Identifying genetic factors associated with AEs [adverse events] might allow screening before vaccinia [smallpox vaccine] administration and provide a rational basis for the development of improved vaccine candidates.
Two independent clinical trials in healthy, vaccinia-naïve adult volunteers were conducted with the Aventis Pasteur smallpox vaccine (APSV). Volunteers were assessed repeatedly for local and systemic AEs to vaccine and were genotyped…
In the first study, thirty-six SNPs [single nucleotide polymorphism] in 26 genes were associated with systemic AEs.
In the final analysis, three SNPs were associated consistently with AEs in [two independent] studies.
[An] SNP in methylenetetrahydrofolate reductase (MTHFR) was associated with AE risk in both trials.
Two SNPs in the interferon regulatory factor 1 (IRF1) gene were associated with AE risk in both sample sets.
Genetic polymorphisms in an enzyme previously associated with adverse reactions to a variety of pharmacologic agents (MTHFR) and an immunological transcription factor (IRF1) were associated with AEs after smallpox vaccination…
Although reactions following inoculation with vaccinia virus were common in the recent population-wide vaccination programs, the biological basis for these adverse events (AEs) is not well understood.
[W]e questioned whether subjects encountering AEs exhibited unique genetic polymorphisms… that made them more susceptible to these reactions.
[W]e sought to repeat the assessment on an additional study group. Independent replication of the results of our first study with the second strengthens the plausibility of these genetic associations.
Subjects with systemic AEs including fever, lymphadenopathy, or generalized acneiform rash, were compared with those who did not experience these reactions.
Both trials were conducted at Vanderbilt University in the NIH-funded Vaccine and Treatment Evaluation Unit.
A total of 36 SNPs (within 26 genes) that showed significant associations in the first study were tested for potential associations in the second study. Three variant genotypes were confirmed to be associated with AEs in the second study. These included one SNP in MTHFR and two SNPs in IRF1. The strong significance of the association in the replication study suggested a high level of plausibility that the gene products were involved in the pathogenesis of the AEs.
The candidate genes identified with the strongest association with AEs in both studies include a metabolism gene previously associated with adverse reactions to a variety of pharmacologic agents (MTHFR) and an immunological transcription factor (IRF1).
A SNP in the 5,10-methylenetetrahydrofolate reductase (MTHFR) gene (rs1801133) was associated strongly with AE risk in both studies.
MTHFR function provides pools of methyl groups that are crucial for the control of DNA synthesis and repair mechanisms. MTHFR is a key enzyme in homocysteine metabolism, which plays a major role in regulating endothelial function. It may be of interest in the future to examine the association of genetic variation in this gene with the rare cardiac events that occur after vaccination.
Genetic variation of MTHFR has been associated with a range of clinical outcomes, including altered cardiovascular function, organ transplantation, toxicity of immunosuppressive drugs, and systemic inflammation.
[S]ince vaccination elicits immune responses involving the rapid proliferation of cells, demand for DNA synthesis metabolites would be elevated, and alterations in the level or activity of MTHFR enzyme may exert significant influence over this process.
Polymorphisms in the gene coding for a transcription factor with such far-reaching effects as IRF1 could have profound effects on the proper immune response and clearance of vaccinia virus. Mice deficient in interferon receptors are especially susceptible to vaccinia virus infection, suggesting an important role for these molecules in controlling vaccinia infection.
Genetic polymorphisms in this major cytokine gene involved in adaptive immunity to viruses also may be associated with AEs…
We found three SNPs in IL4 that may be associated with AEs in both studies.
IL4 controls humoral immune responses…
Thus, genetic polymorphisms related to inappropriate regulation of IL4 expression and/or activity of IL-4 cytokine could be associated with over-stimulated inflammatory responses leading to the development of clinical AEs.
The genes with variants for which we discovered an association with AEs are all potentially involved in pathways that are in line with our previously hypothesized mechanism of AEs involving excess stimulation of inflammatory pathways and the imbalance of tissue damage repair pathways.
For subjects experiencing AEs, vaccination appears to trigger an acute inflammatory response that is excessive. Antigen presentation to T cells in the dermis leads to the release of T-cell cytokines that trigger a cascade of cytokines and chemokines whose release enhances the inflammatory response by promoting the migration of monocytes into the lesion and their maturation into macrophages and by further attracting T cells.
[S]ystemic AEs following smallpox vaccination may be consistent with low-grade macrophage activation syndrome caused by virus replication and vigorous tissue injury and repair.