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1.
Vaccines (Basel) ; 9(11)2021 Oct 28.
Article in English | MEDLINE | ID: covidwho-1488802

ABSTRACT

Adenovirus vectored vaccines have entered global use during the COVID-19 pandemic, and are in development for multiple other human and veterinary applications. An attraction of the technology is the suitability of the vaccines for storage at 2-8 °C for months. Widely used COVID-19 vaccine ChAdOx1 nCoV-19 (University of Oxford/AstraZeneca) is based on a species E simian adenovirus. Species E simian serotypes have been used in a wide range of other development programs, but the stability of such vectors has not been extensively described in the peer-reviewed literature. Here, we explore the stability of two candidate vaccines based on two species E serotypes: a Rift Valley fever vaccine based upon the ChAdOx1 vector (Y25 serotype) used in ChAdOx1 nCoV-19, and a rabies vaccine based upon a ChAdOx2 vector (AdC68 serotype). We describe each vector's stability in liquid and lyophilised formulations using in vitro and in vivo potency measurements. Our data support the suitability of liquid formulations of these vectors for storage at 2-8 °C for up to 1 year, and potentially for nonrefrigerated storage for a brief period during last-leg distribution (perhaps 1-3 days at 20 °C-the precise definition of acceptable last-leg storage conditions would require further product-specific data). Depending upon the level of inprocess potency loss that is economically acceptable, and the level of instorage loss that is compatible with maintenance of acceptable end-of-storage potency, a previously reported lyophilised formulation may enable longer term storage at 20 °C or storage for a number of days at 30 °C.

2.
Br J Clin Pharmacol ; 87(9): 3385-3387, 2021 09.
Article in English | MEDLINE | ID: covidwho-1379556
3.
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
4.
Nat Commun ; 12(1): 3966, 2021 06 25.
Article in English | MEDLINE | ID: covidwho-1281718

ABSTRACT

Observed SARS-CoV-2 infections and deaths are low in tropical Africa raising questions about the extent of transmission. We measured SARS-CoV-2 IgG by ELISA in 9,922 blood donors across Kenya and adjusted for sampling bias and test performance. By 1st September 2020, 577 COVID-19 deaths were observed nationwide and seroprevalence was 9.1% (95%CI 7.6-10.8%). Seroprevalence in Nairobi was 22.7% (18.0-27.7%). Although most people remained susceptible, SARS-CoV-2 had spread widely in Kenya with apparently low associated mortality.


Subject(s)
Antibodies, Viral/immunology , COVID-19/diagnosis , SARS-CoV-2/immunology , Spike Glycoprotein, Coronavirus/immunology , Adolescent , Adult , Antibodies, Viral/blood , Bayes Theorem , COVID-19/epidemiology , COVID-19/virology , Enzyme-Linked Immunosorbent Assay , Epidemics , Female , Humans , Immunoglobulin G/blood , Immunoglobulin G/immunology , Kenya/epidemiology , Male , Middle Aged , Prevalence , SARS-CoV-2/metabolism , SARS-CoV-2/physiology , Seroepidemiologic Studies , Spike Glycoprotein, Coronavirus/metabolism , Young Adult
7.
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
9.
Nat Med ; 27(2): 270-278, 2021 02.
Article in English | MEDLINE | ID: covidwho-1065916

ABSTRACT

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of Coronavirus Disease 2019 (COVID-19), has caused a global pandemic, and safe, effective vaccines are urgently needed1. Strong, Th1-skewed T cell responses can drive protective humoral and cell-mediated immune responses2 and might reduce the potential for disease enhancement3. Cytotoxic T cells clear virus-infected host cells and contribute to control of infection4. Studies of patients infected with SARS-CoV-2 have suggested a protective role for both humoral and cell-mediated immune responses in recovery from COVID-19 (refs. 5,6). ChAdOx1 nCoV-19 (AZD1222) is a candidate SARS-CoV-2 vaccine comprising a replication-deficient simian adenovirus expressing full-length SARS-CoV-2 spike protein. We recently reported preliminary safety and immunogenicity data from a phase 1/2 trial of the ChAdOx1 nCoV-19 vaccine (NCT04400838)7 given as either a one- or two-dose regimen. The vaccine was tolerated, with induction of neutralizing antibodies and antigen-specific T cells against the SARS-CoV-2 spike protein. Here we describe, in detail, exploratory analyses of the immune responses in adults, aged 18-55 years, up to 8 weeks after vaccination with a single dose of ChAdOx1 nCoV-19 in this trial, demonstrating an induction of a Th1-biased response characterized by interferon-γ and tumor necrosis factor-α cytokine secretion by CD4+ T cells and antibody production predominantly of IgG1 and IgG3 subclasses. CD8+ T cells, of monofunctional, polyfunctional and cytotoxic phenotypes, were also induced. Taken together, these results suggest a favorable immune profile induced by ChAdOx1 nCoV-19 vaccine, supporting the progression of this vaccine candidate to ongoing phase 2/3 trials to assess vaccine efficacy.


