A pan-influenza monoclonal antibody neutralizes H5 strains and prophylactically protects through intranasal administration.

Avian A(H5N1) influenza virus poses an elevated zoonotic threat to humans, and no pharmacological products are currently registered for fast-acting pre-exposure protection in case of spillover leading to a pandemic. Here, we show that an epitope on the stem domain of H5 hemagglutinin is highly conserved and that the human monoclonal antibody CR9114, targeting that epitope, potently neutralizes all pseudotyped H5 viruses tested, even in the rare case of substitutions in its epitope. Further, intranasal administration of CR9114 fully protects mice against A(H5N1) infection at low dosages, irrespective of pre-existing immunity conferred by the quadrivalent seasonal influenza vaccine.

Genetic Correlates of Biological Aging and the Influence on Prediction of Mortality.

Longevity and disease-free survival are influenced by a combination of genetics and lifestyle. Biological age (BioAge), a measure of aging based on composite biomarkers, may outperform chronological age in predicting health and longevity. This study investigated the relationship between genetic risks, lifestyle factors, and delta age (Δage), estimated as the difference between biological and chronological age.

SARS-CoV-2 elicits non-sterilizing immunity and evades vaccine-induced immunity: implications for future vaccination strategies.

Neither vaccination nor natural infection result in long-lasting protection against SARS-COV-2 infection and transmission, but both reduce the risk of severe COVID-19. To generate insights into optimal vaccination strategies for prevention of severe COVID-19 in the population, we extended a Susceptible-Exposed-Infectious-Removed (SEIR) mathematical model to compare the impact of vaccines that are highly protective against severe COVID-19 but not against infection and transmission, with those that block SARS-CoV-2 infection. Our analysis shows that vaccination strategies focusing on the prevention of severe COVID-19 are more effective than those focusing on creating of herd immunity.

Exploring the Role of Antiviral Nasal Sprays in the Control of Emerging Respiratory Infections in the Community.

Introduction: The COVID-19 pandemic has demonstrated that there is an unmet need for the development of novel prophylactic antiviral treatments to control the outbreak of emerging respiratory virus infections. Passive antibody-based immunisation approaches such as intranasal antibody prophylaxis have the potential to provide immediately accessible universal protection as they act directly at the most common route of viral entry, the upper respiratory tract. The need for such products is very apparent for SARS-CoV-2 at present, given the relatively low effectiveness of vaccines to prevent infection and block virus onward transmission.

Biological Aging for Risk Prediction of First-Ever Intracerebral Hemorrhage and Cerebral Infarction in Advanced Age.

Background And Objectives: successful interventions to prevent cerebrovascular disease and stroke require early identification of persons at risk before clinical manifestation of disease. The literature remains to be sparse on accessible plasma-based biomarkers for monitoring brain health and cerebrovascular disease in advanced age. We assessed the predictive value of biological age (BA) as an early indicator for cerebrovascular disease and risk of first-ever intracerebral hemorrhage (ICH) and cerebral infarction (CI) in advanced age and compared these relationships with chronological age (CA) and commonly used biomarkers including tau and Aβ40 and Aβ42.

Biological age in healthy elderly predicts aging-related diseases including dementia.

Application of biological age as a measure of an individual´s health status offers new perspectives into extension of both lifespan and healthspan. While algorithms predicting mortality and most aging-related morbidities have been reported, the major shortcoming has been an inability to predict dementia. We present a community-based cohort study of 1930 participants with a mean age of 72 years and a follow-up period of over 7 years, using two variants of a phenotypic blood-based algorithm that either excludes (BioAge1) or includes (BioAge2) neurofilament light chain (NfL) as a neurodegenerative marker.

Immune age and biological age as determinants of vaccine responsiveness among elderly populations: the Human Immunomics Initiative research program.

The Human Immunomics Initiative (HII), a joint project between the Harvard T.H. Chan School of Public Health and the Human Vaccines Project (HVP), focuses on studying immunity and the predictability of immuneresponsiveness to vaccines in aging populations.

