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Biological challenges to effective vaccines: learning from variation in vaccine immunogenicity and efficacy

Event

Starts:

November
122014

09:00

Ends:

November
132014

17:00

Location

Kavli Royal Society Centre, Chicheley Hall, Newport Pagnell, Buckinghamshire, MK16 9JJ

Overview

Satellite meeting organised by Professor Nicholas Grassly, Professor Gagandeep Kang and Professor Beate Kampmann

Event details

Variation in vaccine immunogenicity and efficacy among populations is a public health challenge. However, it also offers an opportunity to understand and overcome the causes of vaccine failure. Building on the themes of the discussion meeting, the satellite meeting will discuss recent findings and challenge participants to identify key research questions that will yield more effective vaccines in low-income countries.

You can download the draft programme (PDF), and abstracts and biographies of the speakers are available below.

Attending this event

This event has already taken place. Recorded audio of the presentations can be found below.

Enquiries: Contact the events team

Schedule of talks

Session 1: What is the epidemiological evidence for population differences in vaccine response, how important is it and what does it tell us about the biological mechanisms?

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Conjugate bacterial vaccines

Professor Kim Mulholland, London School of Hygiene & Tropical Medicine, UK and Murdoch Childrens Research Institute, Australia

Abstract

Conjugate vaccines to combat invasive bacterial infections were first developed during the 1980s. In 1990 the first Hib conjugate vaccine was licensed for use in infants and in 2000 the first 7-valent pneumococcal conjugate vaccine was licensed. In 2014 most countries are using Hib vaccine, although major countries in Asia have yet to introduce it due to doubts about its effectiveness. New pneumococcal conjugate vaccines (covering 10 or 13 serotypes) are used extensively although there is a perception that they have no role in Asia. 4-valent meningococcal conjugate vaccines are widely available in the private sector, while a monovalent meningococcal A vaccine has been introduced in the meningitis belt of Africa. Regional variations in immunogenicity have been profound, with Hib vaccines producing very high antibody levels in Latin America and pneumococcal vaccines producing high antibody levels in North Asia. However, observed differences in effectiveness are better explained by other factors.

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BCG!

Professor Paul Fine, London School of Hygiene & Tropical Medicine, UK

Abstract

The observation that BCG vaccines appear to vary in effectiveness between populations was first made more than 50 years ago, and it has generated a substantial literature. Several possible mechanisms have been proposed to explain the observed data, including: methodological differences between studies; genetic differences between the vaccines, the human populations, or the M tuberculosis; local differences in the epidemiology of tuberculosis; differences in nutrition; or differences in background exposure to “environmental mycobacteria” which may either block or mask the action of BCG. Though there may still be no consensus, and the mechanism may be multifactorial, there is much evidence that background exposure to mycobacterial antigens, both of M tuberculosis and of a variety of environmental mycobacteria, is an important contributor to the observed variation. This story has important implications for both the development and the evaluation of new vaccines against tuberculosis.

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Oral rotavirus vaccines

Dr Umesh Parashar, Centers for Disease Control and Prevention, USA

Abstract

Rotavirus is the leading cause of severe diarrhoea among children <5 years worldwide. Two vaccines against rotavirus were licensed in 2006, and are currently being used in the national immunisation programs of  >60 countries globally. These vaccines have been efficacious and effective, with many countries reporting substantial declines in diarrheal and rotavirus-specific morbidity and mortality. However, the full public health impact of these vaccines has not been realised as many countries, including low income countries with the highest disease burden, have not yet introduced rotavirus vaccines into their national immunisation programs. Because of many potential factors that could interfere with the performance of oral rotavirus vaccine in low income settings – such as concurrent enteric infections, malnutrition, environmental enteropathy, higher levels of maternal antibody, and breastfeeding – a better understanding of vaccine effectiveness in these low income settings is required. These issues will be discussed in the presentation and strategies to overcome these challenges will be described.

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Session 2: Mechanisms of variable vaccine response among populations

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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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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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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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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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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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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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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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Session 3: What should we measure in vaccine trials in addition to antibody to understand vaccine failure and develop better vaccines?

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How are the principles of basic immunology best applied to vaccine development: TB vaccines as example?

Dr Thomas Scriba, University of Cape Town, South Africa

Abstract

Tuberculosis (TB) is a leading cause of morbidity and mortality from infection globally. The only licensed vaccine against TB, BCG, which has been given to billions globally, affords highly variable and mostly poor protection against adult pulmonary TB disease. Decades of immunology studies in animal models and humans have highlighted important roles for classical macrophage activation, IFN-g-expressing Th1 cells and long-lived memory T cells in protective immunity against M. tuberculosis. As a consequence, most novel TB vaccine candidates have been designed to capitalise on these functions and arms of immunity. A dozen of these candidate vaccines have reached clinical development phases in the human. I will discuss highlights of the fundamental immunology underlying our understanding of immunity against TB and how this has informed design of novel vaccine candidates. I will also cover recent successes and setbacks in TB vaccinology, with an emphasis on results from clinical trials in South Africa, where TB is endemic.

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Dissecting the response to vaccination in the youngest – do we have the tools?

Professor Tobias Kollmann, University of British Columbia, Canada

Abstract

Vaccine-induced immune responses are complex involving functions beyond antibodies. For example, correlates of protection from disease may be cell-mediated, and the non-specific protective effects of live vaccines may involve innate immunity. Systems vaccinology, i.e. unbiased OMIC approaches, has begun to provide some of the missing mechanistic insight into this complex network of interactions. Most systems vaccinology studies have so far focused on adults or older children - not on newborns or very young infants. Furthermore, most of these studies have relied on transcriptomic approaches alone, although other systems biology fields already realise its full potential by combining epigenomic, with transcriptomic, proteomic and metabolomic platforms, which provides a fuller assessment from gene to function. The omission of the newborn and young infant from this revolution likely is the result of concerns about small sample volumes and higher biological complexity due to e.g. age as an additional variable. However, as outlined in this presentation, these hurdles have successfully been overcome, allowing full application of the modern tools to the age group in most need of vaccine-mediated protection.

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Session 4: What are our research priorities now to achieve more effective vaccines in low-income countries in the future? Panel discussion and meeting summary

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Panel discussion feedback

Dr Allan Saul, Novartis Vaccines Institute for Global Health, Italy
Professor Gagandeep Kang, Christian Medical College, Vellore, India
Professor Beate Kampmann, Imperial College London, UK and MRC Unit The Gambia
Professor Nicholas Grassly, Imperial College London, UK
Professor Andrew Pollard, University of Oxford, UK
Professor Adrian Hill, University of Oxford, UK

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Science in progress presentations

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Biological challenges to effective vaccines: learning from variation in vaccine immunogenicity and efficacy Satellite meeting organised by Professor Nicholas Grassly, Professor Gagandeep Kang and Professor Beate Kampmann Kavli Royal Society Centre, Chicheley Hall Newport Pagnell Buckinghamshire MK16 9JJ
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