Generation of Effector Memory T Cell-Based Mucosal and Systemic Immunity with Pulmonary Nanoparticle Vaccination

Many pathogens infiltrate the body and initiate infection via mucosal surfaces. Hence, eliciting cellular immune responses at mucosal portals of entry is of great interest for vaccine development against mucosal pathogens. We describe a pulmonary vaccination strategy combining Toll-like receptor (TLR) agonists with antigen-carrying lipid nanocapsules [interbilayer-crosslinked multilamellar vesicles (ICMVs)], which elicit high-frequency, long-lived, antigen-specific effector memory T cell responses at multiple mucosal sites. Pulmonary immunization using protein- or peptide-loaded ICMVs combined with two TLR agonists, polyinosinic-polycytidylic acid (polyI:C) and monophosphoryl lipid A, was safe and well tolerated in mice, and led to increased antigen transport to draining lymph nodes compared to equivalent subcutaneous vaccination. This response was mediated by the vast number of antigen-presenting cells (APCs) in the lungs. Nanocapsules primed 13-fold more T cells than did equivalent soluble vaccines, elicited increased expression of mucosal homing integrin α4β7+, and generated long-lived T cells in both the lungs and distal (for example, vaginal) mucosa strongly biased toward an effector memory (TEM) phenotype. These TEM responses were highly protective in both therapeutic tumor and prophylactic viral vaccine settings. Together, these data suggest that targeting cross-presentation–promoting particulate vaccines to the APC-rich pulmonary mucosa can promote robust T cell responses for protection of mucosal surfaces.Howard Hughes Medical Institute (Investigator)National Institutes of Health (U.S.) (AI095109)United States. Dept. of Defense (contract W911NF-07-D-0004)Bill & Melinda Gates FoundationRagon Institute of MGH, MIT, and HarvardNational Cancer Institute (U.S.)David H. Koch Institute for Integrative Cancer Research at MIT (Koch Institute Support (core) Grant P30-CA14051

Antigen-Displaying Lipid-Enveloped PLGA Nanoparticles as Delivery Agents for a Plasmodium vivax Malaria Vaccine

The parasite Plasmodium vivax is the most frequent cause of malaria outside of sub-Saharan Africa, but efforts to develop viable vaccines against P. vivax so far have been inadequate. We recently developed pathogen-mimicking polymeric vaccine nanoparticles composed of the FDA-approved biodegradable polymer poly(lactide-co-glycolide) acid (PLGA) “enveloped” by a lipid membrane. In this study, we sought to determine whether this vaccine delivery platform could be applied to enhance the immune response against P. vivax sporozoites. A candidate malaria antigen, VMP001, was conjugated to the lipid membrane of the particles, and an immunostimulatory molecule, monophosphoryl lipid A (MPLA), was incorporated into the lipid membranes, creating pathogen-mimicking nanoparticle vaccines (VMP001-NPs). Vaccination with VMP001-NPs promoted germinal center formation and elicited durable antigen-specific antibodies with significantly higher titers and more balanced Th1/Th2 responses in vivo, compared with vaccines composed of soluble protein mixed with MPLA. Antibodies raised by NP vaccinations also exhibited enhanced avidity and affinity toward the domains within the circumsporozoite protein implicated in protection and were able to agglutinate live P. vivax sporozoites. These results demonstrate that these VMP001-NPs are promising vaccines candidates that may elicit protective immunity against P. vivax sporozoites.United States. Dept. of Defense (contract W911NF-07-D-0004)Ragon Institute of MGH, MIT and Harvar

Region-specific amyloid-β accumulation in the olfactory system influences olfactory sensory neuronal dysfunction in 5xFAD mice

