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Pre-vaccination inflammation and B-cell signalling predict age-related hyporesponse to hepatitis B vaccination.

ABSTRACT: Aging is associated with hyporesponse to vaccination, whose mechanisms remain unclear. In this study hepatitis B virus (HBV)-naive older adults received three vaccines, including one against HBV. Here we show, using transcriptional and cytometric profiling of whole blood collected before vaccination, that heightened expression of genes that augment B-cell responses and higher memory B-cell frequencies correlate with stronger responses to HBV vaccine. In contrast, higher levels of inflammatory response transcripts and increased frequencies of pro-inflammatory innate cells correlate with weaker responses to this vaccine. Increased numbers of erythrocytes and the haem-induced response also correlate with poor response to the HBV vaccine. A transcriptomics-based pre-vaccination predictor of response to HBV vaccine is built and validated in distinct sets of older adults. This moderately accurate (area under the curve?65%) but robust signature is supported by flow cytometry and cytokine profiling. This study is the first that identifies baseline predictors and mechanisms of response to the HBV vaccine.

SUBMITTER: Fourati S

PROVIDER: S-EPMC4729923 | biostudies-literature | 2016 Jan

REPOSITORIES: biostudies-literature

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Pre-vaccination inflammation and B-cell signalling predict age-related hyporesponse to hepatitis B vaccination.

Fourati Slim S Cristescu Razvan R Loboda Andrey A Talla Aarthi A Filali Ali A Railkar Radha R Schaeffer Andrea K AK Favre David D Gagnon Dominic D Peretz Yoav Y Wang I-Ming IM Beals Chan R CR Casimiro Danilo R DR Carayannopoulos Leonidas N LN Sékaly Rafick-Pierre RP

Nature communications 20160108

Aging is associated with hyporesponse to vaccination, whose mechanisms remain unclear. In this study hepatitis B virus (HBV)-naive older adults received three vaccines, including one against HBV. Here we show, using transcriptional and cytometric profiling of whole blood collected before vaccination, that heightened expression of genes that augment B-cell responses and higher memory B-cell frequencies correlate with stronger responses to HBV vaccine. In contrast, higher levels of inflammatory re ...[more]

PMID: 26742691

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Project description:Hepatitis B virus is a worldwide leading cause of acute and chronic liver disease including cirrhosis and hepatocellular carcinoma. Effective vaccines have been available since the early '80s and vaccination has proved highly successful in reducing the disease burden, the development of the carrier state and the HB-related morbidity and mortality in the countries where vaccination has been implemented. Neutralizing (protective) antibodies (anti-HBs) induced by vaccination are targeted largely towards the amino acid hydrophilic region, referred to as the common a determinant which is present on the outer protein coat or surface antigen (HBsAg), spanning amino acids 124-149. This provides protection against all HBV genotypes (from A to H) and is responsible for the broad immunity afforded by hepatitis B vaccination. Thus, alterations of residues within this region of the surface antigen may determine conformational changes that can allow replication of the mutated HBV in vaccinated people. An important mutation in the surface antigen region was identified in Italy some 25 years ago in infants born to HBsAg carrier mothers who developed breakthrough infections despite having received HBIG and vaccine at birth. This virus had a point mutation from guanosine to adenosine at nucleotide position 587, resulting in aa substitution from glycine (G) to arginine (R) at position 145 in the a determinant. Since the G145R substitution alters the projecting loop (aa 139-147) of the a determinant, the neutralizing antibodies induced by vaccination are no longer able to recognize the mutated epitope. Beside G145R, other S-gene mutations potentially able to evade neutralizing anti-HBs and infect vaccinated people have been described worldwide. In addition, the emergence of Pol mutants associated with resistance to treatment with nucleos(t)ide analogues can select viruses with crucial changes in the overlapping S-gene, potentially able to alter the S protein immunoreactivity. Thus such mutants have the potential to infect both naïve and immunized people, negatively affecting the efficacy of both the antiviral treatment and the vaccination programs. Despite concern, at present the overall impact of vaccine escapes mutants seems to be low and they do not pose a public health threat or a need to modify the established hepatitis B vaccination programs. The development of novel NAs with a high barrier to resistance is warranted.

Project description:Background:Prevention of infectious diseases is of high priority in the rapidly aging population. Unfortunately, vaccine responses in the elderly are frequently diminished. Timely vaccination of middle-aged adults might improve the immune responses to vaccines, although knowledge on pathogen-specific immune responses and factors affecting these responses, in middle-aged adults is currently limited. We thus investigated the immune responses after vaccination with Zostavax consisting of live-attenuated varicella zoster virus (VZV). Methods:Blood samples were taken pre-, 14?days, 28?days, and 1?year after a primary VZV vaccination (Zostavax) at middle age (N?=?53, 50-65?years of age). VZV-specific IFN?-producing cells were measured by ELISpot, activated T-cells by flow cytometry, antibody levels and cytokine responses by fluorescent bead-based multiplex immunoassays, and whole blood cellular kinetics by TruCOUNT analysis. Results:Robust short-term enhancement of the VZV-specific IFN?-producing cell numbers was observed post-vaccination in the middle-aged adults. Remarkably, long-term enhancement of VZV-specific IFN?-producing cell numbers was induced only in participants with low numbers of VZV-specific pre-vaccination IFN?-producing cells, who were significantly older. These participants also showed enhancement of VZV-specific activated CD4 T-cells, contrary to "exhausted" VZV-specific CD8 T-cells in participants with high numbers of VZV-specific pre-vaccination IFN?-producing cells. Finally, a high CD4/CD8 T-cell ratio was associated with low numbers of pre-vaccination VZV-specific IFN?-producing cells. Conclusion:These results suggest that adults in their early sixties, who showed a high CD4/CD8 T-cell ratio and low numbers of VZV-specific IFN?-producing cells, benefit from VZV vaccination. This provides important knowledge on factors affecting VZV-specific immune responses in middle-aged adults as well as for strategies to strengthen immunity before reaching old age.

Dataset Information

Pre-vaccination inflammation and B-cell signalling predict age-related hyporesponse to hepatitis B vaccination.

Publications

Pre-vaccination inflammation and B-cell signalling predict age-related hyporesponse to hepatitis B vaccination.

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