Subject(s)
Antibody Formation/immunology , COVID-19 Vaccines/immunology , T-Lymphocytes/immunology , Adolescent , CD4-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/immunology , COVID-19/immunology , COVID-19/virology , Dose-Response Relationship, Immunologic , Female , Humans , Immunity, Cellular , Immunity, Humoral , Immunoglobulin A/immunology , Immunoglobulin M/immunology , Interferon-gamma/metabolism , Lymphocyte Activation/immunology , Male , Middle Aged , Protein Subunits/immunology , SARS-CoV-2/immunology , Spike Glycoprotein, Coronavirus/immunology , Vaccination , Young Adult
10.
Nat Med ; 27(2): 279-288, 2021 02.
Article in English | MEDLINE | ID: covidwho-1065913

ABSTRACT

More than 190 vaccines are currently in development to prevent infection by the novel severe acute respiratory syndrome coronavirus 2. Animal studies suggest that while neutralizing antibodies against the viral spike protein may correlate with protection, additional antibody functions may also be important in preventing infection. Previously, we reported early immunogenicity and safety outcomes of a viral vector coronavirus vaccine, ChAdOx1 nCoV-19 (AZD1222), in a single-blinded phase 1/2 randomized controlled trial of healthy adults aged 18-55 years ( NCT04324606 ). Now we describe safety and exploratory humoral and cellular immunogenicity of the vaccine, from subgroups of volunteers in that trial, who were subsequently allocated to receive a homologous full-dose (SD/SD D56; n = 20) or half-dose (SD/LD D56; n = 32) ChAdOx1 booster vaccine 56 d following prime vaccination. Previously reported immunogenicity data from the open-label 28-d interval prime-boost group (SD/SD D28; n = 10) are also presented to facilitate comparison. Additionally, we describe volunteers boosted with the comparator vaccine (MenACWY; n = 10). In this interim report, we demonstrate that a booster dose of ChAdOx1 nCoV-19 is safe and better tolerated than priming doses. Using a systems serology approach we also demonstrate that anti-spike neutralizing antibody titers, as well as Fc-mediated functional antibody responses, including antibody-dependent neutrophil/monocyte phagocytosis, complement activation and natural killer cell activation, are substantially enhanced by a booster dose of vaccine. A booster dose of vaccine induced stronger antibody responses than a dose-sparing half-dose boost, although the magnitude of T cell responses did not increase with either boost dose. These data support the two-dose vaccine regime that is now being evaluated in phase 3 clinical trials.


Subject(s)
Antibody Formation/immunology , COVID-19 Vaccines/immunology , COVID-19/immunology , Immunization, Secondary , SARS-CoV-2/immunology , Adolescent , Adult , Antibodies, Neutralizing/immunology , Dose-Response Relationship, Drug , Genetic Vectors/immunology , Humans , Middle Aged , Spike Glycoprotein, Coronavirus/immunology , Time Factors , Young Adult
12.
Med (N Y) ; 2(3): 243-262.e8, 2021 Mar 12.
Article in English | MEDLINE | ID: covidwho-978369

ABSTRACT

Background: The spread of SARS-CoV-2 has caused a worldwide pandemic that has affected almost every aspect of human life. The development of an effective COVID-19 vaccine could limit the morbidity and mortality caused by infection and may enable the relaxation of social-distancing measures. Age is one of the most significant risk factors for poor health outcomes after SARS-CoV-2 infection; therefore, it is desirable that any new vaccine candidates elicit a robust immune response in older adults. Methods: Here, we use in-depth immunophenotyping to characterize the innate and adaptive immune response induced upon intramuscular administration of the adenoviral vectored ChAdOx1 nCoV-19 (AZD-1222) COVID-19 vaccine candidate in mice. Findings: A single vaccination generates spike-specific Th1 cells, Th1-like Foxp3+ regulatory T cells, polyfunctional spike-specific CD8+ T cells. and granzyme-B-producing CD8 effectors. Spike-specific IgG and IgM are generated from both the early extrafollicular antibody response and the T follicular helper cell-supported germinal center reaction, which is associated with the production of virus-neutralizing antibodies. A single dose of this vaccine generated a similar type of immune response in aged mice but of a reduced magnitude than in younger mice. We report that a second dose enhances the immune response to this vaccine in aged mice. Conclusions: This study shows that ChAdOx1 nCoV-19 induces both cellular and humoral immunity in adult and aged mice and suggests a prime-boost strategy is a rational approach to enhance immunogenicity in older persons. Funding: This study was supported by BBSRC, Lister institute of Preventative Medicine, EPSRC VaxHub, and Innovate UK.