Lower complexity and higher variability in beat-to-beat systolic blood pressure are associated with elevated long-term risk of dementia: The Rotterdam Study.

Introduction: We hypothesized that subclinical disruption in blood pressure (BP) dynamics, captured by lower complexity and higher variability, may contribute to dementia risk, above and beyond BP levels.

Methods: This prospective cohort study followed 1835 older adults from 1997 to 2016, with BP complexity quantified by sample entropy and BP variability quantified by coefficient of variation using beat-to-beat BP measured at baseline.

Results: Three hundred thirty-four participants developed dementia over 20 years.

External validity of phase III trials on vaccines against SARS-CoV-2 to a middle-aged and elderly Western European population.

Initial results from various phase-III trials on vaccines against SARS-CoV-2 are promising. For proper translation of these results to clinical guidelines, it is essential to determine how well the general population is reflected in the study populations of these trials. This study was conducted among 7162 participants (age-range: 51-106 years; 58% women) from the Rotterdam Study.

Development and deployment of COVID-19 vaccines for those most vulnerable.

Development of safe and effective COVID-19 vaccines is a global priority and the best hope for ending the COVID-19 pandemic. Remarkably, in less than 1 year, vaccines have been developed and shown to be efficacious and are already being deployed worldwide. Yet, many challenges remain.

Dissecting strategies to tune the therapeutic potential of SARS-CoV-2-specific monoclonal antibody CR3022.

The rapid spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), coupled with a lack of therapeutics, has paralyzed the globe. Although significant effort has been invested in identifying antibodies that block infection, the ability of antibodies to target infected cells through Fc interactions may be vital to eliminate the virus. To explore the role of Fc activity in SARS-CoV-2 immunity, the functional potential of a cross-SARS-reactive antibody, CR3022, was assessed.

Twenty-seven-year time trends in dementia incidence in Europe and the United States: The Alzheimer Cohorts Consortium.

Objective: To determine changes in the incidence of dementia between 1988 and 2015.

Methods: This analysis was performed in aggregated data from individuals >65 years of age in 7 population-based cohort studies in the United States and Europe from the Alzheimer Cohort Consortium. First, we calculated age- and sex-specific incidence rates for all-cause dementia, and then defined nonoverlapping 5-year epochs within each study to determine trends in incidence.

Plasma tau, neurofilament light chain and amyloid-β levels and risk of dementia; a population-based cohort study.

CSF biomarkers, including total-tau, neurofilament light chain (NfL) and amyloid-β, are increasingly being used to define and stage Alzheimer's disease. These biomarkers can be measured more quickly and less invasively in plasma and may provide important information for early diagnosis of Alzheimer's disease. We used stored plasma samples and clinical data obtained from 4444 non-demented participants in the Rotterdam study at baseline (between 2002 and 2005) and during follow-up until January 2016.

Quantification of biological age as a determinant of age-related diseases in the Rotterdam Study: a structural equation modeling approach.

Chronological age alone is not a sufficient measure of the true physiological state of the body. The aims of the present study were to: (1) quantify biological age based on a physiological biomarker composite model; (2) and evaluate its association with death and age-related disease onset in the setting of an elderly population. Using structural equation modeling we computed biological age for 1699 individuals recruited from the first and second waves of the Rotterdam study.

A small-molecule fusion inhibitor of influenza virus is orally active in mice.

Recent characterization of broadly neutralizing antibodies (bnAbs) against influenza virus identified the conserved hemagglutinin (HA) stem as a target for development of universal vaccines and therapeutics. Although several stem bnAbs are being evaluated in clinical trials, antibodies are generally unsuited for oral delivery. Guided by structural knowledge of the interactions and mechanism of anti-stem bnAb CR6261, we selected and optimized small molecules that mimic the bnAb functionality.

Naturally occurring antibodies isolated from PD patients inhibit synuclein seeding in vitro and recognize Lewy pathology.

Deposition of α-synuclein into Lewy bodies and Lewy neurites is the hallmark of Parkinson's disease (PD). It is hypothesized that α-synuclein pathology spreads by a "prion-like" mechanism (i.e.

