Twin studies of immunogenicity — determining the genetic contribution to vaccine failure
Introduction
The degree to which genetic variation contributes to the failure to respond to a vaccine is unknown. Nevertheless, important genetic associations between specific genes and vaccine antibody levels have been identified [1], [2], [3]. Estimating the magnitude of the relative genetic contribution to the overall variation of antibody levels among individuals following measles, mumps, and rubella immunization should help clarify the role of genetic associations in the biological mechanism of vaccine response and failure. In turn, this might guide the design of improved vaccines with enhanced efficacy — not just for measles, mumps, and rubella but for other viral diseases as well.
Several investigations have demonstrated important associations of antibody levels following immunization and specific alleles of both the human leukocyte antigen (HLA) genes and the immunoglobulin allotype genes. Studies of hepatitis B immunization in Caucasian subjects found the presence of the HLA-B8-SC01-DR3 haplotype associated with the lack of antibodies [3], [4], [5]. An early study failed to demonstrate an association between specific HLA loci and antibody levels following measles immunization; [6] but, in a study of 881 school children previously vaccinated against measles, we were able to demonstrate several HLA associations [7], [8], [9]. Very low levels of measles antibody correlated with the presence of the HLA-DRB1*07 allele and the absence of HLA-DRB1*13 alleles [7]. Similarly, very low antibody levels correlated with the presence of HLA-DQA1*05 and the absence of HLA-DQA1*01 [8]. Very low levels also correlated with Class II HLA homozygosity [8]. With respect to Class I, we found that HLA-B13, -B44, and -C5 correlated with measles-specific seronegativity, and HLA-B7 and -B51 correlated with serohyperpositivity [9] and the Class I HLA-B homozygosity correlated with seronegativity [9]. Other studies of the antibody levels following immunizations with polysaccharide vaccines like group B meningococcal polysaccharide vaccine [10] and Haemophilus influenzae type b polysaccharide vaccine [11] have demonstrated associations between allotype-linked genes and the antibody levels to these vaccines as well.
Many environmental factors may affect the antibody levels following immunization. These factors include vaccine handling and storage, the length of the needle used during immunization, route of administration of the vaccine (e.g. intra-muscular vs. subcutaneous), the number of doses, the presence of intercurrent illnesses or co-morbidity (e.g. obesity, tobacco use), the presence of placentally acquired maternal antibodies, the age at immunization, and the time elapsed from immunization [12], [13], [14], [15], [16], [17]. Unfortunately, many studies of vaccine immunogenicity and efficacy fail to report and thus apparently fail to address these variables [18]. For immunity, as for many other biological phenomena, the relative genetic contribution as contrasted to that of environmental factors is important but difficult to determine in the general population. Studies of twins overcome this difficulty by providing some control over both environmental and genetic factors and thus can provide important insight into the study of the relative importance of genetic versus environmental influence [6], [19], [20], [21], [22], [23], [24].
What is not yet understood is the relative important of genetics to the overall variation observed in antibody levels following immunization. In this study, we sought to estimate the heritability of antibody levels following routine childhood immunization against measles, mumps and rubella. Specifically, we sought to explore the magnitude of genetic influence on the circulating, quantitative antibody levels for measles, mumps and rubella by comparing monozygotic twins to dizygotic twins. We tested the hypothesis that antibody levels following immunization would show greater correlation of within pair levels in monozygotic twins than in dizygotic twins. The size of that disparity would permit us to quantify the magnitude of heritability.
Section snippets
Sampling
After approval from the Institutional Review Board, we recruited 100 healthy twin-pair volunteers, recruiting through advertising in the Olmsted County, Minnesota region. We included subjects 2–18-years old who had received at least one dose of each of childhood vaccines routinely recommended, including the measles–mumps–rubella vaccine, and yet were young enough to remain living together in the same household. We only included subjects who were in good health. We excluded those with a history
Results
We enrolled a total of 100 pairs of twins. Forty-five pairs were monozygotic. Table 1 displays the demographic characteristics of the subjects. Of note, the study cohort consisted of a disproportionate number of females.
Our analysis failed to find significant differences in the distributions of non-genetic variables between the monozygotic and dizygotic twins. This analysis included the number of vaccine-doses (P=0.106), the age at first vaccination (P=0.225), the time from first dose to
Discussion
Our data support the concept that genetic influence plays a substantial role in the antibody level following immunization against measles and, to a lesser extent, mumps and rubella. Twins raised together are highly likely to share environmental factors including any exposure to measles, mumps, or rubella in the community before and after immunization as well as any exposure to cross-reacting viral infections before and after immunization. Furthermore, twins raised together are highly likely to
Acknowledgements
We would like to acknowledge the critical assistance of Daniel J. Schaid, Ph.D., in the analysis of the data, the enthusiastic efforts of our nurses, Carol Smidt and Chris Voeltz, and the financial support from Mayo Clinic and specifically the Department of Pediatric and Adolescent Medicine.
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Present address: Mayo Vaccine Research Group, Mayo Clinic, Rochester, Minnesota, USA.