Imperial College London

ProfessorRosemaryBoyton

Faculty of MedicineDepartment of Infectious Disease

Professor of Immunology and Respiratory Medicine
 
 
 
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r.boyton

 
 
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Location

 

8N22Commonwealth BuildingHammersmith Campus

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Summary

 

Publications

Publication Type
Year
to

136 results found

Alexander J, Powell N, Liu Z, Constable L, Ibraheim H, Anandabaskaran S, Saifuddin M, Castro Seoane R, Balarajah S, Hicks L, Williams H, Teare J, Altmann D, Boyton R, Hart Aet al., 2022, A prospective, case-control study of COVID-19 vaccine-induced antibody responses in immunosuppressed patients with IBD, The Lancet Gastroenterology & Hepatology, ISSN: 2468-1253

Journal article

Gois BM, Peixoto RF, Guerra-Gomes IC, Henrique de Sousa Palmeira P, Nóbrega de Sousa Dias C, Galvão Araújo JM, Veras RC, Medeiros IA, de Lourdes Assunção Araújo de Azevedo F, Boyton RJ, Altmann DM, Lima Keesen TSet al., 2021, Regulatory T Cells in acute and chronic human Chikungunya infection., Microbes Infect

Chikungunya virus (CHIKV) infection generates strong immune responses that are associated with the disease pathophysiology. Regulatory T cells (Treg-cluster of differentiation (CD)-4+CD25highforkhead box P3 (FOXP3+)) are essential for the induction and maintenance of peripheral tolerance. Thus, they play key roles in determining the patient prognosis by preventing excessive immune responses via different suppression immune mechanisms. However, the regulatory mechanisms involved in human CHIKV infection are still poorly understood. Here, we characterize for the first time the Treg cell molecule-associated-mechanism during acute and chronic human Chikungunya disease. Here, we assessed the Treg cell population and molecule-associated mechanism in the peripheral blood samples of acute and chronic patients with Chikungunya. Our results indicate that CHIKV infection is associated with reduced frequency of Tregs, along with the impaired expression and production of Treg functional markers, including CD39, CD73, perforin, granzyme, programmed death 1 (PD-1), cytotoxic T lymphocyte antigen (CTLA)-4, and transforming growth factor (TGF)-β. This observation suggests that Treg cells possess poor regulatory capacity in both acute and chronic phases of the disease. Taken together, these data provide significant evidence that the imbalanced response of Treg cells plays an essential role in establishing the pathogenesis of Chikungunya.

Journal article

Reynolds CJ, Gibbons JM, Pade C, Lin K-M, Sandoval DM, Pieper F, Butler DK, Liu S, Otter AD, Joy G, Menacho K, Fontana M, Smit A, Kele B, Cutino-Moguel T, Maini MK, Noursadeghi M, COVIDsortium Immune Correlates Network, Brooks T, Semper A, Manisty C, Treibel TA, Moon JC, McKnight Á, Altmann DM, Boyton RJet al., 2021, Heterologous infection and vaccination shapes immunity against SARS-CoV-2 variants., Science, Pages: eabm0811-eabm0811, ISSN: 0036-8075

The impact of initial severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infecting strain on downstream immunity to heterologous variants of concern (VOC) is unknown. Studying a longitudinal healthcare worker cohort, we found that after three antigen exposures (infection+two vaccine doses), S1 antibody, memory B cells and heterologous neutralization of B.1.351, P.1 and B.1.617.2 plateaued, while B.1.1.7 neutralization and spike T cell responses increased. Serology using Wuhan Hu-1 spike receptor binding domain poorly predicted neutralizing immunity against VOCs. Neutralization potency against VOCs changed with heterologous virus encounter and number of antigen exposures. Neutralization potency fell differentially depending on targeted VOCs over 5-months from the second vaccine dose. Heterologous combinations of spike encountered during infection and vaccination shape subsequent cross-protection against VOC, with implications for future-proof next-generation vaccines.

