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Immunocompromised individuals, particularly autologous hematopoietic stem cell transplant (auHSCT) recipients, are at high risk for herpes zoster (HZ). We provide an in-depth description of humoral and cell-mediated immune (CMI) responses by age (protocol-defined) or underlying disease (post-hoc) as well as efficacy by underlying disease (post-hoc) of the adjuvanted recombinant zoster vaccine (RZV) in a randomized observer-blind phase III trial (ZOE-HSCT, NCT01610414). 1846 adult auHSCT recipients were randomized to receive a first dose of either RZV or placebo 50-70 days post-auHSCT, followed by the second dose at 1-2 months (M) later. In cohorts of 114-1721 participants, at 1 M post-second vaccine dose: Anti-gE antibody geometric mean concentrations (GMCs) and median gE-specific CD4[2+] T-cell frequencies (CD4 T cells expressing ≥2 of four assessed activation markers) were similar between 18-49 and ≥50-year-olds. Despite lower anti-gE antibody GMCs in non-Hodgkin B-cell lymphoma (NHBCL) patients, CD4[2+] T-cell frequencies were similar between NHBCL and other underlying diseases. The proportion of polyfunctional CD4 T cells increased over time, accounting for 79.6% of gE-specific CD4 T cells at 24 M post-dose two. Vaccine efficacy against HZ ranged between 42.5% and 82.5% across underlying diseases and was statistically significant in NHBCL and multiple myeloma patients. In conclusion, two RZV doses administered early post-auHSCT induced robust, persistent, and polyfunctional gE-specific immune responses. Efficacy against HZ was also high in NHBCL patients despite the lower humoral response.

Background In the previous (parent) study, 2 doses of different formulations of an investigational vaccine against respiratory syncytial virus (RSVPreF3 OA) were well tolerated and immunogenic in older adults. This multicenter phase 2b extension study assessed safety and immunogenicity of a revaccination (third) dose of the 120 μg RSVPreF3-AS01E formulation. Methods In total, 122 older adults (60–80 years), previously vaccinated with 2 doses of RSVPreF3-AS01E formulations (containing 30, 60, or 120 μg RSVPreF3 antigen), received an additional 120 μg RSVPreF3-AS01E dose 18 months after dose 2. Vaccine safety was evaluated in all participants up to 6 months and immunogenicity in participants who received 120 μg RSVPreF3-AS01E doses until 1 month after dose 3. Results Similar to the parent study, mostly mild-to-moderate solicited adverse events and no vaccine-related serious adverse events or potential immune-mediated disorders were reported. Neutralizing titers and cell-mediated immune responses persisted for 18 months after 2-dose vaccination. Dose 3 increased RSV-specific neutralizing titers against RSV-A and RSV-B and median CD4+ T-cell frequencies. After dose 3, RSV-specific neutralizing titers but not CD4+ T-cell frequencies were below levels detected 1 month after dose 1. Conclusions Revaccination with 120 μg RSVPreF3-AS01E 18 months after dose 2 is well tolerated and immunogenic in older adults. Clinical Trials Registration NCT04657198; EudraCT, 2020-000692-21. [ABSTRACT FROM AUTHOR]

Background The aim of this study was to investigate safety and immunogenicity of vaccine formulations against respiratory syncytial virus (RSV) containing the stabilized prefusion conformation of RSV fusion protein (RSVPreF3). Methods This phase 1/2, randomized controlled, observer-blind study enrolled 48 young adults (YAs; aged 18–40 years) and 1005 older adults (OAs; aged 60–80 years) between January and August 2019. Participants were randomized into equally sized groups to receive 2 doses of unadjuvanted (YAs and OAs) or AS01-adjuvanted (OAs) vaccine or placebo 2 months apart. Vaccine safety and immunogenicity were assessed until 1 month (YAs) or 12 months (OAs) after second vaccination. Results The RSVPreF3 vaccines boosted humoral (RSVPreF3-specific immunoglobulin G [IgG] and RSV-A neutralizing antibody) responses, which increased in an antigen concentration-dependent manner and were highest after dose 1. Compared to prevaccination, the geometric mean frequencies of polyfunctional CD4+ T cells increased after each dose and were significantly higher in adjuvanted than unadjuvanted vaccinees. Postvaccination immune responses persisted until end of follow-up. Solicited adverse events were mostly mild to moderate and transient. Despite a higher observed reactogenicity of AS01-containing vaccines, no safety concerns were identified for any assessed formulation. Conclusions Based on safety and immunogenicity profiles, the AS01E-adjuvanted vaccine containing 120 μg of RSVPreF3 was selected for further clinical development. Clinical Trials Registration NCT03814590. [ABSTRACT FROM AUTHOR]

