 2032-2040, 2021 11.
Article in English | MEDLINE | ID: covidwho-1442795

ABSTRACT

The global supply of COVID-19 vaccines remains limited. An understanding of the immune response that is predictive of protection could facilitate rapid licensure of new vaccines. Data from a randomized efficacy trial of the ChAdOx1 nCoV-19 (AZD1222) vaccine in the United Kingdom was analyzed to determine the antibody levels associated with protection against SARS-CoV-2. Binding and neutralizing antibodies at 28 days after the second dose were measured in infected and noninfected vaccine recipients. Higher levels of all immune markers were correlated with a reduced risk of symptomatic infection. A vaccine efficacy of 80% against symptomatic infection with majority Alpha (B.1.1.7) variant of SARS-CoV-2 was achieved with 264 (95% CI: 108, 806) binding antibody units (BAU)/ml: and 506 (95% CI: 135, not computed (beyond data range) (NC)) BAU/ml for anti-spike and anti-RBD antibodies, and 26 (95% CI: NC, NC) international unit (IU)/ml and 247 (95% CI: 101, NC) normalized neutralization titers (NF50) for pseudovirus and live-virus neutralization, respectively. Immune markers were not correlated with asymptomatic infections at the 5% significance level. These data can be used to bridge to new populations using validated assays, and allow extrapolation of efficacy estimates to new COVID-19 vaccines.

6.
Biotechnol Bioeng ; 119(1): 48-58, 2022 01.
Article in English | MEDLINE | ID: covidwho-1441944

ABSTRACT

Manufacturing has been the key factor limiting rollout of vaccination during the COVID-19 pandemic, requiring rapid development and large-scale implementation of novel manufacturing technologies. ChAdOx1 nCoV-19 (AZD1222, Vaxzevria) is an efficacious vaccine against SARS-CoV-2, based upon an adenovirus vector. We describe the development of a process for the production of this vaccine and others based upon the same platform, including novel features to facilitate very large-scale production. We discuss the process economics and the "distributed manufacturing" approach we have taken to provide the vaccine at globally-relevant scale and with international security of supply. Together, these approaches have enabled the largest viral vector manufacturing campaign to date, providing a substantial proportion of global COVID-19 vaccine supply at low cost.


Subject(s)
COVID-19 Vaccines , COVID-19/prevention & control , Drug Industry/methods , Animals , Escherichia coli , Geography , HEK293 Cells , Humans , Pan troglodytes , SARS-CoV-2 , Technology, Pharmaceutical , Vaccination/instrumentation
7.
Lancet Infect Dis ; 21(10): 1337-1338, 2021 10.
Article in English | MEDLINE | ID: covidwho-1386924
8.
Lancet ; 398(10304): 981-990, 2021 09 11.
Article in English | MEDLINE | ID: covidwho-1386827

