The indirect effects of cytomegalovirus infection: mechanisms and consequences
Discussion meeting organised by Dr Tom Yates and Dr Helen Payne.
Cytomegalovirus (CMV) is common. The term ‘indirect effects’ describes a statistical excess of cardiovascular disease, non-CMV infections, and other pathology seen in people with CMV absent histological evidence of CMV-associated tissue damage. This meeting brought together laboratory scientists, paediatric and adult clinical academics, epidemiologists and trialists, to discuss the latest research on indirect effects, from mechanisms to clinical significance.
Attending the meeting
This meeting was free to attend and intended for researchers in a relevant field.
Enquiries: please contact the Scientific Meetings team.
Organisers
Schedule
Chair
Hermione Lyall, Imperial College Healthcare NHS Trust, UK
Hermione Lyall, Imperial College Healthcare NHS Trust, UK
Hermione Lyall is a consultant in paediatric infectious diseases at Imperial College Healthcare NHS Trust and Professor of Practice at Imperial College. She run’s both HIV and Congenital infection clinics at St Mary’s Hospital in London. She is a member of the Paediatric European Infection Network (PENTA-ID) and participates in HIV treatment and prevention trials for children. She has been actively involved with international courses for education for Paediatric Infections for many years, working with PENTA and the European Society for paediatric Infectious Diseases (ESPID). In 2020, with colleagues from Europe, she set up CCMVNET an international network built around a prospective registry for children with congenital CMV (CCMV), she was the inaugural chair of the network (2020-2023).
Professor Sarah Rowland-Jones, Oxford University, UK
Professor Sarah Rowland-Jones, Oxford University, UK
Sarah Rowland-Jones is a clinical academic professor who leads a research group in Oxford which focuses on host-pathogen interactions in HIV-1 and HIV-2 infection. She was previously Research Director of the MRC Laboratories, the Gambia, where her interest in CMV infection began. A key focus of her current work is investigating the mechanisms that underlie the poor health of many African survivors of perinatal HIV infection (PHIV), in collaboration with Professor Rashida Ferrand in Harare. These studies have suggested that CMV co-infection plays an important role in the comorbidities experienced by young people with PHIV.
Since November 2018 she has divided her time between Oxford and Sheffield University, where she is Florey Professor of Infection and Immunity and an Honorary Consultant in adult Infectious Diseases at Sheffield Teaching Hospital Trust.
| 09:00-09:05 |
Welcome by the Royal Society and lead organisers
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| 09:05-09:30 |
Joining the dots: maternal HIV, CMV, and the placenta
Elucidating mechanisms that disrupt immune homeostasis at the maternal-foetal interface (MFI) can provide a link between HIV and CMV coinfection in pregnancy with abnormalities to infant immunity, especially children HIV exposed but uninfected (CHEU). Vertical transmission of HIV has been mitigated by the successful implementation of antiretroviral therapy (ART) either prior to or during pregnancy. Despite this, the incidence of adverse birth outcomes and the co-morbidities in newborn CHEU remains significantly higher than in infants born to HIV uninfected mothers. It is hypothesised that the immune status of mothers during pregnancy impacts on the placenta and how this in turn impacts on the immune status of the newborn neonate. We are investigating cohorts of pregnant women on different regimens of ART and different birth outcomes, such as pre-term birth and low birth weight, and measuring how placental macrophages (Hofbauer cells, HBC) and T cells change with HIV/ART exposure and impact on T cell clonality in the first 9 months of life. We show that Factor XIIIA1 expression on HBC in term placentas is significantly lower when the birth outcome is pre-term, with levels of expression being dependent on the timing of ART initiation: before or after conception. Clonality of T cells is more oligoclonal in the HEU infant relative to controls with an absence of clones predicted to recognize common viral antigens, including to CMV. Data will be shown that supports our hypothesis that the HIV-and CMV-associated maternal environment during gestation leaves a footprint in the placenta which determines the immune status of HEU newborns. 
Professor Clive Gray, University of Cape Town, South Africa
Professor Clive Gray, University of Cape Town, South AfricaClive Gray is Professor of Immunology in the Division of Immunology, Biomedical Research Institute at Stellenbosch University. His research focuses on HIV immunology and is the director of the Reproductive Immunology Research Consortium in Africa. He is the Chair of the Education Committee of the International Union of Immunology Societies and the Director of the Federation of Clinical Immunology Society Centre of Excellence at Stellenbosch University. He is also the incoming President of the Federation of African Immunology Societies from December 2024 and Director of the Immunopaedia Foundation. He is the recipient of numerous grant awards that allows him to study how maternal HIV and CMV infection impacts on placental immune development. He also leads a newly NIH funded consortium: NexT generatIon traininG in HIV Research: Immunity in the First 1000 days in mother-infant dyadS (TIGRIS), consisting of investigators and educators in Africa, North America and the UK. |
| 09:30-09:55 |
The relationship between maternal CMV viraemia during pregnancy and health outcomes of children in rural Zimbabwe
Children in many sub-Saharan African settings are at risk of poor outcomes in early childhood, including infectious morbidity and mortality, and growth and neurodevelopmental impairment. The reasons are likely multifactorial but include antenatal early life exposures. The First 1000 Days refers to the period from conception through 2 years of age; a child’s body, brain and immune system grow and develop during this period, and each may be critically affected by infections including HIV and CMV. In a birth cohort from rural Zimbabwe, children born to mothers with HIV had a higher risk of mortality and growth and developmental impairment compared to children born to mothers without HIV. It was hypothesised that CMV co-infection may have mediated these increased risks. Maternal CMV viraemia during pregnancy was independently associated with infant mortality amongst children who were perinatally exposed to HIV but not amongst children who were born to mothers without HIV. Amongst children who survived, neurodevelopmental outcomes were poorer amongst those born to mothers with CMV viraemia during pregnancy compared to those without exposure to CMV viraemia, regardless of maternal HIV infection. In summary, exposure to CMV may be one explanation for an increased risk of infant mortality and neurodevelopmental delay in high HIV-burden settings. By adulthood, CMV infection is almost ubiquitous in sub-Saharan Africa, and CMV frequently reactivates during pregnancy, particularly in the context of maternal HIV infection; these findings may therefore have important public health implications. 
Dr Ceri Evans University of Liverpool, UK
Dr Ceri Evans University of Liverpool, UKCeri is a Clinical Lecturer in Paediatric Infectious Diseases funded by the National Institute for Health and Care Research (NIHR). He splits his time between research at the University of Liverpool/ Zvitambo Institute for Maternal and Child Health Research in Harare, Zimbabwe, and NHS clinical practice at Alder Hey Children’s Hospital. Ceri is interested in the relationship between maternal and child health in low resource settings, with a particular focus on children living with HIV or those who are HIV-exposed but uninfected. His research combines epidemiology and laboratory immunology in this field, and his current efforts lie in trying to better understand the interactions between inflammation, co-infections (including CMV), immune development and preterm birth in mediating the long-term outcomes of children with HIV exposure, and in co-designing potential new interventions with community members in rural Zimbabwe, with the ultimate aim of improving outcomes of children born to mothers with HIV. |
| 09:55-10:20 |
Immune profile in early infant CMV
In low- and middle-income countries, early acquisition of CMV is almost universal, with the majority of infants acquiring CMV in the first year after birth. Infants with CMV infection have a distinct immune profile characterised by an activated, differentiated T-cell pool. Whether this immune activation associated with CMV is consequential remains uncertain. CMV acquisition may be more likely in infants who are exposed to HIV, or living with HIV, and CMV may act as a cofactor in disease progression. This talk will review the epidemiology of congenital and acquired CMV in LMIC settings; the immune footprint left by the virus; and the clinical consequences of early-life CMV infection in infants with and without HIV exposure. 
