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Older adults are at high risk of major acute cardiovascular events (MACE) linked to influenza illness andpreventable by influenza vaccination. It is unknown whether high-dose vaccine might incrementally reduce the risk of MACE.We conducted a post-hoc analysis of data collected from a pragmatic cluster randomized study of 823 nursing homes (NH) randomized to standard-dose (SD) or high-dose (HD) influenza vaccine in the 2013-14 season. Adults age 65 year or older who are Medicare-enrolled long-stay residents were included in the analysis.There were no statistically significant differences in hospitalization for MACE, acute coronary syndromes (ACS), stroke or heart failure between the HD and SD arms. However, in the fee-for-service group, participants in the HD arm had significantly decreased risk of hospitalization for respiratory problems, which was not observed in the Medicare Advantage group.High-dose influenza vaccine was not shown to be incrementally protective against MACE relative to standard-dose vaccine.

BackgroundLatent cytomegalovirus (CMV) infection is immunomodulatory and could affect mRNA vaccine responsiveness. We sought to determine the association of CMV serostatus and prior severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection with antibody (Ab) titers after primary and booster BNT162b2 mRNA vaccinations in healthcare workers (HCWs) and nursing home (NH) residents.MethodsNursing home residents (N = 143) and HCWs (N = 107) were vaccinated and serological responses monitored by serum neutralization activity against Wuhan and Omicron (BA.1) strain spike proteins, and by bead-multiplex immunoglobulin G immunoassay to Wuhan spike protein and its receptor-binding domain (RBD). Cytomegalovirus serology and levels of inflammatory biomarkers were also measured.ResultsSevere acute respiratory syndrome coronavirus 2-naive CMV seropositive (CMV+) HCWs had significantly reduced Wuhan-neutralizing Ab (P = .013), anti-spike (P = .017), and anti-RBD (P = .011) responses 2 weeks after primary vaccination series compared with responses among CMV seronegative (CMV−) HCWs, adjusting for age, sex, and race. Among NH residents without prior SARS-CoV-2 infection, Wuhan-neutralizing Ab titers were similar 2 weeks after primary series but were reduced 6 months later (P = .012) between CMV+ and CMV− subjects. Wuhan-neutralizing Ab titers from CMV+ NH residents who had prior SARS-CoV-2 infection consistently trended lower than titers from SARS-CoV-2 experienced CMV− donors. These impaired Ab responses in CMV+ versus CMV− individuals were not observed after booster vaccination or with prior SARS-CoV-2 infection.ConclusionsLatent CMV infection adversely affects vaccine-induced responsiveness to SARS-CoV-2 spike protein, a neoantigen not previously encountered, in both HCWs and NH residents. Multiple antigenic challenges may be required for optimal mRNA vaccine immunogenicity in CMV+ adults.

We examined whether the second monovalent SARS-CoV-2 mRNA booster increased antibody levels and their neutralizing activity to Omicron variants in nursing home residents (NH) residents and healthcare workers (HCW). We sampled 367 NH residents and 60 HCW after primary mRNA vaccination, first and second boosters, for antibody response and pseudovirus neutralization assay against SARS-CoV-2 wild-type (WT) (Wuhan-Hu-1) strain and Omicron BA1 variant. Antibody levels and neutralizing activity progressively increased with each booster but subsequently waned over weeks. NH residents, both those without and with prior infection, had a robust geometric mean fold rise (GMFR) of 10.2 (95% CI 5.1, 20.3) and 6.5 (95% CI 4.5, 9.3) respectively in Omicron-BA.1 subvariant specific neutralizing antibody levels following the second booster vaccination (p

After BNT162b2 messenger RNA vaccination, antibody levels to spike, receptor-binding domain, and virus neutralization were examined in 149 nursing home residents and 110 healthcare worker controls. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)–naive nursing home residents’ median post–second vaccine dose antibody neutralization titers are one-quarter that of SARS-CoV-2–naive healthcare workers.

Objective To describe the frequency and timing of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antibody detection in a convenience sample of skilled nursing facility (SNF) residents with and without confirmed SARS-CoV-2 infection. Design Retrospective analysis of SNF electronic health records. Setting Qualitative SARS-CoV-2 antibody test results were available from 81 SNFs in 16 states. Participants 669 SNF residents who underwent both polymerase chain reaction (PCR) and antibody testing for SARS-CoV-2. Measurements Presence of SARS-CoV-2 antibodies following the first positive PCR test for confirmed cases, or first PCR test for non-cases. Results Among 397 residents with PCR-confirmed infection, antibodies were detected in 4 of 7 (57.1%) tested within 7-14 days of their first positive PCR test; in 44 of 47 (93.6%) tested within 15-30 days; in 182 of 219 (83.1%) tested within 31-60 days; and in 110 of 124 (88.7%) tested after 60 days. Among 272 PCR negative residents, antibodies were detected in 2 of 9 (22.2%) tested within 7-14 days of their first PCR test; in 41 of 81 (50.6%) tested within 15-30 days; in 65 of 148 (43.9%) tested within 31-60 days; and in 9 of 34 (26.5%) tested after 60 days. No significant differences in baseline resident characteristics or symptoms were observed between those with vs. without antibodies. Conclusions These findings suggest that vulnerable older adults can mount an antibody response to SARS-CoV-2, and that antibodies are most likely to be detected within 15-30 days of diagnosis. That antibodies were detected in a large proportion of residents with no confirmed SARS-CoV-2 infection highlights the complexity of identifying who is infected in real time. Frequent surveillance and diagnostic testing based on low thresholds of clinical suspicion for symptoms and/or exposure will remain critical to inform strategies designed to mitigate outbreaks in SNFs while community SARS-CoV-2 prevalence remains high. This article is protected by copyright. All rights reserved.