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Altmann DM, Boyton RJ, 2021, SARS-Cov-2 immune waning and reinfection in care-home settings, The Lancet Healthy Longevity, Vol: 2, Pages: E776-E777, ISSN: 2666-7568

Journal article

Altmann DM, Boyton RJ, 2021, Waning immunity to SARS-CoV-2: implications for vaccine booster strategies., The Lancet Respiratory Medicine, Vol: 9, Pages: 1356-1358, ISSN: 2213-2600

Journal article

Tomás-Cortázar J, Bossi L, Quinn C, Reynolds CJ, Butler DK, Corcoran N, Murchú MÓ, McMahon E, Singh M, Rongkard P, Anguita J, Blanco A, Dunachie SJ, Altmann D, Boyton RJ, Arnold J, Giltaire S, McClean Set al., 2021, BpOmpW antigen stimulates the Necessary Protective T-Cell Responses Against Melioidosis., Frontiers in Immunology, Vol: 12, ISSN: 1664-3224

Melioidosis is a potentially fatal bacterial disease caused by Burkholderia pseudomallei and is estimated to cause 89,000 deaths per year in endemic areas of Southeast Asia and Northern Australia. People with diabetes mellitus are most at risk of melioidosis, with a 12-fold increased susceptibility for severe disease. Interferon gamma (IFN-γ) responses from CD4 and CD8 T cells, but also from natural killer (NK) and natural killer T (NKT) cells, are necessary to eliminate the pathogen. We previously reported that immunization with B. pseudomallei OmpW (BpOmpW antigen) protected mice from lethal B. pseudomallei challenge for up to 81 days. Elucidating the immune correlates of protection of the protective BpOmpW vaccine is an essential step prior to clinical trials. Thus, we immunized either non-insulin-resistant C57BL/6J mice or an insulin-resistant C57BL/6J mouse model of type 2 diabetes (T2D) with a single dose of BpOmpW. BpOmpW induced strong antibody responses, stimulated effector CD4+ and CD8+ T cells and CD4+ CD25+ Foxp3+ regulatory T cells, and produced higher IFN-γ responses in CD4+, CD8+, NK, and NKT cells in non-insulin-resistant mice. The T-cell responses of insulin-resistant mice to BpOmpW were comparable to those of non-insulin-resistant mice. In addition, as a precursor to its evaluation in human studies, humanized HLA-DR and HLA-DQ (human leukocyte antigen DR and DQ isotypes, respectively) transgenic mice elicited IFN-γ recall responses in an enzyme-linked immune absorbent spot (ELISpot)-based study. Moreover, human donor peripheral blood mononuclear cells (PBMCs) exposed to BpOmpW for 7 days showed T-cell proliferation. Finally, plasma from melioidosis survivors with diabetes recognized our BpOmpW vaccine antigen. Overall, the range of approaches used strongly indicated that BpOmpW elicits the necessary immune responses to combat melioidosis and bring this vaccine closer to clinical trials.

Journal article

Altmann D, Boyton R, 2021, Covid-19 caseload in the UK-assessments and mitigations, BMJ: British Medical Journal, Vol: 375, ISSN: 0959-535X

Journal article

Altmann DM, Boyton RJ, 2021, Vaccine efficacy and immune interference: co-administering COVID-19 and influenza vaccines., The Lancet Respiratory Medicine, ISSN: 2213-2600

Journal article

Swadling L, Diniz MO, Schmidt NM, Amin OE, Chandran A, Shaw E, Pade C, Gibbons JM, Le Bert N, Tan AT, Jeffery-Smith A, Tan CCS, Tham CYL, Kucykowicz S, Aidoo-Micah G, Rosenheim J, Davies J, Johnson M, Jensen MP, Joy G, McCoy LE, Valdes AM, Chain BM, Goldblatt D, Altmann DM, Boyton RJ, Manisty C, Treibel TA, Moon JC, COVIDsortium investigators, Dorp LV, Balloux F, McKnight Á, Noursadeghi M, Bertoletti A, Maini MKet al., 2021, Pre-existing polymerase-specific T cells expand in abortive seronegative SARS-CoV-2, Nature, ISSN: 0028-0836

Individuals with potential exposure to SARS-CoV-2 do not necessarily develop PCR or antibody positivity, suggesting some may clear sub-clinical infection before seroconversion. T-cells can contribute to the rapid clearance of SARS-CoV-2 and other coronavirus infections1-3. We hypothesised that pre-existing memory T-cell responses, with cross-protective potential against SARS-CoV-24-11, would expand in vivo to support rapid viral control, aborting infection. We measured SARS-CoV-2-reactive T-cells, including those against the early transcribed replication transcription complex (RTC)12,13, in intensively monitored healthcare workers (HCW) remaining repeatedly negative by PCR, antibody binding, and neutralisation (seronegative HCW, SN-HCW). SN-HCW had stronger, more multispecific memory T-cells than an unexposed pre-pandemic cohort, and more frequently directed against the RTC than the structural protein-dominated responses seen post-detectable infection (matched concurrent cohort). SN-HCW with the strongest RTC-specific T-cells had an increase in IFI27, a robust early innate signature of SARS-CoV-214, suggesting abortive infection. RNA-polymerase within RTC was the largest region of high sequence conservation across human seasonal coronaviruses (HCoV) and SARS-CoV-2 clades. RNA-polymerase was preferentially targeted (amongst regions tested) by T-cells from pre-pandemic cohorts and SN-HCW. RTC epitope-specific T-cells cross-recognising HCoV variants were identified in SN-HCW. Enriched pre-existing RNA-polymerase-specific T-cells expanded in vivo to preferentially accumulate in the memory response after putative abortive compared to overt SARS-CoV-2 infection. Our data highlight RTC-specific T-cells as targets for vaccines against endemic and emerging Coronaviridae.