Dr Andrew Prendergast, Queen Mary University of London, UK
Dr Andrew Prendergast, Queen Mary University of London, UKProfessor Prendergast’s group focuses on global child health research, with the goal of helping children survive and thrive. His research investigates the interactions between infection, immunity and malnutrition, particularly in settings of high HIV prevalence. He is Professor of Paediatric Infection and Immunology at Queen Mary University of London, and Director of the Zvitambo Institute for Maternal and Child Health Research in Zimbabwe. |
| 10:20-10:45 |
Predicting the outcome of congenital and post-natal cytomegalovirus infections: the urgent search for biomarkers in the emerging era of universal congenital CMV screening
Congenital cytomegalovirus (cCMV) infection is the most common infectious cause of childhood disability. Most infants with cCMV have a prognosis for normal outcomes, but up to 20% will have disabilities, including sensorineural hearing loss (SNHL). Infants without clinical findings of CMV disease are still at risk for these consequences of congenital infection, but in spite of a complete diagnostic evaluation, including blood tests, ophthalmologic and audiologic evaluations, and neuroimaging, disease categorisation is challenging. This observation raises the question of whether there are heretofore undetected indirect effects of infection that might be contributing to neurodevelopmental injury. Driven by Minnesota’s new initiative for universal cCMV screening, other states in the US and provinces in Canada are adopting universal newborn screening for cCMV. There is therefore an urgency to identify biomarkers of infection that correlate with enhanced risk for long-term CMV disease. Toward the goal of addressing unmet need, the Schleiss laboratory leveraged a unique collection of ~25,000 newborn saliva samples, collected in a universal cCMV screening study performed in Minnesota that compared the diagnostic sensitivity of saliva and dried blood spot (DBS) PCR. Saliva and DBS PCR identified a prevalence of cCMV of 0.35% (87 total cases). Using the stored saliva swabs, comparisons of the salivary microbiome and proteome from cCMV+ and control infants demonstrated that the microbial community in cCMV- control infants clustered stably and consistently away from cCMV+ infants. Infants with cCMV demonstrated, by 16S rDNA analysis, dramatic alterations in the salivary microbiome. Proteomic comparisons of the two groups further suggested cCMV infection was associated with altered salivary expression of host immune response proteins. These observations suggest that cCMV, through both direct and indirect effects, has a dramatic impact on shaping neonatal microbial ecology, with a possible ensuing impact on neurodevelopmental outcomes.
Mark R Schleiss, University of Minnesota Medical School, USA
Mark R Schleiss, University of Minnesota Medical School, USADr Mark R Schleiss, Professor of Paediatrics, holds the American Legion Endowed Chair at the University of Minnesota (UMN) Medical School. His laboratory studies vaccines for prevention of congenital cytomegalovirus (cCMV) infection. As a practicing clinician, he provides expertise in the evaluation and management of cCMV. His research program is funded by the NIH and the CDC, and he is engaged in advocacy for universal cCMV screening. His work with the Minnesota Legislature, in collaboration with families who have children with cCMV, led to successful passage in 2021 of the “Vivian Act”, novel legislation that enabled universal CMV screening in Minnesota newborn infants. Minnesota subsequently became the first state in the USA to adopt universal cCMV screening in 2023. He is also the principal investigator of a CDC-funded MAT-LINK site in Minnesota that is currently engaged in cCMV surveillance and follow-up (https://ctsi.umn.edu/news/ctsi-part-team-studying-follow-infants-cmv-infections). His laboratory also studies the immunology and molecular virology of congenital and post-natally acquired CMV infections in preterm infants, and long-term impacts of such infections. |
| 10:45-11:10 |
Break
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| 11:10-11:35 |
CMV/ HIV coinfection in perinatally infected children in sub-Saharan Africa: lung disease and immune ageing
In healthy adults, CMV is generally asymptomatic but is associated with immune aging characterised by memory CD8 T cell inflation, decreased CD4 T cell receptor diversity, and chronic subclinical inflammation, which impair immune function with age. However, CMV disproportionately impacts the high proportion of children in developing countries who acquire CMV perinatally. The seroprevalence among healthy children in sub-Saharan African countries ranges from 80-100% and is likely universal among those living with HIV. The immune consequences of CMV disease burden and/ or reactivation in children with perinatally-acquired HIV/ CMV coinfection remains understudied. Children with HIV/CMV coinfection are susceptible to stunted growth and morbidities related to CMV-mediated premature immune aging such as chronic lung disease and encephalopathy. In cohorts of Zimbabwean children living with HIV/ CMV coinfection, CMV viremia was detected in 7-23% of participants, depending on age, HIV viremia, and ART status. CMV viremia was also associated with low CD4 count, reduced lung function, and stunting. A wide range of CMV IgG was observed among the same population, again dependent on age and HIV viremia. High CMV IgG was associated with reduced lung function. Telomere length was significantly shorter among children with unsuppressed HIV viremia. A trend was observed between shorter telomere length and higher CMV IgG, but this observation did not reach significance. More data is required and is being collected to elucidate the specific impact of CMV on immune ageing in children living with HIV/ CMV coinfection. 
Anthony Hsieh, University of Oxford, UK
Anthony Hsieh, University of Oxford, UKAnthony is a postdoctoral research scientist at Oxford studying immune ageing in children and adolescents living with HIV/ CMV coinfection. He did his PhD characterising immune ageing in Canadian adults living with HIV, during which he observed that biomarkers for accelerated ageing linked with HIV viremia and CMV coinfection. This led to the realisation that other chronic and/ or recurring viruses such as CMV and SARS-CoV-2 may exert a similar accelerated ageing effect. He is currently investigating longitudinal changes in immune ageing in a cohort of children and adolescents living with perinatal HIV/ CMV coinfection using biomarkers such as telomere length. |
| 11:35-12:00 |
Respiratory syncytial virus
Respiratory Syncytial Virus (RSV) is a common cause of severe paediatric bronchiolitis. Previous studies have shown that replication of RSV in the airway is linked with an increased risk of colonisation by bacteria such as the pneumococcus and Haemophilus influenzae. Less well known is the impact of RSV infection on other common childhood viral infections. We conducted a longitudinal surveillance study in RSV-naïve Kenyan infants, who were recruited just prior to the local RSV season and sampled intensively over the course of the season in order to track the natural cause of infection. We conducted deep shotgun metagenomic sequencing to determine how kinetic changes in RSV viral load correlated with the broader airway microbiome and virome. We found that primary RSV infections were frequently followed by an increase in CMV viral load which often persisted beyond the initial RSV infection. We hypothesised that this rise in CMV was the a result of an incidental upregulation of the cell surface receptor of CMV in airway epithelia (NRP2) that was triggered by the host innate immune response to RSV. To confirm this, we recruited a separate cohort of children who had been admitted to hospital with pneumonia and tracked them through the course of infection in order to determine whether NRP2 was selectively expressed in the nasopharyngeal epithelia of RSV-infected children. Using flow cytometric analysis, we found that RSV-infected children had a significantly higher frequency of NRP-2 positive goblet cells relative to RSV-negative children. We conclude that RSV replication in the airway increases the risk of CMV replication through the selective upregulation of the cell surface receptor for CMV on airway epithelia.