Background: Hyposmia in Alzheimer’s disease (AD) is a typical early symptom according to numerous previous clinical studies. Although amyloid-β (Aβ), which is one of the toxic factors upregulated early in AD, has been identified in many studies, even in the peripheral areas of the olfactory system, the pathology involving olfactory sensory neurons (OSNs) remains poorly understood. Methods: Here, we focused on peripheral olfactory sensory neurons (OSNs) and delved deeper into the direct relationship between pathophysiological and behavioral results using odorants. We also confirmed histologically the pathological changes in 3-month-old 5xFAD mouse models, which recapitulates AD pathology. We introduced a numeric scale histologically to compare physiological phenomenon and local tissue lesions regardless of the anatomical plane. Results: We observed the odorant group that the 5xFAD mice showed reduced responses to odorants. These also did not physiologically activate OSNs that propagate their axons to the ventral olfactory bulb. Interestingly, the amount of accumulated amyloid-β (Aβ) was high in the OSNs located in the olfactory epithelial ectoturbinate and the ventral olfactory bulb glomeruli. We also observed irreversible damage to the ectoturbinate of the olfactory epithelium by measuring the impaired neuronal turnover ratio from the basal cells to the matured OSNs. Conclusions: Our results showed that partial and asymmetrical accumulation of Aβ coincided with physiologically and structurally damaged areas in the peripheral olfactory system, which evoked hyporeactivity to some odorants. Taken together, partial olfactory dysfunction closely associated with peripheral OSN’s loss could be a leading cause of AD-related hyposmia, a characteristic of early AD. © 2021, The Author(s).1

Search for the standard model Higgs boson decaying to a bbˉb\bar{b} pair in events with no charged leptons and large missing transverse energy using the full CDF data set

We report on a search for the standard model Higgs boson produced in association with a vector boson in the full data set of proton-antiproton collisions at $\sqrt{s} = 1.96$ TeV recorded by the CDF II detector at the Tevatron, corresponding to an integrated luminosity of 9.45 fb$^{-1}$. We consider events having no identified charged lepton, a transverse energy imbalance, and two or three jets, of which at least one is consistent with originating from the decay of a $b$ quark. We place 95% credibility level upper limits on the production cross section times standard model branching fraction for several mass hypotheses between 90 and $150 \mathrm{GeV}/c^2$. For a Higgs boson mass of $125 \mathrm{GeV}/c^2$, the observed (expected) limit is 6.7 (3.6) times the standard model prediction.Comment: Accepted by Phys. Rev. Let

Search for the Higgs boson in events with missing transverse energy and b quark jets produced in proton-antiproton collisions at s**(1/2)=1.96 TeV

We search for the standard model Higgs boson produced in association with an electroweak vector boson in events with no identified charged leptons, large imbalance in transverse momentum, and two jets where at least one contains a secondary vertex consistent with the decay of b hadrons. We use ~1 fb-1 integrated luminosity of proton-antiproton collisions at s**(1/2)=1.96 TeV recorded by the CDF II experiment at the Tevatron. We find 268 (16) single (double) b-tagged candidate events, where 248 +/- 43 (14.4 +/- 2.7) are expected from standard model background processes. We place 95% confidence level upper limits on the Higgs boson production cross section for several Higgs boson masses ranging from 110 GeV/c2 to 140 GeV/c2. For a mass of 115 GeV/c2 the observed (expected) limit is 20.4 (14.2) times the standard model prediction.Comment: 8 pages, 2 figures, submitted to Phys. Rev. Let

Observation and Mass Measurement of the Baryon Ξb−\Xi^-_b

We report the observation and measurement of the mass of the bottom, strange baryon $\Xi^-_b$ through the decay chain $\Xi^-_b \to J/\psi \Xi^-$, where $J/\psi \to \mu^+ \mu^-$, $\Xi^- \to \Lambda \pi^-$, and $\Lambda \to p \pi^-$. Evidence for observation is based on a signal whose probability of arising from the estimated background is 6.6 x 10^{-15}, or 7.7 Gaussian standard deviations. The $\Xi^-_b$ mass is measured to be $5792.9\pm 2.5$ (stat.) $\pm 1.7$ (syst.) MeV/$c^2$.Comment: Minor text changes for the second version. Accepted by Phys. Rev. Let

Search for the standard model Higgs boson decaying to a bb pair in events with one charged lepton and large missing transverse energy using the full CDF data set

We present a search for the standard model Higgs boson produced in association with a W boson in sqrt(s) = 1.96 TeV p-pbar collision data collected with the CDF II detector at the Tevatron corresponding to an integrated luminosity of 9.45 fb-1. In events consistent with the decay of the Higgs boson to a bottom-quark pair and the W boson to an electron or muon and a neutrino, we set 95% credibility level upper limits on the WH production cross section times the H->bb branching ratio as a function of Higgs boson mass. At a Higgs boson mass of 125 GeV/c2 we observe (expect) a limit of 4.9 (2.8) times the standard model value.Comment: Submitted to Phys. Rev. Lett (v2 contains clarifications suggested by PRL