Journal article

Boyton RJ, Altmann DM, 2021, The immunology of asymptomatic SARS-CoV-2 infection: what are the key questions?, Nature Reviews Immunology, Vol: 21, Pages: 762-768, ISSN: 1474-1733

An important challenge during the COVID-19 pandemic has been to understand asymptomatic disease and the extent to which this may be a source of transmission. As asymptomatic disease is by definition hard to screen for, there is a lack of clarity about this aspect of the COVID-19 spectrum. Studies have considered whether the prevalence of asymptomatic disease is determined by differences in age, demographics, viral load, duration of shedding, and magnitude or durability of immunity. It is clear that adaptive immunity is strongly activated during asymptomatic infection, but some features of the T cell and antibody response may differ from those in symptomatic disease. Areas that need greater clarity include the extent to which asymptomatic disease leads to persistent symptoms (long COVID), and the quality, quantity and durability of immune priming required to confer subsequent protection.

Journal article

Guerra-Gomes IC, Goisa BM, Peixoto RF, Palmeira PHDS, Dias CNDS, Csordas BG, Araujo JMG, Veras RC, Medeiros IAD, Azevedox FDLAAD, Boyton RJ, Altmann DM, Keesen TSLet al., 2021, Phenotypical characterization of regulatory T cells in acute Zika infection, Cytokine, Vol: 146, Pages: 1-7, ISSN: 1096-0023

Zika virus (ZIKV), alongside Dengue virus (DENV), Chikungunya virus (CHIKV), and Yellow Fever Virus (YFV) are prevalent arboviruses in the Americas. Each of these infections is associated with the development of associated disease immunopathology. Immunopathological processes are an outcome of counter-balancing impacts between effector and regulatory immune mechanisms. In this context, regulatory T cells (Tregs) are key in modulating the immune response and, therefore, in tissue damage control. However, to date, Treg phenotypes and mechanisms during acute infection of the ZIKV in humans have not been fully investigated. The main aim of this work was to characterize Tregs and their immunological profile related to cytokine production and molecules that are capable of controlling the exacerbated inflammatory profile in acute Zika infected patients. Using whole blood analyses of infected patients, an ex vivo phenotypical characterization of Tregs, circulating during acute Zika virus infection, was conducted by flow cytometry. We found that though there are no differences in absolute Treg frequency between infected and healthy control groups. However, pro-inflammatory cytokine up-regulation such as IFN-γ and LAP was observed in the acute disease. Furthermore, acute ZIKV patients expressed increased levels of CD39/CD73, perforin/granzyme B, PD-1, and CTLA-4, all markers involved in mechanisms used by Tregs to attempt to control strong inflammatory responses. Thus, the data indicates a potential contribution of Tregs during the inflammatory ZIKV infection response.

Journal article

Gupta RK, Rosenheim J, Bell LC, Chandran A, Guerra-Assuncao JA, Pollara G, Whelan M, Artico J, Joy G, Kurdi H, Altmann DM, Boyton RJ, Maini MK, McKnight A, Lambourne J, Cutino-Moguel T, Manisty C, Treibel TA, Moon JC, Chain BM, Noursadeghi M, COVIDsortium Investigatorset al., 2021, Blood transcriptional biomarkers of acute viral infection for detection of pre-symptomatic SARS-CoV-2 infection: a nested, case-control diagnostic accuracy study., The Lancet Microbe, Vol: 2, Pages: e508-e517, ISSN: 2666-5247