Background Seasonal influenza vaccines approved and offered in the United States have varying reported degrees of effectiveness year over year and between manufacturers. Influenza vaccines produced from live virus may include single stranded RNA (ssRNA) that is a potent activator of the innate Toll-like receptor 7 (TLR-7) ligand. Plasmacytoid dendritic cells (pDC) can be activated by ssRNA to produce type I interferons such as IFN-α, which has been shown to have an adjuvant-like effect. Objective Our aim was to determine if IFN-α induction in peripheral blood mononuclear cells (PBMCs) exposed to eight different commercial influenza vaccines is a pDC-dependent process mediated through TLR-7 signaling. Results We demonstrate the ability of multiple vaccines to induce IFN-α in a TLR-7-dependent fashion. A number of vaccines however lacked IFN-α induction. The significance of these differences between vaccines is unclear, since all the approved vaccine formulations offer some degree of protection.

Nursing home (NH) residents have borne a disproportionate share of SARS-CoV-2 morbidity and mortality. Vaccines have limited hospitalisation and death from earlier variants in this vulnerable population. With the rise of Omicron and future variants, it is vital to sustain and broaden vaccine-induced protection. We examined the effect of boosting with BNT162b2 mRNA vaccine on humoral immunity and Omicron-specific neutralising activity among NH residents and healthcare workers (HCWs).We longitudinally enrolled 85 NH residents (median age 77) and 48 HCWs (median age 51), and sampled them after the initial vaccination series; and just before and 2 weeks after booster vaccination. Anti-spike, anti-receptor binding domain (RBD) and neutralisation titres to the original Wuhan strain and neutralisation to the Omicron strain were obtained.Booster vaccination significantly increased vaccine-specific anti-spike, anti-RBD, and neutralisation levels above the pre-booster levels in NH residents and HCWs, both in those with and without prior SARS-CoV-2 infection. Omicron-specific neutralisation activity was low after the initial 2 dose series with only 28% of NH residents' and 28% HCWs' titres above the assay's lower limit of detection. Omicron neutralising activity following the booster lifted 86% of NH residents and 93% of HCWs to the detectable range.With boosting, the vast majority of HCWs and NH residents developed detectable Omicron-specific neutralising activity. These data provide immunologic evidence that strongly supports booster vaccination to broaden neutralising activity and counter waning immunity in the hope it will better protect this vulnerable, high-risk population against the Omicron variant.NIH AI129709-03S1, U01 CA260539-01, CDC 200-2016-91773, and VA BX005507-01.

Antibody decline occurred from 2 weeks to 6 months post-BNT162b2 mRNA vaccination in nursing home (NH) residents and healthcare workers. Antispike, receptor-binding domain, and neutralization levels dropped >81% irrespective of prior infection. Notably, 69% of infection-naive NH residents had neutralizing antibodies at or below the assay’s limit of detection.

High COVID-19 mortality among nursing home (NH) residents led to their prioritization for SARS-CoV-2 vaccination; most NH residents received BNT162b2 mRNA vaccination under the Emergency Use Authorization due to first to market and its availability. With NH residents’ poor initial vaccine response, the rise of NH breakthrough infections and outbreaks, characterization of the durability of immunity to inform public health policy on the need for boosting is needed. We report on humoral immunity from 2 weeks to 6-months post-vaccination in 120 NH residents and 92 ambulatory healthcare worker controls with and without pre-vaccination SARS-CoV-2 infection. Anti-spike and anti-receptor binding domain (RBD) IgG, and serum neutralization titers, were assessed using a bead-based ELISA method and pseudovirus neutralization assay. Anti-spike, anti-RBD and neutralization levels dropped more than 84% over 6 months’ time in all groups irrespective of prior SARS-CoV-2 infection. At 6 months post-vaccine, 70% of the infection-naive NH residents had neutralization titers at or below the lower limit of detection compared to 16% at 2 weeks after full vaccination. These data demonstrate a significant reduction in levels of antibody in all groups. In particular, those infection-naive NH residents had lower initial post-vaccination humoral immunity immediately and exhibited the greatest declines 6 months later. Healthcare workers, given their younger age and relative good-health, achieved higher initial antibody levels and better maintained them, yet also experienced significant declines in humoral immunity. Based on the rapid spread of the delta variant and reports of vaccine breakthrough in NH and among younger community populations, boosting NH residents may be warranted.

Background The BNT162b2 SARS-CoV-2 mRNA vaccination has mitigated the burden of COVID-19 among residents of long-term care facilities considerably, despite being excluded from the vaccine trials. Data on reactogenicity (vaccine side effects) in this population are limited. Aims To assess reactogenicity among nursing home (NH) residents. To provide a plausible proxy for predicting vaccine response among this population. Methods We enrolled and sampled NH residents and community-dwelling healthcare workers who received the BNT162b2 mRNA vaccine, to assess local or systemic reactogenicity and antibody levels (immunogenicity). Results NH residents reported reactions at a much lower frequency and lesser severity than the community-dwelling healthcare workers. These reactions were mild and transient with all subjects experiencing more local than systemic reactions. Based on our reactogenicity and immunogenicity data, we developed a linear regression model predicting log-transformed anti-spike, anti-receptor-binding domain (RBD), and neutralizing titers, with a dichotomous variable indicating the presence or absence of reported reactions which revealed a statistically significant effect, with estimated shifts in log-transformed titers ranging from 0.32 to 0.37 (all p Discussion With a significantly lower incidence of post-vaccination reactions among NH residents as reported in this study, the BNT162b2 mRNA vaccine appears to be well-tolerated among this vulnerable population. If validated in larger populations, absence of reactogenicity could help guide clinicians in prioritizing vaccine boosters. Conclusions Reactogenicity is significantly mild among nursing home residents and overall, subjects who reported post-vaccination reactions developed higher antibody titers.

