ORCID Profile
0000-0002-4036-4269
Current Organisations
The Francis Crick Institute
,
The Royal College of Pathologists
,
University College London Hospitals NHS Foundation Trust
,
University College London
,
Royal College of Physicians
,
Oxford University Hospitals NHS Trust
,
University of Oxford
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Publications
Expanding community engagement and advocacy in chronic viral hepatitis
Publisher: Elsevier BV
Date: 10-2022
Illumina and Nanopore methods for whole genome sequencing of hepatitis B virus (HBV)
Publisher: Springer Science and Business Media LLC
Date: 08-05-2019
DOI: 10.1038/S41598-019-43524-9
Abstract: Advancing interventions to tackle the huge global burden of hepatitis B virus (HBV) infection depends on improved insights into virus epidemiology, transmission, within-host ersity, drug resistance and pathogenesis, all of which can be advanced through the large-scale generation of full-length virus genome data. Here we describe advances to a protocol that exploits the circular HBV genome structure, using isothermal rolling-circle lification to enrich HBV DNA, generating concatemeric licons containing multiple successive copies of the same genome. We show that this product is suitable for Nanopore sequencing as single reads, as well as for generating short-read Illumina sequences. Nanopore reads can be used to implement a straightforward method for error correction that reduces the per-read error rate, by comparing multiple genome copies combined into a single concatemer and by analysing reads generated from plus and minus strands. With this approach, we can achieve an improved consensus sequencing accuracy of 99.7% and resolve intra-s le sequence variants to form whole-genome haplotypes. Thus while Illumina sequencing may still be the most accurate way to capture within-s le ersity, Nanopore data can contribute to an understanding of linkage between polymorphisms within in idual virions. The combination of isothermal lification and Nanopore sequencing also offers appealing potential to develop point-of-care tests for HBV, and for other viruses.
Oxford Screening CSF and Respiratory samples (‘OSCAR’): results of a pilot study to screen clinical samples from a diagnostic microbiology laboratory for viruses using Illumina next generation sequenc
Publisher: Springer Science and Business Media LLC
Date: 09-02-2018
Case Report: Application of hepatitis B virus (HBV) deep sequencing to distinguish between acute and chronic infection
Publisher: F1000 Research Ltd
Date: 25-01-2021
DOI: 10.12688/WELLCOMEOPENRES.16157.2
Abstract: Deep sequencing of the full-length hepatitis B virus (HBV) genome provides the opportunity to determine the extent to which viral ersity, genotype, polymorphisms, insertions and deletions may influence presentation and outcomes of disease. Increasing experience with analysis of HBV genomic data opens up the potential for using these data to inform insights into pathophysiology of infection and to underpin decision making in clinical practice. We here set out to undertake whole genome HBV sequencing from an adult who presented acutely unwell with a new diagnosis of HBV infection, and tested positive for both HBV anti-core IgM and IgG, possibly representing either acute hepatitis B infection (AHB) or chronic hepatitis B with an acute reactivation (CHB-AR). The distinction between these two scenarios may be important in predicting prognosis and underpinning treatment decisions, but can be challenging based on routine laboratory tests. Through application of deep whole-genome sequencing we typed the isolate as genotype-D1, and identified several minority variants including G1764A and G1986A substitutions in the pre-core promoter and pre-core regions, which support CHB-AR rather than AHB. In the longer term, enhanced deep sequencing data for HBV may provide improved evidence to distinguish between acute and chronic infection, to predict outcomes and to stratify treatment.