Background: We hypothesised that host-response biomarkers of viral infections might contribute to early identification of individuals infected with SARS-CoV-2, which is critical to breaking the chains of transmission. We aimed to evaluate the diagnostic accuracy of existing candidate whole-blood transcriptomic signatures for viral infection to predict positivity of nasopharyngeal SARS-CoV-2 PCR testing. Methods: We did a nested case-control diagnostic accuracy study among a prospective cohort of health-care workers (aged ≥18 years) at St Bartholomew's Hospital (London, UK) undergoing weekly blood and nasopharyngeal swab sampling for whole-blood RNA sequencing and SARS-CoV-2 PCR testing, when fit to attend work. We identified candidate blood transcriptomic signatures for viral infection through a systematic literature search. We searched MEDLINE for articles published between database inception and Oct 12, 2020, using comprehensive MeSH and keyword terms for "viral infection", "transcriptome", "biomarker", and "blood". We reconstructed signature scores in blood RNA sequencing data and evaluated their diagnostic accuracy for contemporaneous SARS-CoV-2 infection, compared with the gold standard of SARS-CoV-2 PCR testing, by quantifying the area under the receiver operating characteristic curve (AUROC), sensitivities, and specificities at a standardised Z score of at least 2 based on the distribution of signature scores in test-negative controls. We used pairwise DeLong tests compared with the most discriminating signature to identify the subset of best performing biomarkers. We evaluated associations between signature expression, viral load (using PCR cycle thresholds), and symptom status visually and using Spearman rank correlation. The primary outcome was the AUROC for discriminating between samples from participants who tested negative throughout the study (test-negative controls) and samples from participants with PCR-conf

Journal article

Pinato D, Murray S, Forner A, Kaneko T, Fessas P, Toniutto P, Minguez B, Cacciato V, Avellini C, Diaz A, Boyton R, Altmann D, Goldin R, Akarca A, Marafioti T, Mauri F, Casagrande E, Grillo F, Giannini E, Bhoori S, Mazzaferro Vet al., 2021, Trans-arterial chemoembolization as a loco-regional inducer of immunogenic cell death in hepatocellular carcinoma: implications for immunotherapy., Journal for ImmunoTherapy of Cancer, ISSN: 2051-1426

Background: Modulation of adaptive immunity may underscore the efficacy of TACE. We evaluated the influence of TACE on T-cell function by phenotypic lymphocyte characterization in samples of patients undergoing surgery with (T+) or without (T-) prior-TACE treatment.Methods: We profiled intra-tumoural (IT), peri-tumoural (PT) and non-tumoural background tissue (NT) to evaluate regulatory CD4+/FOXP3+ (T-reg) and immune-exhausted CD8+/PD1+ T-cells across T+ (n=58) and T- (n=61). We performed targeted transcriptomics and T-cell receptor sequencing in a restricted subset of samples (n=24) evaluated in relationship with the expression of actionable drivers of anti-cancer immunity including PD-L1, IDO-1, CTLA-4, Lag-3, Tim-3 and CD163.Results: We analyzed 119 patients resected (n=25, 21%) or transplanted (n=94, 79%) for Child-Pugh A (n=65, 55%) and Barcelona Clinic Liver Cancer stage A (n=92, 77%) HCC. T+ samples displayed lower IT CD4+/FOXP3+ (p=0.006), CD8+ (p=0.002) and CD8+/PD1+ and NT CD8+/PD1+ (p<0.001) compared to T-. Lower IT (p=0.005) and NT CD4+/FOXP3+ (p=0.03) predicted for improved recurrence-free survival. In a subset of samples (n=24), transcriptomic analysis revealed up-regulation of a pro-inflammatory response in T+. T+ samples were enriched for IRF2 expression (p=0.01), an interferon-regulated transcription factor implicated in cancer immune-evasion. T-cell clonality and expression of PD-L1, IDO-1, CTLA-4, Lag-3, Tim-3 and CD163 was similar in T+ versus T-.Conclusions: TACE is associated with lower IT density of immune-exhausted effector cytotoxic and T-regs, with significant up-regulation of pro-inflammatory pathways. This highlights the pleiotropic effects of TACE in modulating the tumour microenvironment and strengthens the rationale for developing immunotherapy alongside TACE.

Journal article

Reynolds CJ, Pade C, Gibbons JM, Butler DK, Otter AD, Menacho K, Fontana M, Smit A, Sackville-West JE, Cutino-Moguel T, Maini MK, Chain B, Noursadeghi M, UK COVIDsortium Immune Correlates Network, Brooks T, Semper A, Manisty C, Treibel TA, Moon JC, UK COVIDsortium Investigators, Valdes AM, McKnight Á, Altmann DM, Boyton Ret al., 2021, Prior SARS-CoV-2 infection rescues B and T cell responses to variants after first vaccine dose, Science, Vol: 372, Pages: 1418-1423, ISSN: 0036-8075

