Publications by authors named "Marta Ulaszewska"

15 Publications

  • Page 1 of 1

Evaluation of the immunogenicity of prime-boost vaccination with the replication-deficient viral vectored COVID-19 vaccine candidate ChAdOx1 nCoV-19.

NPJ Vaccines 2020 Jul 27;5(1):69. Epub 2020 Jul 27.

The Jenner Institute, University of Oxford, Old Road Campus Research Building, Roosevelt Drive, Oxford, OX3 7DQ, UK.

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.
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http://dx.doi.org/10.1038/s41541-020-00221-3DOI Listing
July 2020

Solar inactivated Typhimurium induces an immune response in BALB/c mice.

Heliyon 2021 Jan 6;7(1):e05903. Epub 2021 Jan 6.

The Jenner Institute, University of Oxford, Old Road Campus Research Building, Roosevelt Drive, Oxford, OX3 7DQ, United Kingdom.

is contracted through the consumption of untreated water and contaminated food. The contraction and spread of water-related in resource-poor communities can be reduced by using solar disinfection (SODIS) to treat the water before its consumption. SODIS is a water sanitizing technique that relies on natural sunshine. It is a cost-effective, inexpensive, environmentally, and user-friendly means of treating microbiologically contaminated water. This water disinfection method has saved many lives in communities vulnerable to water-related infections worldwide. At present, the success of SODIS has mainly been attributed to permanent inactivation of water pathogens ability to grow. However, little to no information exists as to whether immune responses to the solar inactivated pathogens are induced in SODIS water consumers. This study assessed the potential for solar inactivated . Typhimurium to induce an immune response in mice. Results show that solar inactivated . Typhimurium can induce bactericidal antibodies against . Typhimurium. Furthermore, an increase in the secretion of interferon-gamma (IFN-γ) was observed in mice given the solar inactivated . Typhimurium. These findings suggest that solar inactivated . Typhimurium induces a humoral and cellular immune response. However, the level of protection afforded by these responses requires further investigation.
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http://dx.doi.org/10.1016/j.heliyon.2021.e05903DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7855330PMC
January 2021

MAIT cell activation augments adenovirus vector vaccine immunogenicity.

Science 2021 01;371(6528):521-526

Translational Gastroenterology Unit, Nuffield Department of Medicine, University of Oxford, Oxford, UK.

Mucosal-associated invariant T (MAIT) cells are innate sensors of viruses and can augment early immune responses and contribute to protection. We hypothesized that MAIT cells may have inherent adjuvant activity in vaccine platforms that use replication-incompetent adenovirus vectors. In mice and humans, ChAdOx1 (chimpanzee adenovirus Ox1) immunization robustly activated MAIT cells. Activation required plasmacytoid dendritic cell (pDC)-derived interferon (IFN)-α and monocyte-derived interleukin-18. IFN-α-induced, monocyte-derived tumor necrosis factor was also identified as a key secondary signal. All three cytokines were required in vitro and in vivo. Activation of MAIT cells positively correlated with vaccine-induced T cell responses in human volunteers and MAIT cell-deficient mice displayed impaired CD8 T cell responses to multiple vaccine-encoded antigens. Thus, MAIT cells contribute to the immunogenicity of adenovirus vectors, with implications for vaccine design.
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http://dx.doi.org/10.1126/science.aax8819DOI Listing
January 2021

Native-like SARS-CoV-2 spike glycoprotein expressed by ChAdOx1 nCoV-19/AZD1222 vaccine.

bioRxiv 2021 Jan 19. Epub 2021 Jan 19.

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 confirms the use of ChAdOx1 adenovirus vectors as a leading platform technology for SARS-CoV-2 vaccines.
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http://dx.doi.org/10.1101/2021.01.15.426463DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7836103PMC
January 2021

Evaluation of the immunogenicity of prime-boost vaccination with the replication-deficient viral vectored COVID-19 vaccine candidate ChAdOx1 nCoV-19.

NPJ Vaccines 2020 27;5:69. Epub 2020 Jul 27.

The Jenner Institute, University of Oxford, Old Road Campus Research Building, Roosevelt Drive, Oxford, OX3 7DQ UK.

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.
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http://dx.doi.org/10.1038/s41541-020-00221-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7385486PMC
July 2020

ChAdOx1 nCoV-19 vaccine prevents SARS-CoV-2 pneumonia in rhesus macaques.

Nature 2020 10 30;586(7830):578-582. Epub 2020 Jul 30.