ABSTRACT

BACKGROUND: COVID-19 vaccine supply shortages are causing concerns about compromised immunity in some countries as the interval between the first and second dose becomes longer. Conversely, countries with no supply constraints are considering administering a third dose. We assessed the persistence of immunogenicity after a single dose of ChAdOx1 nCoV-19 (AZD1222), immunity after an extended interval (44-45 weeks) between the first and second dose, and response to a third dose as a booster given 28-38 weeks after the second dose. METHODS: In this substudy, volunteers aged 18-55 years who were enrolled in the phase 1/2 (COV001) controlled trial in the UK and had received either a single dose or two doses of 5 × 1010 viral particles were invited back for vaccination. Here we report the reactogenicity and immunogenicity of a delayed second dose (44-45 weeks after first dose) or a third dose of the vaccine (28-38 weeks after second dose). Data from volunteers aged 18-55 years who were enrolled in either the phase 1/2 (COV001) or phase 2/3 (COV002), single-blinded, randomised controlled trials of ChAdOx1 nCoV-19 and who had previously received a single dose or two doses of 5 × 1010 viral particles are used for comparison purposes. COV001 is registered with ClinicalTrials.gov, NCT04324606, and ISRCTN, 15281137, and COV002 is registered with ClinicalTrials.gov, NCT04400838, and ISRCTN, 15281137, and both are continuing but not recruiting. FINDINGS: Between March 11 and 21, 2021, 90 participants were enrolled in the third-dose boost substudy, of whom 80 (89%) were assessable for reactogenicity, 75 (83%) were assessable for evaluation of antibodies, and 15 (17%) were assessable for T-cells responses. The two-dose cohort comprised 321 participants who had reactogenicity data (with prime-boost interval of 8-12 weeks: 267 [83%] of 321; 15-25 weeks: 24 [7%]; or 44-45 weeks: 30 [9%]) and 261 who had immunogenicity data (interval of 8-12 weeks: 115 [44%] of 261; 15-25 weeks: 116 [44%]; and 44-45 weeks: 30 [11%]). 480 participants from the single-dose cohort were assessable for immunogenicity up to 44-45 weeks after vaccination. Antibody titres after a single dose measured approximately 320 days after vaccination remained higher than the titres measured at baseline (geometric mean titre of 66·00 ELISA units [EUs; 95% CI 47·83-91·08] vs 1·75 EUs [1·60-1·93]). 32 participants received a late second dose of vaccine 44-45 weeks after the first dose, of whom 30 were included in immunogenicity and reactogenicity analyses. Antibody titres were higher 28 days after vaccination in those with a longer interval between first and second dose than for those with a short interval (median total IgG titre: 923 EUs [IQR 525-1764] with an 8-12 week interval; 1860 EUs [917-4934] with a 15-25 week interval; and 3738 EUs [1824-6625] with a 44-45 week interval). Among participants who received a third dose of vaccine, antibody titres (measured in 73 [81%] participants for whom samples were available) were significantly higher 28 days after a third dose (median total IgG titre: 3746 EUs [IQR 2047-6420]) than 28 days after a second dose (median 1792 EUs [IQR 899-4634]; Wilcoxon signed rank test p=0·0043). T-cell responses were also boosted after a third dose (median response increased from 200 spot forming units [SFUs] per million peripheral blood mononuclear cells [PBMCs; IQR 127-389] immediately before the third dose to 399 SFUs per milion PBMCs [314-662] by day 28 after the third dose; Wilcoxon signed rank test p=0·012). Reactogenicity after a late second dose or a third dose was lower than reactogenicity after a first dose. INTERPRETATION: An extended interval before the second dose of ChAdOx1 nCoV-19 leads to increased antibody titres. A third dose of ChAdOx1 nCoV-19 induces antibodies to a level that correlates with high efficacy after second dose and boosts T-cell responses. FUNDING: UK Research and Innovation, Engineering and Physical Sciences Research Council, National Institute for Health Research, Coalition for Epidemic Preparedness Innovations, National Institute for Health Research Oxford Biomedical Research Centre, Chinese Academy of Medical Sciences Innovation Fund for Medical Science, Thames Valley and South Midlands NIHR Clinical Research Network, AstraZeneca, and Wellcome.


Subject(s)
COVID-19 Vaccines/administration & dosage , Immunogenicity, Vaccine/immunology , Randomized Controlled Trials as Topic , Vaccination , Adult , Female , Humans , Leukocytes, Mononuclear/immunology , Male , Middle Aged , Time Factors , United Kingdom
9.
Lancet HIV ; 8(9): e568-e580, 2021 09.
Article in English | MEDLINE | ID: covidwho-1366764

