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Influenza A virus (IAV) causes up to half a million deaths worldwide annually, 90% of which occur in older adults. We show that IAV-infected monocytes from older humans have impaired antiviral interferon production but retain intact inflammasome responses. To understand the in vivo consequence, we used mice expressing a functional Mx gene encoding a major interferon-induced effector against IAV in humans. In Mx1-intact mice with weakened resistance due to deficiencies in Mavs and TIr7, we found an elevated respiratory bacterial burden. Notably, mortality in the absence of Mavs and TIr7 was independent of viral load or MyD88-dependent signaling but dependent on bacterial burden, caspase-1/11, and neutrophil-dependent tissue damage. Therefore, in the context of weakened antiviral resistance, vulnerability to IAV disease is a function of caspase-dependent pathology.

Recent discoveries demonstrate a critical role for circadian rhythms and sleep in immune system homeostasis. Both innate and adaptive immune responses - ranging from leukocyte mobilization, trafficking, and chemotaxis to cytokine release and T cell differentiation -are mediated in a time of day-dependent manner. The National Institutes of Health (NIH) recently sponsored an interdisciplinary workshop, \"Sleep Insufficiency, Circadian Misalignment, and the Immune Response,\" to highlight new research linking sleep and circadian biology to immune function and to identify areas of high translational potential. This Review summarizes topics discussed and highlights immediate opportunities for delineating clinically relevant connections among biological rhythms, sleep, and immune regulation.

[...]despite the availability of influenza vaccines specially formulated for older adults, vaccination coverage varies widely among different countries/regions and older adults continue to suffer disproportionally high morbidity and mortality from seasonal influenza. [...]understanding of and improving influenza immunization for older adults remain a priority in translational aging research. [...]the conventional approach, i.e., measuring pre-vaccination HAI antibody titers using current season vaccine strain antigens, appeared to underestimate residual HAI antibody titers from prior season vaccination and, thus, overestimate interseason waning. [...]interseason waning and prior season post-vaccination HAI antibody titers had significant and independent impact on pre-existing humoral immunity. [...]the review article by Cadar et al.

The impact of Coronavirus Disease 2019 (COVID-19) mRNA vaccination on pregnancy and fertility has become a major topic of public interest. We investigated 2 of the most widely propagated claims to determine (1) whether COVID-19 mRNA vaccination of mice during early pregnancy is associated with an increased incidence of birth defects or growth abnormalities; and (2) whether COVID-19 mRNA-vaccinated human volunteers exhibit elevated levels of antibodies to the human placental protein syncytin-1. Using a mouse model, we found that intramuscular COVID-19 mRNA vaccination during early pregnancy at gestational age E7.5 did not lead to differences in fetal size by crown-rump length or weight at term, nor did we observe any gross birth defects. In contrast, injection of the TLR3 agonist and double-stranded RNA mimic polyinosinic-polycytidylic acid, or poly(I:C), impacted growth in utero leading to reduced fetal size. No overt maternal illness following either vaccination or poly(I:C) exposure was observed. We also found that term fetuses from these murine pregnancies vaccinated prior to the formation of the definitive placenta exhibit high circulating levels of anti-spike and anti-receptor-binding domain (anti-RBD) antibodies to Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) consistent with maternal antibody status, indicating transplacental transfer in the later stages of pregnancy after early immunization. Finally, we did not detect increased levels of circulating anti-syncytin-1 antibodies in a cohort of COVID-19 vaccinated adults compared to unvaccinated adults by ELISA. Our findings contradict popular claims associating COVID-19 mRNA vaccination with infertility and adverse neonatal outcomes.

Key Points The diverse cell lineages that mediate innate immunity show heterogeneous ageing phenotypes that reflect their different developmental, tissue and activation contexts. In general, ageing of the innate immune system is characterized by dysregulated inflammatory responses that may contribute to a heightened pro-inflammatory milieu, particularly in humans. In the context of such persistent inflammation, failure in innate immune activation may occur in response to pathogens or vaccines. Neutrophils in aged humans show decreased functions, as assessed by intracellular killing, chemotaxis and phagocytosis, and these defects may be due to reduced signalling induced by granulocyte/macrophage colony-stimulating factor, triggering receptor expressed on myeloid cells 1, and alterations in membrane lipid raft domains. Intracellular killing and phagocytosis by neutrophils from aged mice are generally preserved, although deficits in neutrophil extracellular trap formation, chemokine production and recruitment are seen. Toll-like receptor (TLR) function in monocytes, macrophages and dendritic cell (DC) populations is generally decreased with age in humans and in mice. Both transcriptional and post-transcriptional mechanisms contribute to alterations in TLR expression. Furthermore, examples of increased TLR function in monocyte-derived DCs and West Nile virus-infected macrophages, together with evidence for increased basal cytokine production by DCs, reflect innate immune dysregulation. Systemic factors, such as age-associated alterations in sex steroids, chronic viral infections (for example, with cytomegalovirus), lipotoxicity arising from metabolic syndrome and DNA damage, could contribute ligands for pattern recognition receptors, such as TLRs and NLRP3 (NOD-, LRR- and pyrin domain-containing 3), thereby potentiating an age-associated inflammatory environment. The consequences of innate immune ageing are reflected in diverse tissues and organs, and this has potential implications for age-associated chronic inflammatory conditions, including Alzheimer's disease, atherosclerosis and metabolic syndrome. Ageing is associated with impaired immune responses to pathogens and vaccines. As described in this Review, ageing results in disrupted regulation of immune cell functions and innate immune receptor signalling, and in the establishment of a persistent pro-inflammatory milieu. The authors explain how this age-associated dysregulation might contribute to chronic inflammatory diseases in the elderly. As we age, the innate immune system becomes dysregulated and is characterized by persistent inflammatory responses that involve multiple immune and non-immune cell types and that vary depending on the cell activation state and tissue context. This ageing-associated basal inflammation, particularly in humans, is thought to be induced by several factors, including the reactivation of latent viral infections and the release of endogenous damage-associated ligands of pattern recognition receptors (PRRs). Innate immune cell functions that are required to respond to pathogens or vaccines, such as cell migration and PRR signalling, are also impaired in aged individuals. This immune dysregulation may affect conditions associated with chronic inflammation, such as atherosclerosis and Alzheimer's disease.

