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Summary Background The seroprotection rate (SPR) of hepatitis B vaccination in adults is suboptimal. The aim of this study was to compare the SPR of a tri-antigenic hepatitis B vaccine (TAV), with a mono-antigenic vaccine (MAV) in adults of all ages. Methods This was a multicentre, double-blind, phase 3, randomised controlled trial (PROTECT) comparing the immunogenicity and safety of TAV with MAV in 28 community and hospital sites in the USA, Finland, Canada, and Belgium. Adults (aged ≥18 years) seronegative for hepatitis B virus (HBV), including those with well-controlled common chronic conditions, were randomly assigned (1:1) and stratified by study centre and age according to a web-based permuted blocked randomisation. Participants received either TAV or MAV which were administered as an intramuscular dose (1 mL) of TAV (10 μg; Sci-B-Vac, VBI Vaccines [SciVac, Rehovot, Israel]) or MAV (20 μg; Engerix-B [GlaxoSmithKline Biologicals, Rixensart, Belgium]) on days 0, 28, and 168 with six study visits and 24 weeks of follow-up after the third vaccination. Participants, investigators, and those assessing outcomes were masked to group assignment. The co-primary outcomes were to show non-inferiority of the SPRs 4 weeks after the third vaccination with TAV versus MAV in adults aged 18 years and older, as well as superiority in adults aged 45 years and older. SPR was defined as the percentage of participants attaining anti-HBs titres of 10 mIU/mL or higher. Non-inferiority of TAV to MAV was concluded if the lower limit of the 95% CI for the between-group difference was greater than −5%. Non-inferiority was assessed in the per-protocol set of participants (aged ≥18 years) and superiority was assessed in all participants (aged ≥45 years) who received at least one vaccination and had at least one evaluable immunogenicity sample after baseline (full analysis set). Safety analyses were a secondary outcome and included all participants who received at least one injection. This trial is registered at Clinicaltrials.gov ( NCT03393754 ) and EudraCT (2017–001819–36) and is closed to new participants. Findings Between Dec 13, 2017, and April 8, 2019, 1607 participants (796 allocated to TAV and 811 allocated to MAV) were randomly assigned and distributed across age cohorts of 18–44 years (299 of 1607; 18·6%), 45–64 years (716 of 1607; 44·6%), and 65 years and older (592 of 1607; 36·8%). In participants aged 18 years and older, SPR was 91·4% (656 of 718) in the TAV group versus 76·5% (553 of 723) in the MAV group (difference 14·9%, 95% CI 11·2–18·6), showing non-inferiority in the per-protocol set. In participants aged 45 years and older, SPR was 89·4% (559 of 625) in the TAV group versus 73·1% (458 of 627) in the MAV group (difference 16·4%, 95% CI 12·2–20·7), showing superiority in the full analysis set. TAV was associated with higher rates of mild or moderate injection site pain (63·2% [503 of 796] in TAV vs 36·3% [294 of 811] in MAV), tenderness (60·8% [484 of 796] in TAV vs 34·8% [282 of 811] in MAV), and myalgia (34·7% [276 of 796] vs 24·3% [197 of 811] in MAV). Otherwise, the safety profile of TAV was similar to that of MAV. Interpretation The safety and efficacy of TAV shows its usefulness for the prevention of HBV infection in adults, including those with stable and controlled chronic conditions. Funding VBI Vaccines.

Background Inactivated influenza vaccines (IV) efficacy is variable and sometimes poor. In this phase 1 trial the safety and immunogenicity of a novel nanoparticle adjuvant (Papaya Mosaic Virus (PapMV or PAL) at different dose levels combined with inactivated trivalent IV (TIV; FLUVIRAL® 2013–2014, GSK, Kirkland PQ) was assessed. Nonpathogenic in mammals, PAL is recognized as a pathogen-associated molecular pattern (PAMP) which stimulates innate, cell-mediated immunity (CMI) and adaptive immunity in naïve mice through activation of toll like receptor 7 and 8. Methods Healthy persons 18–50 years of age were randomized to one of 6 study groups: 30 µg, 60 µg, 120 µg or 240 µg of PAL with 0.25 mL TIV, 240 µg of PAL with 0.125 mL TIV, or control (0.5 mL TIV). Solicited local and general adverse events (AE) were collected Day (D)0 to 6, unsolicited AE to D28, and serious AE to D1095. Hemagglutination-inhibition assays (HI), antibody to Influenza A virus nucleoprotein (NP), and peripheral blood mononuclear cells (PBMC) for measurement of interferon-gamma (IFNg) ELISPOT (response to PepMix influenza A H2N2 Ann Arbour NP, MP1, and an influenza peptide pool), granzyme B, and IFNg:IL:10 ratio were collected on D0, 7, 28, 120, and 180. Results The most common solicited AEs were transient mild-to-moderate local pain (62.5%–87.5% of participants/group), drowsiness (≤37.5% of participants/group) and generalized muscle aches (12.5–50% of participants/group). There was one unrelated SAE. All participants had HI and anti-NP titers at baseline. HI GMTs increased at D28 post vaccine in most groups (Figure 1) and waned over time. HI fold Ab (Far) responses to TIV strains were poor in all groups (≤37.5% of participants/group had 4-Far to any strain). CMI results were consistent with humoral responses. Conclusion The PAL adjuvant in doses of 30 to 240µg combined with reduced TIV dosages was safe with no signals up to 3 years after vaccine. Reduced doses of TIV co-presented with 240 µg PAL had similar HI GMTs as TIV. The CMI results suggest that the assessment of PAL efficacy on TIV immunization would have to be conducted in an influenza naïve population. Disclosures Scott Halperin, MD, GlaxoSmithKline: Ad hoc advisory boards, Other Financial or Material Support, Research Grant; Janssen Pharm: Research Grant; sanofi pasteur: Ad hoc advisory boards, Other Financial or Material Support, Research Grant.