Tuberculosis (TB) remains a worldwide public health threat. Development of a more effective vaccination strategy to prevent pulmonary TB, the most common and contagious form of the disease, is a research priority for international TB control. A key to reaching this goal is improved understanding of the mechanisms of local immunity to Mycobacterium tuberculosis, the causative organism of TB. In this study, we evaluated global M. tuberculosis–induced gene expression in airway immune cells obtained by bronchoalveolar lavage (BAL) of individuals with latent TB infection (LTBI) and M. tuberculosis–naive controls. In prior studies, we demonstrated that BAL cells from LTBI individuals display substantial enrichment for M. tuberculosis–responsive CD4+ T cells compared with matched peripheral blood samples. We therefore specifically assessed the impact of the depletion of CD4+ and CD8+ T cells on M. tuberculosis–induced BAL cell gene expression in LTBI. Our studies identified 12 canonical pathways and a 47-gene signature that was both sensitive and specific for the contribution of CD4+ T cells to local recall responses to M. tuberculosis. In contrast, depletion of CD8+ cells did not identify any genes that fit our strict criteria for inclusion in this signature. Although BAL CD4+ T cells in LTBI displayed polyfunctionality, the observed gene signature predominantly reflected the impact of IFN-γ production on a wide range of host immune responses. These findings provide a standard for comparison of the efficacy of standard bacillus Calmette–Guérin vaccination as well as novel TB vaccines now in development at impacting the initial response to re-exposure to M. tuberculosis in the human lung.

T follicular helper cells (Tfh), a subset of CD4+ T cells, provide requisite help to B cells in the germinal centers (GC) of lymphoid tissue. GC Tfh are identified by high expression of the chemokine receptor CXCR5 and the inhibitory molecule PD-1. Although more accessible, blood contains lower frequencies of CXCR5+ and PD-1+ cells that have been termed circulating Tfh (cTfh). However, it remains unclear whether GC Tfh exit lymphoid tissues and populate this cTfh pool. To examine exiting cells, we assessed the phenotype of Tfh present within the major conduit of efferent lymph from lymphoid tissues into blood, the human thoracic duct. Unlike what was found in blood, we consistently identified a CXCR5-bright PD-1-bright (CXCR5BrPD-1Br) Tfh population in thoracic duct lymph (TDL). These CXCR5BrPD-1Br TDL Tfh shared phenotypic and transcriptional similarities with GC Tfh. Moreover, components of the epigenetic profile of GC Tfh could be detected in CXCR5BrPD-1Br TDL Tfh and the transcriptional imprint of this epigenetic signature was enriched in an activated cTfh subset known to contain vaccine-responding cells. Together with data showing shared TCR sequences between the CXCR5BrPD-1Br TDL Tfh and cTfh, these studies identify a population in TDL as a circulatory intermediate connecting the biology of Tfh in blood to Tfh in lymphoid tissue.

The SARS-CoV-2 pandemic impact on nursing home (NH) residents prompted their prioritization for early vaccination. To fill the data gap for vaccine immunogenicity in NH residents, we examined antibody levels after BNT162b2 mRNA vaccine to spike, receptor binding domain (RBD) and for virus neutralization in 149 NH residents and 111 health care worker controls. SARS-CoV-2-naive NH residents mount antibody responses with nearly 4-fold lower median neutralization titers and half the anti-spike level compared to SARS-CoV-2-naive healthcare workers. By contrast, SARS-CoV-2-recovered vaccinated NH residents had neutralization, anti-spike and anti-RBD titers similar to SARS-CoV-2-recovered vaccinated healthcare workers. NH residents’ blunted antibody responses have important implications regarding the quality and durability of protection afforded by neoantigen vaccines. We urgently need better longitudinal evidence on vaccine effectiveness specific to NH resident populations to inform best practices for NH infection control measures, outbreak prevention and potential indication for a vaccine boost.

Vaccines are less effective in older adults, and efforts to improve vaccine efficacy generally show limited clinical improvement. However, the vaccine Shingrix, developed by GlaxoSmithKline, is FDA approved and recommended for adults over the age of 50 for the prevention of shingles. Shingrix contains the novel adjuvant AS01 and shows remarkably high (>90%) effectiveness at both preventing shingles and reducing the development of postherpetic neuralgia, even in adults over 80. We seek to examine AS01-induced activation of myeloid cells and determine their impacts on T cell memory differentiation and function in an effort to understand how this vaccine’s high clinical efficacy is produced. We use peripheral blood samples to examine AS01-induced innate immune cell activation, including interactions with T cells once activated. We find that AS01 induces costimulatory marker upregulation and cytokine production in myeloid dendritic cells and monocytes in a synergistic manner, with the most upregulation seen in monocytes. Naïve and memory CD4 T cells incubated with AS01-treated monocytes have increased frequencies of TH17 (CCR6+ CXCR3−) cells and decreased frequencies of TH1 cells compared to controls. Naïve CD4 T cells proliferate more when incubated with AS01-treated monocytes than with controls. AS01-treated monocytes additionally induce 2x less IFN-γ and IL-5 in response to mitogen (SEB) from CD4 T cells, suggesting a modulation of response. We propose that AS01 influences monocytes to diversify the existing memory T cell repertoire and skews naïve T cells towards more cytotoxic phenotypes such as TH17, contributing to greater clinical efficacy in preventing shingles in vivo. Supported by VA Merit grant (CX002060)

