High-Dimensional Gene Expression Profiling Studies in High and Low Responders to Primary Smallpox Vaccination
ABSTRACT Background. The mechanisms underlying smallpox vaccine-induced variations in immune responses are not well understood, but are of considerable interest to a deeper understanding of poxvirus immunity and correlates of protection. Methods. We assessed transcriptional messenger RNA expression changes in 197 recipients of primary smallpox vaccination representing the extremes of humoral and cellular immune responses. Results. The 20 most significant differentially expressed genes include a tumor necrosis factor-receptor superfamily member, an interferon (IFN) gene, a chemokine gene, zinc finger protein genes, nuclear factors, and histones (P ≤ 1.06E(-20), q ≤ 2.64E(-17)). A pathway analysis identified 4 enriched pathways with cytokine production by the T-helper 17 subset of CD4+ T cells being the most significant pathway (P = 3.42E(-05)). Two pathways (antiviral actions of IFNs, P = 8.95E(-05); and IFN-α/β signaling pathway, P = 2.92E(-04)), integral to innate immunity, were enriched when comparing high with low antibody responders (false discovery rate, < 0.05). Genes related to immune function and transcription (TLR8, P = .0002; DAPP1, P = .0003; LAMP3, P = 9.96E(-05); NR4A2, P ≤ .0002; EGR3, P = 4.52E(-05)), and other genes with a possible impact on immunity (LNPEP, P = 3.72E(-05); CAPRIN1, P = .0001; XRN1, P = .0001), were found to be expressed differentially in high versus low antibody responders. Conclusion. We identified novel and known immunity-related genes and pathways that may account for differences in immune response to smallpox vaccination.
SourceAvailable from: Inna G. Ovsyannikova[Show abstract] [Hide abstract]
ABSTRACT: Smallpox was eradicated 34 years ago due to the success of the smallpox vaccine; yet, the vaccine continues to be studied because of its importance in responding to potential biological warfare and the adverse events associated with current smallpox vaccines. Interindividual variations in vaccine response are observed and are, in part, due to genetic variation. In some cases, these varying responses lead to adverse events, which occur at a relatively high rate for the smallpox vaccine compared with other vaccines. Here, we aim to summarize the cytokine responses associated with smallpox vaccine response to date. Along with a description of each of these cytokines, we describe the genetic and adverse event data associated with cytokine responses to smallpox vaccination.Immunotherapy 10/2014; 6(10):1097-112. DOI:10.2217/imt.14.72 · 2.44 Impact Factor
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ABSTRACT: Infectious pathogens are responsible for high utilisation of healthcare resources globally. Attributable morbidity and mortality remains exceptionally high. Vaccines offer the potential to prime a pathogen-specific immune response and subsequently reduce disease burden. Routine vaccination has fundamentally altered the natural history of many frequently observed and serious infections. Vaccination is also recommended for persons at increased risk of severe vaccine-preventable disease. Many current nonadjuvanted vaccines are poorly effective in the elderly and immunocompromised populations, resulting in nonprotective postvaccine antibody titres, which serve as surrogate markers for protection. The vaccine-induced immune response is influenced by: (i.) vaccine factors i.e., type and composition of the antigen(s), (ii.) host factors i.e., genetic differences in immune-signalling or senescence, and (iii.) external factors such as immunosuppressive drugs or diseases. Adjuvanted vaccines offer the potential to compensate for a lack of stimulation and improve pathogen-specific protection. In this review we use influenza vaccine as a model in a discussion of the different mechanisms of action of the available adjuvants. In addition, we will appraise new approaches using "vaccine-omics" to discover novel types of adjuvants.Swiss medical weekly: official journal of the Swiss Society of Infectious Diseases, the Swiss Society of Internal Medicine, the Swiss Society of Pneumology 05/2014; 144:w13940. DOI:10.4414/smw.2014.13940 · 1.88 Impact Factor
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ABSTRACT: The RV144 HIV-1 vaccine trial demonstrated partial efficacy of 31% against HIV-1 infection. Studies into possible correlates of protection found that antibodies specific to the V1/V2 region of envelope correlated inversely with infection risk and that viruses isolated from trial participants contained genetic signatures of vaccine-induced pressure in the V1/V2 region. We explored the hypothesis that the genetic signatures in V1/V2 could be partly attributed to selection by vaccine primed T cells. We performed a T-cell based sieve analysis of breakthrough viruses in the RV144 trial and found evidence of predicted HLA binding escape that was greater in vaccine versus placebo recipients. The predicted escape depended on class I HLA A*02 and A*11 restricted epitopes in the MN-strain rgp120 vaccine immunogen. Though we hypothesized that this was indicative of post-acquisition selection pressure, we also found that vaccine efficacy (VE) was greater in A*02(+) compared to A*02(-) participants (VE=54% vs. 3%, p=0.05). Vaccine efficacy against viruses with a lysine residue at site 169, important to antibody binding and implicated in vaccine-induced immune pressure, was also greater in A*02(+) participants (VE=74% vs. 15%, p=0.02). Additionally, a reanalysis of vaccine-induced immune responses focused on those that were shown to correlate with infection risk, suggested that the humoral response may have differed in A*02(+) participants. These exploratory and hypothesis-generating analyses indicate there may be an association between a class I HLA allele and vaccine efficacy, highlighting the importance of considering HLA alleles and host immune genetics in HIV vaccine trials. The RV144 trial was the first to show efficacy against HIV-1 infection. Subsequently, much effort has been directed towards understanding the mechanisms of protection, including this T-cell based sieve analysis which compared the genetic sequences of viruses isolated from infected vaccine and placebo recipients. Though we hypothesized that the observed sieve effect indicated post-acquisition T-cell selection, we also found that vaccine efficacy was greater for participants who expressed HLA A*02, an allele implicated in the sieve analysis. Though HLA alleles have been associated with disease progression and viral load in HIV-1 infection, these data are the first to suggest the association of a class I HLA allele and vaccine efficacy. While these statistical analyses do not provide mechanistic evidence of protection in RV144, they generate testable hypotheses for the HIV vaccine community and they highlight the importance of assessing the impact of host immune genetics in vaccine-induced immunity and protection.Journal of Virology 05/2014; DOI:10.1128/JVI.01164-14 · 4.65 Impact Factor