Human genetics: from infectious diseases to vaccine responses
Professor Adrian Hill, University of Oxford, UK
Abstract
Genetic analysis of vaccine responses in humans is an emerging field driven by the very difficult challenges of designing new vaccines for some major infectious disease and the enormous power of modern genomic technologies. It is likely that a better understanding of genetic factors impacting vaccine immunogenicity and efficacy could lead to improved vaccine design and inter-population differences. Twin studies have indicated that there is substantial genetic control of immune responses to several common childhood vaccines and much of the genetic component appears to lie outside of the major histocompatibility complex. Large scale collections of suitable samples from vaccines in several populations are now underway and initial genome wide association studies have very recently been undertaken for several childhood vaccines. The design of these studies may benefit from lessons learned from similar studies of genetic susceptibility to infectious diseases, undertaken in diverse human populations, and some of these will be reviewed to identify preferred strategies for genomic analyses of vaccine responses.
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Professor Adrian Hill, University of Oxford, UK
Professor Adrian Hill, University of Oxford, UK
Adrian Hill trained at Trinity College Dublin and Oxford is now
Professor of Human Genetics and Director of the Jenner Institute at
Oxford University. He leads research programmes in genetic
susceptibility to tropical infectious diseases and in vaccine design and
development.
As a founder member of the Wellcome Trust Centre for Human Genetics
since 1994 his research group has studied multiple genetic factors
associated with or genetically linked to resistance to malaria,
tuberculosis, bacterial pneumonia, and viral infections such as
hepatitis B and C and HIV. His group has pioneered genome-wide linkage
and association analyses of genetic susceptibility to common human
infectious diseases, particularly tuberculosis, more recently as part of
the Wellcome Trust case control consortium. Data on immunogenetic
susceptibility factors have provided new insights into the impact of
infections on human genomic diversity.
He has published over 350 research papers, is a Fellow of the UK Academy
of Medical Sciences and the Royal College of Physicians, and a NIHR
Senior Investigator.
WHO SAGE recommendations on non-specific vaccine effects
Professor Andrew Pollard, University of Oxford, UK
Abstract
The World Health Organisation has recently systematically considered the evidence that exists to support or refute the presence of an association between vaccination with measles and BCG vaccine with lower infant mortality, or the association of DTP vaccine with changes in mortality in girls. Much of the available evidence arose from one country and many of the studies had a high risk of bias. With regard to studies with a mortality end point, the review found that there was some evidence of a beneficial effect of BCG and measles vaccines but the evidence for DTP vaccine was not of sufficient quality for a conclusion to be drawn. No changes in the current expanded programme on immunisation were recommended by WHO’s SAGE committee. An analysis of the immunological data concluded that non-specific effects on subsequent immune responses following vaccination are plausible but that the current evidence did not make it possible to determine the magnitude, nature or timing of such responses.
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Professor Andrew Pollard, University of Oxford, UK
Professor Andrew Pollard, University of Oxford, UK
Andrew J Pollard, FRCPCH PhD, is Professor of Paediatric Infection and Immunity at the University of Oxford, Director of the Oxford Vaccine Group, James Martin Senior Fellow, Jenner Institute Investigator, Fellow of the Infectious Disease Society of America, Fellow of St Cross College and Honorary Consultant Paediatrician at the Children’s Hospital, Oxford, UK. He obtained his medical degree at St Bartholomew’s Hospital Medical School, University of London in 1989 and trained in Paediatrics at Birmingham Children’s Hospital, UK, specialising in Paediatric Infectious Diseases at St Mary’s Hospital, London, UK and at British Columbia Children’s Hospital, Vancouver, Canada. He obtained his PhD at St Mary’s Hospital, London, UK in 1999 studying immunity to Neisseria meningitidis in children and proceeded to work on anti-bacterial innate immune responses in children in Canada before returning to his current position at the University of Oxford, UK in 2001. He chaired the UK’s NICE meningitis guidelines development group, the NICE topic expert group developing quality standards for management of meningitis and meningococcal septicaemia. He received the 2013 Bill Marshall Award of the European Society for Paediatric Infectious Disease. He chairs the Department of Health’s Joint Committee on Vaccination and Immunisation and the European Medicines Agency scientific advisory group on vaccines. He runs one of the largest research groups in the UK that undertakes clinical trials in children and adults with 70 staff. Current research activities include clinical trials of new and improved vaccines for children and adults, surveillance of invasive bacterial diseases and impact of pneumococcal vaccines in children in Nepal, studies of cellular and humoral immune responses to glycoconjugate, RSV and typhoid vaccines, development of serogroup B meningococcal vaccines and research on a human challenge model of typhoid and paratyphoid. His publications include over 200 manuscripts and books on various topics in paediatrics, infectious diseases, and high altitude medicine.