ABSTRACT

BACKGROUND: People living with HIV are at an increased risk of fatal outcome when admitted to hospital for severe COVID-19 compared with HIV-negative individuals. We aimed to assess safety and immunogenicity of the ChAdOx1 nCoV-19 (AZD1222) vaccine in people with HIV and HIV-negative individuals in South Africa. METHODS: In this ongoing, double-blind, placebo-controlled, phase 1B/2A trial (COV005), people with HIV and HIV-negative participants aged 18-65 years were enrolled at seven South African locations and were randomly allocated (1:1) with full allocation concealment to receive a prime-boost regimen of ChAdOx1 nCoV-19, with two doses given 28 days apart. Eligibility criteria for people with HIV included being on antiretroviral therapy for at least 3 months, with a plasma HIV viral load of less than 1000 copies per mL. In this interim analysis, safety and reactogenicity was assessed in all individuals who received at least one dose of ChAdOx1 nCov 19 between enrolment and Jan 15, 2021. Primary immunogenicity analyses included participants who received two doses of trial intervention and were SARS-CoV-2 seronegative at baseline. This trial is registered with ClinicalTrials.gov, NCT04444674, and the Pan African Clinicals Trials Registry, PACTR202006922165132. FINDINGS: Between June 24 and Nov 12, 2020, 104 people with HIV and 70 HIV-negative individuals were enrolled. 102 people with HIV (52 vaccine; 50 placebo) and 56 HIV-negative participants (28 vaccine; 28 placebo) received the priming dose, 100 people with HIV (51 vaccine; 49 placebo) and 46 HIV-negative participants (24 vaccine; 22 placebo) received two doses (priming and booster). In participants seronegative for SARS-CoV-2 at baseline, there were 164 adverse events in those with HIV (86 vaccine; 78 placebo) and 237 in HIV-negative participants (95 vaccine; 142 placebo). Of seven serious adverse events, one severe fever in a HIV-negative participant was definitely related to trial intervention and one severely elevated alanine aminotranferase in a participant with HIV was unlikely related; five others were deemed unrelated. One person with HIV died (unlikely related). People with HIV and HIV-negative participants showed vaccine-induced serum IgG responses against wild-type Wuhan-1 Asp614Gly (also known as D614G). For participants seronegative for SARS-CoV-2 antigens at baseline, full-length spike geometric mean concentration (GMC) at day 28 was 163·7 binding antibody units (BAU)/mL (95% CI 89·9-298·1) for people with HIV (n=36) and 112·3 BAU/mL (61·7-204·4) for HIV-negative participants (n=23), with a rising day 42 GMC booster response in both groups. Baseline SARS-CoV-2 seropositive people with HIV demonstrated higher antibody responses after each vaccine dose than did people with HIV who were seronegative at baseline. High-level binding antibody cross-reactivity for the full-length spike and receptor-binding domain of the beta variant (B.1.351) was seen regardless of HIV status. In people with HIV who developed high titre responses, predominantly those who were receptor-binding domain seropositive at enrolment, neutralising activity against beta was retained. INTERPRETATION: ChAdOx1 nCoV-19 was well tolerated, showing favourable safety and immunogenicity in people with HIV, including heightened immunogenicity in SARS-CoV-2 baseline-seropositive participants. People with HIV showed cross-reactive binding antibodies to the beta variant and Asp614Gly wild-type, and high responders retained neutralisation against beta. FUNDING: The Bill & Melinda Gates Foundation, South African Medical Research Council, UK Research and Innovation, UK National Institute for Health Research, and the South African Medical Research Council.


Subject(s)
COVID-19 Vaccines/immunology , COVID-19/prevention & control , HIV Infections/epidemiology , SARS-CoV-2/immunology , Adult , Antibodies, Neutralizing/blood , Antibodies, Viral/blood , COVID-19/epidemiology , COVID-19 Vaccines/administration & dosage , COVID-19 Vaccines/adverse effects , Cross Reactions , Double-Blind Method , Female , Humans , Immunogenicity, Vaccine , Male , Mutation , SARS-CoV-2/genetics , Safety , Vaccination
10.
Cell ; 184(11): 2939-2954.e9, 2021 05 27.
Article in English | MEDLINE | ID: covidwho-1343152

ABSTRACT

Terminating the SARS-CoV-2 pandemic relies upon pan-global vaccination. Current vaccines elicit neutralizing antibody responses to the virus spike derived from early isolates. However, new strains have emerged with multiple mutations, including P.1 from Brazil, B.1.351 from South Africa, and B.1.1.7 from the UK (12, 10, and 9 changes in the spike, respectively). All have mutations in the ACE2 binding site, with P.1 and B.1.351 having a virtually identical triplet (E484K, K417N/T, and N501Y), which we show confer similar increased affinity for ACE2. We show that, surprisingly, P.1 is significantly less resistant to naturally acquired or vaccine-induced antibody responses than B.1.351, suggesting that changes outside the receptor-binding domain (RBD) impact neutralization. Monoclonal antibody (mAb) 222 neutralizes all three variants despite interacting with two of the ACE2-binding site mutations. We explain this through structural analysis and use the 222 light chain to largely restore neutralization potency to a major class of public antibodies.