Impact of HLA-driven HIV adaptation on virulence in populations of high HIV seroprevalence
Publisher: Proceedings of the National Academy of Sciences
Date: 12-2014
Abstract: Factors that influence the virulence of HIV are of direct relevance to ongoing efforts to contain, and ultimately eradicate, the HIV epidemic. We here investigate in Botswana and South Africa, countries severely affected by HIV, the impact on HIV virulence of adaptation of HIV to protective HLA alleles such as HLA-B*57. In Botswana, where the epidemic started earlier and reached higher adult seroprevalence than in South Africa, HIV replication capacity is lower. HIV is also better adapted to HLA-B*57, which in Botswana has no protective effect, in contrast to its impact in South Africa. Modelling studies indicate that increasing antiretroviral therapy access may also contribute to accelerated declines in HIV virulence over the coming decades.
Case Report: Application of hepatitis B virus (HBV) deep sequencing to distinguish between acute and chronic infection
Publisher: F1000 Research Ltd
Date: 14-10-2020
DOI: 10.12688/WELLCOMEOPENRES.16157.1
Abstract: Deep sequencing of the full-length hepatitis B virus (HBV) genome provides the opportunity to determine the extent to which viral ersity, genotype, polymorphisms, insertions and deletions may influence presentation and outcomes of disease. Increasing experience with analysis of HBV genomic data opens up the potential for using these data to inform insights into pathophysiology of infection and to underpin decision making in clinical practice. We here set out to undertake whole genome HBV sequencing from an adult who presented acutely unwell with a new diagnosis of HBV infection, and tested positive for both HBV anti-core IgM and IgG, possibly representing either acute hepatitis B infection (AHB) or chronic hepatitis B with an acute reactivation (CHB-AR). The distinction between these two scenarios may be important in predicting prognosis and underpinning treatment decisions, but can be challenging based on routine laboratory tests. Through application of deep whole-genome sequencing we typed the isolate as genotype-D1, and identified several minority variants including G1764A and G1986A substitutions in the pre-core promoter and pre-core regions, which support CHB-AR rather than AHB. In the longer term, enhanced deep sequencing data for HBV may provide improved evidence to distinguish between acute and chronic infection, to predict outcomes and to stratify treatment.
Antibody responses to SARS-CoV-2 vaccines in 45,965 adults from the general population of the United Kingdom
Publisher: Springer Science and Business Media LLC
Date: 21-07-2021
DOI: 10.1038/S41564-021-00947-3
Abstract: We report that in a cohort of 45,965 adults, who were receiving either the ChAdOx1 or the BNT162b2 SARS-CoV-2 vaccines, in those who had no prior infection with SARS-CoV-2, seroconversion rates and quantitative antibody levels after a single dose were lower in older in iduals, especially in those aged years. Two vaccine doses achieved high responses across all ages. Antibody levels increased more slowly and to lower levels with a single dose of ChAdOx1 compared with a single dose of BNT162b2, but waned following a single dose of BNT162b2 in older in iduals. In descriptive latent class models, we identified four responder subgroups, including a ‘low responder’ group that more commonly consisted of people aged years, males and in iduals with long-term health conditions. Given our findings, we propose that available vaccines should be prioritized for those not previously infected and that second doses should be prioritized for in iduals aged years. Further data are needed to better understand the extent to which quantitative antibody responses are associated with vaccine-mediated protection.
