Publications by authors named "Ariane C Gomes"

12 Publications

  • Page 1 of 1

IgA binds to the AD-2 epitope of glycoprotein B and neutralizes human cytomegalovirus.

Immunology 2021 Mar 13;162(3):314-327. Epub 2020 Dec 13.

Cellular and Molecular Immunology Research Centre, London Metropolitan University, London, UK.

Human cytomegalovirus (HCMV) is a ubiquitous pathogen that is potentially pathogenic in immunosuppressed individuals and pregnant females during primary infection. The HCMV envelope glycoprotein B (gB) facilitates viral entry into all cell types and induces a potent immune response. AD-2 epitope is a highly conserved linear neutralizing epitope of gB and a critical target for antibodies; however, only 50% of sero-positive individuals make IgG antibodies to this site and IgA responses have not been fully investigated. This study aimed to compare IgG and IgA responses against gB and the AD-2 epitope in naturally exposed individuals and those receiving a recombinant gB/MF59 adjuvant vaccine. Thus, vaccination of sero-positive individuals improved pre-existing gB-specific IgA and IgG levels and induced de novo gB-specific IgA and IgG responses in sero-negative recipients. Pre-existing AD-2 IgG and IgA responses were boosted with vaccination, but de novo AD-2 responses were not detected. Naturally exposed individuals had dominant IgG responses towards gB and AD-2 compared with weaker and variable IgA responses, although a significant IgA binding response to AD-2 was observed within human breastmilk samples. All antibodies binding AD-2 contained kappa light chains, whereas balanced kappa/lambda light chain usage was found for those binding to gB. V region-matched AD-2-specific recombinant IgG and IgA bound both to gB and to AD-2 and neutralized HCMV infection in vitro. Overall, these results indicate that although human IgG responses dominate, IgA class antibodies against AD-2 are a significant component of human milk, which may function to protect neonates from HCMV.
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http://dx.doi.org/10.1111/imm.13286DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7884650PMC
March 2021

Seronegative patients vaccinated with cytomegalovirus gB-MF59 vaccine have evidence of neutralising antibody responses against gB early post-transplantation.

EBioMedicine 2019 Dec 15;50:45-54. Epub 2019 Nov 15.

Institute for Immunity and Transplantation, UCL, Royal Free Campus, London NW3 2PF, United Kingdom. Electronic address:

Background: Human cytomegalovirus (HCMV) causes a ubiquitous infection which can pose a significant threat for immunocompromised individuals, such as those undergoing solid organ transplant (SOT). Arguably, the most successful vaccine studied to date is the recombinant glycoprotein-B (gB) with MF59 adjuvant which, in 3 Phase II trials, demonstrated 43-50% efficacy in preventing HCMV acquisition in seronegative healthy women or adolescents and reduction in virological parameters after SOT. However, the mechanism of vaccine protection in seronegative recipients remains undefined.

Methods: We evaluated samples from the cohort of seronegative SOT patients enroled in the Phase II glycoprotein-B/MF59 vaccine trial who received organs from seropositive donors. Samples after SOT (0-90 days) were tested by real-time quantitative PCR for HCMV DNA. Anti-gB antibody levels were measured by ELISA. Neutralization was measured as a decrease in infectivity for fibroblast cell cultures revealed by expression of immediate-early antigens.

Findings: Serological analyses revealed a more rapid increase in the humoral response against gB post transplant in vaccine recipients than in those randomised to receive placebo. Importantly, a number of patient sera displayed HCMV neutralising responses - neutralisation which was abrogated by pre-absorbing the sera with recombinant gB.

Interpretation: We hypothesise that the vaccine primed the immune system of seronegative recipients which, when further challenged with virus at time of transplant, allowed the host to mount rapid immunological humoral responses even under conditions of T cell immune suppression during transplantation.
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http://dx.doi.org/10.1016/j.ebiom.2019.11.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6921368PMC
December 2019

Early Transcriptional Signature in Dendritic Cells and the Induction of Protective T Cell Responses Upon Immunization With VLPs Containing TLR Ligands-A Role for CCL2.

Front Immunol 2019 2;10:1679. Epub 2019 Aug 2.

