Genetic Variation Influences Effectiveness of Vaccines

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Three-month-old baby receiving oral vaccination

A genome-wide association study GWAS, headed by a team at the University of Oxford, U.K., and involving thousands of children in the U.K. and the Netherlands, has linked a number of genetic variations with the level of protective antibodies generated following routine childhood immunizations. The scientists say that with further research it may be feasible to incorporate genetic tests into neonatal screening programs that can predict immunity to vaccines, and so guide personalized vaccination regimens.

“This study is the first to use a genome-wide genotyping approach, assessing several million genetic variants, to investigate the genetic determinants of immune responses to three routine childhood vaccines,” said Daniel O’Connor, PhD, a postdoctoral researcher at the department of pediatrics, University of Oxford, who is first author of the team’s published paper in Cell Reports. “While this study is a good start, it also clearly demonstrates that more work is needed to fully describe the complex genetics involved in vaccine responses, and to achieve this aim we will need to study many more individuals.” The team’s paper is titled, “Common Genetic Variations Associated with the Persistence of Immunity following Childhood Immunization.”

Vaccines have “revolutionized public health,” and prevented millions of deaths every year, particularly in children, the authors noted. However, continued protection against the pathogen after vaccination depends on the body’s ability to maintain antibody levels. For some vaccines antibody levels decline quite quickly after immunization during infancy, and so boosters are required during childhood. There is also significant variation in both the magnitude and persistence of vaccine-induced immunity between different people.

“Evoking robust and sustained vaccine-induced immunity from early life is a crucial component of global health initiatives to combat the burden of infectious disease,” O’Connor noted. “The mechanisms underlying the persistence of antibody is of major interest, since effectiveness and acceptability of vaccines would be improved if protection were sustained after infant immunization without the need for repeated boosting through childhood.”

Vaccine response and antibody persistence after vaccination are affected by a range of factors, including age, sex, ethnicity, infectious disease, and nutrition. Twin studies have also shown that vaccine-induced immunity is partly heritable. For their reported study the University of Oxford researchers and their colleagues carried out a two-stage GWAS involving 3,602 children in the U.K. and the Netherlands, to investigate the link between genetic variation and levels of immunity to three routine childhood vaccinations: capsular group C meningococcal (MenC), Haemophilus influenzaetype b (Hib), and tetanus toxoid (TT) vaccines. MenC protects against the pathogen Neisseria meningitides, which is the leading cause of bacterial meningitis, and is estimated to cause more than 500,000 serious infections and 50,000 deaths every year. The Haemophilus influenzae type b pathogen is estimated to cause in excess of eight million serious infections every year, and result in more than 150,000 deaths. The tetanus toxoid vaccine protects against the bacterium Clostridium tetani. WHO estimates indicate that more than 61,000 deaths resulted from neonatal tetanus in 2011 alone, the authors reported.

The results of the GWAS identified two genetic loci associated with the persistence of vaccine-induced immunity in immunized children. MenC immunity persistence was linked with single nucleotide polymorphisms (SNPs) in a region of the genome containing a family of signal-regulatory protein genes, SIRPA, SIRPB, and SIRPG, which are involved in immunological signaling. TT-specific immunity persistence was linked with SNPs in the human leukocyte antigen (HLA) locus, which contains the genes coding for HLA molecules that present peptides to T cells, which in turn induce B cells to produce antibodies. “We also identified a region within the HLA gene complex that contained SNPs associated with the persistence of TT-specific IgG,” the researchers wrote. “Given their role, HLA genes have frequently been candidates in studies exploring the genetic determinants of vaccine responses.”

The authors acknowledge that the identified variants will likely account for just a fraction of all the genetic determinants that impact on vaccine-induced immunity persistence. “In our study, we estimated the heritability of vaccine-induced immunity to vary from 14% to 81%,” they noted. “… TT immunity was estimated to be the most heritable of these measures … it is likely that the study of larger vaccinee cohorts will yield more loci associated with immunity to vaccine antigens.”

The authors also pointed out that their study included primarily Caucasian children, so it is not clear whether the results would apply to different ethnicities. “We are now carrying out in-depth investigations into the biology of the genetic variants we described in this study,” O’Connor said. “We also planned further research, in larger cohorts of children and other populations that benefit from vaccination, to further our understanding of how our genetic makeup shapes vaccine responses.”

The team says that as far as they are aware there isn’t any system yet in place for identifying children whose vaccine-induced immunity has diminished and who would benefit from additional boosters. Developing and implementing such a system may become possible, they suggest, as the costs of genetic analysis decrease and our understanding of how genetics affect immunity increases. “ … we envisage genetic markers of vaccine response could soon prove their clinical utility,” the investigators concluded … “It is realistic to conceive that neonatal screening approaches will soon incorporate a number of genetic risk factors (potentially derived from whole-genome sequencing at birth). Therefore, it is feasible that in the near future that the persistence of immunity could be predicted and vaccine regimens personalized to maximize vaccine effectiveness.”

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