Lymphocyte migration is essential for adaptive immune surveillance. However, our current understanding of this process is rudimentary, because most human studies have been restricted to immunological analyses of blood and various tissues. To address this, we used an integrated approach to characterize tissue-emigrant immune cells in thoracic duct lymph (TDL). The most prevalent immune cells in human and non-human primate efferent lymph were T cells. Cytolytic CD8(+) T cell subsets with effector-like epigenetic and transcriptional signatures were clonotypically skewed and selectively confined to the intravascular circulation, whereas non-cytolytic CD8(+) T cell subsets with stem-like epigenetic and transcriptional signatures predominated in tissues and TDL. Moreover, these anatomically distinct gene expression profiles were recapitulated within individual antigen-specific clonotypes, suggesting parallel differentiation programs independent of the expressed antigen receptor. Our collective dataset provides a framework of the migratory immune system and defines the nature of tissue-emigrant CD8(+) T cells that recirculate via TDL.

Tuberculosis (TB) caused by Mycobacterium tuberculosis (MTB) kills about 1.5 million people each year and the widely used Bacille Calmette-Guérin (BCG) vaccine provides a partial protection against TB in children and adults. Because BCG vaccine evades lysosomal fusion in antigen presenting cells (APCs), leading to an inefficient production of peptides and antigen presentation required to activate CD4 T cells, we sought to boost its efficacy using novel agonists of RIG-I and NOD2 as adjuvants. We recently reported that the dinucleotide SB 9200 (Inarigivir) derived from our small molecule nucleic acid hybrid (SMNH)® platform, activated RIG-I and NOD2 receptors and exhibited a broad-spectrum antiviral activity against hepatitis B and C, Norovirus, RSV, influenza and parainfluenza. Inarigivir increased the ability of BCG-infected mouse APCs to secrete elevated levels of IL-12, TNF-α, and IFN-β, and Caspase-1 dependent IL-1β cytokine. Inarigivir also increased the ability of macrophages to kill MTB in a Caspase-1-, and autophagy-dependent manner. Furthermore, Inarigivir led to a Capsase-1 and NOD2- dependent increase in the ability of BCG-infected APCs to present an Ag85B-p25 epitope to CD4 T cells in vitro. Consistent with an increase in immunogenicity of adjuvant treated APCs, the Inarigivir-BCG vaccine combination induced robust protection against tuberculosis in a mouse model of MTB infection, decreasing the lung burden of MTB by 1-log10 more than that afforded by BCG vaccine alone. The Inarigivir-BCG combination was also more efficacious than a muramyl-dipeptide-BCG vaccine combination against tuberculosis in mice, generating better memory T cell responses supporting its novel adjuvant potential for the BCG vaccine.

The HIV-1 epidemic originated from a cross-species transmission of a primate lentivirus from chimpanzees to humans near the turn of the 18thcentury. Simian immunodeficiency viruses have been jumping between old world monkeys in West/Central Africa for thousands of years. So why did HIV-1 only emerge in the past century? This study examined the replicative fitness, transmission, restriction, and cytopathogenicity of 26 primate lentiviruses. Pairwise competitions of these primate lentiviruses revealed that SIVcpz had the highest replicative fitness in human or chimpanzee peripheral blood mononuclear cells, even higher fitness than HIV-1 group M strains responsible for 37 million infections worldwide. In contrast the “HIV-2 lineage” (SIVsmm, SIVmac, SIVagm, and HIV-2) had the lowest replicative fitness. SIVcpz strains were less inhibited by human restriction factors than the “HIV-2 lineage” strains, a restriction that was inversely correlated with replicative fitness. SIVcpz from the chimpanzee subspeciesPan troglodytes troglodytes(Ptt) was slightly more fit in human cells than the strains fromPt schweinfurthii(Pts). However, unlike all other primate lentiviruses (including the HIV-2 lineage), SIVcpz was nonpathogenic in human tonsillar tissue and did not deplete CD4+ T-cells, consistent with the slow or nonpathogenic disease observed in chimpanzees. Despite the close phylogenetic relationship between SIVcpz_Ptt and HIV-1, this epidemic was either caused by cross species transmission of a rare, undiscovered SIVcpz strain of higher virulence or higher virulence differentially evolved among HIV-1 subtypes during the human epidemic.Author summaryInvasion of wild animal habitats by humans can have devastating consequences for the human population as evident by the HIV-1 and SARS-CoV-2 epidemics. With SARS-CoV-2, a recent zoonotic jump, likely from bats, will help to identify a coronavirus progenitor. In contrast, simian immunodeficiency virus (SIV) jumped into humans over 100 years ago from a possibly extinct sub-species of chimpanzees and/or extinct lineage of SIV. We examined replicative fitness and pathogenesis of 26 different primate lentiviruses in human and chimpanzee primary lymphoid cells from blood and within tonsils. SIV from a specific chimpanzee species and lowland gorillas were the most capable of infecting and replicating in human and chimp lymphoid cells but they did not result in the pathogenesis related to disease in humans. In contrast, SIV from other old world monkeys were pathogenic but could not replicate efficiently in human cells. We propose the main HIV-1 is derived from a distinct jump of a very rare SIV strain in chimps leading to AIDS pandemic.