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

Inducing T cell responses by therapeutic vaccination requires appropriate activation of antigen presenting cells (APCs). The use of virus-like particles (VLPs) containing Toll-like receptor (TLR) ligands has demonstrated remarkable potential in activating APCs and modulating the immune response both for prophylactic vaccines as well as immunotherapy. Here, we employed VLPs associated to TLR ligands as tools to modulate cytotoxic response mediated by CD8 T cells and provide further insight in the development of T cell-based immunotherapy. We have investigated the transcriptional signature in dendritic cells (DCs) from mice immunized with VLPs containing distinct classes of nucleic acid and correlated the expression patterns with the efficiency of induced T cell responses. We identified key pathways activated in DCs that are involved in the appropriated induction of T cell responses and show evidence for the modulatory effect of CCL2 in CD8 T cells responses. These insights shed light on immune networks that are pivotal for the induction of potent cytotoxic T cell responses and identify key genes for appropriate DC activation and subsequent modulation of the adaptive immune response.
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http://dx.doi.org/10.3389/fimmu.2019.01679DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6687836PMC
October 2020

The Humoral Immune Response Against the gB Vaccine: Lessons Learnt from Protection in Solid Organ Transplantation.

Vaccines (Basel) 2019 Jul 17;7(3). Epub 2019 Jul 17.

Institute for Immunity and Transplantation, University College London, London NW3 2PF, UK.

Human cytomegalovirus (hCMV) is considered to be the highest priority for vaccine development. This view is underscored by the significant morbidity associated with congenital hCMV infection and viraemia in transplant patients. Although a number of vaccines have been trialed, none have been licensed. The hCMV vaccine candidate that has performed best in clinical trials to date is the recombinant glycoprotein B (gB) vaccine that has demonstrated protection, ranging from a 43% to 50% efficacy in three independent phase II trials. In this review, we focus on data from the phase II trial performed in solid organ transplant patients and the outcomes of follow-up studies attempting to identify immunological and mechanistic correlates of protection associated with this vaccine strategy. We relate this to other vaccine studies of gB as well as other vaccine strategies to determine areas of commonality and divergence. Finally, through the review, we discuss the unique challenges and opportunities presented with vaccine studies in transplant populations with recommendations that could empower subsequent trials.
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http://dx.doi.org/10.3390/vaccines7030067DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6789498PMC
July 2019

Type of RNA Packed in VLPs Impacts IgG Class Switching-Implications for an Influenza Vaccine Design.

Vaccines (Basel) 2019 Jun 4;7(2). Epub 2019 Jun 4.

The Jenner Institute, Oxford University, Oxford OX3 7BN, UK.

Nucleic acid packed within virus-like particles (VLPs) is shown to shape the immune response and to induce stronger B cell responses in different immunisation models. Here, using a VLP displaying the highly conserved extracellular domain of the M2 protein (M2e) from the influenza viruses as an antigen, we demonstrate that the type of RNA packaged into VLPs can alter the quality of the induced humoral response. By comparing prokaryotic RNA (pRNA), eukaryotic RNA (eRNA) and transfer RNA (tRNA), we find that pRNA induces the most protective IgG subclasses using a murine influenza model. We provide evidence that this process is predominantly dependent on endosomal Toll-like receptor (TLR7), and rule out a role for cytoplasmic mitochondrial antiviral signalling protein (MAVS) and its upstream retinoic acid-inducible gene-I-like receptors (RIG-I). Our findings provide considerations for the rational design of VLP-based vaccines and the immunomodulation exerted by TLR7 ligands packaged within the particles. Based on this work, we conclude that VLPs packing prokaryotic RNA must be preferred whenever a response dominated by IgG2 is desired, while eukaryotic RNA should be employed in order to induce a response dominated by IgG1.
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http://dx.doi.org/10.3390/vaccines7020047DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6630894PMC
June 2019

Targeting Mutated Plus Germline Epitopes Confers Pre-clinical Efficacy of an Instantly Formulated Cancer Nano-Vaccine.

Front Immunol 2019 15;10:1015. Epub 2019 May 15.

Nuffield Department of Medicine, Jenner Institute, University of Oxford, Oxford, United Kingdom.

Personalized cancer vaccines hold promises for future cancer therapy. Targeting neoantigens is perceived as more beneficial compared to germline, non-mutated antigens. However, it is a practical challenge to identify and vaccinate patients with neoantigens. Here we asked whether two neoantigens are sufficient, and whether the addition of germline antigens would enhance the therapeutic efficacy. We developed and used a personalized cancer nano-vaccine platform based on virus-like particles loaded with toll-like receptor ligands. We generated three sets of multi-target vaccines (MTV) to immunize against the aggressive B16F10 murine melanoma: one set based on germline epitopes (GL-MTV) identified by immunopeptidomics, another set based on mutated epitopes (Mutated-MTV) predicted by whole exome sequencing and a last set combines both germline and mutated epitopes (Mix-MTV). Our results demonstrate that both germline and mutated epitopes induced protection but the best therapeutic effect was achieved with the combination of both. Our platform is based on Cu-free click chemistry used for peptide-VLP coupling, thus enabling bedside production of a personalized cancer vaccine, ready for clinical translation.
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http://dx.doi.org/10.3389/fimmu.2019.01015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6532571PMC
September 2020

Interaction of Viral Capsid-Derived Virus-Like Particles (VLPs) with the Innate Immune System.