SARS-CoV-2 vaccine rollout has coincided with the spread of variants of concern. We investigated if single dose vaccination, with or without prior infection, confers cross protective immunity to variants. We analyzed T and B cell responses after first dose vaccination with the Pfizer/BioNTech mRNA vaccine BNT162b2 in healthcare workers (HCW) followed longitudinally, with or without prior Wuhan-Hu-1 SARS-CoV-2 infection. After one dose, individuals with prior infection showed enhanced T cell immunity, antibody secreting memory B cell response to spike and neutralizing antibodies effective against B.1.1.7 and B.1.351. By comparison, HCW receiving one vaccine dose without prior infection showed reduced immunity against variants. B.1.1.7 and B.1.351 spike mutations resulted in increased, abrogated or unchanged T cell responses depending on human leukocyte antigen (HLA) polymorphisms. Single dose vaccination with BNT162b2 in the context of prior infection with a heterologous variant substantially enhances neutralizing antibody responses against variants.

Journal article

Altmann DM, Reynolds CJ, Boyton RJ, 2021, SARS-CoV-2 variants: Subversion of antibody response and predicted impact on T cell recognition., Cell Reports Medicine, Vol: 2, Pages: 1-3, ISSN: 2666-3791

COVID-19 variants of concern, including B.1.1.7, B.1.351, and P.1, encompass mutations facilitating immune evasion. Neutralizing antibody recognition and function may be variably impaired. We considered the impact of mutations on T cell responses. Mutations could be neutral or result in either loss or gain of predicted epitopes depending on HLA type.

Journal article

McDonald I, Murray S, Reynolds C, Altmann D, Boyton Ret al., 2021, Comparative systematic review and meta-analysis of reactogenicity, immunogenicity and efficacy of vaccines against SARS-CoV-2, npj Vaccines, Vol: 6, ISSN: 2059-0105

As SARS-CoV-2 vaccines are deployed worldwide, a comparative evaluation is important to underpin decision-making. We here report a systematic literature review and meta-analysis of Phase I/II/III human trials and non-human primates (NHP) studies, comparing reactogenicity, immunogenicity and efficacy across different vaccine platforms for comparative evaluation (updated to March 22, 2021). Twenty-three NHP and 32 human studies are included. Vaccines result in mostly mild, self-limiting adverse events. Highest spike neutralizing antibody (nAb) responses are identified for the mRNA-1273-SARS-CoV and adjuvanted NVX-CoV2373-SARS-CoV-2 vaccines. ChAdOx-SARS-CoV-2 produces the highest T cell ELISpot responses. Pre-existing nAb against vaccine viral vector are identified following AdH-5-SARS-CoV-2 vaccination, halving immunogenicity. The mRNA vaccines depend on boosting to achieve optimal immunogenicity especially in the elderly. BNT162b2, and mRNA-1273 achieve >94%, rAd26/5 > 91% and ChAdOx-SARS-CoV-2 > 66.7% efficacy. Across different vaccine platforms there are trade-offs between antibody binding, functional nAb titers, T cell frequency, reactogenicity and efficacy. Emergence of variants makes rapid mass rollout of high efficacy vaccines essential to reduce any selective advantage.

Journal article

Boyton RJ, Altmann DM, 2021, Risk of SARS-CoV-2 reinfection after natural infection, The Lancet, Vol: 397, Pages: 1161-1163, ISSN: 0140-6736

Journal article

Manisty C, Otter AD, Treibel TA, McKnight A, Altmann DM, Brooks T, Noursadeghi M, Boyton RJ, Semper A, Moon JCet al., 2021, Antibody response to first BNT162b2 dose in previously SARS-CoV-2-infected individuals, The Lancet, Vol: 397, Pages: 1057-1058, ISSN: 0140-6736

Journal article

Altmann DM, Boyton RJ, Beale R, 2021, Immunity to SARS-CoV-2 variants of concern, Science, Vol: 371, Pages: 1103-1104, ISSN: 1095-9203

Journal article

Manisty C, Treibel TA, Jensen M, Semper A, Joy G, Gupta RK, Cutino-Moguel T, Andiapen M, Jones J, Taylor S, Otter A, Pade C, Gibbons J, Lee J, Bacon J, Thomas S, Moon C, Jones M, Williams D, Lambourne J, Fontana M, Altmann DM, Boyton R, Maini M, McKnight A, Chain B, Noursadeghi M, Moon JCet al., 2021, Time series analysis and mechanistic modelling of heterogeneity and sero-reversion in antibody responses to mild SARS‑CoV-2 infection, EBioMedicine, Vol: 65, ISSN: 2352-3964