Structural Basis for Recognition of a Unique Epitope by a Human Anti-tau Antibody.

Aggregation of the hyperphosphorylated protein tau into neurofibrillary tangles and neuropil threads is a hallmark of Alzheimer disease (AD). Identification and characterization of the epitopes recognized by anti-tau antibodies might shed light on the molecular mechanisms of AD pathogenesis. Here we report on the biochemical and structural characterization of a tau-specific monoclonal antibody CBTAU-24.

A common antigenic motif recognized by naturally occurring human V5-51/V4-1 anti-tau antibodies with distinct functionalities.

Misfolding and aggregation of tau protein are closely associated with the onset and progression of Alzheimer's Disease (AD). By interrogating IgG memory B cells from asymptomatic donors with tau peptides, we have identified two somatically mutated V5-51/V4-1 antibodies. One of these, CBTAU-27.

Temporal association patterns and dynamics of amyloid-β and tau in Alzheimer's disease.

The elusive relationship between underlying pathology and clinical disease hampers diagnosis of Alzheimer's disease (AD) and preventative intervention development. We seek to understand the relationship between two classical AD biomarkers, amyloid-β (Aβ) and total-tau (t-tau), and define their trajectories across disease development, as defined by disease onset at diagnosis of mild cognitive impairment (MCI). Using longitudinal data from the Alzheimer's Disease Neuroimaging Initiative (ADNI), we performed a correlation analysis of biomarkers CSF Aβ and t-tau, and longitudinal quantile analysis.

Neutralization Is Not Predictive of Prophylactic Efficacy of Broadly Neutralizing Monoclonal Antibodies CR6261 and CR9114 against Lethal H2 Influenza Virus Challenge in Mice.

Influenza viruses of the H1N1, H2N2, and H3N2 subtypes have caused previous pandemics. H2 influenza viruses represent a pandemic threat due to continued circulation in wild birds and limited immunity in the human population. In the event of a pandemic, antiviral agents are the mainstay for treatment, but broadly neutralizing antibodies (bNAbs) may be a viable alternative for short-term prophylaxis or treatment.

Potent peptidic fusion inhibitors of influenza virus.

Influenza therapeutics with new targets and mechanisms of action are urgently needed to combat potential pandemics, emerging viruses, and constantly mutating strains in circulation. We report here on the design and structural characterization of potent peptidic inhibitors of influenza hemagglutinin. The peptide design was based on complementarity-determining region loops of human broadly neutralizing antibodies against the hemagglutinin (FI6v3 and CR9114).

Maternal antibodies protect offspring from severe influenza infection and do not lead to detectable interference with subsequent offspring immunization.

Background: Various studies have shown that infants under the age of 6 months are especially vulnerable for complications due to influenza. Currently there are no vaccines licensed for use in this age group. Vaccination of pregnant women during the last trimester, recommended by the WHO as protective measure for this vulnerable female population, may provide protection of newborns at this early age.

Immunological memory to hyperphosphorylated tau in asymptomatic individuals.

Several reports have described the presence of antibodies against Alzheimer's disease-associated hyperphosphorylated forms of tau in serum of healthy individuals. To characterize the specificities that can be found, we interrogated peripheral IgG memory B cells from asymptomatic blood donors for reactivity to a panel of phosphorylated tau peptides using a single-cell screening assay. Antibody sequences were recovered, cloned, and expressed as full-length IgGs.

HA Antibody-Mediated FcγRIIIa Activity Is Both Dependent on FcR Engagement and Interactions between HA and Sialic Acids.

Interactions with receptors for the Fc region of IgG (FcγRs) have been shown to contribute to the protection against influenza A viruses provided by broadly neutralizing antibodies (bnAbs) that bind to the viral hemagglutinin (HA) stem. In particular, Fc-mediated antibody-dependent cellular cytotoxicity (ADCC) has been shown to contribute to protection by stem-binding bnAbs. Fc-mediated effector functions appear not to contribute to protection provided by strain-specific HA head-binding antibodies.