Downfall of the current antibody correlates of influenza vaccine response in yearly vaccinated subjects: Toward qualitative rather than quantitative assays

George

et al. 2017

Aging

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Combination antiretroviral therapies (cART) can lead to normal life expectancy in HIV-infected persons, and people aged >50 yrs represent the fastest growing HIV group. Although HIV and aging are independently associated with impaired humoral immunity, immune status in people aging with HIV is relatively unexplored. In this study influenza vaccination was used to probe age associated perturbations in the B cell compartment of HIV-negative “healthy controls” (HC) and virologically controlled HIV-infected participants on cART (HIV) (n=124), grouped by age as young (<40 yrs), middle-aged (40-59yrs) or old (≥60 yrs). H1N1 antibody response at d21 post-vaccination correlated inversely with age in both HC and HIV. Immunophenotyping of cryopreserved PBMC demonstrated increased frequencies of double negative B cells and decreased plasmablasts in old compared to young HC. Remarkably, young HIV were different from young HC but similar to old HC in B cell phenotype, influenza specific spontaneous (d7) or memory (d21) antibody secreting cells. We conclude that B cell immune senescence is a prominent phenomenon in young HIV in comparison to young HC, but distinctions between old HIV and old HC are less evident though both groups manifest age-associated B cell dysfunction.

Section: Discussionmentioning

confidence: 99%

Paradoxical aging in HIV: immune senescence of B Cells is most prominent in young age

Rinaldi

George

et al. 2017

Aging

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“…The definitions imposed on influenza vaccinees for responder status, while accepted in the field, can be problematic when individuals have a protective titer at baseline. Higher baseline titers result in lower fold increases following vaccination (48). Thus, by integrating gene expression results with the post-vaccination antibody production rather than fold change we were able to identify features that may be predictive for influenza vaccine responses in HIV-infected individuals.…”

Section: Discussionmentioning

confidence: 99%

Induction of IL21 in Peripheral T Follicular Helper Cells Is an Indicator of Influenza Vaccine Response in a Previously Vaccinated HIV-Infected Pediatric Cohort

Armas

Cotugno

The Journal of Immunology

et al. 2017

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HIV-infected patients of all ages frequently underperform in responsiveness to seasonal influenza vaccination despite virologic control of HIV. Molecular mechanisms governing this impairment as well as predictive biomarkers for responsiveness remain unknown. This study was performed in pre-vaccination samples (T0) of HIV-infected children who received the 2012–2013 seasonal influenza vaccine. Response status was determined based on established criteria of hemagglutination inhibition (HAI) titer; participants with HAI ≥ 1:40 plus ≥ 4-fold increase over T0 at three weeks post-vaccination (T1) were designated as responders. All children had a history of prior influenza vaccinations. At T0, frequencies of CD4 T cell subsets, including peripheral T follicular helper (pTfh) cells which provide help to B cells for developing into Ab secreting cells were similar between responders and non-responders. However, in response to in vitro stimulation with H1N1 antigen, differential gene expression related to pTfh function was observed by Fluidigm high density RT-PCR between responders and non-responders. In responders, H1N1 stimulation at pre-vaccination also resulted in CXCR5 induction (mRNA and protein) in CD4 T cells and IL21 gene induction in pTfh cells that strongly associated with H1N1-specific B cell responses post-vaccination. In contrast, CD4 T cells of non-responders exhibited increased expression of IL2 and STAT5 genes which are known to antagonize pTfh function. These results suggest that the quality of pTfh at the time of immunization are important for influenza vaccine responses and provide a rationale for targeted, ex vivo antigen-driven molecular profiling of purified immune cells to detect predictive biomarkers of vaccine response.

“…The driving question was derived from the observation that current biomarkers of influenza vaccine response (i.e. serum titers) are not fully informative especially in populations with acquired immune deficiencies 25 . Hence, novel correlates of functional memory B cell responses are needed.…”

Section: Discussionmentioning

confidence: 99%

Single Cell Profiling Reveals PTEN Overexpression in Influenza-Specific B cells in Aging HIV-infected individuals on Anti-retroviral Therapy

Armas

et al. 2019

Sci Rep

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Memory B cells (MBC) respond to secondary antigen challenge to protect against infection and to boost immunity following vaccinations. Despite effective treatment, chronic HIV infection disturbs MBCs by reducing numbers and altering functionality due to hyper-activation and increased apoptosis leading to suboptimal antibody responses against common infectious agents. We used single cell gene expression analysis to evaluate antigen-specific memory B cells in peripheral blood of virally-suppressed HIV-infected individuals and healthy controls stratified by serum H1N1 antibody response 3 weeks post-administration of the seasonal trivalent inactivated influenza vaccine. We used a fluorescent probe to isolate influenza H1N1-specific B cells and a multiplexed and targeted RT-PCR approach to measure expression levels of 96 genes involved in B cell activation and function. Gene profiling revealed a 4-gene predictive signature containing the phosphoinositide-3 kinase (PI3K) inhibitor, PTEN , for identifying antigen-specific MBC from HIV-infected individuals compared to healthy controls. Gene co-expression analysis showed that in addition to overexpression of PTEN , there was increased co-expression of type I interferon-associated genes with PTEN on single cell level in HIV compared to controls. This study highlights the persistent defects in MBC from HIV-infected individuals and points to the PI3K signaling pathway as a target for potential immune intervention.