Professor Charles Sande, KEMRI-Welcome Trust, Kenya
Professor Charles Sande, KEMRI-Welcome Trust, KenyaProfessor Sande is a viral immunologist, with an interest in paediatric respiratory infections. His work focusses on the biological mechanisms associated with severe disease and death in children with severe pneumonia from low and middle income countries. The primary focus of their work has been in, understanding how the respiratory viruses interact with the host and the resident airway microbiota. |
| 12:00-12:20 |
Facilitated discussion about the limitations of research in children, and what further studies are needed
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| 12:20-12:50 |
Keynote: Vaccinating against CMV and its indirect effects
Vaccines against cytomegalovirus have been in development since the 1970s, but their use has been inhibited by both biological complexity and scientific unknowns. The target populations would be women before pregnancy in order to protect future fetuses, and recipients of solid organs or bone marrow transplants. Prevention against both primary and recurrent infection would be desirable. Experimental CMV vaccines have been developed using attenuated strains; inactivated CMV proteins such as gB, pentamer, and pp65 protein; vectored CMV proteins, and more recently mRNA. Efficacy has been demonstrated for many of these approaches but has been moderate. Vaccine composition may vary according to the target population, and whether antibody or T cell responses are preferred. It appears clear that a CMV vaccine is feasible, but the composition may vary with intended use, and may not be better than the partial protection produced by prior infection. 
Stanley A Plotkin, University of Pennsylvania, USA
Stanley A Plotkin, University of Pennsylvania, USADr Stanley A Plotkin is Emeritus Professor of the University of Pennsylvania. Until 1991, he was Professor of Pediatrics and Microbiology at the University of Pennsylvania, Professor of Virology at the Wistar Institute and at the same time, Director of Infectious Diseases and Senior Physician at the Children’s Hospital of Philadelphia. For seven years he was Medical and Scientific Director of Sanofi Pasteur, based at Marnes-la-Coquette, outside Paris. He is now consultant to vaccine developers and non-profit research organisations. He is a member of the Institute of Medicine of the National Academy of Sciences and the French Academy of Medicine. His bibliography includes over 800 articles and he has edited several books including the textbook on vaccines. Dr Plotkin has received honorary doctoral degrees from the University of Pennsylvania, the University of Rouen and the Complutense University of Madrid, He also has received the French Legion of Honor. Dr Plotkin developed the rubella vaccine now in standard use throughout the world, is codeveloper of the pentavalent rotavirus vaccine, and has worked extensively on the development and application of other vaccines including anthrax, oral polio, rabies, varicella, and cytomegalovirus. |
Chair
Paul Griffiths, University College London, UK
Paul Griffiths, University College London, UK
Paul Griffiths is Emeritus Professor of Virology at University College, London. His research concerns cytomegalovirus infection, where he helped to define the natural history and pathogenesis of this infection and used the information to design randomised controlled trials of antiviral drugs and prototype vaccines. His clinical laboratory provided diagnosis of all viruses that infect humans. He served on the JCVI committee for 8 years and remains Chair of the Department of Health WHO committees on eradication of poliovirus and measles. He is Editor of Reviews in Medical Virology and also Patron of the charity CMV Action.
Professor Nathan Ford, World Health Organisation, Switzerland
Professor Nathan Ford, World Health Organisation, Switzerland
Nathan Ford, BSc, MPH, PhD, DSc, FRCPE is a Scientific Officer within the Department of HIV/AIDS, Viral Hepatis and STIs at the World Health Organization in Geneva, and Chair of WHO’s Guidelines Review Committee. Prior to joining WHO in 2012 he worked with Médecins Sans Frontières (MSF) for 14 years supporting HIV programmes in a number of countries in southern Africa and South-East Asia. He holds a degree in Microbiology and Virology, a Masters in Public Health and Epidemiology, a PhD in Clinical Epidemiology, a Doctor of Science, and is a Fellow of the Royal College of Physicians of Edinburgh. He is an honorary Professor at the Centre for Infectious Disease Epidemiology and Research at the University of Cape Town. He has published over 500 articles in peer review publications and is on the editorial board of Clinical Infectious Diseases, Cochrane Infectious Diseases, JAIDS, JIAS, Tropical Medicine & International Health, and the WHO Bulletin.
| 13:40-14:05 |
Human cytomegalovirus and endothelial dysfunction
Cardiovascular disease (CVD) is the global leading cause of mortality. Persons living with HIV (PLWH) are particularly susceptible to endothelial dysfunction, significantly amplifying the risk of CVD. This study aims to investigate the potential contribution of cytomegalovirus (CMV) to the pathogenesis of CVD, focusing on its effects on endothelial movement as a measure of function and endothelial nitric oxide synthase (eNOS) expression. To this end, ex-vivo experiments were conducted using a primary human arterial endothelial cell line (HAECs). Time-lapse imaging was used to track endothelial movement and quantify function in the presence of metabolic pathway inhibitors (glucose and oxidative phosphorylation) and after infection with a recombinant CMV-expressing red fluorescent protein (RFP) for enhanced visualization. Recombinant CMV.RFP infection significantly increased eNOS expression and superoxide in HAECs. Moreover, cell tracking analysis demonstrated decreased total distance travelled by HAECs after infection with CMV compared to uninfected cells over 24 hours. However, all other aspects of endothelial cell movement, including persistence and rate of movement, were unchanged by CMV infection. In conclusion, an increase in eNOS/superoxide may indicate oxidative stress mechanisms are activated, contributing to endothelial dysfunction manifested by decreased movement, which may be important in endothelial homeostasis. While this study used one laboratory strain of CMV, additional studies of molecular pathways using different CMV strains may provide insights into the pathophysiology of CVD, particularly in high-risk populations such as PLWH. Further research will elucidate the underlying mechanisms and potential therapeutic strategies for targeting CMV-associated endothelial dysfunction. 
Celestine N Wanjalla, Vanderbilt University Medical Centre, USA
Celestine N Wanjalla, Vanderbilt University Medical Centre, USADr Celestine Wanjalla, MD PhD, is an Assistant professor and physician-scientist in the Division of Infectious Diseases at Vanderbilt University Medical Center. Clinically, she cares for people living with HIV at the Comprehensive Care Clinic. The goal of her research is to understand the role of virus-specific immune cells and molecular mechanisms that promote atherosclerotic cardiovascular disease progression in people living with HIV. She earned her undergraduate degree in Biological Sciences with a distinction in research from Cornell University, worked as a research assistant at Columbia University in the Division of Pharmacology, completed her MD and PhD in Immunology and Microbial pathogenesis at Thomas Jefferson University in Philadelphia, Internal Medicine, and Infectious Diseases training at Vanderbilt as a Harrison Scholar. She is a recipient of a K23 from NHLBI, the Career Awards for Medical Scientists (CAMS) from Burroughs Wellcome Fund, the Doris Duke Clinical Scientist Development Award, and a Gilead HIV Scholar. |
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| 14:05-14:30 |
CMV mismatch and health outcomes following kidney or liver transplant, a systematic review
People living with cytomegalovirus are likely to differ from people who are uninfected. Differences in baseline immune function, social contact patterns and socioeconomic position are expected and cannot easily be measured or accounted for in observational analyses. Deceased donor solid organ transplant offers a useful natural experiment, as the overwhelming determinant of whether recipients acquire CMV is the serostatus of their donor. In this context, confounding is a tractable function of the organ allocation algorithm, which allows cautious causal inference. In this session, Tom will share results from a systematic review of observational studies describing the association between donor-recipient CMV mismatch and post-transplant health outcomes in kidney and liver recipients. The focus is on all-cause mortality. The review follows the approach advocated in the COSMOS-E guidelines. 