Laboratory of Virology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Hamilton, MT, USA.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged in December 2019 and is responsible for the coronavirus disease 2019 (COVID-19) pandemic. Vaccines are an essential countermeasure and are urgently needed to control the pandemic. 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.
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http://dx.doi.org/10.1038/s41586-020-2608-yDOI Listing
October 2020

ChAdOx1 nCoV-19 vaccination prevents SARS-CoV-2 pneumonia in rhesus macaques.

bioRxiv 2020 May 13. Epub 2020 May 13.

Laboratory of Virology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Hamilton, MT, USA.

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) emerged in December 2019 and is responsible for the COVID-19 pandemic. Vaccines are an essential countermeasure urgently needed to control the pandemic. Here, we show that the adenovirus-vectored vaccine ChAdOx1 nCoV-19, encoding the spike protein of SARS-CoV-2, is immunogenic in mice, eliciting a robust humoral and cell-mediated response. This response was not Th2 dominated, as demonstrated by IgG subclass and cytokine expression profiling. A single vaccination with ChAdOx1 nCoV-19 induced a humoral and cellular immune response in rhesus macaques. We observed a significantly reduced viral load in bronchoalveolar lavage fluid and respiratory tract tissue of vaccinated animals challenged with SARS-CoV-2 compared with control animals, and no pneumonia was observed in vaccinated rhesus macaques. Importantly, no evidence of immune-enhanced disease following viral challenge in vaccinated animals was observed. ChAdOx1 nCoV-19 is currently under investigation in a phase I clinical trial. Safety, immunogenicity and efficacy against symptomatic PCR-positive COVID-19 disease will now be assessed in randomised controlled human clinical trials.
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http://dx.doi.org/10.1101/2020.05.13.093195DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7241103PMC
May 2020

A Multi-Filovirus Vaccine Candidate: Co-Expression of Ebola, Sudan, and Marburg Antigens in a Single Vector.

Vaccines (Basel) 2020 May 21;8(2). Epub 2020 May 21.

Nuffield Department of Medicine, Jenner Institute, University of Oxford, Oxford OX3 7DQ, UK.

In the infectious diseases field, protective immunity against individual virus species or strains does not always confer cross-reactive immunity to closely related viruses, leaving individuals susceptible to disease after exposure to related virus species. This is a significant hurdle in the field of vaccine development, in which broadly protective vaccines represent an unmet need. This is particularly evident for filoviruses, as there are multiple family members that can cause lethal haemorrhagic fever, including Zaire ebolavirus, Sudan ebolavirus, and Marburg virus. In an attempt to address this need, both pre-clinical and clinical studies previously used mixed or co-administered monovalent vaccines to prevent filovirus mediated disease. However, these multi-vaccine and multi-dose vaccination regimens do not represent a practical immunisation scheme when considering the target endemic areas. We describe here the development of a single multi-pathogen filovirus vaccine candidate based on a replication-deficient simian adenoviral vector. Our vaccine candidate encodes three different filovirus glycoproteins in one vector and induces strong cellular and humoral immunity to all three viral glycoproteins after a single vaccination. Crucially, it was found to be protective in a stringent Zaire ebolavirus challenge in guinea pigs in a one-shot vaccination regimen. This trivalent filovirus vaccine offers a tenable vaccine product that could be rapidly translated to the clinic to prevent filovirus-mediated viral haemorrhagic fever.
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http://dx.doi.org/10.3390/vaccines8020241DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7349952PMC
May 2020

Targeting Antigen to the Surface of EVs Improves the Immunogenicity of Human and Non-human Adenoviral Vaccines in Mice.

Mol Ther Methods Clin Dev 2020 Mar 24;16:108-125. Epub 2019 Dec 24.

Department of Microbiology, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USA.

Adenoviral (Ad) vectors represent promising vaccine platforms for infectious disease. To overcome pre-existing immunity to commonly used human adenovirus serotype 5 (Ad5), vectors based on rare species or non-human Ads are being developed. However, these vectors often exhibit reduced potency compared with Ad5, necessitating the use of innovative approaches to augment the immunogenicity of the encoded antigen (Ag). To achieve this, we engineered model Ag, enhanced green fluorescent protein (EGFP), for targeting to the surface of host-derived extracellular vesicles (EVs), namely exosomes. Exosomes are nano-sized EVs that play important roles in cell-to-cell communication and in regulating immune responses. Directed targeting of Ag to the surface of EVs/exosomes is achieved by "exosome display," through fusion of Ag to the C1C2 domain of lactadherin, a protein highly enriched in exosomes. Herein, we engineered chimpanzee adenovirus ChAdOx1 and Ad5-based vaccines encoding EGFP, or EGFP targeted to EVs (EGFP_C1C2), and compared vaccine immunogenicity in mice. We determined that exosome display substantially increases Ag-specific humoral immunity following intramuscular and intranasal vaccination, improving the immunological potency of both ChAdOx1 and Ad5. We propose that this Ag-engineering approach could increase the immunogenicity of diverse Ad vectors that exhibit desirable manufacturing characteristics, but currently lack the potency of Ad5.
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http://dx.doi.org/10.1016/j.omtm.2019.12.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6953706PMC
March 2020

Preclinical Development and Assessment of Viral Vectors Expressing a Fusion Antigen of Plasmodium falciparum LSA1 and LSAP2 for Efficacy against Liver-Stage Malaria.