Vaccine responses in HIV-exposed, uninfected infants
Dr Chrissie Jones, St George's, University of London, UK
Abstract
Infants exposed to HIV in utero who remain uninfected represent a vulnerable group with increased rates of morbidity and mortality in infancy and early childhood compared to unexposed infants, particularly in sub-Saharan Africa. The reasons for this are likely to be myriad, not least of which are socio-economic constraints. However, in utero HIV-exposure is associated with immunological alterations that can persist into childhood, therefore it is plausible that responses to immunisation may be different in these infants. Given the large numbers of HIV-exposed, uninfected infants globally any reduction in the immunogenicity and protective efficacy of vaccination would likely have significant public health implications. The literature on vaccine responses in these HIV-exposed, uninfected infants will be reviewed, including cellular responses to BCG and humoral responses to other EPI vaccines.
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Dr Chrissie Jones, St George's, University of London, UK
Dr Chrissie Jones, St George's, University of London, UK
Dr Chrissie Jones is an Associate Professor in Paediatric Infectious Diseases at the University of Southampton. Her research interests include interventions in pregnancy to prevent infection in early life. She has particular expertise in the field of maternal vaccination and leads pertussis and RSV clinical trials in pregnancy. She serves on the executive committee of GAIA (http://gaia-consortium.net), a large international consortium. As part of this initiative, Dr Jones has authored international guidelines to provide a standard for data collection in clinical trials of vaccines in pregnancy, which are recommended by the WHO.
Dr Jones is the chief investigator of RACE-FIT, a NIHR-funded feasibility study to assess an educational intervention to reduce the risk of CMV acquisition in pregnancy.
With postgraduate training in medical education, Dr Jones is involved with multiple initiatives to train and equip others in paediatric infectious diseases.
Innate immune training by BCG vaccination
Professor Mihai Netea, Radboud University Nijmegen Medical Centre, The Netherlands
Abstract
The inability of innate immunity to build an immunological memory, considered one of the main characteristics differentiating it from adaptive immunity, has been recently challenged by studies in plants, invertebrates, and mammals. The increasing evidence for immunological memory within innate immunity is the focus of intense investigation. BCG vaccination has been recently shown to induce a long-term strong potentiation of innate immune responses. This long-term reprogramming of innate immunity, that induces adaptive traits and has been termed “trained immunity,” characterizes prototypical innate immune cells such as natural killer cells and monocytes, and provides protection against reinfection in a T/B-cell-independent manner. Both specific signaling mechanisms and non-specific epigenetic reprogramming have been implicated in mediating these effects. This concept represents a paradigm change in immunity and its putative role in resistance to reinfection may represent the next step in the design of future vaccines.
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Professor Mihai Netea, Radboud University Nijmegen Medical Centre, The Netherlands
Professor Mihai Netea, Radboud University Nijmegen Medical Centre, The Netherlands
Mihai Netea was born and studied medicine in Cluj-Napoca, Romania. He completed his PhD at the Radboud University Nijmegen, The Netherlands, on studies investigating the cytokine network in sepsis. After working as a post-doc at the University of Colorado, he returned to Nijmegen where he finished his clinical training as an infectious diseases specialist, and where he currently heads the division of Experimental Medicine, Department of Internal Medicine, Nijmegen University Nijmegen Medical Center. His main research interests are pattern recognition of fungal pathogens and the induction of antifungal immunity, primary immunodeficiencies in innate immune system, and the study of the memory traits of innate immunity.
Enteric infection and oral vaccine immunogenicity
Professor Nicholas Grassly, Imperial College London, UK
Abstract
Oral poliovirus and rotavirus vaccines, in common with other oral vaccines, show reduced immunogenicity and efficacy in low-income countries. This was observed during early trials of oral poliovirus vaccines (OPV), when other enteroviruses were found to interfere with vaccine virus replication and seroconversion. However, the biological mechanisms for this interference and potential significance of other intestinal pathogens are not known. We used novel card-array PCR and next-generation sequencing to characterise the intestinal microbiota in Indian infants receiving OPV or Rotarix at 6 and 10 weeks. We found infants with pathogenic bacterial, viral, eukaryotic or mixed intestinal infections at the time of vaccination were less likely to develop serum neutralising antibodies to poliovirus compared with uninfected infants. This was not apparent for the serum antibody (IgA) response to Rotarix, but pathogenic bacteria were associated with a reduction in vaccine take as measured by virus shedding. No large compositional differences in the intestinal microbiota were observed between infant groups, as assessed by 16S rDNA sequencing. I will discuss the implications of these findings for likely mechanisms and potential interventions to improve live-attenuated oral vaccine immunogenicity.