Human macrophages play a major role in controlling tuberculosis (TB), but their anti-mycobacterial mechanisms remain unclear among individuals with metabolic alterations like obesity (TB protective) or diabetes (TB risk). To help discern this, we aimed to: i) Evaluate the impact of the host's TB status or their comorbidities on the anti-mycobacterial responses of their monocyte-derived macrophages (MDMs), and ii) determine if the autophagy inducer rapamycin, can enhance these responses. We used MDMs from newly diagnosed TB patients, their close contacts and unexposed controls. The MDMs from TB patients had a reduced capacity to activate T cells (surrogate for antigen presentation) or kill M. tuberculosis (Mtb) when compared to non-TB controls. The MDMs from obese participants had a higher antigen presenting capacity, whereas those from chronic diabetes patients displayed lower Mtb killing. The activation of MDMs with rapamycin led to an enhanced anti-mycobacterial activity irrespective of TB status but was not as effective in patients with diabetes. Further studies are warranted using MDMs from TB patients with or without metabolic comorbidities to: i) elucidate the mechanisms through which host factors affect Mtb responses, and ii) evaluate host directed therapy using autophagy-inducing drugs like rapamycin to enhance macrophage function.

Summary Although the BCG vaccine offers partial protection, tuberculosis remains a leading cause of infectious disease death, killing ∼1.5 million people annually. We developed mucosal vaccines expressing the autophagy-inducing peptide C5 and mycobacterial Ag85B-p25 epitope using replication-defective human adenovirus (HAdv85C5) and bovine adenovirus (BAdv85C5) vectors. BAdv85C5-infected dendritic cells (DCs) expressed a robust transcriptome of genes regulating antigen processing compared to HAdv85C5-infected DCs. BAdv85C5-infected DCs showed enhanced galectin-3/8 and autophagy-dependent in vitro Ag85B-p25 epitope presentation to CD4 T cells. BCG-vaccinated mice were intranasally boosted using HAdv85C5 or BAdv85C5 followed by infection using aerosolized Mycobacterium tuberculosis (Mtb). BAdv85C5 protected mice against tuberculosis both as a booster after BCG vaccine (>1.4-log10 reduction in Mtb lung burden) and as a single intranasal dose (>0.5-log10 reduction). Protection was associated with robust CD4 and CD8 effector (TEM), central memory (TCM), and CD103+/CD69+ lung-resident memory (TRM) T cell expansion, revealing BAdv85C5 as a promising mucosal vaccine for tuberculosis., Graphical abstract, Highlights BCG-vaccinated infants need a booster for better protection against tuberculosis The BAdv85C5 vaccine increased protection in BCG-vaccinated mice against tuberculosis The BAdv85C5 vaccine increased antigen presentation and memory T cells responses Mucosal vaccination strengthens lung defense against tuberculosis, Khan et al. describe a bovine-adenovirus-based BAdv85C5 mucosal vaccine, which induced a galectin 3/8-dependent autophagy increasing antigen presentation in dendritic cells ex vivo. BAdv85C5 nasal booster in BCG-vaccinated mice enhanced the protection against tuberculosis and increased antigen-specific CD4 T cells and memory T cells.

Background Influenza leads in preventable infection-related hospitalization in nursing home (NH) residents. The adjuvanted trivalent influenza vaccine (aTIV) is more immunogenic than similarly dosed nonadjuvanted trivalent influenza vaccine (TIV), and observational studies suggest aTIV better prevents hospitalizations in older adults. We prospectively tested this in an NH setting. Methods NHs with ≥50 long-stay residents aged ≥65 years were randomized to offer aTIV or TIV for residents for the 2016–2017 influenza season. Using intent-to-treat resident-level analysis with Cox proportional hazards regression models adjusted for clustering by facility and a priori baseline covariates (eg, age, heart failure, and facility-level characteristics), we assessed relative aTIV:TIV effectiveness for hospitalization (ie, all-cause, respiratory, and pneumonia and influenza [P&I]). Results We randomized 823 NHs, housing 50 012 eligible residents, to aTIV or TIV. Residents were similar between groups by age (mean, ~79 years), heart failure, lung disease, and influenza and pneumococcal vaccine uptake, except aTIV homes housed fewer Black residents (14.5 vs 18.9%). Staff vaccine uptake was similar (~55%). P&I and all-cause resident hospitalization rates were lower (adjusted HR [aHR], .80 [95% CI, .66–.98; P = .03] and .94 [.89–.99; P = .02], respectively) for aTIV versus TIV, while the respiratory hospitalization rate was similar, in a season where vaccine effectiveness was considered poor. Conclusions aTIV was more effective than TIV in preventing all-cause and P&I hospitalization from NHs during an A/H3N2-predominant season when TIV was relatively ineffective. Clinical Trials Registration NCT02882100.

