What causes vaccination failure and which new therapies are possible?

What is this research project about?

non-responder muscle mapping

What is this research project about?

Hepatitis B Virus (HBV) infection often causes chronic infection, which may lead to liver cirrhosis that can progress to hepatocellular carcinoma. HBV vaccines are considered highly efficacious and are successfully applied worldwide. However, approximately 5% of HBV vaccinated individuals do not mount protective antibody responses after vaccination (non-responders). Previous studies revealed reduced responsiveness to influenza virus vaccination in the elderly. In contrast, HBV vaccination non-responsiveness cannot be explained by increasing age as also young adults are affected. Consequently, factors causing non-responsiveness are largely unclear.

What’s the current status?

It has been observed that non-responders mostly show an overall normal immunoexcitability and normal responses against many other vaccines. So far, only few molecular parameters have been identified that may play a role in conferring the non-responder status. Different genetic components of the innate and adaptive immune system were discussed to be associated with the phenomenon. Multiple Genome Wide Association Studies (GWAS) claimed that certain genetic factors predispose individuals to HBV vaccination failure. The conclusions of the previous studies range from antigen presentation defects to absence of certain antigen-specific T cells. However, a comprehensive model explaining the phenomenon of HBV vaccination non-responsiveness and biomarkers that allow identification of potential non-responders has not been formulated. Accordingly, no vaccination regimen has been developed that would allow successful vaccination of non-responders. This creates challenges particularly for health care workers who are in frequent contact with patients and therefore are recommended to be vaccinated against HBV. Additionally, it is not clear whether those relatively few individuals who develop chronic infection after HBV exposure during adulthood are also HBV vaccination non-responders.
Even though virus propagation can be inhibited by antiviral therapy, HBV infection cannot be eliminated from chronically infected patients.

What are the project goals?

Currently, we are building up a HBV vaccination non-responder cohort. This cohort will be the basis for studying causes of non-responsiveness in single individuals. This will be performed by deep immunoprofiling of peripheral immune cells at different time points after HBV vaccination as well as whole genome sequencing. Furthermore, cytokine responses induced upon in vitro stimulation of PBMCs from responders and non-responders will be analyzed.
The objective is to generate a comprehensive model of HBV vaccination non-responsiveness. Based on this knowledge, improved vaccination schemes for HBV vaccination non-responders as well as innovative vaccination strategies will be developed. To this end, new HBV vaccines will be tested in preclinical assays. Additionally, besides determining genes responsible for non-responsiveness, we strive towards a better understanding of how protective immunity against HBV is induced. In particular, we will address whether the HBV vaccination non-responder status favors for the development of chronic HBV infection. Such information could be crucial for developing better treatment strategies of chronically infected people and might open new doors for the concerned patients and doctors. An improved understanding of HBV-induced immune responses has implications on the Stop-NA study.

How do we get there?

Together with the Occupational Health Physicians of the MHH, we are building up cohorts of HBV vaccination responders and non-responders, which constitute an essential element for research towards the molecular basis of HBV non-responsiveness. Currently, first immunomonitoring studies in HBV vaccinated responders and non-responders are being carried out. Additionally, whole genome sequencing and HLA-typing is being performed to identify genetic characteristics associated with non-responsiveness.

Projectleaders

Project title: Non-responsiveness to hepatitis B virus (HBV) vaccination

Prof. Dr. Ulrich Kalinke

Projekte: A4, B9

 
  Institut für Experimentelle Infektionsforschung
Helmholtz-Zentrum für Infektionsforschung (HZI)
  TWINCORE, Zentrum für Experimentelle und Klinische Infektionsforschung
Feodor-Lynen-Str. 7
30625 Hannover
  +49 511 220027-112
  +49 511 220027-186
 
  Ulrich.Kalinke
@twincore.de
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Prof. Dr. Markus Cornberg

Projekte: B8, B9, B10

 
  Klinik für Gastroenterologie, Hepatologie und Endokrinologie, Medizinische Hochschule Hannover
  Carl-Neuberg-Str. 1
30625 Hannover
 
 
 
  Cornberg.Markus
@mh-hannover.de
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Prof. Dr. Immo Prinz

Projekte: B5, B8, B9

 
  Institut für Immunologie , Medizinische Hochschule Hannover
  Carl-Neuberg-Str. 1
30625 Hannover
  +49 511 532-9739
  +49 511 532-9722
 
  Prinz.Immo
@mh-hannover.de
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Prof. Dr. Reinhold Förster

Projekte: B5, B9, C2

  Leiter
  Institut für Immunologie, Medizinische Hochschule Hannover
  Carl-Neuberg-Str. 1
30625 Hannover
  +49 511 532-9721
  +49 511 532-9722
 
  Foerster.Reinhold
@mh-hannover.de
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Prof. Dr. Luka Čičin-Šain

Projekte: B6, B9

  Leiter
  Forschungsgruppe Immunalterung und chronische Infektionen, Helmholtz-Zentrum für Infektionsforschunge (HZI)
  Braunschweig
  +49 531 6181-4616
  +49 531 6181-4616
 
  Luka.Cicin-Sain
@helmholtz-hzi.de
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Reply to: “Lack of Kupffer cell depletion in diethylnitrosamine-induced hepatic inflammation”. Borst K, Graalmann T, Kalinke U. J Hepatol. 2019 Apr;70(4):815-816. doi: 10.1016/j.jhep.2018.12.034. Epub 2019 Feb 1. No abstract available.

Reply to: “Lack of Kupffer cell depletion in diethylnitrosamine-induced hepatic inflammation”. Borst K, Graalmann T, Kalinke U. J Hepatol. 2019 Apr;70(4):815-816. doi: 10.1016/j.jhep.2018.12.034. Epub 2019 Feb 1. No abstract available.

Project B9
Publications