Subject(s)
Antibodies, Monoclonal/immunology , Antibodies, Neutralizing/immunology , Antibodies, Viral/immunology , COVID-19/immunology , SARS-CoV-2/immunology , Spike Glycoprotein, Coronavirus/immunology , Binding Sites , COVID-19/therapy , COVID-19/virology , Cell Line , Humans , Immune Evasion , Immunization, Passive , Mutation , Protein Binding , Protein Domains , SARS-CoV-2/genetics , Sequence Deletion , Spike Glycoprotein, Coronavirus/chemistry , Spike Glycoprotein, Coronavirus/genetics , Vaccination , Vaccines/immunology
11.
Sci Transl Med ; 13(607)2021 08 18.
Article in English | MEDLINE | ID: covidwho-1329033

ABSTRACT

ChAdOx1 nCoV-19/AZD1222 is an approved adenovirus-based vaccine for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) currently being deployed globally. Previous studies in rhesus macaques revealed that intramuscular vaccination with ChAdOx1 nCoV-19/AZD1222 provided protection against pneumonia but did not reduce shedding of SARS-CoV-2 from the upper respiratory tract. Here, we investigated whether intranasally administered ChAdOx1 nCoV-19 reduces detection of virus in nasal swabs after challenging vaccinated macaques and hamsters with SARS-CoV-2 carrying a D614G mutation in the spike protein. Viral loads in swabs obtained from intranasally vaccinated hamsters were decreased compared to control hamsters, and no viral RNA or infectious virus was found in lung tissue after a direct challenge or after direct contact with infected hamsters. Intranasal vaccination of rhesus macaques resulted in reduced virus concentrations in nasal swabs and a reduction in viral loads in bronchoalveolar lavage and lower respiratory tract tissue. Intranasal vaccination with ChAdOx1 nCoV-19/AZD1222 reduced virus concentrations in nasal swabs in two different SARS-CoV-2 animal models, warranting further investigation as a potential vaccination route for COVID-19 vaccines.


Subject(s)
COVID-19 , SARS-CoV-2 , Animals , COVID-19 Vaccines , Cricetinae , Macaca mulatta , Vaccination , Virus Shedding
12.
Commun Biol ; 4(1): 915, 2021 07 26.
Article in English | MEDLINE | ID: covidwho-1327224

ABSTRACT

Vaccines against SARS-CoV-2 are urgently required, but early development of vaccines against SARS-CoV-1 resulted in enhanced disease after vaccination. Careful assessment of this phenomena is warranted for vaccine development against SARS CoV-2. Here we report detailed immune profiling after ChAdOx1 nCoV-19 (AZD1222) and subsequent high dose challenge in two animal models of SARS-CoV-2 mediated disease. We demonstrate in rhesus macaques the lung pathology caused by SARS-CoV-2 mediated pneumonia is reduced by prior vaccination with ChAdOx1 nCoV-19 which induced neutralising antibody responses after a single intramuscular administration. In a second animal model, ferrets, ChAdOx1 nCoV-19 reduced both virus shedding and lung pathology. Antibody titre were boosted by a second dose. Data from these challenge models on the absence of enhanced disease and the detailed immune profiling, support the continued clinical evaluation of ChAdOx1 nCoV-19.


Subject(s)
COVID-19 Vaccines/immunology , SARS-CoV-2/immunology , Animals , Antibodies, Neutralizing/immunology , Ferrets , Macaca mulatta
14.
Cell ; 184(16): 4220-4236.e13, 2021 08 05.
Article in English | MEDLINE | ID: covidwho-1272328

ABSTRACT

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has undergone progressive change, with variants conferring advantage rapidly becoming dominant lineages, e.g., B.1.617. With apparent increased transmissibility, variant B.1.617.2 has contributed to the current wave of infection ravaging the Indian subcontinent and has been designated a variant of concern in the United Kingdom. Here we study the ability of monoclonal antibodies and convalescent and vaccine sera to neutralize B.1.617.1 and B.1.617.2, complement this with structural analyses of Fab/receptor binding domain (RBD) complexes, and map the antigenic space of current variants. Neutralization of both viruses is reduced compared with ancestral Wuhan-related strains, but there is no evidence of widespread antibody escape as seen with B.1.351. However, B.1.351 and P.1 sera showed markedly more reduction in neutralization of B.1.617.2, suggesting that individuals infected previously by these variants may be more susceptible to reinfection by B.1.617.2. This observation provides important new insights for immunization policy with future variant vaccines in non-immune populations.