Dok1 is an abundant Ras-GTPase-activating protein-associated tyrosine kinase substrate that negatively regulates cell growth and promotes migration. We now find that I[kappa]B kinase [beta] (IKK[beta]) associated with and phosphorylated Dok1 in human epithelial cells and B lymphocytes. IKK[beta] phosphorylation of Dok1 depended on Dok1 [S.sub.439], [S.sub.443], [S.sub.446], and [S.sub.450]. Recombinant IKK[beta] also phosphorylated Dok1 or Dok1 amino acids 430-481 in vitro. TNF-[alpha], IL-1, [gamma] radiation, or IKK[beta] overexpression phosphorylated Dok1 [S.sub.443], [S.sub.446], and [S.sub.450] in vivo, as detected with Dok1 phospho-S site-specific antisera. Moreover, Dok1 with [S.sub.439], [S.sub.443], [S.sub.446], and [S.sub.450] mutated to A was not phosphorylated by IKK[beta] in vivo. Surprisingly, mutant Dok1 [A.sub.439] [A.sub.443], [A.sub.446], and [A.sub.450] differed from wild-type Dok1 in not inhibiting platelet-derived growth factor-induced extracellular signal-regulated kinase 1/2 phosphorylation or cell growth. Mutant Dok1 [A.sub.439], [A.sub.443], [A.sub.446], and [A.sub.450] also did not promote cell motility, whereas wild-type Dok1 promoted cell motility, and Dok1 [E.sub.439], [E.sub.443], [E.sub.446], and [E.sub.450] further enhanced cell motility. These data indicate that IKK[beta] phosphorylates Dok1 [S.sub.439][S.sub.443] and [S.sub.446][S.sub.450] after TNF-[alpha], IL-1, or [gamma]-radiation and implicate the critical Dok1 serines in Dok1 effects after tyrosine kinase activation. NF-[kappa]B | serine phosphorylation | cell migration

Background: The adjuvanted recombinant zoster vaccine (RZV) is highly immunogenic and efficacious in adults ≥50 years of age. We evaluated (1) long-term immunogenicity of an initial 2-dose RZV schedule, by following up adults vaccinated at ≥60 years of age and by modeling, and (2) immunogenicity of 2 additional doses administered 10 years after initial vaccination.Methods: Persistence of humoral and cell-mediated immune (CMI) responses to 2 initial RZV doses was assessed through 10 years after initial vaccination, and modeled through 20 years using a Piecewise, Power law and Fraser model. The immunogenicity and safety of 2 additional RZV doses were also evaluated.Results: Seventy adults were enrolled. Ten years after initial vaccination, humoral and CMI responses were approximately 6-fold and 3.5-fold, respectively, above those before the initial vaccination levels. Predicted immune persistence through 20 years after initial vaccination was similar across the 3 models. Sixty-two participants (mean age [standard deviation], 82.6 [4.4] years) received ≥1 additional RZV dose. Strong anamnestic humoral and CMI responses were elicited by 1 additional dose, without further increases after a second additional dose.Conclusions: Immune responses to an initial 2-dose RZV course persisted for many years in older adults. Strong anamnestic immune responses can be induced by additional dosing 10 years after the initial 2-dose course.Clinical Trials Registration: NCT02735915. [ABSTRACT FROM AUTHOR]

