Human leukocyte antigen polymorphisms and variation in the immune response to vaccines.
Despite availability of effective vaccines, disease outbreaks can occur in highly vaccinated populations. For example, 20-40% of subjects in the 1989-1991 US measles outbreak had been previously immunized against measles. One of the most logical places to explain the variation in the individual response to vaccines lies within the highly polymorphic human leukocyte antigen (HLA) system. For vaccines to be immunogenic, each individual must be capable of presenting vaccine antigens bound to the specific HLA alleles carried by the individual to the T cells, thus stimulating an effective immune response to the foreign antigen. Because of this HLA-restricted antigen recognition and presentation and because of the variations in HLA distribution across populations, different vaccines may not be uniformly effective across populations.
Several genetic association population-based studies have identified associations between specific class I and II HLA alleles and the antibody response to several vaccines including Measles, Mumps, Rubella, Hepatitis B and Influenza. These associations range from ‘poor’ to ‘hyper’ humoral immune responses to vaccines. For example, Ovsyannikova et al have extensively studied the association between measles vaccine induced antibody response and HLA genes. They found that class I HLA-B alleles, including HLA-B8, HLA-B13 and HLA-B44 were associated with seronegativity, whereas alleles HLA-B7 and HLA-B51 were associated with seropositivity. Among class II alleles, seronegative individuals had an excess of HLA-DRB1*03 and HLA-DPA1*0201 alleles compared to seropositives. They also studied the associations between HLA genes and very high levels of measles antibodies (hyper-responsiveness) and found that HLA alleles B7, DQA1*0104 and DPA1*0202 were over-represented in the group of measles vaccine hyperseropositive individuals.
The effect of the HLA alleles on immune response to vaccines can have important implications in understanding vaccine immunogenicity as well as for directed vaccine development - to build cocktails of vaccine antigen epitopes that provide immunological coverage for populations by binding antigens across a diverse range of HLA types.
References:
G. A. Poland and R. M. Jacobson. Failure to reach the goal of measles elimination. Apparent paradox of measles infections in immunized persons. Archives of Internal Medicine 154 (16):1815-1820, 1994.
I. G. Ovsyannikova, N. Dhiman, R. M. Jacobson, and G. A. Poland. Human leukocyte antigen polymorphisms: variable humoral immune responses to viral vaccines. Expert Review of Vaccines 5 (1):33-43, 2006.
I. G. Ovsyannikova, R. M. Jacobson, and G. A. Poland. Variation in vaccine response in normal populations. Pharmacogenomics 5 (4):417-427, 2004.
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I recently worked on a Phase-I, dose-escalation study to look at the safety and immunogenicity of an epitope-based DNA vaccine in 40 HIV-1-infected subjects on HAART [i.e. the subjects were HIV-infected, but had viral suppression (HIV RNA < 50 copies/ml)] (Wilson, 2003). As mentioned in the class notes, HIV-specific cytotoxic CD8+ T lymphocytes (CTL) play a role in controlling viral replication (Cao, 1995; Pantaleo 1995). The study vaccine was designed to induce and/or augment existing CTL. The trial vaccine encoded 21 HLA Class I supertype-restricted CTL epitopes 7 epitopes restricted each to HLA-A2, -A3 and B7 supertypes, which was estimated to cover 85% of the general population. (This was based on HLA frequencies of four major ethnic groups, Asians, Blacks, European, and North American Caucasians; on average 8.5 epitopes would be recognized by an individual.) As a safety trial, HLA testing was not used as eligibility criteria; although we did consider HLA type in some secondary efficacy analyses (manuscript in progress).
Wilson, C.C., McKinney, D., Anders, M, et al., Development of a DNA Vaccine Designed to Induce Cytotoxic T Lymphocyte Responses to Multiple Conserved Epitopes in HIV-1. Journal of Immunology. 2003; 171:5611-5623.
Cao Y, Qin L, Zhang L, Safrit J, and Ho DD. Virologic and immunologic characterization of long-term survivors of human immunodeficiency virus type 1 infection. N Engl J Med 1995; 332:201-8.
Pantaleo G, Menzo S, Vaccarezza M et al. Studies in subjects with long-term nonprogressive human immunodeficiency virus infection. N Engl J Med 1995; 332:209-16.
Very interesting. A question for both of you: how reasonable do you think vaccine cocktails (taking into account HLA types and possibly other factors) will be to generate? Not only the time and money involved, but the research (like samm's) that needs to be conducted. How easy is it to get one's HLA types?
To add to Barteld's question, where can we get our HLA tested and are we moving towards performing the HLA test on all young people? It seems like you would want to know if your child was in a group that didn't respond well to vaccination.
To Author:
Perhaps you could enlighten us about how this blog relates to your dissertation :)
Studies have shown that majority of class I and class II HLA molecules can be grouped into broad supertypes characterized by overlapping peptide-binding motifs. Viral derived peptides, which play a role in immune response and can be bound and presented by various alleles of an HLA supertype could lead to a vaccine that would be immunogenic for defined HLA supertypes carried by the population. Though this approach is unlikely to influence clinical practice in the immediate future, it could represent an important advance in personalized medicine in the coming years.
As discussed in class, HLA typing can be done by serological methods using anti-HLA antisera and complement; and by DNA sequencing. Using DNA for HLA typing gives a detailed picture of the alleles which is not possible with the serological method.
HLA typing is not done as a routine test and I think we are far from performing it on all young people. It is mainly done for matching donors and recipients in solid organ/stem cell/bone marrow transplantation, for disease detection and for research applications.
MDS, I am working on vaccine adverse effects for my dissertation.
I. G. Ovsyannikova, R. M. Jacobson et al HLA supertypes and immune responses to measles–mumps–rubella viral vaccine: Findings and implications for vaccine design. Vaccine 25 (16):3090-3100, 2007.
In addition to vaccination, given the HLA links to various autoimmune diseases, i.e. rheumatoid arthritis, IDDM, multiple sclerosis, this seems yet more ample reasoning into an investigation of HLA-typing for the future. Could it maybe serve a purpose in the preventative arena or delaying onset of disease, as opposed to solely diagnosis?
This has interesting implications in terms of people who are less prone to certain disease. I believe in some rhesus monkey studies, they've seen that MAMU*A01monkeys have an attenuate phenotype of SHIV. This perhaps suggests that this specific allele of MHC in rhesus macaques present SHIV antigen more efficiently thereby have better protection against the disease.
Related Articles, LinksZhang ZQ, Fu TM, Casimiro DR, Davies ME, Liang X, Schleif WA, Handt L, Tussey L, Chen M, Tang A, Wilson KA, Trigona WL, Freed DC, Tan CY, Horton M, Emini EA, Shiver JW.Mamu-A*01 allele-mediated attenuation of disease progression in simian-human immunodeficiency virus infection.J Virol. 2002 Dec;76(24):12845-54. PMID: 12438610 [PubMed - indexed for MEDLINE]
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