Learning to Appreciate Our Differences
Despite overall levels of genetic similarity and shared physiological characteristics across the species, humans vary quite a bit in their individual responses to biological stress and noxious stimuli. Sometimes variant responses are dramatic and clinically important. This is certainly the case with respect to the responses of humans to microbial pathogens and their antigens. The consequences of infection by a pathogen in a host population vary from benign to catastrophic, as a complex function of the host genetics, the history of prior exposures and experiences, the current state of immune activation (both local and systemic), and, probably, a variety of other factors, including host nutritional status and the composition and structure of the indigenous microbiota. Although typical responses to vaccines are favorable, occasional responses are pathologic and costly to the host. If these aberrant responses could be predicted and understood mechanistically (the first element does not necessarily require the second), we would be able to reduce the number and/or severity of vaccine adverse events (AEs), improve vaccine design, and create personalized strategies for eliciting immune protection. In this issue of the Journal, Reif et al. address this goal and provide an opportunity to discuss challenges and possible solutions.
Reif et al. collected host genetic sequence data from 2 independent studies of the smallpox vaccine (Aventis Pasteur) in vaccinia virus–naive adults. Of 85 vaccinated subjects included in the first study, 16 developed a systemic AE (fever, lymphadenopathy, or generalized rash). Twenty‐four of the 46 vaccinated subjects included in the second study developed 1 of these 3 systemic AEs.
The investigators obtained data on 1442 single‐nucleotide polymorphisms (SNPs) located in or near 386 genes, as drawn from the National Cancer Institute Cancer Genome Anatomy Project SNP500Cancer Database, which includes genes or specific genetic variants associated with signaling pathways, immune response, and oncogenesis. These SNPs were assayed using a highly parallel genotyping technology based on allele‐specific primer extension, ligation, amplification, and hybridization to bead‐based oligonucleotide arrays (Illumina). Only the 36 SNPs (linked to 26 genes) that were found to have an AE‐associated P value .05 in the first study were assessed in the second study. Of these 36 SNPs, 3 were found to have an AE‐associated P value .05. One SNP is located in the 5,10‐methylenetetrahydrofolate reductase (MTHFR) gene, and 2 SNPs are located in the interferon regulatory factor–1 (IRF1) gene. In addition, 3 SNPs in the interleukin‐4 (IL4) gene were significantly associated with AEs in the first study but did not quite achieve statistical significance in the second study.