Dr Tom Yates, University College London, UK
Dr Tom Yates, University College London, UKTom Yates is a specialist registrar in infectious diseases and general medicine. He holds an MSc in Epidemiology from LSHTM. His doctoral research was on the epidemiology and control of Mycobacterium tuberculosis in high burden settings, particularly South Africa. His UCL affiliations are with the Institute of Health Informatics and the Division of Infection and Immunity. Before joining UCL as a clinical lecturer, Tom worked at Imperial College London (2018-21), the KEMRI-Wellcome Trust Research Programme in Kilifi (2016), Africa Centre (now part of AHRI) in KwaZulu-Natal (2013-14) and at Oxford Vaccine Group (2010-11). Tom was an Associate PI for the RECOVERY Trial. Tom's research currently focuses on quantifying the indirect effects of cytomegalovirus (CMV) infection. |
| 14:30-14:55 |
Interactions between CMV and respiratory viruses
CMV increases the risk of bacterial and fungal infections in immunocompromised patients. However, there is limited data on the impact of CMV on respiratory virus infections. This presentation will review the evidence of a possible interaction of CMV and respiratory viruses. Specifically, Dr Boeckh will address whether CMV increases the risk of respiratory virus acquisition and progressive infection as well as adaptive immune responses. 
Michael Boeckh, Fred Hutchinson Cancer Center, USA
Michael Boeckh, Fred Hutchinson Cancer Center, USADr Michael Boeckh is an internationally recognized expert in infections in the immunocompromised host with a focus on viral infections, including cytomegalovirus, SARS-CoV-2, and respiratory viruses. He is a Professor in Vaccine and Infectious Disease Division and Head of the Infectious Disease Sciences Program at Fred Hutchinson Cancer Center in Seattle, WA, and is also a Professor at the University of Washington. He is an elected member of the Association of American Physicians and a fellow of the Infectious Disease Society of America, as well as the recipient of the 2019 IDSA John F Enders Lecture. Dr Boeckh has published more than 380 original articles in peer-reviewed journals, numerous review articles, book chapters, and editorials. |
| 14:55-15:20 |
Break
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| 15:20-16:15 |
CMV viraemia as a potentially modifiable risk factor to improve outcomes in adults with advanced HIV disease
Despite the widespread roll-out of anti-retroviral therapy, 30-40% of people living with HIV still present to care with advanced HIV disease (CD4 < 200 cells/mm3 or WHO stage 3 or 4 disease). Mortality amongst people living with advanced HIV disease is devastatingly high, especially amongst hospitalised adults in whom inpatient mortality exceeds 20%. This session will report upon the prevalence of CMV viraemia, and CMV central nervous system co-infections amongst this high-risk group, explore the co-pathogenic role of CMV infection, and potential for therapeutic interventions to improve outcomes in advanced HIV disease.
Dr Jayne Ellis, London School of Hygiene & Tropical Medicine, UK
Dr Jayne Ellis, London School of Hygiene & Tropical Medicine, UKJayne Ellis is Infectious Diseases and Microbiology clinician and a Wellcome Global Health Research Clinical PhD Fellow. Her research interests are focussed on improving outcomes for adults living with advanced HIV disease including management of CMV disease. Jayne Ellis PI of the IMPROVE study: Integrated management of cryptococcal meningitis and concurrent opportunistic infections to improve outcomes in advanced HIV disease. 
Professor Joseph N Jarvis, London School of Hygiene and Tropical Medicine, UK
Professor Joseph N Jarvis, London School of Hygiene and Tropical Medicine, UKJoe Jarvis is a Professor at the London School of Hygiene and Tropical Medicine, and Research Associate at the Botswana Harvard Health Partnership, based between Gaborone, Botswana, and London, UK. His main research interests are advanced HIV disease and opportunistic infections. He was the Chief Investigator for the Ambition Study, a multi-centre phase 3 trial investigating novel treatments for HIV-associated cryptococcal meningitis in Africa. He has worked with the World Health Organization on their advanced HIV disease activities since early 2023 and led a recent AHD research landscape mapping consultation and report. He also works a consultant physician in infectious diseases and HIV medicine.
Caleb Skipper, University of Minnesota, USA
Caleb Skipper, University of Minnesota, USADr Skipper is an infectious diseases specialist from the University of Minnesota. He has been working in Uganda since 2017, where he focuses on neuroinfections in persons with advanced HIV disease. He has been studying the role of CMV viremia in this populations, and especially how it may impact the host’s ability to clear intracellular opportunistic infections, such as Cryptococcus or TB. |
| 16:15-16:40 |
The effect of CMV on ‘inflammaging’
Cytomegalovirus (CMV) is a widespread herpesvirus that establishes lifelong latency in the human body. Emerging evidence suggests that CMV significantly impacts the aging immune system, a phenomenon often referred to as "inflammaging." This presentation will explore the intricate relationship between CMV and inflammaging, highlighting how chronic CMV exacerbates systemic inflammation and accelerates immunosenescence. We will discuss the underlying mechanisms, including CMV-driven alterations in immune cell function and cytokine profiles, with a particular focus on individuals with HIV. Understanding the role of CMV in inflammaging can reveal potential therapeutic targets to mitigate its deleterious effects on health span and longevity. 
Sara Gianella Weibel, University of California San Diego, USA
Sara Gianella Weibel, University of California San Diego, USADr Gianella is a leading figure in the field of clinical and translational virology. She serves as the Director of the San Diego Center for AIDS Research (CFAR) Translational Virology Core and the AIDS Clinical Trial Group (ACTG) San Diego Virology Specialty Laboratory. With a rich background in virology, molecular biology, and immunology, Dr Gianella leverages cutting-edge laboratory techniques and rigorous analytical methods to confront the most pressing challenges in infectious diseases. Her pioneering research delves into HIV persistence across various tissues and anatomical compartments, including her pivotal involvement in the end-of-life Last Gift program (lastgift.ucsd.edu). She is deeply committed to understanding HIV transmission dynamics in the genital tract, interactions with co-infecting viruses such as Cytomegalovirus, and exploring the critical roles of sex and gender in HIV pathogenesis and persistence. Dr Gianella and her team are committed to enhancing the diversity of the biomedical workforce, improving educational experiences, fostering scientific discovery and innovation, and addressing health disparities. Dr Gianella is particularly passionate about conducting research involving women, transgender individuals, and other under-represented populations, striving to increase public trust and the impact of research on diverse communities. |
| 16:40-17:00 |
Facilitated discussion about the limitations of research in immunocompromised adults, and what further studies are needed
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Chair
Professor Frank Cobelens, Amsterdam University Medical Center, Netherlands
Professor Frank Cobelens, Amsterdam University Medical Center, Netherlands
Frank Cobelens is professor of global health at the Amsterdam University Medical Centers and the Amsterdam Institute for Global health and Development in The Netherlands. Trained as a physician and epidemiologist, he has worked for over 25 years in research on tuberculosis in various TB high-burden countries. Among his research interests are risk factors for and prediction of progression to tuberculosis disease.