Background. Innate immunity, including Toll-like receptor (TLR)–mediated expression of the B7 costimulatory molecules CD80 and CD86, is critical for vaccine immunity. We examined whether CD80 and CD86 expression vary with aging and predict response to the trivalent inactivated influenza vaccine. Methods. One hundred sixty-two subjects between 21 and 30 years of age (the young group) or⩾65 years of age (the older group) enrolled before vaccination. We determined TLR-induced monocyte CD80/CD86 expression by flow cytometry and vaccine antibody responses by hemagglutination inhibition. Results. The mean increase in TLR-induced CD80+ monocytes was reduced in older, compared with young, adults by 68% (P = .0002), and each decile increase of CD80+ cells was associated with an 8.5% increase in mean number of vaccine strains with a⩾4-fold titer increase (P = .01 ) and a 3.8% increase in mean number of strains with a postvaccine titer⩾1:64 (P = .037 ). Each decile decrease of CD86+ cells was associated with an 11% increase in the mean number of strains with a 4-fold increase (P = .002) and a 3.9% increase in the mean number of strains with a postvaccine titer⩾1:64 (P = .07). Conclusions. CD80 and CD86 expression on activated monocytes is highly associated with influenza vaccine response. This approach prospectively identifies adults unlikely to respond to immunization who may benefit from alternative vaccines or antiviral prophylaxis during influenza outbreaks.

[This corrects the article DOI: 10.1371/journal.ppat.1005943.].

BACKGROUNDWhile B cell depletion is associated with attenuated antibody responses to SARS-CoV-2 mRNA vaccination, responses vary among individuals. Thus, elucidating the factors that affect immune responses after repeated vaccination is an important clinical need.METHODSWe evaluated the quality and magnitude of the T cell, B cell, antibody, and cytokine responses to a third dose of BNT162b2 or mRNA-1273 mRNA vaccine in patients with B cell depletion.RESULTSIn contrast with control individuals (n = 10), most patients on anti-CD20 therapy (n = 48) did not demonstrate an increase in spike-specific B cells or antibodies after a third dose of vaccine. A third vaccine elicited significantly increased frequencies of spike-specific non-naive T cells. A small subset of B cell-depleted individuals effectively produced spike-specific antibodies, and logistic regression models identified time since last anti-CD20 treatment and lower cumulative exposure to anti-CD20 mAbs as predictors of those having a serologic response. B cell-depleted patients who mounted an antibody response to 3 vaccine doses had persistent humoral immunity 6 months later.CONCLUSIONThese results demonstrate that serial vaccination strategies can be effective for a subset of B cell-depleted patients.FUNDINGThe NIH (R25 NS079193, P01 AI073748, U24 AI11867, R01 AI22220, UM 1HG009390, P01 AI039671, P50 CA121974, R01 CA227473, U01CA260507, 75N93019C00065, K24 AG042489), NIH HIPC Consortium (U19 AI089992), the National Multiple Sclerosis Society (CA 1061-A-18, RG-1802-30153), the Nancy Taylor Foundation for Chronic Diseases, Erase MS, and the Claude D. Pepper Older Americans Independence Center at Yale (P30 AG21342).

The role of the immune response in influencing leptospirosis clinical outcomes is not yet well understood. We hypothesized that acute-phase serum cytokine responses may play a role in disease progression, risk for death, and severe pulmonary hemorrhage syndrome (SPHS). We performed a case-control study design to compare cytokine profiles in patients with mild and severe forms of leptospirosis. Among patients hospitalized with severe disease, we compared those with fatal and nonfatal outcomes. During active outpatient and hospital-based surveillance we prospectively enrolled 172 patients, 23 with mild disease (outpatient) and 149 with severe leptospirosis (hospitalized). Circulating concentrations of pro- and anti-inflammatory cytokines at the time of patient presentation were measured using a multiplex bead array assay. Concentrations of IL-1β, IL-2, IL-4, IL-6, IL-8, IL-10, IL-17A, and TNF-α were significantly higher (P<0.05) in severe disease compared to mild disease. Among severe patients, levels of IL-6 (P<0.001), IL-8 (P = 0.0049) and IL-10 (P<0.001), were higher in fatal compared to non-fatal cases. High levels of IL-6 and IL-10 were independently associated (P<0.05) with case fatality after adjustment for age and days of symptoms. IL-6 levels were higher (P = 0.0519) among fatal cases who developed SPHS than among who did not. This study shows that severe cases of leptospirosis are differentiated from mild disease by a \"cytokine storm\" process, and that IL-6 and IL-10 may play an immunopathogenic role in the development of life-threatening outcomes in human leptospirosis.

The former members of the Advisory Committee on Immunization Practices consider paths forward for U.S. vaccine policy in the wake of their dismissal by the Secretary of Health and Human Services in June 2025.