122 results found
Penn R, Tregoning J, Flight K, et al., 2022, Levels of Influenza defective viral genomes determine pathogenesis in the BALB/c mouse model, Journal of Virology, Vol: 96, Pages: 1-18, ISSN: 0022-538X
Defective viral genomes (DVGs), which are generated by the viral polymerase in error during RNA replication, can trigger innate immunity and are implicated in altering the clinical outcome of infection. Here, we investigated the impact of DVGs on innate immunity and pathogenicity in a BALB/c mouse model of influenza virus infection. We generated stocks of influenza viruses containing the internal genes of an H5N1 virus that contain different levels of DVGs (indicated by different genome to PFU ratios). In lung epithelial cells, the high DVG stock was immunostimulatory at early time points post infection. DVGs were amplified during virus replication in myeloid immune cells and triggered pro-inflammatory cytokine production. In the mouse model, infection with the different virus stocks produced divergent outcomes. The high DVG stock induced an early type I IFN resonse that limited viral replication in the lungs resulting in minimal weight loss. In contrast, the virus stock with low levels of DVGs replicated to hightitres and amplified DVGs over time resulting in elevated pro-inflammatory cytokines accompanied by rapid weight loss and increased morbidity and mortality. Our results suggest that the timing and levels of immunostimulatory DVGs generated duringinfection contribute to H5N1 pathogenesis.
Tregoning J, 2022, Balance is needed when discussing academic careers., Nature
Haeusler IL, Daniel O, Isitt C, et al., 2022, Group B Streptococcus (GBS) colonisation is dynamic over time, whilst GBS capsular polysaccharides-specific antibody remains stable, Clinical and Experimental Immunology, Vol: 209, Pages: 188-200, ISSN: 0009-9104
Group B Streptococcus (GBS) is a leading cause of adverse pregnancy outcomes due to invasive infection. This study investigated longitudinal variation in GBS rectovaginal colonisation, serum and vaginal GBS capsular polysaccharide (CPS)-specific antibody levels. Non-pregnant women were recruited in the UK, and were sampled every two weeks over a 12-week period. GBS isolates were taken from recto-vaginal swabs and serotyped by polymerase chain reaction. Serum and vaginal immunoglobulin G (IgG) and nasal immunoglobulin A (IgA) specific to CPS were measured by Luminex, and total IgG/A by ELISA. 70 women were enrolled, of median age 26. Out of the 66 participants who completed at least three visits: 14/47 (29.8%) women that were GBS negative at screening became positive in follow up visits and 16/19 (84.2%) women who were GBS positive at screening became negative. There was 50% probability of becoming negative 36 days after the first positive swab. The rate of detectable GBS carriage fluctuated over time, although serum, vaginal and nasal CPS-specific antibody levels remained constant. Levels of CPS-specific antibodies were higher in the serum of individuals colonised with GBS than in non-colonised, but similar in the vaginal and nasal mucosa. We found correlations between antibody levels in serum and the vaginal and nasal mucosa. Our study demonstrates the feasibility of elution methods to retrieve vaginal and nasal antibodies, and the optimisation of immunoassays to measure GBS-CPS specific antibodies. The difference between the dynamics of colonisation and antibody response is interesting and further investigation is required for vaccine development.
Mosscrop LC, Williams TC, Tregoning JS, 2022, Respiratory syncytial virus after the SARS-CoV-2 pandemic - what next?, NATURE REVIEWS IMMUNOLOGY, ISSN: 1474-1733
McKay PF, Zhou J, Frise R, et al., 2022, Polymer formulated self-amplifying RNA vaccine is partially protective against influenza virus infection in ferrets, Oxford Open Immunology, Vol: 3, ISSN: 2633-6960
COVID-19 has demonstrated the power of RNA vaccines as part of a pandemic response toolkit. Another virus with pandemic potential is influenza. Further development of RNA vaccines in advance of a future influenza pandemic will save time and lives. As RNA vaccines require formulation to enter cells and induce antigen expression, the aim of this study was to investigate the impact of a recently developed bioreducible cationic polymer, pABOL for the delivery of a self-amplifying RNA (saRNA) vaccine for seasonal influenza virus in mice and ferrets. Mice and ferrets were immunized with pABOL formulated saRNA vaccines expressing either haemagglutinin (HA) from H1N1 or H3N2 influenza virus in a prime boost regime. Antibody responses, both binding and functional were measured in serum after immunization. Animals were then challenged with a matched influenza virus either directly by intranasal inoculation or in a contact transmission model. While highly immunogenic in mice, pABOL-formulated saRNA led to variable responses in ferrets. Animals that responded to the vaccine with higher levels of influenza virus-specific neutralizing antibodies were more protected against influenza virus infection. pABOL-formulated saRNA is immunogenic in ferrets, but further optimization of RNA vaccine formulation and constructs is required to increase the quality and quantity of the antibody response to the vaccine.