Professor Helen Fletcher, Johnson & Johnson, UK
Professor Helen Fletcher, Johnson & Johnson, UK
Helen Fletcher is a Senior Distinguished Scientist in the Communicable Diseases Unit, Johnson & Johnson. Leading the J&J Centres for Global Health Discovery, industry-academic drug discovery partnerships accelerating early-stage small molecule drug discovery in the UK, South Africa and Singapore. Before joining J&J, Helen was Professor of Immunology at London School of Hygiene & Tropical Medicine (LSHTM), with more than 20 years’ experience in TB vaccine development at UCL, University of Oxford and LSHTM. In the last decade, Helen’s work focused on understanding CMV as a driver of TB disease risk. From 2017-2021, Helen was on secondment to UK Research and Innovation (UKRI) as Director of International Development, responsible for the Global Challenges Research Fund (GCRF) and the Newton Fund. Helen has a BSC and PhD in Microbiology from the University of Leeds. She is Trustee of the Jenner Vaccine Foundation and has published more than 100 articles and book chapters.
| 09:00-09:30 |
Keynote: Cytomegalovirus as a viral adjuvant for immune function across the life course
Herpesviruses are present throughout the vertebrate lineage, and it is likely that the great majority of members of the Homo Sapiens species were, or will become, infected with cytomegalovirus during their lifetime. CMV replication in controlled by sustained immune surveillance and the virus elicits arguably the largest virus-specific immune response that has been identified to date. This metabolic investment is so large that the CMV serostatus of an individual is broadly identifiable by the scale of the overall memory T cell pool within blood. The major clinical complications of CMV are seen following infection within immune suppressed individuals and the considerable burden from primary fetal infection is clearly sufficient to warrant development of an effective vaccine. The scale of the CMV-specific immune response is so large that there has been concern that this may impair the immune response to heterologous infection and accelerate immune senescence. Indeed, there is considerable evidence to support this concern. However, CMV infection can also impact positively on immune function and act to attenuate risk from other virus-associated conditions. Most humans acquire CMV infection very early in life where it acts to markedly enhance the cytotoxic profile of the peripheral immune system, a feature that may act to support pathogen control. Studies across the early phase of the life course have shown that CMV infection can boost the immune response to vaccine challenge. Vaccine studies in children have also revealed that the virus acts to temper the detrimental impact of other persistent infection. This latter observation is notable given the epidemiological evidence that CMV infection reduces the relative risk of multiple sclerosis, a condition now acknowledged to be strongly associated with EBV infection. These studies do not preclude the potential for CMV to impact negatively on immune function in the latter phases of the life course. As such, a case can be made that CMV has evolved the capacity to support immune function in the reproductive phase of life. The impact, however subtle, of a CMV-seronegative legacy for Homo Sapiens following the implementation of effective vaccination is of interest.
Professor Paul Moss OBE, University of Birmingham, UK
Professor Paul Moss OBE, University of Birmingham, UKPaul Moss is Professor of Haematology and Deputy Head of the College of Medicine at the University of Birmingham. He runs an immunology research group with a focus on viral and cancer immunology. He has a longstanding interest in the immune response against herpesviruses, first describing the enormous T cell immune response against CMV following infection and then using this to develop a novel form of virus-specific cellular therapy for immune suppressed patients. He led the UK Coronavirus Immunology Consortium in 2020. |
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| 09:30-09:55 |
CMV and incident tuberculosis in young children
Dr Martinez will go over the current available empirical data supporting a relationship between CMV and tuberculosis, discuss open questions and data gaps, and present published and unpublished data on this topic from the Drakenstein Child Health Study, a birth cohort from Cape Town, South Africa. 
Leonardo Martinez, Boston University School of Public Health, USA
Leonardo Martinez, Boston University School of Public Health, USADr Martinez uses epidemiological and quantitative approaches to study early-life risk factors for pediatric tuberculosis in high-burden settings, tuberculosis transmission dynamics in high-risk populations (eg prisoners, persons living with HIV or diabetes), and the relationship between tuberculosis and non-communicable diseases. |
| 09:55-10:20 |
CMV infection in a paediatric TB cohort
Cytomegalovirus (CMV) and tuberculosis (TB) are highly prevalent pathogens with similar epidemiological characteristics. Recent evidence suggests that CMV-TB co-infection affects the risk for TB infection and TB disease progression. Olbrich and colleagues here assess the burden of CMV-TB co-infections in children with presumptive TB and describe their immunological response against CMV antigens. RaPaed-TB was a prospective paediatric TB diagnostic study enrolling children <15 years with suspected TB from five lower-middle income countries. Case definition for TB disease followed NIH-consensus case definitions (confirmed, unconfirmed, unlikely TB). T-cell activation marker CMV assay (TAM-CMV) is a blood based immunological assay using flow-cytometry to measure functional and phenotypic markers on CMV-specific CD4 T-cells (CD38 and CD27). CMV-viral load (VL, blood and urine) and serology were captured alongside TAM-CMV at baseline, month 1, 3, and 6. 115 TAM-CMV results at baseline were available for children with defined TB disease status. In children with confirmed TB, 25.5% (12/47) had a positive CMV-specific IFNγ CD8 response at baseline, compared to 46.8% (22/47) of children with unlikely TB (p<0.05), suggesting that a positive CMV-specific CD8 response might be associated with an unlikely TB disease status. At baseline, urine CMV viral load (log values) was significantly associated with TB status, with higher levels in children with confirmed TB (p=0.03). CMV-specific IgG levels were also associated with TB status, with higher levels in children with unlikely TB (p=0.03). Taken together, the results suggest an altered and likely exhausted CMV-immune response in children with TB. This could not only explain higher progression rates from TB infection to disease in this population, but might also reflect a higher likelihood of CMV transmission, both of which are of high clinical interest to address these two epidemics.
Dr Laura Olbrich, LMU Klinkum, Germany
Dr Laura Olbrich, LMU Klinkum, GermanyDr Laura Olbrich is a clinician-scientist working on childhood TB who graduated with a DPhil from the Department of Paediatrics at the University of Oxford, UK. Her main research interest is the evaluation of new diagnostic approaches and tests, aiming to identify feasible diagnostic solutions for low resource settings. Dr Olbrich was the coordinating scientist of the multi-country RaPaed-TB project, a large prospective study evaluating a number of diagnostic tests for TB in children. Currently, she is work package lead in the Decide-TB consortium, aiming to assess effectiveness and accuracy of treatment decision algorithm-based approaches. |
| 10:20-10:50 |
Break
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| 10:50-11:15 |
Cytomegalovirus infection is a risk factor for tuberculosis disease but not tuberculosis infection
Evidence exists of human cytomegalovirus (HCMV) and immune activation as risk factors for tuberculosis (TB) disease. It is not known whether other herpes viruses are also implicated, nor if a dose-response relationship exists between TB risk and herpes co-infection. This work describes a nested case-control study which used stored serum samples from 25 TB cases up to 10 years prior to TB diagnosis from a rural Ugandan cohort. Case and matched control samples were investigated for Epstein Barr (EBV), Herpes Simplex (HSV), and HCMV-specific IgG, serum markers of inflammation, and mycobacterial antibody levels. HCMV IgG, but not EBV or HSV was associated with increased risk of active TB disease up to 10 years prior to diagnosis. Individuals with medium HCMV IgG were 2.8 times more likely to have TB, and those with high HCMV IgG 3.4 times more likely to have TB (p=0.006). Mycobacterial antibody levels were not associated with differences in odds of TB disease. IP-10 was independently associated with increased odds of TB; OR 4.2, p=0.009. These data provide evidence of a dose response between magnitude of HCMV IgG with risk of TB disease. An inflammatory environment, characterized by serum IP-10 and IL1α, are independently associated with increased risk of TB disease.
