Human genetics: from infectious diseases to vaccine responses
Professor Adrian Hill, University of Oxford, UK
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.
WHO SAGE recommendations on non-specific vaccine effects
Professor Andrew Pollard, University of Oxford, UK
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.
Vaccine responses in HIV-exposed, uninfected infants
Dr Chrissie Jones, St George's, University of London, UK
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.
Innate immune training by BCG vaccination
Professor Mihai Netea, Radboud University Nijmegen Medical Centre, The Netherlands
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.
Enteric infection and oral vaccine immunogenicity
Professor Nicholas Grassly, Imperial College London, UK
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.
Genetic polymorphisms affecting innate immunity and Hib vaccine failure
Dr Shamez Ladhani, Public Health England, UK
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.
Maternal antibodies, infant microbiota and vaccine response
Professor Yvonne Maldonado, Stanford University, USA
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.