Background: Efficacy of the live-attenuated herpes zoster (HZ) vaccine (ZVL) wanes substantially over time. We evaluated immunogenicity and safety of the adjuvanted recombinant zoster vaccine (RZV) in previous ZVL recipients.Methods: Adults aged ≥65 years who were previously vaccinated with ZVL ≥5 years earlier (n = 215) were group-matched with ZVL-naive individuals (n = 215) and vaccinated with RZV. Glycoprotein E (gE)-specific humoral and cell-mediated immune responses and the correlation between them, polyfunctional gE-specific CD4 T-cell responses, safety, and confirmed HZ cases were assessed.Results: Through 12 months after dose 2, anti-gE antibody concentrations, gE-specific CD4 T-cell frequencies, and activation marker profiles were similar between groups. Safety outcomes were also similar. No HZ episodes were confirmed.Conclusions: RZV induced strong humoral and polyfunctional cell-mediated immune responses that persisted above prevaccination levels through 1 year after dose 2 in adults aged ≥65 years irrespective of previous ZVL vaccination. The RZV safety profile was not affected.Clinical Trials Registration: NCT02581410. [ABSTRACT FROM AUTHOR]

Abstract Background The differentiation of CD8+ T lymphocytes following priming of naïve cells is central in the establishment of the adaptive immune response. Yet, the molecular events underlying this process are not fully understood. MicroRNAs have been recently shown to play a key role in the regulation of haematopoiesis in mouse, but their implication in peripheral lymphocyte differentiation in humans remains largely unknown. Methods In order to explore the potential implication of microRNAs in CD8+ T cell differentiation in humans, microRNA expression profiles were analysed using microarrays and quantitative PCR in several human CD8+ T cell subsets defining the major steps of the T cell differentiation pathway. Results We found expression of a limited set of microRNAs, including the miR-17~92 cluster. Moreover, we reveal the existence of differentiation-associated regulation of specific microRNAs. When compared to naive cells, miR-21 and miR-155 were indeed found upregulated upon differentiation to effector cells, while expression of the miR-17~92 cluster tended to concomitantly decrease. Conclusions This study establishes for the first time in a large panel of individuals the existence of differentiation associated regulation of microRNA expression in human CD8+ T lymphocytes in vivo, which is likely to impact on specific cellular functions.

Background: Non‐neutralizing antibodies inducing complement‐dependent lysis (CDL) and antibody‐dependent cell‐mediated cytotoxicity (ADCC) activity may contribute to protection against influenza infection. We investigated CDL and ADCC responses in healthy adults randomized to receive either non‐adjuvanted or AS03‐adjuvanted monovalent A(H1N1)pdm09 vaccine (containing 15 µg/3.75 μg of hemagglutinin, respectively) on a 2‐dose schedule 21 days apart. Methods: We conducted an exploratory analysis of a subset of 106 subjects having no prior history of A(H1N1)pdm09 infection or seasonal influenza vaccination enrolled in a previously reported study (NCT00985673). Antibody responses against the homologous A/California/7/2009 (H1N1) vaccine strain and a related A/Brisbane/59/2007 (H1N1) seasonal influenza strain were analyzed up to Day 42. Results: Baseline seropositivity determined with hemagglutination inhibition (HI), CDL and ADCC antibody titers against viral strains was high; A/California/7/2009 (HI [40.4‐48.1%]; CDL [34.6‐36.0%]; ADCC [92.1‐92.3%]); A/Brisbane/59/2007 (HI [73.1‐88.9%]; CDL [38.0‐42.0%]; ADCC [86.8‐97.0%]). CDL seropositivity increased following vaccination with both adjuvanted and non‐adjuvanted formulations (A/California/7/2009 [95.9‐100%]; A/Brisbane/59/2007 [75.5‐79.6%]). At Day 21, increases in CDL and ADCC antibody geometric mean titers against both strains were observed for both formulations. After 2 doses of AS03‐adjuvanted vaccine, vaccine responses of 95.8% (≥9‐fold increase from baseline in CDL titers) and 34.3% (≥16‐fold increase from baseline in ADCC titers) were seen against A/California/7/2009; and 22.4% and 42.9%, respectively, against A/Brisbane/59/2007. Vaccine responses after 2 doses of the non‐adjuvanted vaccine were broadly similar. Conclusions: Broadly comparable non‐neutralizing immune responses were observed following vaccination with non‐adjuvanted and AS03‐adjuvanted A(H1N1)pdm09 formulations; including activity against a related vaccine strain. [ABSTRACT FROM AUTHOR]