Dr Lisa Stockdale, University of Oxford, UK
Dr Lisa Stockdale, University of Oxford, UKLisa is the Senior immunologist in the pre-erythrocytic malaria vaccine group at the Jenner Institute, University of Oxford. She leads the immunology of vaccine clinical trials on R21 malaria vaccine. Lisa’s research interests include correlates of vaccine-induced protection, antibody glycosylation and immunological interactions between different pathogens. Lisa has worked on a variety of pathogens including S.typhi, tuberculosis, CMV, SARS-Cov2, leishmaniasis, Ebola and malaria. |
| 11:15-11:40 |
Impact of human cytomegalovirus viremia on the progression of TB disease among people with HIV on long-term ART
The use of ART has led to a remarkable reduction in mortality and has improved life expectancy of people with HIV (PWH), yet TB remains a leading preventable cause of death among PWH. Recent evidence indicates that the spectrum from TB infection to TB disease is including a continuum of stages reported as TB infection, incipient TB, subclinical TB and TB disease. Identification of such high-risk individuals who will develop active TB in the near future would be beneficial in terms of contract tracing and TB preventive therapy. There is increasing evidence showing the link between HIV and TB, TB and HCMV, and likely the 3-way interaction between HIV, TB and HCMV. The temporal relationship of acquisition of HCMV and subsequent development of TB disease has been investigated in previous studies in which the majority of participants were HIV-negative. Dr Gatechompol will present the result from a nested case-control study within a Thai HIV cohort. This study aims to evaluate whether HCMV viremia could predict the occurrence of active TB disease over a period of 6-24 months among virally suppressed PWH in long-term ART cohort. 
Sivaporn Gatechompol, Mahidol University, Thailand
Sivaporn Gatechompol, Mahidol University, ThailandDr Sivaporn Gatechompol trained as an infectious disease specialist at Ramathibodi Hospital, Mahidol University and obtained her PhD in predicting tuberculosis (TB) among people living with HIV (PWH) at the University of Amsterdam. Her research interests include biomarkers, non-sputum-based approaches to predict and diagnose TB among PWH in resourced limited setting. She previously worked at HIV-NAT, Thai Red Cross – AIDS Research Centre, a not-for-profit, research organisation in Thailand. She has been involved in several TB and HIV clinical trials in the AIDS Clinical Trials Group (ACTG) and served as an investigator in ACTG Tuberculosis Transformative Science Group. Now, she is working as consultant and lecturer at Division of Infectious Diseases, Faculty of Medicine Ramathibodi Hospital, Mahidol University. |
| 11:40-12:05 |
Investigating causes of mortality in adults hospitalised with HIV associated tuberculosis: the role of CMV infection
Tuberculosis is the leading cause of death in people with HIV. Whether co-infection with CMV confers additional mortality risk is not definitively known. Sossen and colleagues aimed to: (1) ascertain if CMV viraemia was more prevalent in HIV-positive inpatients with TB than HIV-positive inpatient controls without TB; (2) if CMV viraemia was associated with mortality, and if a dose-response association between CMV-VL and mortality was apparent in patients with HIV-associated TB; and (3) if any CMV mortality association was independent of TB blood stream infection bacilli load (MTB-BSI), a known determinant of mortality in severe HIV-TB. Adult patients with HIV, CD4 ≤350cells/μl and high suspicion for tuberculosis, that were recruited to a well characterised cohort study, had CMV viral load (VL) measured prospectively on plasma at time of admission to Khayelitsha Hospital, Cape Town. Vital status outcome was captured at 12 weeks. CMV-VL, MTB-BSI (defined by blood Xpert-ultra positivity) and HIV-VL were modelled as predictors of mortality on a 13-level ordinal scale incorporating below-limit-of-detection results as the lowest ordinal category. Of 659 participants, 165 (25%) had MTB-BSI, 258 (40%) had detectable CMV-VL and 146/659 (22%) died by 12 weeks. A similar CMV prevalence was seen in those with microbiologically confirmed tuberculosis (41% with CMV), those treated empirically for tuberculosis (37%) and in those with no tuberculosis (41%). CMV viraemic participants had lower CD4 counts (median CD4 count 42cells/μl versus 78 cells/μl) and more MTB-BSI (38% blood Xpert-ultra positive), compared to those without CMV (22%). CMV viraemia showed a dose response association with mortality: expected probability of death rising from 18% (95%CI 14-22%) to 36% (95%CI 23-56%) from lowest to highest ordinal category. This magnitude of association was less than the equivalent for MTB-BSI bacilli load (16%, (95%CI 13-20%) rising to 60%, (38-86%)). The association of CMV-VL with mortality was reduced by adjusting for MTB-BSI, but the converse was not observed: predicted mortality for a given level of MTB-BSI was unaffected by magnitude of CMV-VL. CMV viraemia is highly prevalent in hospitalised people living with HIV, irrespective of TB co-infection. Although CMV-VL shows a dose-response association with mortality in severe HIV-TB, this association does not appear to be independent of MTB-BSI bacilli load, suggesting that CMV viraemia may be a marker of TB disease severity rather than an independent driver of mortality. The high prevalence of CMV-viraemia in this population suggests an interventional trial to test causality would be feasible. 
Bianca Sossen, University of Cape Town, South Africa
Bianca Sossen, University of Cape Town, South Africa |
| 12:05-12:25 |
Facilitated discussion about the limitations of CMV: TB research, and what further studies are needed
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Chair
Charlotte Warren-Gash, London School of Hygiene & Tropical Medicine, UK
Charlotte Warren-Gash, London School of Hygiene & Tropical Medicine, UK
Charlotte Warren-Gash is a clinical professor of epidemiology and an honorary consultant in public health medicine. Based at LSHTM, she leads the Brain Health Group and sits on the steering committee for the Electronic Health Records Research Group. Her research aims to investigate relationships between infections and key components of brain health (mental health, cognitive health and sensorimotor function) in older age, funded by a Wellcome Career Development Award. This programme uses large, longitudinal datasets from across populations to generate new insights into infection-brain health relationships and inform the design of interventions to improve brain health worldwide. Charlotte has extensive experience of investigating cardiovascular and neurological complications of herpesviruses, as well as vaccine epidemiology, inequalities and phenotyping methods.
Professor John Sinclair, University of Cambridge, UK
Professor John Sinclair, University of Cambridge, UK
Professor Sinclair’s research interests are in the molecular biology and pathogenesis of human herpes viruses, particularly human cytomegalovirus (HCMV). HCMV is a major cause of disease in transplant patients and patients with AIDS and his research program aims to understand the basic molecular biology of latency and reactivation of this persistent human virus and how the host immune response combats virus disease. More recently, his work has been directed to targeting the latent viral reservoir to reduce post-transplant HCMV disease.
| 13:25-13:50 |
Can supressing CMV replication delay tumour progression in glioblastoma?