Vaccines (Basel) 2018 Jul 2;6(3). Epub 2018 Jul 2.

Jenner Institute, University of Oxford, Oxford OX3 7BN, UK.

Virus-like particles (VLPs) derived from viral nucleocapsids are an important class of nanoparticles. The structure, uniformity, stability, and function of these VLPs have attracted scientists in utilizing them as a unique tool in various applications in biomedical fields. Their interaction with the innate immune system is of major importance for the adaptive immune response they induce. The innate immune cells and molecules recognize and interact with VLPs on the basis of two major characteristics: size and surface geometry. This review discusses the interaction of viral capsid-derived VLPs with the innate immune system.
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http://dx.doi.org/10.3390/vaccines6030037DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6161069PMC
July 2018

Microcrystalline Tyrosine (MCT): A Depot Adjuvant in Licensed Allergy Immunotherapy Offers New Opportunities in Malaria.

Vaccines (Basel) 2017 Sep 27;5(4). Epub 2017 Sep 27.

Nuffield Department of Medicine, Centre for Cellular and Molecular Physiology (CCMP), The Jenner Institute, University of Oxford, Oxford OX3 7BN, UK.

Microcrystalline Tyrosine (MCT) is a widely used proprietary depot excipient in specific immunotherapy for allergy. In the current study we assessed the potential of MCT to serve as an adjuvant in the development of a vaccine against malaria. To this end, we formulated the circumsporozoite protein (CSP) of in MCT and compared the induced immune responses to CSP formulated in PBS or Alum. Both MCT and Alum strongly increased immunogenicity of CSP compared to PBS in both C57BL/6 and BALB/c mice. Challenge studies in mice using a chimeric expressing CSP of demonstrated clinically improved symptoms of malaria with CSP formulated in both MCT and Alum; protection was, however, more pronounced if CSP was formulated in MCT. Hence, MCT may be an attractive biodegradable adjuvant useful for the development of novel prophylactic vaccines.
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http://dx.doi.org/10.3390/vaccines5040032DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5748599PMC
September 2017

Virus-Like Particle (VLP) Plus Microcrystalline Tyrosine (MCT) Adjuvants Enhance Vaccine Efficacy Improving T and B Cell Immunogenicity and Protection against Plasmodium berghei/vivax.

Vaccines (Basel) 2017 May 2;5(2). Epub 2017 May 2.

The Jenner Institute, Nuffield Department of Medicine, Centre for Cellular and Molecular Physiology (CCMP), University of Oxford, Oxford OX3 7BN, UK.

Vaccination is the most effective prophylactic tool against infectious diseases. Despite continued efforts to control malaria, the disease still generally represents a significant unmet medical need. Microcrystalline tyrosine (MCT) is a well described depot used in licensed allergy immunotherapy products and in clinical development. However, its proof of concept in prophylactic vaccines has only recently been explored. MCT has never been used in combination with virus-like particles (VLPs), which are considered to be one of the most potent inducers of cellular and humoral immune responses in mice and humans. In the current study we assessed the potential of MCT to serve as an adjuvant in the development of a vaccine against malaria either alone or combined with VLP using thrombospondin-related adhesive protein (TRAP) as a target antigen. We chemically coupled PvTRAP to VLPs derived from the cucumber mosaic virus fused to a universal T-cell epitope of the tetanus toxin (CMVtt), formulated with MCT and compared the induced immune responses to PvTRAP formulated in PBS or Alum. The protective capacity of the various formulations was assessed using expressing PvTRAP. All vaccine formulations using adjuvants and/or VLP increased humoral immunogenicity for PvTRAP compared to the antigen alone. The most proficient responder was the group of mice immunized with the vaccine formulated with PvTRAP-VLP + MCT. The VLP-based vaccine formulated in MCT also induced the strongest T cell response and conferred best protection against challenge with recombinant . Thus, the combination of VLP with MCT may take advantage of the properties of each component and appears to be an alternative biodegradable depot adjuvant for development of novel prophylactic vaccines.
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http://dx.doi.org/10.3390/vaccines5020010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5492007PMC
May 2017

Adjusted Particle Size Eliminates the Need of Linkage of Antigen and Adjuvants for Appropriated T Cell Responses in Virus-Like Particle-Based Vaccines.

Front Immunol 2017 6;8:226. Epub 2017 Mar 6.

The Jenner Institute, Oxford University, Oxford, UK; Immunology, Inselspital, Bern, Switzerland.