13.
Science ; 371(6524): 79-82, 2021 01 01.
Article in English | MEDLINE | ID: covidwho-920888

ABSTRACT

The spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in Africa is poorly described. The first case of SARS-CoV-2 in Kenya was reported on 12 March 2020, and an overwhelming number of cases and deaths were expected, but by 31 July 2020, there were only 20,636 cases and 341 deaths. However, the extent of SARS-CoV-2 exposure in the community remains unknown. We determined the prevalence of anti-SARS-CoV-2 immunoglobulin G among blood donors in Kenya in April-June 2020. Crude seroprevalence was 5.6% (174 of 3098). Population-weighted, test-performance-adjusted national seroprevalence was 4.3% (95% confidence interval, 2.9 to 5.8%) and was highest in urban counties Mombasa (8.0%), Nairobi (7.3%), and Kisumu (5.5%). SARS-CoV-2 exposure is more extensive than indicated by case-based surveillance, and these results will help guide the pandemic response in Kenya and across Africa.


Subject(s)
Antibodies, Viral/blood , Blood Donors , COVID-19/epidemiology , Immunoglobulin G/blood , Adolescent , Adult , Aged , Communicable Disease Control , Humans , Kenya/epidemiology , Middle Aged , SARS-CoV-2/physiology , Seroepidemiologic Studies , Young Adult
14.
NPJ Vaccines ; 5(1): 69, 2020.
Article in English | MEDLINE | ID: covidwho-689622

ABSTRACT

Clinical development of the COVID-19 vaccine candidate ChAdOx1 nCoV-19, a replication-deficient simian adenoviral vector expressing the full-length SARS-CoV-2 spike (S) protein was initiated in April 2020 following non-human primate studies using a single immunisation. Here, we compared the immunogenicity of one or two doses of ChAdOx1 nCoV-19 in both mice and pigs. Whilst a single dose induced antigen-specific antibody and T cells responses, a booster immunisation enhanced antibody responses, particularly in pigs, with a significant increase in SARS-CoV-2 neutralising titres.

15.
Nature ; 586(7830): 578-582, 2020 10.
Article in English | MEDLINE | ID: covidwho-691215

ABSTRACT

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged in December 20191,2 and is responsible for the coronavirus disease 2019 (COVID-19) pandemic3. Vaccines are an essential countermeasure and are urgently needed to control the pandemic4. Here we show that the adenovirus-vector-based vaccine ChAdOx1 nCoV-19, which encodes the spike protein of SARS-CoV-2, is immunogenic in mice and elicites a robust humoral and cell-mediated response. This response was predominantly mediated by type-1 T helper cells, as demonstrated by the profiling of the IgG subclass and the expression of cytokines. Vaccination with ChAdOx1 nCoV-19 (using either a prime-only or a prime-boost regimen) induced a balanced humoral and cellular immune response of type-1 and type-2 T helper cells in rhesus macaques. We observed a significantly reduced viral load in the bronchoalveolar lavage fluid and lower respiratory tract tissue of vaccinated rhesus macaques that were challenged with SARS-CoV-2 compared with control animals, and no pneumonia was observed in vaccinated SARS-CoV-2-infected animals. However, there was no difference in nasal shedding between vaccinated and control SARS-CoV-2-infected macaques. Notably, we found no evidence of immune-enhanced disease after viral challenge in vaccinated SARS-CoV-2-infected animals. The safety, immunogenicity and efficacy profiles of ChAdOx1 nCoV-19 against symptomatic PCR-positive COVID-19 disease will now be assessed in randomized controlled clinical trials in humans.


Subject(s)
Betacoronavirus/immunology , Coronavirus Infections/immunology , Coronavirus Infections/prevention & control , Disease Models, Animal , Macaca mulatta , Pandemics/prevention & control , Pneumonia, Viral/prevention & control , Viral Vaccines/immunology , Adenoviridae/genetics , Animals , Bronchoalveolar Lavage Fluid , COVID-19 , COVID-19 Vaccines , Coronavirus Infections/genetics , Coronavirus Infections/virology , Cytokines/immunology , Female , Immunity, Cellular , Immunity, Humoral , Immunoglobulin G/immunology , Lung/immunology , Lung/pathology , Lung/virology , Macaca mulatta/immunology , Macaca mulatta/virology , Male , Mice , Pneumonia, Viral/immunology , Pneumonia, Viral/virology , SARS-CoV-2 , Spike Glycoprotein, Coronavirus/genetics , Spike Glycoprotein, Coronavirus/immunology , Th1 Cells/immunology , Vaccination , Viral Load , Viral Vaccines/administration & dosage , Viral Vaccines/genetics
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