A proprietary extract from North American ginseng (Panax quinquefolium), COLD-FX ® (CVT-E002), has been found to be effective in the prevention of upper respiratory infections in a number of different groups including institutionalized seniors, community-dwelling seniors and healthy adults. These effects of COLD-FX are thought to be mediated by its ability to stimulate both the natural and acquired immune systems. Excessive exercise has been known to induce immune suppression and to increase the susceptibility for contracting recurrent upper respiratory tract infections. The purpose of the present study, therefore, was to determine if COLD-FX supplementation to players of National Hockey League caliber would be effective in altering the response of their leukocytes to influenza virus ex vivo. Periph- eral blood leukocytes (PBLs) were isolated from 2 groups of NHL players and immediately cultured for 2.5 days in the presence of 3 strains of influenza virus. One group (n=18) had been taking COLD-FX (400 mg/day) for 30 days, while the control group (n=19) was supplement free. Cultured PBLs isolated from those taking COLD-FX (400 mg/day) and stimulated with 3 strains of influenza virus released more TNF-α and IL-2, however, moderated granzyme-B release. This indicates that COLD-FX supplementation enhanced cell-mediated immune response of PBLs to influenza viruses and likely moderated the levels of cytotoxic T-cell effector molecules, sustained release of which may lead to autoimmune conditions. Additional studies on elite athletes, whose immune systems may be compromised, are warranted.

Frailty is a still-evolving concept of a complex phenomenon. There are several algorithms and strategies for assessing frailty syndrome, but currently, no universally accepted definition or measurement protocol has been determined. Consequently, the biological cause(s) of frailty are also poorly defined. Much circumstantial experimental data point to the dysregulation of several key physiological systems, including the neuroendocrine, musculoskeletal, metabolic and immune/inflammatory systems, resulting from alterations in functional reserves. Immune dysregulation and inflammation as causes of frailty have gained some support from the results of longitudinal studies, but a true causal relationship has not been established. This chapter will describe the immune/inflammatory alterations found in frailty and their putative causal relationships with this state.

Evaluate five different recruitment strategies for their capacity to enroll and retain both healthy and vulnerable older adults as part of a multiyear influenza vaccination study.We analyzed recruitment methods and other characteristics ofindividuals who participated in or were considered for five sequential one-year studies.Of 940 screened individuals, 820 met eligibility criteria with 795 enrolled over the five-year study (307 primary participants). Among these enrollees, 63.4% were female and 95.5% were white, with mean ages of 75.3 (older group) and 30.6 (younger group). More than a half (56.7%) of the participants enrolled more than once, participating an average of 2.56 (SD = 1.6) times. The majority (81.9%) of individuals recruited each year were return participants identified during earlier recruitments. Physician referrals resulted in only 5.3% recruitments.Recruitment and retention of study subjects, especially older adults, was facilitated by the existence ofa database listing past participants.

To answer frequently asked questions surrounding the use of the new herpes zoster (HZ) vaccine.Published results of clinical trials and other studies, recommendations from the Canadian National Advisory Committee on Immunization, and the US Advisory Committee on Immunization Practices; data were also obtained from the vaccine's Health Canada-approved product monograph.Herpes zoster results from reactivation of the varicella-zoster virus; postherpetic neuralgia (PHN) is its most common and serious complication. The incidence of PHN after HZ is directly related to age, with 50% of affected individuals older than 60 years experiencing persistent and unrelieved pain. The live virus HZ vaccine reduces the incidence of HZ by about 50% and the occurrence of PHN by two-thirds, with vaccinated individuals experiencing attenuated or shortened symptoms. The vaccine is contraindicated in many immunocompromised patients and might not be effective in patients taking antiviral medications active against the HZ virus. Physicians should be aware of the different recommendations for these groups.The HZ vaccine is a safe and effective preventive measure for reducing the overall burden and severity of HZ in older adults. The vaccine appears to be cost-effective when administered to adults aged 60 years and older.