Background During combined anti-retroviral treatment, a latent HIV reservoir persists within resting memory CD4 T cells that initiates viral recrudescence upon treatment interruption. Strategies for HIV-1 cure have largely focused on latency reversing agents (LRAs) capable of reactivating and eliminating this viral reservoir. Previously investigated LRAs have largely failed to achieve a robust latency reversal sufficient for reduction of latent HIV pool or the potential of virus-free remission in the absence of treatment. Methods We utilize a polyvalent virus-like particle (VLP) formulation called Activator Vector (ACT-VEC) to ‘shock’ provirus into transcriptional activity. Ex vivo co-culture experiments were used to evaluate the efficacy of ACT-VEC in relation to other LRAs in individuals diagnosed and treated during the acute stage of infection. IFN-γ ELISpot, qRT-PCR and Illumina MiSeq were used to evaluate antigenicity, latency reversal, and diversity of induced virus respectively. Findings Using samples from HIV+ patients diagnosed and treated at acute/early infection, we demonstrate that ACT-VEC can reverse latency in HIV infected CD4 T cells to a greater extent than other major recall antigens as stimuli or even mitogens such as PMA/Iono. Furthermore, ACT-VEC activates more latent HIV-1 than clinically tested HDAC inhibitors or protein kinase C agonists. Interpretation Taken together, these results show that ACT-VEC can induce HIV reactivation from latently infected CD4 T cells collected from participants on first line combined antiretroviral therapy for at least two years after being diagnosed and treated at acute/early stage of infection. These findings could provide guidance to possible targeted cure strategies and treatments. Funding NIH and CIHR

The global coronavirus pandemic is unlike any other since 1918. A century of dramatic medical advances has produced a public expectation that the medical field will rapidly provide solutions to restore normalcy. In less than 6 months, since severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was identified, the massive international effort to develop a SARS-CoV-2 vaccine has generated more than 140 vaccines in different stages of development, with 9 already recruiting into clinical trials posted on ClinicalTrials.gov. The long-term strategy to handle coronavirus disease 2019 (COVID-19) will almost certainly rely on vaccines. But what type of protection can we realistically expect to achieve from vaccines and when?

Background Lymph node tuberculosis (LNTB) is the most frequent extrapulmonary form of tuberculosis (TB). Studies of human tuberculosis at sites of disease are limited. LNTB provides a unique opportunity to compare local in situ and peripheral blood immune response in active Mycobacterium tuberculosis (Mtb) disease. The present study analysed T regulatory cells (Treg) frequency and activation along with CD4+ T cell function in lymph nodes from LNTB patients. Results Lymph node mononuclear cells (LNMC) were compared to autologous peripheral blood mononuclear cells (PBMC). LNMC were enriched for CD4+ T cells with a late differentiated effector memory phenotype. No differences were noted in the frequency and mutifunctional profile of memory CD4+ T cells specific for Mtb. The proportion of activated CD4+ and Tregs in LNMC was increased compared to PBMC. The correlation between Tregs and activated CD4+ T cells was stronger in LNMC than PBMC. Tregs in LNMC showed a strong positive correlation with Th1 cytokine production (IL2, IFNγ and TNFα) as well as MIP-1α after Mtb antigen stimulation. A subset of Tregs in LNMC co-expressed HLA-DR and CD38, markers of activation. Conclusion Further research will determine the functional relationship between Treg and activated CD4+ T cells at lymph node sites of Mtb infection. Electronic supplementary material The online version of this article (10.1186/s12865-018-0266-8) contains supplementary material, which is available to authorized users.

Individuals over the age of 65 comprise a substantial portion of the world population and become more susceptible to vaccine-preventable infections with age as vaccination response diminishes. The underlying reason for this impaired vaccine response in older individuals is not entirely clear. We evaluated potential differences in phenotypic and functional responses of B cells from healthy younger (22–45 years) and older (64–95 years) individuals that may associate with a diminished antibody response to influenza vaccination. We report that age is associated with expansion of atypical memory B cells (CD10(−)CD20(+)CD21(−)CD27(−)) and an age-associated B cell (ABC, CD21(−)T-bet(+)CD11c(+)) phenotype. Reduced expression of PAX5 was also seen in older individuals. Poor influenza-specific antibody production following vaccination was associated with low PAX5 expression and a distinct composition of the ABC compartment. Collectively, these findings demonstrate that the characteristics of the ABC populations of older individuals are associated with antibody production following influenza vaccination.

Sayin et al. describe the spatial distribution and functional characteristics of T follicular regulatory (Tfr) cells in human lymph nodes. Contrary to existing paradigms, Tfr-mediated suppression appears to be most efficient at the T-B border and within the follicle, not in the germinal center., T follicular regulatory (Tfr) cells are a population of CD4+ T cells that express regulatory T cell markers and have been shown to suppress humoral immunity. However, the precise mechanisms and location of Tfr-mediated suppression in the lymph node (LN) microenvironment are unknown. Using highly multiplexed quantitative imaging and functional assays, we examined the spatial distribution, suppressive function, and preferred interacting partners of Tfr cells in human mesenteric LNs. We find that the majority of Tfr cells express low levels of PD-1 and reside at the border between the T cell zone and B cell follicle, with very few found in the germinal centers (GCs). Although PD-1+ Tfr cells expressed higher levels of CD38, CTLA-4, and GARP than PD-1Neg Tfr cells, both potently suppressed antibody production in vitro. These findings highlight the phenotypic diversity of human Tfr cells and suggest that Tfr-mediated suppression is most efficient at the T-B border and within the follicle, not in the GC., Graphical Abstract

Herpes Zoster (HZ) is the result of reactivation of latent varicella zoster virus (VZV) and occurs most frequently in older adults. Generally, HZ presents as a unilateral, self-limited dermatomal rash. Postherpetic neuralgia (PHN) is a common sequela; presenting as severe pain that persists after the rash has resolved. It occurs more commonly in older age and can be very debilitating. Management of HZ in the elderly requires a prompt diagnosis, treatment with antivirals, and adequate pain control. A longer- term pain management strategy is required if PHN occurs. A modestly effective vaccine exists and is recommended for older individuals.