Glioblastoma is an incurable brain tumour with very poor prognosis. The 2-year survival is 15%–26% and the median overall survival (OS) time is 12–14 months. Only marginal improvements in survival rates have been observed over the past decades, regardless of the treatment strategy evaluated in clinical trials. In fact, since the latest standard treatment was introduced in 2005, over 450 trials have been conducted, and only two, treatment with electrical fields and dendritic cell therapy, have shown any positive effect on survival. Söderberg-Naucler´s team previously treated 139 patients with glioblastoma with valganciclovir, which targets cytomegalovirus (CMV), and observed that these patients have a substantially longer survival time. CMV can enhance tumour aggressiveness and is found in almost all glioblastoma tumours. Among 102 patients with primary glioblastoma, 49% of valganciclovir-treated patients were alive at 2 years, compared with 18% of control patients2 (n = 231). Median OS was 24.1 months and extended to 29.7 months in optimally treated patients (VIGAS2 protocol), as compared with 13.5 months in controls (p = 0.0001). Twenty-nine patients with recurrent glioblastoma also benefitted from valganciclovir treatment; their 2-year survival was 23.1% compared with 6.7% among control patients (p = 0.0156)3. The median OS was 15.8 months vs. 8.3 months in the controls (p = 0.0083). Antiviral therapy could prevent radiation induced clinical reactivation of CMV occurring in 42% of patents and prohibited early recurrencies. Hence, valganciclovir can possibly more than double the life expectancy of patients with glioblastoma at 2 years after diagnosis. 
Cecilia Söderberg-Naucler, Karolinska Institutet, Sweden
Cecilia Söderberg-Naucler, Karolinska Institutet, SwedenCecilia Söderberg-Naucler received her MD from Karolinska Institutet in 1994, and her PhD from the same Institute in 1995. After a successful post doc at OHSU in Portland Oregon with prof Jay Nelson in 1995-1995 resulting in two Cell publications, one J Clin Invest article and two in J of Virology, she established her research group at Karolinska Institutet. She became Associate professor in Experimental Medicine at Karolinska Institutet in 2002, and Professor of Medical Microbial Pathogenesis in 2008. Since 2022 she is also a Professor of Immunology at University of Turku, Turku, Finland. She has published over 180 research articles and reviews on the topic of human cytomegalovirus (HCMV) Pathogenesis with impact on the understanding of the role of this virus in inflammatory diseases and cancer. She and her co-workers discovered the key mechanisms leading to reactivation of latent virus in myeloid lineage cells and in cancer cells, have discovered two receptors for HCMV, described many immune evasion mechanisms for HCMV and how this virus drives inflammation and oncomodulatory mechanisms. She has shown the frequent present of HCMV in many different tumour types, and she pioneered anti-viral treatment in patients with glioblastoma. Currently her team holds the most promising treatment data for this group of patients giving hope for almost one-year extended survival time, while over 450 clinical trials have failed to show any benefit for these patients. Antiviral treatment is currently under evaluation in a randomized clinical trial in 220 patients with glioblastoma, currently having recruited 201 patients. |
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| 13:50-14:15 |
Indirect effects of cytomegalovirus in depression
A subgroup of individuals with major depressive disorder (MDD) displays low-grade systemic inflammation that co-occurs with impaired adaptive immunity. Given that inflammation and stress-induced beta-adrenergic signalling can lead to cytomegalovirus (CMV) reactivation we hypothesised that CMV may act as a pathological co-factor in psychiatric disorders. Published results show an association between CMV infection and brain abnormalities (reduced grey matter volume and white matter microstructural changes) in depressed individuals as well as increased expression of inflammation-linked genes and more activated microglia in the prefrontal cortex in postmortem samples from people with mood disorders and schizophrenia. In an RNAseq study, we examined the relationship between CMV infection and gene expression in peripheral blood mononuclear cells from 60 individuals with MDD and 60 healthy controls. Preliminary analyses indicate that CMV-positive subjects showed increased activity of both classical and non-classical monocytes but no difference in interferon response factor (IRF) or NF-kB signalling pathways. Higher CMV titer was associated with increased NF-kB activity but decreased IRF activity, perhaps reflecting poorer control of the infection. If CMV reactivation drives inflammation that negatively impacts brain structure, this raises the question of whether treatment with anti-viral medication could be therapeutic for people with depression. In a pilot clinical trial, 16 individuals with MDD were randomized (1:1) to 8 weeks of treatment with valganciclovir (900mg/day, PO) or placebo to evaluate antidepressant efficacy. Blinded preliminary analyses suggest a small effect in favour of “Group A” but the direction of this effect remains to be determined. 
Dr Jonathan Savitz, Laureate Institute for Brain Research, USA
Dr Jonathan Savitz, Laureate Institute for Brain Research, USAJonathan Savitz received his PhD in human genetics from the University of Cape Town and subsequently completed a post-doctoral fellowship in neuroimaging at the National Institutes of Health in the USA. He is currently a Principal Investigator at the Laureate Institute for Brain Research in Tulsa, Oklahoma. Dr Savitz’s research focuses on how immune dysregulation predisposes to the development of mood disorders. Methodologically, this generally entails performing experimental human studies using methods to manipulate the inflammatory response such as lipopolysaccharide infusion and exercise challenge. He is also interested in understanding the biological effects of CMV in the context of depression as well as sports-related concussion. |
| 14:15-14:40 |
Exploring interactions between human cytomegalovirus and immunological and clinical responses to checkpoint immunotherapy
The relationship between the development of metastatic malignancy and infection with human cytomegalovirus (HCMV) is poorly understood. Data from solid organ transplant registries indicates HCMV infection is associated with reduced rates of certain malignancies including Non-Hodgkin’s Lymphoma in organ recipients. Furthermore, analysis of tumour infiltrating lymphocytes has demonstrated that the majority of T cells found within cancers express T cell receptors conferring reactivity to viral antigens, with HCMV forming a key source of antigen for these bystander T cells. Metastatic melanoma forms the archetypal immunosensitive cancer and shows relatively high response rates (up to 60%) to combination anti-PD1 and anti-CTLA-4 checkpoint immunotherapy. These treatments have transformed clinical outcomes such that approximately 50% of patients with metastatic disease survive for beyond 5 years post initiation of treatment. The Oxford Cancer Immunotherapy Response Observational Study (OxCIROS) incorporates a cohort of >420 patients receiving checkpoint immunotherapy for cancer for which we have developed high resolution immune-phenotyping at serial timepoints across treatment. These data are integrated with clinical outcome enabling identification of immune correlates of response and toxicity to immunotherapy. I will describe new work demonstrating a complex relationship between HCMV status and metastatic melanoma in this cohort.
Professor Benjamin Fairfax, University of Oxford, UK
Professor Benjamin Fairfax, University of Oxford, UKBenjamin Fairfax is Professor of Cancer Immunogenetics at Oxford University and an Honorary Consultant in Medical Oncology at the Oxford Cancer Centre. His research is primarily funded by the Wellcome Trust and he has a group based in the Weatherall Institute for Molecular Medicine. The key interests of the group are understanding the relationship between germline genetic variation and divergent human immune responses. Much of the current focus of the group is defining determinants of response and toxicity to immune checkpoint blockade given to treat cancer. |
| 14:40-15:10 |
Break
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| 15:10-15:35 |
Diminished Anti-HCMV T cell functionality and antibody neutralisation efficacy in the elderly resulting in virus replication at peripheral sites
Human cytomegalovirus (HCMV) infection and periodic re-activation is, generally, well controlled by T-cell responses in the healthy. In older people, overt HCMV disease is not generally seen despite the association of HCMV with increased risk of mortality; there is evidence from studies of unwell aged that it is an important co-morbidity factor. Detection of HCMV genomes in urine of older people suggest that, although the immune response retains functionality, immunomodulation due to lifelong viral carriage may alter its efficacy. In a previous study, they demonstrated that there were no age-related expansions of T-cell responses to HCMV or increase in latent viral carriage with age and these T-cells were effective, as viremia was very rarely detected. More recently they have shown that there is a decrease in the efficacy of the adaptative immune response (total PBMC and T-cells sub-populations) to control viral infection and spread using a Viral Dissemination Assay (VDA) in the elderly cohort. In addition, they have also demonstrated for the first time, a diminished HCMV neutralisation capacity of sera from the older donors. qPCR analysis for HCMV in blood, saliva and urine in the cohort, detected viral genomes in saliva samples, only from older donors and these donors had a defect in cellular control of viral spread in their in vitro assay. They now have evidence that there is increased expression of inhibitory ligands HLA-E, B7-H3 and PD-L1 on fibroblasts from older donors and preliminary evidence that disrupting the PD-1:PD-L1 axis improves control of HCMV infection in vitro VDA. They are currently investigating the balance between co-stimulation and inhibitory signalling as a driver for poor T cell control. 