Inhaled budesonide in the treatment of early COVID-19 illness: a randomised controlled trial
Publisher: Cold Spring Harbor Laboratory
Date: 08-02-2021
DOI: 10.1101/2021.02.04.21251134
Abstract: Multiple early hospital cohorts of coronavirus disease 2019 (COVID-19) showed that patients with chronic respiratory disease were significantly under-represented. We hypothesised that the widespread use of inhaled glucocorticoids was responsible for this finding and tested if inhaled glucorticoids would be an effective treatment for early COVID-19 illness. We conducted a randomised, open label trial of inhaled budesonide, compared to usual care, in adults within 7 days of the onset of mild Covid-19 symptoms. The primary end point was COVID-19-related urgent care visit, emergency department assessment or hospitalisation. The trial was stopped early after independent statistical review concluded that study outcome would not change with further participant enrolment. 146 patients underwent randomisation. For the per protocol population (n=139), the primary outcome occurred in 10 participants and 1 participant in the usual care and budesonide arms respectively (difference in proportion 0.131, p=0.004). The number needed to treat with inhaled budesonide to reduce COVID-19 deterioration was 8. Clinical recovery was 1 day shorter in the budesonide arm compared to the usual care arm (median of 7 days versus 8 days respectively, logrank test p=0.007). Proportion of days with a fever and proportion of participants with at least 1 day of fever was lower in the budesonide arm. Fewer participants randomised to budesonide had persistent symptoms at day 14 and day 28 compared to participants receiving usual care. Early administration of inhaled budesonide reduced the likelihood of needing urgent medical care and reduced time to recovery following early COVID-19 infection. (Funded by Oxford NIHR Biomedical Research Centre and AstraZeneca ClinicalTrials.gov number, NCT04416399 ) The majority of interventions studied for the COVID-19 pandemic are focused on hospitalised patients. Widely available and broadly relevant interventions for mild COVID-19 are urgently needed. In this open label randomised controlled trial, inhaled budesonide, when given to adults with early COVID-19 illness, reduces the likelihood of requiring urgent care, emergency department consultation or hospitalisation. There was also a quicker resolution of fever, a known poor prognostic marker in COVID-19 and a faster self-reported and questionnaire reported symptom resolution. There were fewer participants with persistent COVID-19 symptoms at 14 and 28 days after budesonide therapy compared to usual care. The STOIC trial potentially provides the first easily accessible effective intervention in early COVID-19. By assessing health care resource utilisation, the study provides an exciting option to help with the worldwide pressure on health care systems due to the COVID-19 pandemic. Data from this study also suggests a potentially effective treatment to prevent the long term morbidity from persistent COVID-19 symptoms.
Global, regional, and national burden of hepatitis B, 1990–2019: a systematic analysis for the Global Burden of Disease Study 2019
Publisher: Elsevier BV
Date: 09-2022
Anti-spike antibody response to natural SARS-CoV-2 infection in the general population
Publisher: Springer Science and Business Media LLC
Date: 29-10-2021
DOI: 10.1038/S41467-021-26479-2
Abstract: Understanding the trajectory, duration, and determinants of antibody responses after SARS-CoV-2 infection can inform subsequent protection and risk of reinfection, however large-scale representative studies are limited. Here we estimated antibody response after SARS-CoV-2 infection in the general population using representative data from 7,256 United Kingdom COVID-19 infection survey participants who had positive swab SARS-CoV-2 PCR tests from 26-April-2020 to 14-June-2021. A latent class model classified 24% of participants as ‘non-responders’ not developing anti-spike antibodies, who were older, had higher SARS-CoV-2 cycle threshold values during infection (i.e. lower viral burden), and less frequently reported any symptoms. Among those who seroconverted, using Bayesian linear mixed models, the estimated anti-spike IgG peak level was 7.3-fold higher than the level previously associated with 50% protection against reinfection, with higher peak levels in older participants and those of non-white ethnicity. The estimated anti-spike IgG half-life was 184 days, being longer in females and those of white ethnicity. We estimated antibody levels associated with protection against reinfection likely last 1.5-2 years on average, with levels associated with protection from severe infection present for several years. These estimates could inform planning for vaccination booster strategies.