Humoral immune responses are dysregulated with aging but details remain incompletely understood. In particular, little is known about the effects of aging on T follicular helper (Tfh) CD4 cells, the subset that provides critical help to B cells for effective humoral immunity. We previously demonstrated that influenza vaccination increases a circulating Tfh (cTfh) subset that expresses ICOS and CD38, contains influenza-specific memory cells, and is correlated with antibody responses. To directly study the effects of aging on the cTfh response, we performed transcriptional profiling and cellular analysis before and after influenza vaccination in young and elderly adults. Several key differences in cTfh responses were revealed in the elderly. First, whole blood transcriptional profiling defined cross-validated genesets of youth versus aging and these genesets were, compared to other T cells, preferentially enriched in ICOS+CD38+ cTfh from young and elderly subjects, respectively, following vaccination. Second, vaccine-induced ICOS+CD38+ cTfh from the elderly were enriched for transcriptional signatures of inflammation including TNF-NFkB pathway activation. Indeed, we reveal a paradoxical positive effect of TNF signaling on Tfh providing help to B cells linked to survival circuits that may explain detrimental effects of TNF blockade on vaccine responses. Finally, vaccine-induced ICOS+CD38+ cTfh displayed strong enrichment for signatures of underlying age-associated biological changes. Thus, these data reveal key biological changes in cTfh during aging and also demonstrate the sensitivity of vaccine-induced cTfh to underlying changes in host physiology. This latter observation suggests that vaccine-induced cTfh could function as sensitive biosensors of underlying inflammatory and/or overall immune health.One sentence summaryTranscriptional profiling of vaccine-induced circulating T follicular helper cell responding to influenza vaccination reveals age-associated effects on Tfh such as alterations in TNF-NFkB signaling.

Uncontrolled IgE responses drive allergies and anaphylaxis. Here, Cañete et al. describe a human follicular regulatory T cell population that does not express FOXP3 and produces abundant IL-10, which limits IgE switching. These cells appear to be key regulators of atopy., Mucosal lymphoid tissues such as human tonsil are colonized by bacteria and exposed to ingested and inhaled antigens, requiring tight regulation of immune responses. Antibody responses are regulated by follicular helper T (TFH) cells and FOXP3+ follicular regulatory T (TFR) cells. Here we describe a subset of human tonsillar follicular T cells identified by expression of TFH markers and CD25 that are the main source of follicular T (TF) cell–derived IL-10. Despite lack of FOXP3 expression, CD25+ TF cells resemble T reg cells in high CTLA4 expression, low IL-2 production, and their ability to repress T cell proliferation. CD25+ TF cell–derived IL-10 dampens induction of B cell class-switching to IgE. In children, circulating total IgE titers were inversely correlated with the frequencies of tonsil CD25+ TF cells and IL-10–producing TF cells but not with total T reg cells, TFR, or IL-10–producing T cells. Thus, CD25+ TF cells emerge as a subset with unique T and B cell regulatory activities that may help prevent atopy.

The last decades of life carry risks for infections related to multiple morbidities, immunosenescence, and increased pathogen exposure. These result in more serious infections, greater functional impact, and increased cost unlike for any other age subset. The costliest three vaccine-preventable diseases (VPDs)—influenza, shingles, and pneumococcal pneumonia—result in billions of potentially averted healthcare dollars spent. Older adults succumb with increasing frequency of lower respiratory tract infections and the cardiovascular and cerebrovascular events resulting from these VPD. The ability of vaccines to attenuate such outcomes shows promise for indirect secondary prevention that can further drive clinical effectiveness. Here we discuss special considerations for vaccines in the context of an aging population, including issues related to vaccine hesitancy, reduced vaccine effectiveness due to the aging immune system, and the consequences of multimorbidity, as well as barriers to vaccine uptake particularly relevant for the older outpatient and long-term care populations.

Background Nursing home residents account for 45% SARS-CoV-2 related deaths in the U.S. but only 0.6% of the population. Our research group conducted a large pragmatic cluster randomized influenza vaccine trial in 965 nursing homes (NCT03965195). Due to the pandemic and its impact after the influenza season, we prospectively collected reports of SARS-CoV-2 outbreaks and performed a prospective study on the association between contract staffing and reported outbreaks of SARS-CoV-2. We hypothesized those using more contract nursing care would have higher risk of an outbreak. Methods From February through April, we collected monthly facility-level, self-reported data on SARS-CoV-2 outbreaks. Facility characteristics were taken from public data from Centers for Medicaid and Medicare services. Predictors of SARS-CoV-2 outbreaks were identified using a LASSO variable selection procedure, with a generalized linear, Poisson family model. Facility characteristics evaluated include demographics (e.g. number of residents), influenza vaccination rates, quality measures (e.g. % with UTI), and functional status (e.g. % with tube feedings). Facilities with contract staffing hours in the upper 25% quantile of direct care (RN, LPN, CNA) were considered ‘heavy use’. Results Of 965 randomized NHs, 663/965 (69%) reported data on SARS-CoV-2 outbreaks. On average, 13% of facilities had at least one outbreak, with 5/842 (0.5%) outbreaks in February, 91/835 (10.8%) in March and 217/686 (30%) in April. SARS-CoV-2 (+) facilities were larger (average total beds, 151 vs. 117), but were mostly similar by functional and cognitive status. Occupancy rate, total residents, Influenza vaccination rate, % with UTI, receiving respiratory treatments, tube feedings, and Medicaid payers were adjusted for in the analysis. The ‘heavy use’ of contract staffing included those with >223 hours per quarter. A multivariable regression found the relative risk SARS-CoV-2 outbreak was 1.56 (95% Confidence Interval: 1.22, 1.99) with heavy use of contract staffing. Conclusion The participating nursing homes in our vaccine trial with SARS-CoV-2 outbreaks were larger. Our study highlights that heavy use of contract staffing was associated with 56% increased risk of an outbreak. Disclosures Kevin McConeghy, Pharm.D., Pfizer (Grant/Research Support)Sanofi-Pasteur (Grant/Research Support)Seqirus Pharmaceuticals (Grant/Research Support) H. Edward Davidson, PharmD, MPH, Sanofi pasteur (Grant/Research Support, Scientific Research Study Investigator, Research Grant or Support)Seqirus (Grant/Research Support, Scientific Research Study Investigator, Research Grant or Support) Lisa Han, MPH, Sanofi Pasteur (Grant/Research Support)Seqirus (Grant/Research Support) David Canaday, M.D., Pfizer (Research Grant or Support)Sanofi Pasteur (Research Grant or Support)Seqirus (Advisor or Review Panel member, Research Grant or Support) Vincent Mor, Ph.D., naviHealth (Consultant)

