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

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 In a yet unpublished study, we showed an altered frequency of B cell subsets in HIV-1 infected children which correlated with anti-HBs Ab titers after vaccination.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.

List of scientific papers

I. Bekele Y, Amu S, Bobosha K, Lantto R, Nilsson A, Endale B, Gebre M, Aseffa A, Rethi B, Howe R, Chiodi F. Impaired Phenotype and Function of T Follicular Helper Cells in HIV-1-Infected Children Receiving ART. Medicine (Baltimore). 2015 Jul; 94(27):e1125.
https://doi.org/10.1097/MD.0000000000001125

II. Bekele Y, Yibeltal D, Bobosha K, Andargie TE, Lemma M, Gebre M, Mekonnen E, Habtewold A, Nilsson A, Aseffa A, Howe R, Chiodi F. T follicular helper cells and antibody response to Hepatitis B virus vaccine in HIV-1 infected children receiving ART. Sci Rep. 2017 Sep 19;7(1):5805.
https://doi.org/10.1038/s41598-017-09165-6

III. Bekele Y, Lantto R, Soeria-Atmadja S, Nasi A, Zazzi M, Vicenti I, Naver L, Nilsson A, Chiodi F. HBV vaccination in HIV-1 infected young adults: a tool to reduce the size of HIV-1 reservoirs? Front Immunol. 2018 Jan 10;8:1966.
https://doi.org/10.3389/fimmu.2017.01966