There are accumulated evidences show that many age related immune defects are attributed to declined T lymphocyte helper and effector function involved CD4+ and CD8+ T cells. The lower efficacy of current influenza vaccine in aged people and other high risk population such as hospitalized patients cause need to develop more effective vaccine adjuvants which can significantly enhance vaccine mediated T cell immune response in response to influenza virus. We investigated the influenza live virus and vaccine induced pre-inflammatory cytokine secretion profile in human PBMCs, evaluated the effects of several key cytokines on vaccine induced T cell homeostasis. Our data show that IL-2, IL-6 and IL-17A can affect the flu vaccine induced human T cell homeostasis by enhancing the naïve T cell proliferation and differentiation as well as driving memory into effector CD8+ T cells through classic cytokine signaling transduction pathway. Our results will be able to help evaluate the efficacy of future possible vaccine adjuvant for developing better influenza vaccine compounds.

An age-related decline in cytolytic activity has been described in CD8+ T cells and we have shown that the poor CD8+ effector T cell response to influenza A/H3N2 challenge is due to a decline in the proportion and function of these cytolytic T lymphocytes (CTL). Here we report that there is a significant decline in the levels of many cytokines and chemokines including IFN-γ, IL-2, IL-10 and IL-17A, but increased IL-4 and IL-6, following influenza-stimulation of PBMCs from vaccinated older compared to young adults. We find that addition of exogenous IL-2 acts to maintain naïve CD8+ T cells survival and strongly enhances the proliferation of existing memory effector CD8+ T cells in response to live influenza virus challenge. In addition exogenous IL-6 plays a similar but lesser role in the proliferative response when compared to IL-2. Our data show that only exogenous IL-4 enhances the proliferative capacity of the CD8+ T cells and particularly the promotion of naïve CD8+ T cell differentiation. However, IL-4 treatment has no effect on the accumulation of CD8+ effector T cells in response to influenza challenge. These results suggest mechanisms that might be exploited to develop influenza vaccines with improved efficacy in older adults.

Little is known about normal human aging and its effects on the function of T cells specific for acutely infecting pathogens. To address this issue, we conducted a multicolour flow cytometry study of older persons’ responses to influenza virus challenge ex vivo. Young and elderly donors were recruited in the fall of 2008. PBMCs were stained directly ex vivo or stimulated with A/Puerto Rico/8/34 (PR8) for 18 hours and assessed for functional markers. The data show that most donors have pre-existing influenza-specific T cells (measured by IFNγ) that are reactivated by PR8, although older donors had smaller pre-vaccination populations of flu-responsive T cells. Effector cells identified upon restimulation with influenza displayed a more terminally differentiated phenotype in older compared to younger adults. This phenotype did not change post-vaccination with trivalent inactivated vaccine, which lacks significant internal viral proteins and is a poor inducer of CD8 T cell responses. For HLA-A2+ donors, it was determined by tetramer staining that elderly influenza-specific CD8 T cells express higher levels of senescence markers KLRG1 and CD57 compared to young controls. Our study shows that influenza specific effector and memory T cells from older individuals show signs of terminal differentiation and senescence. Thus, as has been shown for persistent life-long infections, memory CD8 T cells to an acutely infecting pathogen show signs of deterioration with age.

Age-dependent changes in the cellular immune response have been mainly described in CD8+ T cells, with relative sparing of CD4+ T cells. However, a potential compensatory role for CD4+ T cells in the presence of severe effector functional defects in CD8+ T cells in older adults has not been described. We show that effector memory (CD45RA-CCR7-) and effector (CD45RA+CCR7-) CD8+ T-cell subsets in older compared to young adult PBMC responding to influenza A/H3N2 challenge have limited cytolytic activity against influenza-infected autologous targets. In contrast, effector CD4+ T-cell subsets in older adults demonstrate cytolytic activity in response to influenza challenge and share similar phenotypic and functional characteristics with virus-specific T cell subsets from young adults. Furthermore, we identified influenza virus-specific CD45RA+CCR7-CD25+CD127+ T-cell subsets in both CD4+ and CD8+ T cells , observed the limited effector T cell reponse in healthy young adults who received seasonal influenza split-virus vaccine. We conclude that CD4+ T cells may provide a compensatory response to influenza infection when CD8+ T cells become compromised during the aging process.