Impaired response to HBV vaccination in HIV-1 infected children : immunopathological mechanisms

Sammanfattning: HBV vaccination prevents HBV infection and related liver cancer. Immunological dysfunctions of Tfh and B cells in HIV-1 infected individuals may affect the response to HBV vaccine. The general objective of this thesis was to elucidate HBV vaccine response in HIV-1 infected children receiving ART, to assess functional and phenotypic properties of pTfh cells in HBV vaccinated children and to study whether HBV vaccination may have a role in reducing the size of HIV-1 reservoirs. In paper I, we showed reduced frequencies of pTfh cells in HIV-1 infected children compared to healthy controls and of pTfh cells expressing the co-stimulatory molecules ICOS and PD1, important to mediate the interaction of Tfh cells with B cells. The frequency of IL-4 expressing pTfh cells and of resting memory B cells was also lower in infected children; on the contrary, an expansion of exhausted memory B cells was detected in this group. In paper II, all children who received HBV vaccination, except four, displayed a strong vaccine response at 1 month post-vaccination. Lower plasma levels of anti-HBs antibodies (Abs) were measured in HIV-1 infected children compared to controls at 1 month and 6 months post-vaccination. HIV-1 infected children had elevated plasma CXCL13 levels compared to controls at all time points; changes in plasma CXCL13 concentration were however not observed following vaccination. As the functional and phenotypic properties of pTfh cells were similar in both groups pre- and postvaccination, alterations in pTfh properties could not explain the reduced vaccine response in HIV-1 infected children. In a yet unpublished study, we showed an altered frequency of B cell subsets in HIV-1 infected children which correlated with anti-HBs Ab titers after vaccination. In paper III, the number of HIV-1 DNA copies in PBMCs was unchanged after vaccination with a combined HBV and HAV vaccine in HIV-1 infected children; however, 54% of these individuals showed a decline in the size of HIV-1 DNA reservoir after vaccination. The change was most likely related to vaccination since the children were on ART for a median of 7.2 years and had therefore likely reached a plateau phase for HIV-1 DNA decay after ART initiation. EM CD8+ T cells were the stronger predictors of the change in HIV-1 DNA copies using multivariate analysis. In conclusion, three doses of accelerated HBV vaccination induced high anti-HBs Abs in both HIV-1 infected and control children. A rapid decline of anti-HBs Abs in plasma after 6 months from vaccination suggests the need of an additional booster dose for HBV vaccine. The role of HBV vaccination in reducing HIV-1 DNA reservoirs should be investigated further.