Since the discovery of the first virus-like particle (VLP) derived from hepatitis B virus in 1980 (1), the field has expanded substantially. Besides successful use of VLPs as safe autologous virus-targeting vaccines, the powerful immunogenicity of VLPs has been also harnessed to generate immune response against heterologous and even self-antigens (2-4). Linking adjuvants to VLPs displaying heterologous antigen ensures simultaneous delivery of all vaccine components to the same antigen-presenting cells. As a consequence, antigen-presenting cells, such as dendritic cells, will process and present the antigen displayed on VLPs while receiving costimulatory signals by the VLP-incorporated adjuvant. Similarly, antigen-specific B cells recognizing the antigen linked to the VLP are simultaneously exposed to the adjuvant. Here, we demonstrate in mice that physical association of antigen, carrier (VLPs), and adjuvant is more critical for B than T cell responses. As a model system, we used the E7 protein from human papilloma virus, which spontaneously forms oligomers with molecular weight ranging from 158 kDa to 10 MDa at an average size of 50 nm. E7 oligomers were either chemically linked or simply mixed with VLPs loaded with DNA rich in non-methylated CG motifs (CpGs), a ligand for toll-like receptor 9. E7-specific IgG responses were strongly enhanced if the antigen was linked to the VLPs. In contrast, both CD4 and CD8 T cell responses as well as T cell-mediated protection against tumor growth were comparable for linked and mixed antigen formulations. Therefore, our data show that B cell but not T cell responses require antigen-linkage to the carrier and adjuvant for optimal vaccination outcome.
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http://dx.doi.org/10.3389/fimmu.2017.00226DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5337491PMC
March 2017

Delivering adjuvants and antigens in separate nanoparticles eliminates the need of physical linkage for effective vaccination.

J Control Release 2017 04 28;251:92-100. Epub 2017 Feb 28.

University of Oxford, Roosevelt Dr, Oxford OX3 7BN, UK; Inselspital, Universitatsklinik RIA, Immunologie, Sahlihaus 1, 3010 Bern, Switzerland.

DNA rich in unmethylated CG motifs (CpGs) engage Toll-Like Receptor 9 (TLR-9) in endosomes and are well described stimulators of the innate and adaptive immune system. CpGs therefore can efficiently improve vaccines' immunogenicity. Packaging CpGs into nanoparticles, in particular into virus-like particles (VLPs), improves the pharmacological characteristics of CpGs as the protein shell protects them from DNAse activity and delivers the oligomers to the endosomal compartments of professional antigen presenting cells (APCs). The current consensus in packaging and delivering CpGs in VLP-based vaccines is that both adjuvants and antigens should be kept in close proximity (i.e. physically linked) to ensure delivery of antigens and adjuvants to the same APCs. In the current study, we harness the draining properties of the lymphatic system and show that also non-linked VLPs are efficiently co-delivered to the same APCs in lymph nodes. Specifically, we have shown that CpGs can be packaged in one VLP and mixed with another VLP displaying the antigen prior to administration in vivo. Both VLPs efficiently reached the same draining lymph node where they were taken up and processed by the same APCs, namely dendritic cells and macrophages. This resulted in induction of specific CTLs producing cytokines and killing target cells in vivo at levels seen when using VLPs containing both CpGs and chemically conjugated antigen. Thus, delivery of antigens and adjuvants in separate nanoparticles eliminates the need of physical conjugation and thus can be beneficial when designing precision medicine VLP-based vaccines or help to re-formulate existing VLP vaccines not naturally carrying immunostimulatory sequences.
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http://dx.doi.org/10.1016/j.jconrel.2017.02.031DOI Listing
April 2017

Harnessing Nanoparticles for Immunomodulation and Vaccines.

Vaccines (Basel) 2017 Feb 14;5(1). Epub 2017 Feb 14.

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

The first successful use of nanoparticles (NPs) for vaccination was reported almost 40 years ago with a virus-like particle-based vaccine against Hepatitis B. Since then, the term NP has been expanded to accommodate a large number of novel nano-sized particles engineered from a range of materials. The great interest in NPs is likely not only a result of the two successful vaccines against hepatitis B and Human Papilloma Virus (HPV) that use this technology, but also due to the versatility of those small-sized particles, as indicated by the wide range of applications reported so far, ranging from medicinal and cosmetics to purely technical applications. In this review, we will focus on the use of NPs, especially virus-like particles (VLPs), in the field of vaccines and will discuss their employment as vaccines, antigen display platforms, adjuvants and drug delivery systems.
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http://dx.doi.org/10.3390/vaccines5010006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5371742PMC
February 2017