Insights From Deep Sequencing of the HBV Genome—Unique, Tiny, and Misunderstood
Publisher: Elsevier BV
Date: 2019
Transmission of HIV-1 Gag immune escape mutations is associated with reduced viral load in linked recipients
Publisher: Rockefeller University Press
Date: 21-04-2008
DOI: 10.1084/JEM.20072457
Abstract: In a study of 114 epidemiologically linked Zambian transmission pairs, we evaluated the impact of human leukocyte antigen class I (HLA-I)–associated amino acid polymorphisms, presumed to reflect cytotoxic T lymphocyte (CTL) escape in Gag and Nef of the virus transmitted from the chronically infected donor, on the plasma viral load (VL) in matched recipients 6 mo after infection. CTL escape mutations in Gag and Nef were seen in the donors, which were subsequently transmitted to recipients, largely unchanged soon after infection. We observed a significant correlation between the number of Gag escape mutations targeted by specific HLA-B allele–restricted CTLs and reduced VLs in the recipients. This negative correlation was most evident in newly infected in iduals, whose HLA alleles were unable to effectively target Gag and select for CTL escape mutations in this gene. Nef mutations in the donor had no impact on VL in the recipient. Thus, broad Gag-specific CTL responses capable of driving virus escape in the donor may be of clinical benefit to both the donor and recipient. In addition to their direct implications for HIV-1 vaccine design, these data suggest that CTL-induced viral polymorphisms and their associated in vivo viral fitness costs could have a significant impact on HIV-1 pathogenesis.
Differential Escape Patterns within the Dominant HLA-B*57:03-Restricted HIV Gag Epitope Reflect Distinct Clade-Specific Functional Constraints
Publisher: American Society for Microbiology
Date: 05-2014
DOI: 10.1128/JVI.03303-13
Abstract: HLA-B*57:01 and HLA-B*57:03, the most prevalent HLA-B*57 subtypes in Caucasian and African populations, respectively, are the HLA alleles most protective against HIV disease progression. Understanding the mechanisms underlying this immune control is of critical importance, yet they remain unclear. Unexplained differences are observed in the impact of the dominant cytotoxic T lymphocyte (CTL) response restricted by HLA-B*57:01 and HLA-B*57:03 in chronic infection on the Gag epitope KAFSPEVIPMF (KF11 Gag 162 to 172). We previously showed that the HLA-B*57:03-KF11 response is associated with a -log-lower viral setpoint in C clade virus infection and that this response selects escape mutants within the epitope. We first examined the relationship of KF11 responses in B clade virus-infected subjects with HLA-B*57:01 to immune control and observed that a detectable KF11 response was associated with a -log-higher viral load ( P = 0.02). No evidence of HLA-B*57:01-KF11-associated selection pressure was identified in previous comprehensive analyses of ,800 B clade virus-infected subjects. We then studied a B clade virus-infected cohort in Barbados, where HLA-B*57:03 is highly prevalent. In contrast to findings for B clade virus-infected subjects expressing HLA-B*57:01, we observed strong selection pressure driven by the HLA-B*57:03-KF11 response for the escape mutation S173T. This mutation reduces recognition of virus-infected cells by HLA-B*57:03-KF11 CTLs and is associated with a -log increase in viral load in HLA-B*57:03-positive subjects ( P = 0.009). We demonstrate functional constraints imposed by HIV clade relating to the residue at Gag 173 that explain the differential clade-specific escape patterns in HLA-B*57:03 subjects. Further studies are needed to evaluate the role of the KF11 response in HLA-B*57:01-associated HIV disease protection. IMPORTANCE HLA-B*57 is the HLA class I molecule that affords the greatest protection against disease progression in HIV infection. Understanding the key mechanism(s) underlying immunosuppression of HIV is of importance in guiding therapeutic and vaccine-related approaches to improve the levels of HIV control occurring in nature. Numerous mechanisms have been proposed to explain the HLA associations with differential HIV disease outcome, but no consensus exists. These studies focus on two subtypes of HLA-B*57 prevalent in Caucasian and African populations, HLA-B*57:01 and HLA-B*57:03, respectively. These alleles appear equally protective against HIV disease progression. The CTL epitopes presented are in many cases identical, and the dominant response in chronic infection in each case is to the Gag epitope KF11. However, there the similarity ends. This study sought to better understand the reasons for these differences and what they teach us about which immune responses contribute to immune control of HIV infection.