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Professor Nicholas Grassly, Imperial College London, UK
Professor Nicholas Grassly, Imperial College London, UK
Professor Nicholas Grassly is an infectious disease epidemiologist with a background in biology and mathematics. Grassly heads the Vaccine Epidemiology Research Group in the Department of Infectious Disease Epidemiology, which focuses on characterizing the immunogenicity and effectiveness of vaccines at the individual and population level, with a particular interest in poliovirus. In collaboration with researchers in Asia and Africa, Grassly is carrying out epidemiological studies and clinical trials to characterize the immune response to oral vaccines. A major current interest is the interaction between the intestinal microbiota and the immune response to vaccines against poliovirus and rotavirus. Grassly's group also works closely with the Global Polio Eradication Initiative to ensure eradication activities are aligned with the best possible epidemiological evidence. This work was recognized in 2013 by designation as the WHO collaborating institute for polio data analysis and modelling.
Genetic polymorphisms affecting innate immunity and Hib vaccine failure
Dr Shamez Ladhani, Public Health England, UK
Abstract
The development invasive disease after prior immunisation with highly immunogenic conjugate vaccines (i.e. vaccine failure) is extremely rare, suggesting that affected children may have an underlying genetic susceptibility in their immune response. We investigated 19 single-nucleotide polymorphisms (SNPs) known to affect function in biologically plausible immune response genes in relation to the risk of vaccine failure and its clinical manifestations in 172 UK white children with Haemophilus influenzae type b (Hib) vaccine failure. The Wellcome Trust Case Control Consortium data sets were used as controls. The recessive homozygous genotype for a SNP in the TIRAP (also known as MAL) gene (rs1893352) that is in strong linkage disequilibrium (r2=0.93) with the known functional Ser180Leu polymorphism was strongly associated with non-meningitis cases of Hib vaccine failure (OR, 5.6; 95% CI, 2.7-11.5; P=1.2 x 10-7). This association was confirmed in a subsequent genome wide association study (GWAS). Our findings strongly suggest that the development of invasive Hib disease after prior immunisation is in part genetically determined and may direct the immune response to specific clinical manifestations.
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Dr Shamez Ladhani, Public Health England, UK
Dr Shamez Ladhani, Public Health England, UK
Dr Shamez Ladhani completed his medical training at the United Medical and Dental Schools of Guy’s and St. Thomas’s Hospitals, London, and subsequently specialised in paediatrics. In 2000, he worked in Kenya as a paediatric registrar in a district hospital and then went on to complete a PhD in genetic epidemiology of vaccine preventable infections. During 2007-09, he completed the two-year national grid training programme in paediatric infectious diseases at St. George’s Hospital in South London. Currently, he works as a paediatric infectious disease consultant at St. George’s Hospital, clinical lecturer at St. George’s University of London and clinical epidemiologist at Public Health England. He is the clinical lead for enhanced national surveillance of a number of vaccine-preventable infections, including Haemophilus influenzae, Streptococcus pneumoniae, Neisseria meningitidis and Rotavirus. He is also involved with conducting clinical trials on behalf of the Department of Health to inform national immunisation policy.
Maternal antibodies, infant microbiota and vaccine response
Professor Yvonne Maldonado, Stanford University, USA
Abstract
Vaccines may provide differential age-related immunogenicity, particularly among infants and young children. These differences are largely related to the ontogeny of immune responses, but there is substantial evidence that passively acquired maternal antibodies directly interfere with infant immune responses to vaccines. Maternal antibodies, which cross the placenta late in the third trimester, may persist for the first year of life and can serve as a barrier to vaccine immunogenicity. They inhibit the generation of infant antibodies whereas T cell responses are generally unaffected. Some mechanisms of B cell inhibition are understood; in animals, inhibition can be partially overcome by parenteral administration of antigen-specific IgM. There is also a relationship between the composition of maternal and infant microbiota and subsequent immune responses among infants. Studies have identified specific faecal microbial patterns that are associated with modulation of infant vaccine responses. For example, faecal actinobacteria have been associated with increased T-cell responses to IgG and DTH responses to certain vaccines. In contrast, Enterobacteriales, Pseudomonadales, and Clostridiales have been associated with lower vaccine responses. However, the pathogenesis of the impact of maternal and infant microbiome on infant immune responses is under investigation. Finally, maternal immunisation to provide protection for young infants has been successful for specific diseases such as neonatal tetanus and pertussis. Nonetheless, maternal immunisation will not provide complete and durable protection through childhood and beyond. Therefore, understanding mechanisms of interference by maternal antibodies and the impact of maternal and faecal microbiota on immune responses is necessary to optimise infant immunisation strategies.
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Professor Yvonne Maldonado, Stanford University, USA
Professor Yvonne Maldonado, Stanford University, USA
Dr Maldonado is Professor, Departments of Pediatrics and of Health Research and Policy; Chief, Division of Infectious Diseases; and Senior Associate Dean of Faculty Development and Diversity at Stanford University School of Medicine, USA. Dr Maldonado’s research interests are the epidemiology and prevention of viral vaccine preventable infections, such as measles, polio, rotavirus, conducted internationally in Zimbabwe, Mexico, as well as in the US. She is a Fellow of the American Academy of Pediatrics and the Infectious Disease Society of America, a member of the Society for Pediatric Research, the Pediatric Infectious Disease Society and the American Public Health Association.