Subject(s)
Antibodies, Viral/immunology , COVID-19 Vaccines/immunology , SARS-CoV-2/immunology , Animals , Antibodies, Monoclonal/immunology , Antibodies, Neutralizing/immunology , Antigen-Antibody Complex/chemistry , COVID-19/pathology , COVID-19/therapy , COVID-19/virology , COVID-19 Vaccines/administration & dosage , Chlorocebus aethiops , Crystallography, X-Ray , Humans , Immunization, Passive , Neutralization Tests , Protein Domains/immunology , SARS-CoV-2/genetics , SARS-CoV-2/isolation & purification , Spike Glycoprotein, Coronavirus/chemistry , Spike Glycoprotein, Coronavirus/immunology , Vero Cells
16.
Nat Commun ; 12(1): 2893, 2021 05 17.
Article in English | MEDLINE | ID: covidwho-1232068

ABSTRACT

Several vaccines have demonstrated efficacy against SARS-CoV-2 mediated disease, yet there is limited data on the immune response induced by heterologous vaccination regimens using alternate vaccine modalities. Here, we present a detailed description of the immune response, in mice, following vaccination with a self-amplifying RNA (saRNA) vaccine and an adenoviral vectored vaccine (ChAdOx1 nCoV-19/AZD1222) against SARS-CoV-2. We demonstrate that antibody responses are higher in two-dose heterologous vaccination regimens than single-dose regimens. Neutralising titres after heterologous prime-boost were at least comparable or higher than the titres measured after homologous prime boost vaccination with viral vectors. Importantly, the cellular immune response after a heterologous regimen is dominated by cytotoxic T cells and Th1+ CD4 T cells, which is superior to the response induced in homologous vaccination regimens in mice. These results underpin the need for clinical trials to investigate the immunogenicity of heterologous regimens with alternate vaccine technologies.


Subject(s)
COVID-19 Vaccines/administration & dosage , COVID-19/prevention & control , RNA, Viral/administration & dosage , SARS-CoV-2/immunology , Vaccination/methods , Animals , Antibodies, Neutralizing/immunology , Antibodies, Viral/immunology , COVID-19/immunology , COVID-19 Vaccines/genetics , COVID-19 Vaccines/immunology , Immunization, Secondary , Immunogenicity, Vaccine , Mice , RNA, Viral/genetics , RNA, Viral/immunology , Spike Glycoprotein, Coronavirus/genetics , Spike Glycoprotein, Coronavirus/immunology , T-Lymphocytes, Cytotoxic/immunology , Th1 Cells/immunology , Vaccines, Synthetic/administration & dosage , Vaccines, Synthetic/genetics , Vaccines, Synthetic/immunology
17.
ACS Cent Sci ; 7(4): 594-602, 2021 Apr 28.
Article in English | MEDLINE | ID: covidwho-1225486

ABSTRACT

Vaccine development against the SARS-CoV-2 virus focuses on the principal target of the neutralizing immune response, the spike (S) glycoprotein. Adenovirus-vectored vaccines offer an effective platform for the delivery of viral antigen, but it is important for the generation of neutralizing antibodies that they produce appropriately processed and assembled viral antigen that mimics that observed on the SARS-CoV-2 virus. Here, we describe the structure, conformation, and glycosylation of the S protein derived from the adenovirus-vectored ChAdOx1 nCoV-19/AZD1222 vaccine. We demonstrate native-like post-translational processing and assembly, and reveal the expression of S proteins on the surface of cells adopting the trimeric prefusion conformation. The data presented here confirm the use of ChAdOx1 adenovirus vectors as a leading platform technology for SARS-CoV-2 vaccines.

18.
NPJ Vaccines ; 6(1): 67, 2021 May 10.
Article in English | MEDLINE | ID: covidwho-1223093

ABSTRACT

Vaccines against SARS-CoV-2 are likely to be critical in the management of the ongoing pandemic. A number of candidates are in Phase III human clinical trials, including ChAdOx1 nCoV-19 (AZD1222), a replication-deficient chimpanzee adenovirus-vectored vaccine candidate. In preclinical trials, the efficacy of ChAdOx1 nCoV-19 against SARS-CoV-2 challenge was evaluated in a ferret model of infection. Groups of ferrets received either prime-only or prime-boost administration of ChAdOx1 nCoV-19 via the intramuscular or intranasal route. All ChAdOx1 nCoV-19 administration combinations resulted in significant reductions in viral loads in nasal-wash and oral swab samples. No vaccine-associated adverse events were observed associated with the ChAdOx1 nCoV-19 candidate, with the data from this study suggesting it could be an effective and safe vaccine against COVID-19. Our study also indicates the potential for intranasal administration as a way to further improve the efficacy of this leading vaccine candidate.