Mann JFS, McKay PF, Klein K, et al., 2022, Blocking T-cell egress with FTY720 extends DNA vaccine expression but reduces immunogenicity, Immunology, Vol: 165, Pages: 301-311, ISSN: 0019-2805
Optimal immunogenicity from nucleic acid vaccines requires a balance of antigen expression that effectively engages the host immune system without generating a cellular response that rapidly destroys cells producing the antigen and thereby limiting vaccine antigen expression. We investigated the role of the cellular response on the expression and antigenicity of DNA vaccines using a plasmid DNA construct expressing luciferase. Repeated intramuscular administration led to diminished luciferase expression, suggesting a role for immune-mediated clearance of expression. To investigate the role of cell trafficking, we used the sphingosine 1-phosphate receptor (S1PR) modulator, FTY720 (Fingolimod), which traps lymphocytes within the lymphoid tissues. When lymphocyte trafficking was blocked with FTY720, DNA transgene expression was maintained at a constant level for a significantly extended time period. Both continuous and staggered administration of FTY720 prolonged transgene expression. However, blocking lymphocyte egress during primary transgene administration did not result in an increase of transgene expression during secondary administration. Interestingly, there was a disconnect between transgene expression and immunogenicity, as increasing expression by this approach did not enhance the overall immune response. Furthermore, when FTY720 was administered alongside a DNA vaccine expressing the HIV gp140 envelope antigen, there was a significant reduction in both antigen-specific antibody and T-cell responses. This indicates that the developing antigen-specific cellular response clears DNA vaccine expression but requires access to the site of expression in order to develop an effective immune response.
Costa-Martins AG, Mane K, Lindsey BB, et al., 2022, Erratum: Prior upregulation of interferon pathways in the nasopharynx impacts viral shedding following live attenuated influenza vaccine challenge in children., Cell Reports Medicine, Vol: 3, Pages: 100516-100516, ISSN: 2666-3791
Pyle CJ, Labeur-Iurman L, Groves HT, et al., 2021, Enhanced IL-2 in early life limits the development of TFH and protective antiviral immunity, Journal of Experimental Medicine, Vol: 218, ISSN: 0022-1007
T follicular helper cell (TFH)-dependent antibody responses are critical for long-term immunity. Antibody responses are diminished in early life, limiting long-term protective immunity and allowing prolonged or recurrent infection, which may be important for viral lung infections that are highly prevalent in infancy. In a murine model using respiratory syncytial virus (RSV), we show that TFH and the high-affinity antibody production they promote are vital for preventing disease on RSV reinfection. Following a secondary RSV infection, TFH-deficient mice had significantly exacerbated disease characterized by delayed viral clearance, increased weight loss, and immunopathology. TFH generation in early life was compromised by heightened IL-2 and STAT5 signaling in differentiating naive T cells. Neutralization of IL-2 during early-life RSV infection resulted in a TFH-dependent increase in antibody-mediated immunity and was sufficient to limit disease severity upon reinfection. These data demonstrate the importance of TFH in protection against recurrent RSV infection and highlight a mechanism by which this is suppressed in early life.