Infect Immun 2020 01 22;88(2). Epub 2020 Jan 22.

The Jenner Institute, University of Oxford, Oxford, United Kingdom

Despite promising progress in malaria vaccine development in recent years, an efficacious subunit vaccine against remains to be licensed and deployed. Cell-mediated protection from liver-stage malaria relies on a sufficient number of antigen-specific T cells reaching the liver during the time that parasites are present. A single vaccine expressing two antigens could potentially increase both the size and breadth of the antigen-specific response while halving vaccine production costs. In this study, we investigated combining two liver-stage antigens, LSA1 (PfLSA1) and PfLSAP2, and investigated the induction of protective efficacy by coadministration of single-antigen vectors or vaccination with dual-antigen vectors, using simian adenovirus and modified vaccinia virus Ankara vectors. The efficacy of these vaccines was assessed in mouse malaria challenge models using chimeric parasites expressing the relevant antigens and challenging mice at the peak of the T cell response. Vaccination with a combination of the single-antigen vectors expressing PfLSA1 or PfLSAP2 was shown to improve protective efficacy compared to vaccination with each single-antigen vector alone. Vaccination with dual-antigen vectors expressing both PfLSA1 and PfLSAP2 resulted in responses to both antigens, particularly in outbred mice, and most importantly, the efficacy was equivalent to that of vaccination with a mixture of single-antigen vectors. Based on these promising data, dual-antigen vectors expressing PfLSA1 and PfLSAP2 will now proceed to manufacturing and clinical assessment under good manufacturing practice (GMP) guidelines.
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http://dx.doi.org/10.1128/IAI.00573-19DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6977128PMC
January 2020

Hepcidin deficiency and iron deficiency do not alter tuberculosis susceptibility in a murine M.tb infection model.

PLoS One 2018 11;13(1):e0191038. Epub 2018 Jan 11.

Jenner Institute, University of Oxford, Oxford, United Kingdom.

Tuberculosis (TB), caused by the macrophage-tropic pathogen Mycobacterium tuberculosis (M.tb) is a highly prevalent infectious disease. Since an immune correlate of protection or effective vaccine have yet to be found, continued research into host-pathogen interactions is important. Previous literature reports links between host iron status and disease outcome for many infections, including TB. For some extracellular bacteria, the iron regulatory hormone hepcidin is essential for protection against infection. Here, we investigated hepcidin (encoded by Hamp1) in the context of murine M.tb infection. Female C57BL/6 mice were infected with M.tb Erdman via aerosol. Hepatic expression of iron-responsive genes was measured by qRT-PCR and bacterial burden determined in organ homogenates. We found that hepatic Hamp1 mRNA levels decreased post-infection, and correlated with a marker of BMP/SMAD signalling pathways. Next, we tested the effect of Hamp1 deletion, and low iron diets, on M.tb infection. Hamp1 knockout mice did not have a significantly altered M.tb mycobacterial load in either the lungs or spleen. Up to 10 weeks of dietary iron restriction did not robustly affect disease outcome despite causing iron deficiency anaemia. Taken together, our data indicate that unlike with many other infections, hepcidin is decreased following M.tb infection, and show that hepcidin ablation does not influence M.tb growth in vivo. Furthermore, because even severe iron deficiency did not affect M.tb mycobacterial load, we suggest that the mechanisms M.tb uses to scavenge iron from the host must be extremely efficient, and may therefore represent potential targets for drugs and vaccines.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0191038PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5764373PMC
March 2018

An in vitro assay to measure antibody-mediated inhibition of P. berghei sporozoite invasion against P. falciparum antigens.

Sci Rep 2017 12 5;7(1):17011. Epub 2017 Dec 5.

The Jenner Institute, University of Oxford, Oxford, United Kingdom.