BACKGROUND: SARS-CoV-2 serology is used to identify prior infection at individual and at population level. Extended longitudinal studies with multi-timepoint sampling to evaluate dynamic changes in antibody levels are required to identify the time horizon in which these applications of serology are valid, and to explore the longevity of protective humoral immunity. METHODS: Healthcare workers were recruited to a prospective cohort study from the first SARS-CoV-2 epidemic peak in London, undergoing weekly symptom screen, viral PCR and blood sampling over 16-21 weeks. Serological analysis (n =12,990) was performed using semi-quantitative Euroimmun IgG to viral spike S1 domain and Roche total antibody to viral nucleocapsid protein (NP) assays. Comparisons were made to pseudovirus neutralizing antibody measurements. FINDINGS: A total of 157/729 (21.5%) participants developed positive SARS-CoV-2 serology by one or other assay, of whom 31.0% were asymptomatic and there were no deaths. Peak Euroimmun anti-S1 and Roche anti-NP measurements correlated (r = 0.57, p<0.0001) but only anti-S1 measurements correlated with near-contemporary pseudovirus neutralising antibody titres (measured at 16-18 weeks, r = 0.57, p<0.0001). By 21 weeks' follow-up, 31/143 (21.7%) anti-S1 and 6/150 (4.0%) anti-NP measurements reverted to negative. Mathematical modelling revealed faster clearance of anti-S1 compared to anti-NP (median half-life of 2.5 weeks versus 4.0 weeks), earlier transition to lower levels of antibody production (median of 8 versus 13 weeks), and greater reductions in relative antibody production rate after the transition (median of 35% versus 50%). INTERPRETATION: Mild SARS-CoV-2 infection is associated with heterogeneous serological responses in Euroimmun anti-S1 and Roche anti-NP assays. Anti-S1 responses showed faster rates of clearance, more rapid transition from high to low level production rate and greater reduction in production rate

Journal article

Adrielle Dos Santos L, Filho PGDG, Silva AMF, Santos JVG, Santos DS, Aquino MM, de Jesus RM, Almeida MLD, da Silva JS, Altmann DM, Boyton RJ, Alves Dos Santos C, Santos CNO, Alves JC, Santos IL, Magalhães LS, Belitardo EMMA, Rocha DJPG, Almeida JPP, Pacheco LGC, Aguiar ERGR, Campos GS, Sardi SI, Carvalho RH, de Jesus AR, Rezende KF, de Almeida RPet al., 2021, Recurrent COVID-19 including evidence of reinfection and enhanced severity in thirty Brazilian healthcare workers, Journal of Infection, Vol: 82, Pages: 399-406, ISSN: 0163-4453

BACKGROUND: There is growing concern about individuals reported to suffer repeat COVID-19 disease episodes, these in a small number of cases characterised as de novo infections with distinct sequences, indicative of insufficient protective immunity even in the short term. METHODS: Observational case series and case-control studies reporting 33 cases of recurrent, symptomatic, qRT-PCR positive COVID-19. Recurrent disease was defined as symptomatic recurrence after symptom-free clinical recovery, with release from isolation >14 days from the beginning of symptoms confirmed by qRT-PCR. The case control study-design compared this group of patients with a control group of 62 patients randomly selected from the same COVID-19 database. RESULTS: Of 33 recurrent COVID-19 patients, 26 were female and 30 were HCW. Mean time to recurrence was 50.5 days which was associated with being a HCW (OR 36.4 (p <0.0001)), and blood type A (OR 4.8 (p = 0.002)). SARS-CoV-2 antibodies were signifcantly lower in recurrent patients after initial COVID-19  (2.4 ± 0.610; p<0.0001) and after recurrence (6.4 ± 11.34; p = 0.007).  Virus genome sequencing identified reinfection by a different isolate in one patient. CONCLUSIONS: This is the first detailed case series showing COVID-19 recurrence with qRT-PCR positivity. For one individual detection of phylogenetically distinct genomic sequences in the first and second episodes confirmed bona fide renfection, but in most cases the data do not formally distinguish between reinfection and re-emergence of a chronic infection reservoir. These episodes were significantly associated with reduced Ab response during initial disease and argue the need for ongoing vigilance without an assumption of protection after a first episode.

