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Long-Term Immunity From Childhood Vaccines Linked to Genetic Variants

NEW YORK (GenomeWeb) – A team from the UK, Singapore, and the Netherlands has unearthed common variants at a few main loci — including the human leukocyte antigen (HLA) locus and a locus containing signal regulatory protein-coding genes — that seem to significantly influence how long immunity lasts following a handful of childhood immunizations.

"Currently, we are not aware of any implemented healthcare system to identify children whose vaccine-induced immunity has waned and would benefit from additional immunizations," corresponding author Daniel O'Connor, a pediatrics researcher affiliated with the University of Oxford and the NIHR Oxford Biomedical Research Centre, and his colleagues wrote, adding that "it is feasible that in the near future the persistence of immunity could be predicted and vaccine regimens personalized to maximize vaccine effectiveness."

As they reported online today in Cell Reports, the researchers began with a two-stage genome-wide association analyses involving thousands of children from the UK or the Netherlands, searching for common variants linked to antibody persistence following childhood immunizations targeting meningococcal bacteria, tetanus, or Haemophilus influenzae type B. They went on to incorporate available transcriptional and epigenetic clues to explore both the coding and non-coding contributors to immune persistence.

"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," O'Connor said in a statement.

"We are now carrying out in-depth investigations into the biology of the genetic variants we described in this study," he added. "We [have] 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 cited a 2013 study in the journal Vaccine by investigators in the US, Switzerland, and the UK, which suggested some 23.3 million deaths will be averted in almost a decade leading up to 2020. Even so, the group cautioned, there have been hints that antibody levels — and immunity with them — may flag over time in those who received certain conjugate vaccines in infancy. Moreover, prior twin studies indicate that immune response to vaccination has a strong heritable component.

"Vaccines have revolutionized public health, preventing millions of deaths each year, particularly in childhood," the authors wrote. "Yet, there is considerable variability in the magnitude and persistence of vaccine-induce immunity."

To investigate that, the researchers used Illumina arrays to genotype 2,061 children who received capsular group C meningococcal (MenC) conjugate vaccine, H. influenzae type b (Hib) conjugate vaccine, or tetanus toxoid vaccines.

After imputing SNPs with the help of 1000 Genomes Project data and identifying common variants with possible ties to immune persistence, the team took nearly 200 SNPs forward for validation testing in another 3,970 children with available serological or phenotypic profiles related to vaccine response.

The children were enrolled in nine prior vaccine studies in the UK and one study done in the Netherlands, the authors explained, noting that immunizations in these settings are typically deferred for acute illness, but not for more minor maladies.

For the MenC analyses, for example, the researchers searched for variants involved in immune persistence in 11- to 20-year-olds profiled between three and five years after receiving the Menjugate, Meningitec, or NeisVac-C vaccines from Novartis, Wyeth, and Baxter Vaccines, respectively. They also analyzed data for infants who received three doses of a GSK Biologicals' vaccine called Menitorix when they were two to four months old.

The team's initial search highlighted two-dozen SNPs with suggestive associations to participants' serum levels of IgG immunoglobulin antibodies specific to MenC vaccines, and dozens more variants that had more subtle ties to MenC-related serum bactericidal antibody levels. However, significant associations with serum bactericidal antibody titers turned up at the LOC105369219 locus and at signal-regulatory protein-coding genes such as SIRPA, SIRPB, and SIRPG.

When it came to H. influenzae type b vaccine response, meanwhile, the researchers identified 69 SNPs in five genes that had genome-wide significant associations with IgG concentrations specific to the Hib vaccine concoction. In an analysis of immune persistence related to the tetanus toxoid vaccine, meanwhile, they narrowed in on four HLA alleles — namely HLA DRB1*0301, HLA DQB1*0201, HLA DQB1*0602, and HLA DRB1*1501 — as well as additional SNPs with more suggestive ties to tetanus toxoid vaccine response.

"Although these variants inevitably account for only a small portion of the total genetically determined contribution to persistence of vaccine-induced immunity, this study demonstrates the utility of applying this 'hypothesis-free' approach in generating candidates for future functional and mechanistic investigations," the authors concluded, "the description of which may ultimately influence vaccine development and implementation."

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