Costa-Martins AG, Mane K, Lindsey BB, et al., 2021, Prior upregulation of interferon pathways in the nasopharynx impacts viral shedding following live attenuated influenza vaccine challenge in children, Cell Reports Medicine, Vol: 2, Pages: 1-16, ISSN: 2666-3791
In children lacking influenza-specific adaptive immunity, upper respiratory tract innate immune responses may influence viral replication and disease outcome. We use trivalent live attenuated influenza vaccine (LAIV) as a surrogate challenge model in children aged 24–59 months to identify pre-infection mucosal transcriptomic signatures associated with subsequent viral shedding. Upregulation of interferon signaling pathways prior to LAIV is significantly associated with lower strain-specific viral loads (VLs) at days 2 and 7. Several interferon-stimulated genes are differentially expressed in children with pre-LAIV asymptomatic respiratory viral infections and negatively correlated with LAIV VLs. Upregulation of genes enriched in macrophages, neutrophils, and eosinophils is associated with lower VLs and found more commonly in children with asymptomatic viral infections. Variability in pre-infection mucosal interferon gene expression in children may impact the course of subsequent influenza infections. This variability may be due to frequent respiratory viral infections, demonstrating the potential importance of mucosal virus-virus interactions in children.
Tregoning J, 2021, How I wrote a pop-science book., Nature
Haeusler I, Isitt C, Daniel O, et al., 2021, Optimisation of methods for a human infection model for Group B Streptococcus (the TIMING study): a pilot, prospective cohort study, ISSAD, Publisher: WILEY, Pages: 220-221, ISSN: 1360-2276
Tregoning JS, Flight KE, Higham SL, et al., 2021, Progress of the COVID-19 vaccine effort: viruses, vaccines and variants versus efficacy, effectiveness and escape, Nature Reviews Immunology, Vol: 21, Pages: 626-636, ISSN: 1474-1733
Where 2020 saw the development and testing of vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) at an unprecedented pace, the first half of 2021 has seen vaccine rollout in many countries. In this Progress article, we provide a snapshot of ongoing vaccine efficacy studies, as well as real-world data on vaccine effectiveness and the impact of virus variants of concern. Where they have been deployed in a high proportion of the adult population, the currently approved vaccines have been extremely effective in preventing COVID-19, particularly severe disease. Nonetheless, there are still significant challenges in ensuring equitable vaccine access around the globe and lessons that can be learned for controlling this pandemic and for the next pandemic.
Zhang S, Asquith B, Szydlo R, et al., 2021, Peripheral T cell lymphopenia in COVID-19: potential mechanisms and impact, Immunotherapy Advances, Vol: 1, Pages: 1-18, ISSN: 2732-4303
Immunopathogenesis involving T lymphocytes, which play a key role in defence against viral infection, could contribute to the spectrum of COVID-19 disease and provide an avenue for treatment. To address this question, are view of clinical observational studies and autopsy data in English and Chinese languages was conducted with a search of registered clinical trials. Peripheral lymphopenia affecting CD4 and CD8 T cells was a striking feature of severe COVID-19 compared with non-severe disease. Autopsy data demonstrated infiltration of T cells into organs, particularly the lung. 74 clinical trials are on-going that could target T cell-related pathogenesis, particularly IL-6 pathways. SARS-CoV-2 infection interrupts T cell circulation in patients with severe COVID-19. This could be due to redistribution of T cells into infected organs, activation induced exhaustion, apoptosis or pyroptosis. Measuring T cell dynamics during COVID-19 will inform clinical risk-stratification of hospitalised patients and could identify those who would benefit most from 66treatments that target T cells
Cole ME, Kundu R, Abdulla AF, et al., 2021, Pre-existing influenza specific nasal IgA or nasal viral infection does not affect live attenuated influenza vaccine immunogenicity in children., Clinical and Experimental Immunology, Vol: 204, Pages: 125-133, ISSN: 0009-9104
The United Kingdom has a national immunisation program which includes annual influenza vaccination in school-aged children, using live attenuated influenza vaccine (LAIV). LAIV is given annually, and it is unclear whether repeat administration can affect immunogenicity. Since LAIV is delivered intranasally, pre-existing local antibody might be important. In this study, we analysed banked samples from a study performed during the 2017/18 influenza season to investigate the role of pre-existing influenza-specific nasal IgA in children aged 6-14 years. Nasopharyngeal swabs were collected prior to LAIV immunisation, to measure pre-existing IgA levels and test for concurrent upper respiratory tract viral infections (URTI). Oral fluid samples were taken at baseline and 21-28 days after LAIV to measure IgG as a surrogate of immunogenicity. Antibody levels at baseline were compared with a pre-existing dataset of LAIV shedding from the same individuals, measured by RT-PCR. There was detectable nasal IgA specific to all four strains in the vaccine at baseline. However, baseline nasal IgA did not correlate with the fold change in IgG response to the vaccine. Baseline nasal IgA also did not have an impact on whether vaccine virus RNA was detectable after immunisation. There was no difference in fold change of antibody between individuals with and without an URTI at the time of immunisation. Overall, we observed no effect of pre-existing influenza specific nasal antibody levels on immunogenicity, supporting annual immunisation with LAIV in children.