Journal article

Altmann DM, Boyton RJ, 2021, Decoding the unknowns in long covid, BMJ: British Medical Journal, Vol: 372, Pages: 1-2, ISSN: 0959-535X

Journal article

Reynolds CJ, Swadling L, Gibbons JM, Pade C, Jensen MP, Diniz MO, Schmidt NM, Butler DK, Amin OE, Bailey SNL, Murray SM, Pieper FP, Taylor S, Jones J, Jones M, Lee W-YJ, Rosenheim J, Chandran A, Joy G, Di Genova C, Temperton N, Lambourne J, Cutino-Moguel T, Andiapen M, Fontana M, Smit A, Semper A, O'Brien B, Chain B, Brooks T, Manisty C, Treibel T, Moon JC, COVIDsortium investigators, Noursadeghi M, COVIDsortium immune correlates network, Altmann DM, Maini MK, McKnight Á, Boyton RJet al., 2020, Discordant neutralizing antibody and T cell responses in asymptomatic and mild SARS-CoV-2 infection., Science Immunology, Vol: 5, Pages: 1-19, ISSN: 2470-9468

Understanding the nature of immunity following mild/asymptomatic infection with SARS-CoV-2 is crucial to controlling the pandemic. We analyzed T cell and neutralizing antibody responses in 136 healthcare workers (HCW) 16-18 weeks after United Kingdom lockdown, 76 of whom had mild/asymptomatic SARS-CoV-2 infection captured by serial sampling. Neutralizing antibodies (nAb) were present in 89% of previously infected HCW. T cell responses tended to be lower following asymptomatic infection than in those reporting case-definition symptoms of COVID-19, while nAb titers were maintained irrespective of symptoms. T cell and antibody responses were sometimes discordant. Eleven percent lacked nAb and had undetectable T cell responses to spike protein but had T cells reactive with other SARS-CoV-2 antigens. Our findings suggest that the majority of individuals with mild or asymptomatic SARS-CoV-2 infection carry nAb complemented by multispecific T cell responses at 16-18 weeks after mild or asymptomatic SARS-CoV-2 infection.

Journal article

Gregorova M, Morse D, Brignoli T, Steventon J, Hamilton F, Albur M, Arnold D, Thomas M, Halliday A, Baum H, Rice C, Avison MB, Davidson AD, Santopaolo M, Oliver E, Goenka A, Finn A, Wooldridge L, Amulic B, Boyton RJ, Altmann DM, Butler DK, McMurray C, Stockton J, Nicholls S, Cooper C, Loman N, Cox MJ, Rivino L, Massey RCet al., 2020, Post-acute COVID-19 associated with evidence of bystander T-cell activation and a recurring AMR bacterial pneumonia, eLife, Vol: 9, ISSN: 2050-084X

Here we describe the case of a COVID-19 patient who developed recurring ventilator-associated pneumonia caused by Pseudomonas aeruginosa that acquired increasing levels of antimicrobial resistance (AMR) in response to treatment. Metagenomic analysis revealed the AMR genotype, while immunological analysis revealed massive and escalating levels of T-cell activation. These were both SARS-CoV-2 and P. aeruginosa specific, and bystander activated, which may have contributed to this patient's persistent symptoms and radiological changes.

Journal article

Alcantara DR, Jones C, Altmann DM, Boyton RJ, Haniffa M, Newport MJet al., 2020, Multiplexed gene expression analysis of HLA class II-associated podoconiosis implicates chronic immune activation in its pathogenesis, Transactions of the Royal Society of Tropical Medicine and Hygiene, Vol: 114, Pages: 926-936, ISSN: 0035-9203

BackgroundPodoconiosis is a tropical lymphoedema of the leg resulting from barefoot exposure to irritant volcanic soils. Approximately 4 million people are affected, mainly in African highland regions. The pathogenesis of this neglected tropical disease is still largely unknown, although HLA class II (HLAII) polymorphisms are associated with the disease.MethodsNanoString technology was used to assess expression of 579 immune-related genes in formalin-fixed and paraffin-embedded lymph node archival samples from podoconiosis patients and unaffected controls.ResultsForty-eight genes were upregulated and 21 downregulated in podoconiosis samples compared with controls. Gene ontology analysis showed differentially expressed genes to be closely related to major histocompatibility complex protein, cytokine and TNF receptor binding genes. Pathway enrichment analysis revealed involvement of lymphocyte activation, adaptive immunity, cytokine signalling, antigen processing and the IL-12 pathways.ConclusionsThis exploratory study reports a multiplex gene expression analysis in podoconiosis and shows upregulation of pro-inflammatory transcripts compatible with the notion of local, chronic immune activation in this HLAII-associated disease. Implicated pathways will inform future research into podoconiosis immunopathogenesis.