19.
NPJ Vaccines ; 6(1): 32, 2021 Mar 02.
Article in English | MEDLINE | ID: covidwho-1146187

ABSTRACT

Lassa virus (LASV) infects hundreds of thousands of individuals each year, highlighting the need for the accelerated development of preventive, diagnostic, and therapeutic interventions. To date, no vaccine has been licensed for LASV. ChAdOx1-Lassa-GPC is a chimpanzee adenovirus-vectored vaccine encoding the Josiah strain LASV glycoprotein precursor (GPC) gene. In the following study, we show that ChAdOx1-Lassa-GPC is immunogenic, inducing robust T-cell and antibody responses in mice. Furthermore, a single dose of ChAdOx1-Lassa-GPC fully protects Hartley guinea pigs against morbidity and mortality following lethal challenge with a guinea pig-adapted LASV (strain Josiah). By contrast, control vaccinated animals reached euthanasia criteria 10-12 days after infection. Limited amounts of LASV RNA were detected in the tissues of vaccinated animals. Viable LASV was detected in only one animal receiving a single dose of the vaccine. A prime-boost regimen of ChAdOx1-Lassa-GPC in guinea pigs significantly increased antigen-specific antibody titers and cleared viable LASV from the tissues. These data support further development of ChAdOx1-Lassa-GPC and testing in non-human primate models of infection.

20.
Genome Med ; 13(1): 43, 2021 03 15.
Article in English | MEDLINE | ID: covidwho-1136245

ABSTRACT

BACKGROUND: ChAdOx1 nCoV-19 is a recombinant adenovirus vaccine against SARS-CoV-2 that has passed phase III clinical trials and is now in use across the globe. Although replication-defective in normal cells, 28 kbp of adenovirus genes is delivered to the cell nucleus alongside the SARS-CoV-2 S glycoprotein gene. METHODS: We used direct RNA sequencing to analyse transcript expression from the ChAdOx1 nCoV-19 genome in human MRC-5 and A549 cell lines that are non-permissive for vector replication alongside the replication permissive cell line, HEK293. In addition, we used quantitative proteomics to study over time the proteome and phosphoproteome of A549 and MRC5 cells infected with the ChAdOx1 nCoV-19 vaccine. RESULTS: The expected SARS-CoV-2 S coding transcript dominated in all cell lines. We also detected rare S transcripts with aberrant splice patterns or polyadenylation site usage. Adenovirus vector transcripts were almost absent in MRC-5 cells, but in A549 cells, there was a broader repertoire of adenoviral gene expression at very low levels. Proteomically, in addition to S glycoprotein, we detected multiple adenovirus proteins in A549 cells compared to just one in MRC5 cells. CONCLUSIONS: Overall, the ChAdOx1 nCoV-19 vaccine's transcriptomic and proteomic repertoire in cell culture is as expected. The combined transcriptomic and proteomics approaches provide a detailed insight into the behaviour of this important class of vaccine using state-of-the-art techniques and illustrate the potential of this technique to inform future viral vaccine vector design.


Subject(s)
COVID-19 Vaccines/adverse effects , COVID-19 Vaccines/immunology , COVID-19/immunology , SARS-CoV-2/immunology , Spike Glycoprotein, Coronavirus/immunology , COVID-19/metabolism , COVID-19/prevention & control , COVID-19/virology , COVID-19 Vaccines/genetics , Cell Line , Cells, Cultured , Gene Expression , Gene Expression Profiling , Gene Expression Regulation , Host-Pathogen Interactions/genetics , Host-Pathogen Interactions/immunology , Humans , Polyadenylation , Proteomics/methods , RNA, Messenger , RNA, Viral , SARS-CoV-2/genetics , Spike Glycoprotein, Coronavirus/genetics , Transcription, Genetic
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