A large research effort is currently underway to find an effective and affordable malaria vaccine. Tools that enable the rapid evaluation of protective immune responses are essential to vaccine development as they can provide selection criteria to rank order vaccine candidates. In this study we have revisited the Inhibition of Sporozoite Invasion (ISI) assay to assess the ability of antibodies to inhibit sporozoite infection of hepatocytes. By using GFP expressing sporozoites of the rodent parasite P. berghei we are able to robustly quantify parasite infection of hepatocyte cell lines by flow cytometry. In conjunction with recently produced transgenic P. berghei parasites that express P. falciparum sporozoite antigens, we have been able to use this assay to measure antibody mediated inhibition of sporozoite invasion against one of the lead malaria antigens P. falciparum CSP. By combining chimeric rodent parasites expressing P. falciparum antigens and a flow cytometric readout of infection, we are able to robustly assess vaccine-induced antibodies, from mice, rhesus macaques and human clinical trials, for their functional ability to block sporozoite invasion of hepatocytes.
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http://dx.doi.org/10.1038/s41598-017-17274-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5717233PMC
December 2017

Novel Bivalent Viral-Vectored Vaccines Induce Potent Humoral and Cellular Immune Responses Conferring Protection against Stringent Influenza A Virus Challenge.

J Immunol 2017 Jul 19. Epub 2017 Jul 19.

Jenner Institute, University of Oxford, Oxford OX3 7DQ, United Kingdom;

Seasonal influenza viruses are a common cause of acute respiratory illness worldwide and generate a significant socioeconomic burden. Influenza viruses mutate rapidly, necessitating annual vaccine reformulation because traditional vaccines do not typically induce broad-spectrum immunity. In addition to seasonal infections, emerging pandemic influenza viruses present a continued threat to global public health. Pandemic influenza viruses have consistently higher attack rates and are typically associated with greater mortality compared with seasonal strains. Ongoing strategies to improve vaccine efficacy typically focus on providing broad-spectrum immunity; although B and T cells can mediate heterosubtypic responses, typical vaccine development will augment either humoral or cellular immunity. However, multipronged approaches that target several Ags may limit the generation of viral escape mutants. There are few vaccine platforms that can deliver multiple Ags and generate robust cellular and humoral immunity. In this article, we describe a novel vaccination strategy, tested preclinically in mice, for the delivery of novel bivalent viral-vectored vaccines. We show this strategy elicits potent T cell responses toward highly conserved internal Ags while simultaneously inducing high levels of Abs toward hemagglutinin. Importantly, these humoral responses generate long-lived plasma cells and generate Abs capable of neutralizing variant hemagglutinin-expressing pseudotyped lentiviruses. Significantly, these novel viral-vectored vaccines induce strong immune responses capable of conferring protection in a stringent influenza A virus challenge. Thus, this vaccination regimen induces lasting efficacy toward influenza. Importantly, the simultaneous delivery of dual Ags may alleviate the selective pressure that is thought to potentiate antigenic diversity in avian influenza viruses.
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http://dx.doi.org/10.4049/jimmunol.1600939DOI Listing
July 2017

The Threshold of Protection from Liver-Stage Malaria Relies on a Fine Balance between the Number of Infected Hepatocytes and Effector CD8 T Cells Present in the Liver.

J Immunol 2017 03 13;198(5):2006-2016. Epub 2017 Jan 13.

The Jenner Institute, University of Oxford, Oxford OX3 7DQ, United Kingdom.

Since the demonstration of sterile protection afforded by injection of irradiated sporozoites, CD8 T cells have been shown to play a significant role in protection from liver-stage malaria. This is, however, dependent on the presence of an extremely high number of circulating effector cells, thought to be necessary to scan, locate, and kill infected hepatocytes in the short time that parasites are present in the liver. We used an adoptive transfer model to elucidate the kinetics of the effector CD8 T cell response in the liver following sporozoite challenge. Although effector CD8 T cells require <24 h to find, locate, and kill infected hepatocytes, active migration of Ag-specific CD8 T cells into the liver was not observed during the 2-d liver stage of infection, as divided cells were only detected from day 3 postchallenge. However, the percentage of donor cells recruited into division was shown to indicate the level of Ag presentation from infected hepatocytes. By titrating the number of transferred Ag-specific effector CD8 T cells and sporozoites, we demonstrate that achieving protection toward liver-stage malaria is reliant on CD8 T cells being able to locate infected hepatocytes, resulting in a protection threshold dependent on a fine balance between the number of infected hepatocytes and CD8 T cells present in the liver. With such a fine balance determining protection, achieving a high number of CD8 T cells will be critical to the success of a cell-mediated vaccine against liver-stage malaria.
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http://dx.doi.org/10.4049/jimmunol.1601209DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5318841PMC
March 2017