Journal article

Campbell VL, Nguyen L, Snoey E, McClurkan CL, Laing KJ, Dong L, Sette A, Lindestam Arlehamn CS, Altmann DM, Boyton RJ, Roby JA, Gale M, Stone M, Busch MP, Norris PJ, Koelle DMet al., 2020, Proteome-wide Zika virus CD4 T cell epitope and HLA restriction determination, ImmunoHorizons, Vol: 4, Pages: 444-453, ISSN: 2573-7732

Zika virus (ZIKV) is a mosquito-borne pathogen that caused an epidemic in 2015-2016. ZIKV-specific T cell responses are functional in animal infection models, and helper CD4 T cells promote avid Abs in the vaccine context. The small volumes of blood available from field research limit the determination of T cell epitopes for complex microbes such as ZIKV. The goal of this project was efficient determination of human ZIKV CD4 T cell epitopes at the whole proteome scale, including validation of reactivity to whole pathogen, using small blood samples from convalescent time points when T cell response magnitude may have waned. Polyclonal enrichment of candidate ZIKV-specific CD4 T cells used cell-associated virus, documenting that T cells in downstream peptide analyses also recognize whole virus after Ag processing. Sequential query of bulk ZIKV-reactive CD4 T cells with pooled/single ZIKV peptides and molecularly defined APC allowed precision epitope and HLA restriction assignments across the ZIKV proteome and enabled discovery of numerous novel ZIKV CD4 T cell epitopes. The research workflow is useful for the study of emerging infectious diseases with a very limited human blood sample availability.

Journal article

Altmann DM, Boyton RJ, 2020, SARS-CoV-2 T cell immunity: Specificity, function, durability, and role in protection, Science Immunology, Vol: 5, ISSN: 2470-9468

In efforts to synthesize a clear understanding of SARS-CoV-2 protective immunity, antibody analysis has been paralleled by T cell studies across asymptomatic, mild and severe COVID-19. Defining CD4 and CD8 effector functions in protection is important considering that antibody responses appear short-lived and T cell memory is potentially more durable. To fully understand population level immunity, screening for both antibody and T cell immunity using standardized testing methods would be beneficial.

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Altmann DM, Douek DC, Boyton RJ, 2020, What policy makers need to know about COVID-19 protective immunity, The Lancet, Vol: 395, Pages: 1527-1529, ISSN: 0140-6736

Journal article

Stowell J, Reynolds C, Boyton R, 2020, The impact of mesenchymal stem cells on host immunity and disease outcome in bacterial lung infection., Clin Med (Lond), Vol: 20, Pages: s117-s118

Journal article

Reynolds CJ, Watber P, Santos CNO, Ribeiro DR, Alves JC, Fonseca ABL, Bispo AJB, Porto RLS, Bokea K, de Jesus AMR, de Almeida RP, Boyton RJ, Altmann DMet al., 2020, Strong CD4 T cell responses to Zika virus antigens in a cohort of Dengue virus immune mothers of congenital Zika virus syndrome infants, Frontiers in Immunology, Vol: 11, ISSN: 1664-3224

Background: There is an urgent need to understand the complex relationship between cross-reactive anti-viral immunity, disease susceptibility, and severity in the face of differential exposure to related, circulating Flaviviruses. Co-exposure to Dengue virus and Zika virus in Brazil is a case in point. A devastating aspect of the 2015-2016 South American Zika outbreak was the dramatic increase in numbers of infants born with microcephaly to mothers exposed to Zika virus during pregnancy. It has been proposed that this is more likely to ensue from Zika infection in women lacking cross-protective Dengue immunity. In this case series we measure the prevalence of Dengue immunity in a cohort of mothers exposed to Zika virus during pregnancy in the 2015-2016 Zika outbreak that gave birth to an infant affected by microcephaly and explore their adaptive immunity to Zika virus. Results: Fifty women from Sergipe, Brazil who gave birth to infants with microcephaly following Zika virus exposure during the 2015-16 outbreak were tested for serological evidence of Dengue exposure and IFNγ ELISpot spot forming cell (SFC) response to Zika virus. The majority (46/50) demonstrated Dengue immunity. IFNγ ELISpot responses to Zika virus antigens showed the following hierarchy: Env>NS1>NS3>C protein. Twenty T cell epitopes from Zika virus Env were identified. Responses to Zika virus antigens Env and NS1 were polyfunctional with cells making IFNγ, TNFα, IL-4, IL-13, and IL-10. In contrast, responses to NS5 only produced the immune regulatory TGFβ1 cytokine. There were SFC responses against Zika virus Env (1-20) and variant peptide sequences from West Nile virus, Dengue virus 1-4 and Yellow Fever virus. Conclusion: Almost all the women in our study showed serological evidence of Dengue immunity, suggesting that microcephaly can occur in DENV immune mothers. T cell immunity to Zika virus showed a multifunctional response to the antigens Env and NS1 and i

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