Tregoning J, 2021, Coronavirus diaries: the COVID 19., Nature
Tregoning J, 2021, Coronavirus diaries: Laughter is the best medicine., Nature
Tregoning J, 2021, Coronavirus diaries: making plans in a changing world., Nature
Tregoning J, 2020, Coronavirus diaries: an unexpected career experiment., Nature
Tregoning J, 2020, Coronavirus diaries: Reasons to be cheerful, 1, 2, 3., Nature
Tregoning JS, 2020, First human efficacy study of a plant-derived influenza vaccine, LANCET, Vol: 396, Pages: 1464-1465, ISSN: 0140-6736
Since the emergence of COVID-19, caused by the SARS-CoV-2 virus, at the end of 2019 there has been an explosion of vaccine development. By the 1st September 2020, a staggering number of vaccines (over 200) had started pre-clinical development of which 39 had entered clinical trials, including some approaches that have not previously been licensed for human vaccines. Vaccines have been widely considered as part of the exit strategy to enable the return to previous patterns of working, schooling and socialising. Importantly, to effectively control the COVID-19 pandemic, production needs to be scaled up from a small number of pre-clinical doses to enough filled vials to immunise the world's population, which requires close engagement with manufacturers and regulators. It will require a global effort to control the virus, necessitating equitable access for all countries to effective vaccines. This review explores the immune responses required to protect against SARS-CoV-2 and the potential for vaccine-induced immunopathology. It describes the profile of the different platforms and the advantages and disadvantages of each approach. The review also addresses the critical steps between promising pre-clinical leads and manufacturing at scale. The issues faced during this pandemic and the platforms being developed to address it will be invaluable for future outbreak control. Nine months after the outbreak began, we are at a point where pre-clinical and early clinical data is being generated for the vaccines, an overview of this important area will help our understanding of the next phases.
Tregoning J, 2020, Coronavirus diaries: a new year for science., Nature
Tregoning J, 2020, Coronavirus diaries: give your brain a break from science busywork, it deserves it., NATURE, Vol: 585, Pages: 471-472, ISSN: 0028-0836
Tregoning J, Busse D, Kaforou M, et al., 2020, Interferon-induced Protein-44 and Interferon-induced Protein 44-like restrict replication of Respiratory Syncytial Virus, Journal of Virology, Vol: 94, Pages: 1-15, ISSN: 0022-538X
Cellular intrinsic immunity, mediated by the expression of an array of interferon-stimulated antiviral genes, is a vital part of host defence. We have previously used a bioinformatic screen to identify two interferon stimulated genes (ISG) with poorly characterised function, Interferon-induced protein 44 (IFI44) and interferon-induced protein 44-like (IFI44L), as potentially being important in Respiratory Syncytial Virus (RSV) infection. Using overexpression systems, CRISPR-Cas9-mediated knockout, and a knockout mouse model we investigated the antiviral capability of these genes in the control of RSV replication. Over-expression of IFI44 or IFI44L was sufficient to restrict RSV infection at an early time post infection. Knocking out these genes in mammalian airway epithelial cells increased levels of infection. Both genes express antiproliferative factors that have no effect on RSV attachment but reduce RSV replication in a minigenome assay. The loss of Ifi44 was associated with a more severe infection phenotype in a mouse model of infection. These studies demonstrate a function for IFI44 and IFI44L in controlling RSV infection.
Tregoning J, 2020, Coronavirus diaries: social media in an unsocial age, Nature, ISSN: 0028-0836
Tregoning J, 2020, Coronavirus diaries: a lockdown letter to myself as a PhD student., Nature
Tregoning J, 2020, Coronavirus diaries: back to the lab again., Nature
Tregoning J, 2020, Coronavirus diaries: taking leave, but not holiday., Nature
Tregoning J, 2020, Coronavirus diaries: rejection under lockdown., Nature
Tregoning J, 2020, Coronavirus diaries: finding a place to have new ideas., Nature
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