Mark Wills, University of Cambridge, UK
Mark Wills, University of Cambridge, UKMark studied Microbiology at the University of Surrey where he also carried out his PhD in Virology. Following a first postdoctoral position at the University of Southampton studying the immune response to cancer, he moved to the University of Cambridge in 1993 to the Department of Medicine where he started his work on the viral immunology of Human Cytomegalovirus (HCMV). He is a principal investigator and Director of Research in addition to currently being the Interim Head of Department of Medicine. Mark’s most recent work explores issues of long-term carriage of HCMV on immune senescence and the role of HCMV on long term immune responses in the elderly. He is also interested understanding the failure of immune control in some D+R+ SOT transplant recipients leading to viraemia. The current focus of his research is understanding immune recognition and evasion of latently infected cells, ultimately with a view to targeting and clearing latent virus from infected people. This is of particular importance in immunosuppressed transplant patients. Mark has had long term support from continuous MRC 5-year programme grants over the last 30 years, in addition to funding from the Welcome Trust, NIHR and GSK. |
| 15:35-16:00 |
Impact of CMV infection on heterologous vaccine responses
Advanced age is accompanied by a decline of immune functions, which may play a role in increased vulnerability to emerging pathogens and low efficacy of vaccinations in elderly people. However, its precise determinants are not fully understood. In particular, it is yet unclear at which level age-intrinsic mechanisms and external factors (namely the co-infections with persistent viruses) cooperate, contributing to immunosenescence. The talk will aim at reviewing current evidence on the age-dependent interplay between the host immune system and herpesviruses which are widespread among the general population: HSV-1, EBV and, in particular, CMV. To this aim, different cohorts of donors stratified by age and serological status for common latent herpesviruses will be considered and compared for the capacity to mount competent vaccine-specific humoral T and B cell responses in primo-vaccination clinical trials. To better understand the role of CMV on the induction of immunity heterologous vaccines, the quantity and quality of vaccine-specific responses will be analysed in respect to individual cellular and humoral immune parameters. Data suggest a prevalent effect of CMV infection mainly on CD4+ naive T cells. Consistently, CMV seropositivity is associated with blunted CD4+ T-cell and antibody responses to primary vaccination. This phenomenon is observable also in younger adults, but it is not generalisable to different vaccines.
Professor Francesco Nicoli, University of Ferrara, Italy
Professor Francesco Nicoli, University of Ferrara, ItalyFrancesco Nicoli is associate professor of Microbiology and Clinical microbiology at the University of Ferrara. He holds a PhD in Medical Research-International Health (LMU, Germany) and a PhD in Bimolecular and Biotechnological Sciences (University of Ferrara). He performed his post-doctoral training at the Pierre et Marie Curie University (Paris, France) and at the University of Padua (Italy). His current research is focused on T-cell responses against viruses and vaccines. He is involved in the development of two vaccine candidates against HIV and HSV, as well as in the study of T-cell dysfunctions in infectious diseases. He contributed to the discovery of the role of the Tat protein of HIV on CD4+ and CD8+ T-cell dysfunctions during HIV infection. He supervises projects related to immunosenescence and immunometabolism, to identify the interaction between altered metabolism and chronic infections in the context of ageing, HIV and vaccination. |
| 16:00-16:25 |
The efficacy and safety of CMV suppression in immunocompetent patients needing intensive care
Cytomegalovirus (CMV) is a latent herpesvirus that can reactivate in 15-40% of immunocompetent patients with critical illness from a variety of causes. In observational studies, CMV reactivation is associated with worse clinical outcomes including higher mortality and longer duration of mechanical ventilation. CMV could plausibly cause worse clinical outcomes through one or multiple mechanisms: first, as a result of direct cytopathic injury; second, as a result of systemic or tissue-level inflammatory responses; third, as a contributor to secondary bacterial or fungal infections. The core question is whether CMV contributes to worse clinical outcomes or is a bystander, which can only be answered by randomised controlled studies examining the use of antiviral therapy. Small interventional trials have examined the role of antiviral prophylaxis or therapy among critically ill patients with CMV reactivation. Together these have suggested a higher number of ventilator-free days (VFDs) among patients who received antiviral therapy but no impact on mortality, however, studies have generally been limited by size and heterogeneity. The results of a well-powered clinical trial of pre-emptive ganciclovir use among patients with CMV reactivation, sepsis, and acute respiratory failure are forthcoming.
Hannah Imlay, University of Utah, USA
Hannah Imlay, University of Utah, USAHannah Imlay, MD, MS, is an Associate Professor of Medicine at the University of Utah School of Medicine and the Associate Medical Director of Antimicrobial Stewardship at University of Utah Health and the Salt Lake City Veterans Affairs System. Her clinical and research interests focus on viral infections and antimicrobial stewardship in immunocompromised patients, including organ transplant recipients and patients undergoing chemotherapy and stem cell transplantation. As a part of this work, she has examined risk factors for CMV reactivation among critically ill immunocompetent patients, which has implications for testing and antiviral use. |
| 16:25-16:45 |
Facilitated discussion regards the limitations of research in immunocompetent adults and the elderly, and what further studies are needed
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| 16:45-16:50 |
Concluding remarks by lead organisers
Dr Tom Yates, University College London, UK
Dr Tom Yates, University College London, UKTom Yates is a specialist registrar in infectious diseases and general medicine. He holds an MSc in Epidemiology from LSHTM. His doctoral research was on the epidemiology and control of Mycobacterium tuberculosis in high burden settings, particularly South Africa. His UCL affiliations are with the Institute of Health Informatics and the Division of Infection and Immunity. Before joining UCL as a clinical lecturer, Tom worked at Imperial College London (2018-21), the KEMRI-Wellcome Trust Research Programme in Kilifi (2016), Africa Centre (now part of AHRI) in KwaZulu-Natal (2013-14) and at Oxford Vaccine Group (2010-11). Tom was an Associate PI for the RECOVERY Trial. Tom's research currently focuses on quantifying the indirect effects of cytomegalovirus (CMV) infection. 
Dr Helen Payne, Imperial College London, UK
Dr Helen Payne, Imperial College London, UKDr Helen Payne is a Clinical Lecturer at Imperial College London, dividing her time between research, teaching and working clinically as a registrar in Paediatric Infectious Diseases and Immunology at St Mary’s Hospital in London. She is also an honorary Clinical Lecturer at Stellenbosch University. Dr Payne’s research interests are in congenital infection, co-infections and understanding the role of immune activation in driving or inhibiting infections. The theme of her current work is exploring the host-immune response to cytomegalovirus (CMV) in infants and immunosuppressed children and young people, and she is running several studies within this theme. |