Adaptation of HIV-1 to human leukocyte antigen class I
Publisher: Springer Science and Business Media LLC
Date: 25-02-2009
DOI: 10.1038/NATURE07746
SARS-CoV-2 antibody trajectories after a single COVID-19 vaccination with and without prior infection
Publisher: Springer Science and Business Media LLC
Date: 29-06-2022
DOI: 10.1038/S41467-022-31495-X
Abstract: Given high SARS-CoV-2 incidence, coupled with slow and inequitable vaccine roll-out in many settings, there is a need for evidence to underpin optimum vaccine deployment, aiming to maximise global population immunity. We evaluate whether a single vaccination in in iduals who have already been infected with SARS-CoV-2 generates similar initial and subsequent antibody responses to two vaccinations in those without prior infection. We compared anti-spike IgG antibody responses after a single vaccination with ChAdOx1, BNT162b2, or mRNA-1273 SARS-CoV-2 vaccines in the COVID-19 Infection Survey in the UK general population. In 100,849 adults median (50 (IQR: 37–63) years) receiving at least one vaccination, 13,404 (13.3%) had serological/PCR evidence of prior infection. Prior infection significantly boosted antibody responses, producing higher peak levels and/or longer half-lives after one dose of all three vaccines than those without prior infection receiving one or two vaccinations. In those with prior infection, the median time above the positivity threshold was year after the first vaccination. Single-dose vaccination targeted to those previously infected may provide at least as good protection to two-dose vaccination among those without previous infection.
Phase 1/2 trial of SARS-CoV-2 vaccine ChAdOx1 nCoV-19 with a booster dose induces multifunctional antibody responses
Publisher: Springer Science and Business Media LLC
Date: 17-12-2020
Analysis of genomic-length HBV sequences to determine genotype and subgenotype reference sequences
Publisher: Microbiology Society
Date: 03-2020
DOI: 10.1099/JGV.0.001387
8th IAS Conference on HIV Pathogenesis, Treatment & Prevention 19-22 July 2015, Vancouver, Canada
Publisher: Wiley
Date: 07-2015
Performance characteristics of five immunoassays for SARS-CoV-2: a head-to-head benchmark comparison
Publisher: Elsevier BV
Date: 12-2020
Divergent trajectories of antiviral memory after SARS-CoV-2 infection
Publisher: Springer Science and Business Media LLC
Date: 10-03-2022
DOI: 10.1038/S41467-022-28898-1
Abstract: The trajectories of acquired immunity to severe acute respiratory syndrome coronavirus 2 infection are not fully understood. We present a detailed longitudinal cohort study of UK healthcare workers prior to vaccination, presenting April-June 2020 with asymptomatic or symptomatic infection. Here we show a highly variable range of responses, some of which (T cell interferon-gamma ELISpot, N-specific antibody) wane over time, while others (spike-specific antibody, B cell memory ELISpot) are stable. We use integrative analysis and a machine-learning approach (SIMON - Sequential Iterative Modeling OverNight) to explore this heterogeneity. We identify a subgroup of participants with higher antibody responses and interferon-gamma ELISpot T cell responses, and a robust trajectory for longer term immunity associates with higher levels of neutralising antibodies against the infecting (Victoria) strain and also against variants B.1.1.7 (alpha) and B.1.351 (beta). These variable trajectories following early priming may define subsequent protection from severe disease from novel variants.
Tracking the Emergence of SARS-CoV-2 Alpha Variant in the United Kingdom
Publisher: Massachusetts Medical Society
Date: 30-12-2021
DOI: 10.1056/NEJMC2103227
Two doses of SARS-CoV-2 vaccination induce robust immune responses to emerging SARS-CoV-2 variants of concern
Publisher: Springer Science and Business Media LLC
Date: 17-08-2021
DOI: 10.1038/S41467-021-25167-5
Abstract: The extent to which immune responses to natural infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and immunization with vaccines protect against variants of concern (VOC) is of increasing importance. Accordingly, here we analyse antibodies and T cells of a recently vaccinated, UK cohort, alongside those recovering from natural infection in early 2020. We show that neutralization of the VOC compared to a reference isolate of the original circulating lineage, B, is reduced: more profoundly against B.1.351 than for B.1.1.7, and in responses to infection or a single dose of vaccine than to a second dose of vaccine. Importantly, high magnitude T cell responses are generated after two vaccine doses, with the majority of the T cell response directed against epitopes that are conserved between the prototype isolate B and the VOC. Vaccination is required to generate high potency immune responses to protect against these and other emergent variants.