B cell subsets expressing the transcription factor T-bet are associated with humoral immune responses and autoimmunity. Here we examined the anatomic distribution, clonal relationships, and functional properties of T-bet(+) and T-bet(−) memory B cells (MBCs) in the context of the influenza-specific immune response. In mice, both T-bet(−) and T-bet(+) hemagglutinin-specific B cells arose in germinal centers, acquired memory B cell markers, and persisted indefinitely. Lineage tracing and IgH repertoire analyses revealed minimal interconversion between T-bet(−) and T-bet(+) MBCs, and parabionts showed differential tissue residency and recirculation properties. T-bet(+) MBCs could be subdivided into recirculating T-bet(lo) MBCs and spleen-resident T-bet(hi) MBCs. Human MBCs displayed similar features. Conditional gene deletion studies revealed that T-bet expression in B cells was required for nearly all HA stalk-specific IgG2c antibodies and for durable neutralizing titers to influenza. Thus, T-bet expression distinguishes MBC subsets that have profoundly different homing, residency, and functional properties, and mediate distinct aspects of humoral immune memory.

Current paradigms of CD8 + T cell–mediated protection in HIV infection center almost exclusively on studies of peripheral blood, which is thought to provide a window into immune activity at the predominant sites of viral replication in lymphoid tissues (LTs). Through extensive comparison of blood, thoracic duct lymph (TDL), and LTs in different species, we show that many LT memory CD8 + T cells bear phenotypic, transcriptional, and epigenetic signatures of resident memory T cells (T RMs ). Unlike their circulating counterparts in blood or TDL, most of the total and follicular HIV-specific CD8 + T cells in LTs also resemble T RMs . Moreover, high frequencies of HIV-specific CD8 + T RMs with skewed clonotypic profiles relative to matched blood samples are present in LTs of individuals who spontaneously control HIV replication in the absence of antiretroviral therapy (elite controllers). Single-cell RNA sequencing analysis confirmed that HIV-specific T RMs are enriched for effector-related immune genes and signatures compared with HIV-specific non-T RMs in elite controllers. Together, these data indicate that previous studies in blood have largely failed to capture the major component of HIV-specific CD8 + T cell responses resident within LTs.

First identified as the etiological agent behind Acquired Immunodeficiency Syndrome (AIDS) in the early 1980s, HIV-1 has continued to spread into a global pandemic and major public health concern. Despite the success of antiretroviral therapy at reducing HIV-1 viremia and preventing the dramatic CD4+ T-cell collapse, infected individuals remain HIV positive for life. Unfortunately, it is increasingly clear that natural immunity is not, and may never be, protective against this pathogen. Therefore, efficacious vaccine interventions, which can either prevent infection or eradicate the latent viral reservoir and effect cure, are a major medical priority. Here we describe the development of a safe vaccine platform, currently being utilized in on-going prophylactic and therapeutic preclinical studies and consisting of highly heterogeneous virus-like particle formulations that represent the virus diversity within infected individuals. These VLPs contain no 5′LTR, no functional integrase, and have a severely mutated stem loop 1—thereby preventing any potential reverse transcription, integration, and RNA packaging. Furthermore, we demonstrate that these VLPs are morphologically identical to wild-type virus with polyvalent Env in a functional form. Finally, we show that the VLPs are antigenic and capable of generating strong immune recall responses., HIV: An investigatory vaccine system that mimics natural infection diversity A system has been developed that allows the generation of HIV-mimicking particles which provoke an immune response from human cells. As HIV-1 remains pandemic, vaccination represents a current global research priority for prophylaxis, and could even offer a cure. Jamie Mann, of the University of Western Ontario, Canada, and an international research group have successfully created HIV-1 virus-like particles (VLPs) designed to prime immune systems against a diverse range of viral envelope protein conformations. The VLPs produced are morphologically near-identical to the virulent ‘wild-type’ HIV, and successfully stimulated the production of IFN-γ and Granzyme B from CD4+ and CD8+ T immune cells in vitro, in cell cultures taken from HIV-infected volunteers. The VLPs appeared safe in vitro; however, further investigation will confirm their safety profile in humans. The authors are currently investigating different forms of these VLPs as potential anti-HIV therapeutics.