The duration of protection after hepatitis B vaccination is not exactly known. This phase IV study evaluated antibody persistence and immune memory 20‐30 years after adult immunization with recombinant hepatitis B vaccine (HBsAg vaccine, Engerix‐B) in routine clinical practice. Men and women 40‐60 years old, with documented evidence of vaccination with three or four HBsAg vaccine doses 20‐30 years earlier and without subsequent booster, were enrolled and received HBsAg vaccine as challenge dose. HBsAg‐specific antibodies (anti‐HBs) and frequencies of HBsAg‐specific circulating memory B cells and CD4+ T cells expressing combinations of activation markers (CD40L, IL2, IFNγ, TNFα) were measured prechallenge, 7 and 30 days postchallenge. Of 101 participants in the according‐to‐protocol cohort for immunogenicity, 90.1% had anti‐HBs concentrations ≥ 10 mIU/mL prechallenge administration; 84.2% and 100% mounted an anamnestic response 7 and 30 days postchallenge, respectively. HBsAg‐specific memory B and CD4+ T cells expressing at least two activation markers were low prechallenge and increased markedly postchallenge. These results suggest sustained immune memory and long‐term protection 20‐30 years after a complete primary HBsAg vaccination course during adulthood, in line with current recommendations that a booster is not needed in fully vaccinated immunocompetent adults. [ABSTRACT FROM AUTHOR]

Background: The adjuvanted recombinant zoster vaccine (RZV) has demonstrated >90% efficacy against herpes zoster in adults ≥50 years of age and 68% efficacy in autologous hematopoietic stem cell transplant recipients ≥18 years of age. We report the immunogenicity and safety of RZV administered to patients with solid tumors (STs) before or at the start of a chemotherapy cycle. Method: In this phase 2/3 observer‐blind, multicenter study (NCT01798056), patients with STs who were ≥18 years of age were randomized (1:1) to receive 2 doses of RZV or placebo 1‐2 months apart and stratified (4:1) according to the timing of the first dose with respect to the start of a chemotherapy cycle (first vaccination 8‐30 days before the start or at the start [±1 day] of a chemotherapy cycle). Anti‐glycoprotein E (gE) antibody concentrations, gE‐specific CD4+ T cell frequencies, and vaccine response rates (VRRs) were assessed 1 month after dose 1 and 1 and 12 months after dose 2. Reactogenicity and safety were assessed in the total vaccinated cohort through 12 months after dose 2. Results: There were 232 participants in the total vaccinated cohort, 185 participants in the according‐to‐protocol cohort for humoral immunogenicity, and 58 participants in the according‐to‐protocol cohort for cell‐mediated immunogenicity. Postvaccination anti‐gE antibody concentrations, gE‐specific CD4+ T cell frequencies and VRRs were higher in RZV recipients than in placebo recipients. Solicited adverse events (AEs) were more frequent among RZV recipients than placebo recipients. Incidence of unsolicited AEs, serious AEs, fatalities, and potential immune‐mediated diseases were similar between RZV and placebo recipients. Conclusion: RZV was immunogenic in patients with STs receiving immunosuppressive chemotherapies. Humoral and cell‐mediated immune responses persisted 1 year after vaccination. No safety concerns were identified. In patients with solid tumors treated with immunosuppressive chemotherapies, the adjuvanted recombinant zoster vaccine (RZV) was immunogenic and immunogenicity persisted through 1 year after vaccination. RZV was well tolerated, and no safety concerns were identified. [ABSTRACT FROM AUTHOR]