T-cell and antibody responses to first BNT162b2 vaccine dose in previously infected and SARS-CoV-2-naive UK health-care workers: a multicentre prospective cohort study
Publisher: Elsevier BV
Date: 2022
Antibody responses and correlates of protection in the general population after two doses of the ChAdOx1 or BNT162b2 vaccines
Publisher: Springer Science and Business Media LLC
Date: 14-02-2022
DOI: 10.1038/S41591-022-01721-6
Abstract: Antibody responses are an important part of immunity after Coronavirus Disease 2019 (COVID-19) vaccination. However, antibody trajectories and the associated duration of protection after a second vaccine dose remain unclear. In this study, we investigated anti-spike IgG antibody responses and correlates of protection after second doses of ChAdOx1 or BNT162b2 vaccines for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in the United Kingdom general population. In 222,493 in iduals, we found significant boosting of anti-spike IgG by the second doses of both vaccines in all ages and using different dosing intervals, including the 3-week interval for BNT162b2. After second vaccination, BNT162b2 generated higher peak levels than ChAdOX1. Older in iduals and males had lower peak levels with BNT162b2 but not ChAdOx1, whereas declines were similar across ages and sexes with ChAdOX1 or BNT162b2. Prior infection significantly increased antibody peak level and half-life with both vaccines. Anti-spike IgG levels were associated with protection from infection after vaccination and, to an even greater degree, after prior infection. At least 67% protection against infection was estimated to last for 2–3 months after two ChAdOx1 doses, for 5–8 months after two BNT162b2 doses in those without prior infection and for 1–2 years for those unvaccinated after natural infection. A third booster dose might be needed, prioritized to ChAdOx1 recipients and those more clinically vulnerable.
Immunogenicity of standard and extended dosing intervals of BNT162b2 mRNA vaccine
Publisher: Elsevier BV
Date: 11-2021
A blood atlas of COVID-19 defines hallmarks of disease severity and specificity
Publisher: Elsevier BV
Date: 03-2022
Measuring routine childhood vaccination coverage in 204 countries and territories, 1980–2019: a systematic analysis for the Global Burden of Disease Study 2020, Release 1
Publisher: Elsevier BV
Date: 08-2021
Related Organisations
The Francis Crick Institute
Location: United Kingdom of Great Britain and Northern Ireland
Royal Brompton & Harefield NHS Foundation Trust
Location: United Kingdom of Great Britain and Northern Ireland
The Royal College Of Pathologists
Location: United Kingdom of Great Britain and Northern Ireland
University College London Hospitals NHS Foundation Trust
Location: United Kingdom of Great Britain and Northern Ireland
University College London
Location: United Kingdom of Great Britain and Northern Ireland
Royal College Of Physicians
Location: United Kingdom of Great Britain and Northern Ireland
Oxford University Hospitals NHS Trust
Location: United Kingdom of Great Britain and Northern Ireland
Hammersmith Hospital
Location: United Kingdom of Great Britain and Northern Ireland
King's College Hospital NHS Foundation Trust
Location: United Kingdom of Great Britain and Northern Ireland
University Of Nottingham
Location: United Kingdom of Great Britain and Northern Ireland
University Of Oxford
Location: United Kingdom of Great Britain and Northern Ireland
University Of Liverpool
Location: United Kingdom of Great Britain and Northern Ireland
Related Funding Activities
No related grants have been discovered for Philippa Matthews.